- -- T. == º - ºffl ºffli - ºffli º ºffl ºffl - - - - - == --- == - - ºffl - - º - - - º - |- - --~. --- º º --- º - - - ºffl º - - |- º -- - - - - ==º - tº- - - ºfflº ºffl --~~~~ ºffli - º - --~~~ º º ºffli - - - - ºffl º - - - ºffl ºffl º - - - - --- - --- º º ==# - --~~~~ º - --- - - Eº º - -- --~~~~ - ºffl --> | --- - º - - - - - --- - --~~~~ - - --~~~~ --~~~~ - - --~~ - - ºffli # = ºffli ==== ºffl - º i - - - --~. ºffl - º --- - ºffl - ºffl º º - - - - º- - i - --~~~~ --- - - - º --~~ º - --~~~~ i --~~~~ -- --~~~~ ºffl - - ----------- - ==# º ºfflº ºffli º º º - - ºffli - - º --~~~~ - - ºffli - #º: =# ºffl --~~~~ º - º == ºfflº ºffl i ºffli - --~~~~ --~~~~ º--~~~~ - EFFECTIVE AND EFFICIENT ORTHODONTIC TOOTH MOVEMENT This volume includes the proceedings of the Thirty-Seventh Annual Moyers Symposium February 27–28, 2010 Ann Arbor, Michigan Editors James A. McNamara, Jr. Nan Hatch Sunil D. Kapila Associate Editor Kristin Y. Vanriper Volume 48 Craniofacial Growth Series Department of Orthodontics and Pediatric Dentistry School of Dentistry; and Center for Human Growth and Development The University of Michigan Ann Arbor, Michigan ©2011 by the Department of Orthodontics and Pediatric Dentistry, School of Dentistry and Center for Human Growth and Development The University of Michigan, Ann Arbor, MI 48109 Publisher’s Cataloguing in Publication Data Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development Craniofacial Growth Series Effective and Efficient Orthodontic Tooth Movement Volume 48 ISSN 0.162 7279 ISBN 0-929921-00-3 ISBN 0-929921–44–5 No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the Editor-in- Chief of the Craniofacial Growth Series or designate. CONTRIBUTORS TIZIANO BACCETTI, Research Professor, Department of Ortho- dontics, The University of Florence, Florence, Italy; Thomas M. Graber Visiting Scholar, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, The University of Michigan, Ann Arbor, MI. ELLEN A. BEGOLE, Associate Professor, Department of Statistics, University of Illinois at Chicago, Chicago, IL. ROLF G. BEHRENTS, Professor and Chair, Orthodontic Department, St. Louis University, St. Louis, MO. CHARLES J. BURSTONE, Professor Emeritus, School of Dental Medicine, Craniofacial Sciences/Orthodontics, University of Connecticut Health Center, Farmington, CT. PETER H. BUSCHANG, Professor and Director of Orthodontic Re- search, Baylor College of Dentistry, Dallas, TX. MATTEO CAMPORESI, Research Associate, Department of Ortho- dontics, The University of Florence, Florence, Italy. LUCIA H. CEVIDANES, Assistant Professor, Department of Ortho- dontics, School of Dentistry, University of North Carolina, Chapel Hill, NC. JEFFREY R. CHANDLER, private practice, Salt Lake City, UT. LUCA CONTARDO, Assistant Professor, Department of Biomedicine, School of Dentistry, University of Trieste, Trieste, Italy. ALICE CUTRERA, Fellow, Division of Orthodontics, Department of Craniofacial Sciences, Farmington, CT. - ANTHONY P. ELTINK, Clinical Assistant Professor, Department of Orthodontics, University of Illinois at Chicago, Chicago, IL. PATRICK M. FLOOD, Associate Professor, Department of Perio- dontology, School of Dentistry, University of North Carolina, Chapel Hill, NC. LORENZO FRANCHI, Assistant Professor, Department of Ortho- dontics, The University of Florence, Florence, Italy; Thomas M. Graber Visiting Scholar, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, The University of Michigan, Ann Arbor. SYLVIA A. FRAZIER-BOWERS, Assistant Professor, Department of Orthodontics, University of North Carolina at Chapel Hill, Chapel Hill, NC. EVELINE GAVA, Graduate Orthodontic Program, Department of Orthodontics, Rio de Janeiro State University, Rio de Janeiro, Brazil. VERONICA GIUNTINI, Research Associate, Department of Ortho- dontics, The University of Florence, Florence, Italy. DAN GRAUER, Postdoctoral Fellow, Department of Orthodontics, School of Dentistry, University of North Carolina, Chapel Hill, NC. CHESTER S. HANDELMAN, Clinical Associate Professor of Ortho- dontics, University of Illinois at Chicago, Chicago, IL; private practice, Chicago, IL. JAMES K. HARTSFIELD JR., Professor and E. Preston Hicks Endowed Chair in Orthodontics and Oral Health Research, University of Kentucky College of Dentistry, Professor of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY; Adjunct Professor of Orthodontics and Oral Facial Genetics, Indiana University School of Dentistry, Adjunct Professor of Medical and Molecular Genetics, Indiana University School of Medicine; Adjunct Professor of Orthodontics, University of Illinois at Chicago School of Dentistry, Chicago, IL. NAN HATCH, Assistant Professor, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, The University of Michigan, Ann Arbor, MI. HALUK is ERI, Department of Orthodontics, School of Dentistry, University of Ankara, Ankara, Turkey. LAURA R. IWASAKI, Departments of Orthodontics and Dentofacial Orthopedics and Oral Biology, University of Missouri-Kansas City, Kansas City, MO. MYUNG-RIP KIM, Adjunct Assistant Professor, Department of Orthodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL; Clinical Associate Professor, Department of Orthodontics, Catholic University of Korea, Seoul, South Korea; private practice, Seoul, South Korea. REHA S. KISNISCI, Department of Oral and Maxillofacial Surgery, School of Dentistry, Ankara University, Ankara, Turkey. JOHN S. LIPPINCOTT, Graduate Orthodontic program, The Univ- ersity of Illinois at Chicago, Chicago, IL; private practice, Aurora, IL. DAVID B. MARX, Department of Statistics, University of Nebraska- Lincoln, Lincoln, NE. JOSE AUGUSTO M. MIGUEL, Associate Professor, Department of Orthodontics, Rio de Janeiro State University, Rio de Janeiro, Brazil. PETER G. MILES, Senior Lecturer, University of Queensland Dental School, Queensland, Australia; private practice, Caloundra, Australia. RAVINDRA NANDA, Endowed Chair, Professor and Head, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, Farmington, CT. JEFFREY C. NICKEL, Departments of Orthodontics and Dentofacial Orthopedics and Oral Biology, University of Missouri-Kansas City, Kansas City, MO. p JANARDAN P. PANDEY, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC. SNEHLATA OBEROI, Associate Clinical Professor, Center for Craniofacial Anomalies, University of California San Francisco, San Francisco, CA. TAKASHI ONO, Professor and Chair, Orthodontic Science Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. LISLANE MEIRA PALAGI, private practice, Rio de Janeiro, Brazil. GIUSEPPE PERINETTI, Research Associate, Department of Biomedicine, School of Dentistry, University of Trieste, Trieste, Italy. WILLIAM R. PROFFIT, Kenan Professor, Department of Ortho- dontics, School of Dentistry, University of North Carolina, Chapel Hill, NC. P. EMILE ROSSOUW, Professor and Chair, Orthodontic Department, University of North Carolina, Chapel Hill, NC. CARLOS EDUARDO SABROSA, Associate Professor, Department of Restorative Dentistry, Rio de Janeiro State University, Rio de Janeiro, Brazil. LAUREN M. SIGLER, Research Assistant, Department of Orthodon- tics and Pediatric Dentistry, The University of Michigan, Ann Arbor, MI. KELTON T. STEWART, Assistant Professor of Orthodontics, Department of Orthodontics and Oral Facial Genetics, Indiana University School of Dentistry, Indianapolis, IN. MARTIN A. STYNER, Assistant Professor, Department of Computer Science, School of Arts and Sciences, University of North Carolina, Chapel Hill, NC. DONALD TYNDALL, Professor, Department of Diagnosis and General Dentistry, School of Dentistry, University of North Carolina, Chapel Hill, NC. MADHUR UPADHYAY, Resident, Division of Orthodontics, Department of Craniofacial Sciences, University of Connecticut Health Center, Farmington, CT. FLAVIO URIBE, Program Director, Division of Orthodontics, Department of Craniofacial Sciences, School of Dental Medicine, University of Connecticut, Farmington, CT. KARIN VARGERVIK, Professor and Director, Center for Craniofacial Anomalies, University of California San Francisco, San Francisco, CA. CARLOS VILLEGAS, Assistant Professor, Department of Ortho- dontics and Maxillofacial Surgery, University of CES, Medellin, Colombia. PREFACE Orthodontics is the presumed beneficiary of a variety of new technologies and protocols intended to hasten tooth movement, improve outcomes and streamline treatment. Some are supported by data, some are not. The 2010 Moyers Symposium focused on the biology and biomechanics of tooth movement, with emphasis on effectiveness and efficiency. There has been a need to separate the wheat from the chaff, the essence of evidence-based dentistry. The claims of supporters— ardent and otherwise—were examined via evidence-based studies that have looked at such techniques du jour as corticotomies, self-ligating bracket systems, temporary anchorage devices and proposed pharmacological adjuncts. In addition, canine impaction and primary failure of eruption were discussed. The genetic basis of such clinical problems as root resorption also was considered. An in-depth discussion of these new tooth movement technologies as well as the biological principles underlying them were addressed during the 37" Annual Moyers Symposium that was held on The University of Michigan campus on Saturday, February 27 and Sunday, February 28, 2010. A panel of nine international clinicians and researchers was assembled in Rackham Auditorium to address these issues. As in previous years, the Symposium honored the late Dr. Robert E. Moyers, Professor Emeritus of Dentistry, Fellow Emeritus and Founding Director of the Center for Human Growth and Development. The meeting was co-sponsored by the School of Dentistry and the Center for Human Growth and Development. In addition, the 36" International Annual Conference on Craniofacial Research (the so-called “Presymposium”) was held in the Rackham Amphitheater on the Friday before the Symposium (February 26, 2010). The Presymposium conference featured papers relevant to orthodontics and craniofacial biology that were presented by an international group of investigators. Many of the papers presented at the Presymposium that were germane to the topic of the 2010 Moyers Symposium also are included in this volume. We must recognize Dr. Sunil Kapila—who not only served as co-editor of this Volume with Dr. Nan Hatch, but also as Chair of the Department of Orthodontics and Pediatric Dentistry—has provided the financial resources to underwrite the publication of this book Substantially. We also recognize continued financial and moral support of the Moyers Symposium by the Center for Human Growth and Development, under the direction of Dr. Twila Tardif. Thanks also to those individuals who have purchased a copy of this book—your continued support is appreciated greatly. Finally and most importantly, we recognize the enormous efforts of our Associate Editor, Kris Van Riper. Kris is the “go-to” person involved in the day-to-day preparation of this and several previous volumes. Once again, she has facilitated the publication of this book through interacting with the authors, editing, manipulating a variety of figure formats and formatting the layout of the book. Without her efforts, this book would not exist. James A. McNamara Ann Arbor, Michigan October 2010 FRIENDS OF THE SYMPOSIUM Dr. Gary E. Hall Dr. Chester S. Handelman Robert J. Isaacson Maurizio Manuelli NewConn Orthodontic Foundation Dr. William Patchak Dr. James D. Quarles Michael A. Sales TABLE OF CONTENTS Contributors Preface Friends of the Symposium Self-ligation and Friction: Fact and Fantasy Charles J. Burstone Self-ligation: Evidence versus Claims Peter G. Miles Mechanics to Expedite Orthodontic Treatment Ravindra Nanda, Madhur Upadhyay, Flavio Uribe Efficiency of Alignment of Apically- or Bucally-Malposed Teeth with Low-Friction versus Conventional Systems Lorenzo Franchi, Matteo Camporesi, Veronica Giuntini, Tiziano Baccetti The Biology of Orthodontic Tooth Movement: Current Concepts on and Applications to Clinical Practice Nan Hatch IL-1 Genetic Polymorphisms and IL-1 Protein Secretion in Gingival Crevicular Fluid Predict the Speed of Human Orthodontic Tooth Movement Laura R. Iwasaki, Jeffrey R. Chandler, David B. Marx, Janardan P. Pandey, Jeffrey C. Nickel The Biology of Orthodontic Tooth Movement and the Impact of Anti-inflammatory Drugs Giuseppe Perinetti, Luca Contardo, Lorenzo Franchi, Tiziano Baccetti The Effectiveness of Interceptive Treatment Procedures for Palatally Displaced Canines: A Comparative Evidence-based Appraisal Tiziano Baccetti and Lauren M. Sigler Factors Beyond the Control of the Clinician: Understanding the Genetics Underlying Orthodontic Treatment James K. Hartsfield Jr. 27 45 61 73 93 117 141 155 Primary Failure of Eruption: Clinical Implications of a Genetic Disorder Sylvia A. Frazier-Bowers Distraction Osteogenesis to Accelerate Tooth Movement and Orthodontic Treatment Haluk iseri and Reha S. Kisnisci Corticotomies and Other Adjuncts to Enhance Orthodontic Tooth Movement Flavio Uribe, Alice Cutrera, Carlos Villegas, Ravindra Nanda Experimental Evidence Supporting the Use of Miniscrew Implants in Orthodontic Practice Peter H. Buschang, P. Emile Rossouw, Rolf G. Behrents Immediate and Delayed Orthodontic Loading of Osseointegrated Implants: A Prospective Clinical Study José Augusto M. Miguel, Lisiane Meira Palagi, Carlos Eduardo Sabrosa, Eveline Gava, Tiziano Baccetti Utilization of Miniscrew Implants for Effective Orthodontic Tooth Movement in Mutilated Dentitions Kelton T. Stewart Alveolar Cortical Plate Movement Associated with Incisor Retraction Using Skeletal Anchorage John S. Lippincott, Chester S. Handelman, Myung-Rip Kim A New Measure of Gingival Recession and the Significance of Attrition, Gender and Race Anthony P. Eltink, Chester S. Handelman, Ellen A. BeGole Registration of Orthodontic Digital Models Dan Grauer, Lucia H. Cevidanes, Donald Tyndall, Martin A. Styner, Patrick M. Flood, William R. Proffit Assessing the Outcome of Alveolar Bone Grafting Using Cone-beam Computed Tomography (CBCT) Snehlata Oberoi and Karin Vargervik Control Mechanisms of Tongue Posture Takashi Ono | 9 | 207 233 257 299 3 || 333 353 377 393 4.17 SELF-LIGATION AND FRICTION: FACT AND FANTASY Charles J. Burstone ABSTRACT The prediction of tooth movement requires fully defining the force system act- ing on the teeth. This includes forces from appliances and muscles, as well as friction. Friction forces can operate along with active tooth moving forces or the restraint of the tying mechanism. Friction can be both good and bad. Classic friction theory postulates that friction forces originate from normal forces (forces perpendicular) to the archwire. Two commonly observed normal forces operate in a traditional appliance: the ligation mechanism and desired tooth moving forces. Reducing the ligation forces can be helpful; how- ever, tooth moving friction forces remain. As a consequence, there is no com- pletely friction-free appliance or bracket under clinical conditions. Because the force systems are changing continually in the mouth, it is difficult to predict friction under complicated clinical parameters. Dynamic loading and occlusal forces influence the retention of friction forces. Important topics in regard to friction in orthodontics include overriding friction, friction during canine retraction phases, methods of friction reduction and friction dur- ing leveling and alignment. In general, classic friction formulas are useful but limited in their application in orthodontics. As forces become heavier, abrasion, deformation and notching can occur. At these extremes, classic theory breaks down and lacks predictability. It is the intent of this chapter to delineate the role of friction on a scien- tific basis so the clinician can optimize treatment, providing a conceptual framework to evaluate the utility of so-called low friction brackets. Understand- ing friction can help our selection of a new appliance or improve our use of an older appliance system. It determines in part the efficiency of tooth movement and anchorage and is a factor in eliminating undesirable side effects. Moreover, understanding friction can help reduce commercialism in the marketing of appli- ances and techniques. KEY WORDS: friction, forces, biomechanics, self-ligation, orthodontics Self-ligation and Friction FRICTION FORCES, THEIR ORIGIN AND CLASSIC FORMULAS If a force is applied to a molar from an elastomeric chain or a coil spring as shown in Figure 1, the tooth will not feel the full force if there is friction in the appliance. What the tooth feels is the effective force (FE) not the applied force (FA). Effective Force (FE) = Applied Force (F1) – Friction Force (Fº) When the friction force (FF) is higher than the applied force, the tooth will feel no force from the spring. If the frictional force is lower than applied force, the net effective force (FE) will be less than the ap- plied force. Of course, it is the effective force that causes tooth move- ment and is relevant for the clinician (Smith and Burstone, 1984). Tooth movement is an intermittent start-stop phenomenon and, hence, static friction is appropriate friction from an orthodontic stand- point. Measurement of friction (dynamic or kinetic friction) along mov- ing surfaces will give somewhat smaller values. Rolling friction involves wheels and is not relevant to our appliances (Timoshenko and Goodier, 1951). Where do friction forces come from? Classic friction theory will tell us that forces at 90° to the archwire are responsible for friction. Fig- ure 2 shows a canine sliding along an archwire. For simplicity all mo- ments are ignored. Other assumptions made are that FA is 100 g and the normal force (FN; force that is perpendicular to the wire) is an extrusive force of 50 g on the tooth from the wire. Friction Force (FE) = Coefficient of Friction (u)x Normal Force (FM) The coefficient of friction represents the sliding properties of the material used and the interfaces including lubricants. When the coeffi- cient of friction is 0.16 (typical for a stainless steel wire in a stainless steel bracket), force can be calculated. FF = 50 g x 0.16 = 8 g. Therefore, the net effective force is 100 g – 8 g = 92 g, the friction. SOURCE OF NORMAL FORCES Forces perpendicular to the archwire can come from a number of sources. If the design of the archwire allows teeth to move in any direc- tion (buccal, lingual, occlusal or apical), normal forces are produced in each of these directions (Fig. 3). In addition, ligation by a ligature wire or Burstone 100 Grams Figure 2. Forces perpendicular to the archwire produce friction forces. an “O'” ring produces a normal force and, hence, a friction force. Either of these ligatures types produces a lingual force that can lead to a friction force (Fig. 4). Thus, the ligation method is only one source of friction. Any other forces required for tooth movement if perpendicular to the arch wire also can lead to friction and in many situations can produce more friction than the ligature tie. Of particular importance are forces originating from pure mo- ments or couples (Fig. 5). By definition, couples are equal and opposite forces not in the same line of action. Normal forces exist on the wire al- Self-ligation and Friction | -> Figure 3. Tooth moving normal forces in all directions can lead to friction. Figure 4. Ligation forces are perpendicular to the wire and hence produce friction. Figure 5. Torque, tip and rotation couples are a major cause of friction force. though the sum of the forces is zero. Moments are used in a first order direction to rotate teeth, in a second order direction to change axial me- Sio-distal inclinations and in a third order direction (torque) to change buccal-lingual axial inclinations. In that the bracket is not located at the center of resistance (CR) of the teeth (i.e., somewhere on or near the root center), it is necessary to require a moment (couple) at the bracket to give Burstone an equivalent force system for full tooth control. This is one of major sources of friction using the edgewise appliance. If teeth are allowed to tip or rotate, this source of friction can be eliminated but control of tooth movement is lost (Smith and Burstone, 1984). Sometimes we hear the phrase “friction-free brackets.” Is this possible under typical clinical conditions? These brackets slide easily when placed on a wire because the ligation force can be small or non- existent. In Figure 6, a low friction self-ligation bracket has been used to rotate a second premolar. The arch wire produces a couple that should rotate the premolar around its CR (center of crown; Nagerl et al., 1991). A friction force operates at the distal of the bracket in a mesial direction. Notice that the friction force produced a side effect that opened up space and the crown was moved mesially. This example demonstrates once again that other friction forces are at play beyond the ligation mecha- nism. In other words, we should be careful in using the phrases “friction- free” or “frictionless” brackets. Figure 6. A moment is applied to the rotated premolar from the archwire. The bracket is a self-ligation bracket with supposed low fric- tion (A). Instead of a pure rotation around center of resistance (CR), the friction force causes space to open (B). Self-ligation and Friction Some orthodontists differentiate between simple normal forces and normal forces from couples. Classical friction theory allows couples to be handled like any other forces. Thus, terms such as “binding” used to describe friction resulting from normal forces of couples should not be used to suggest a different theoretical mechanism at work in the situation where a tipping moment or torque is applied. CANINE RETRACTION: SLIDING ON A TRACK An in-depth consideration of canine retraction using sliding me- chanics gives the opportunity to discuss how friction works with a major treatment phase (Burstone, 1991). Without a wire for control, a distal force on a canine produces well-known side effects. The canine rotates distal-in and the crown tips distally (Burstone, 1982; Burstone and Han- ley, 1995). To prevent the unwanted effects an arch wire is used – the archwire elastically deforms and during recovery prevents or minimizes the rotation and tipping (Figs. 7-8). In Figure 9, as the canine tips distally, the deflection of the wire generates the couple that is responsible for the force system that gives control to prevent tipping. Note that these moments give rise to normal forces and, hence, friction forces. For a given effective force, the less stiff the wire or the greater the distal force, the larger the wire tip defor- mation will be (Burstone and Koenig, 1976). So how much friction force do we get during canine retraction? To answer this question, we must consider the phase of canine retraction (Burstone and Koenig, 1974; Tanne et al., 1988). Four phases can be recognized. After a distal force is placed, the canine may have play be- tween the wire and the bracket and initially the tooth will display uncon- trolled tipping. This is Phase I (Fig. 10). Ignoring ligation forces for now, no moments or normal forces operate in this phase or plane. The tooth continues to tip more and the play is eliminated. As the wire deflects, increasing moments are produced and a controlled tipping phase occurs. Perhaps at this phase the center of rotation is at the root apex, resulting in controlled tipping. Note normal forces and low levels of friction are pro- → Figure 8. A force through the CR will translate a canine. Working at the bracket, a force and a moment are required. The moment produces equal and opposite forces leading to friction. Burstone Figure 7. During retraction the canine tends to rotate (A) and tip (B). The arch wire prevents this by applying couples lead- ing to friction forces. Self-ligation and Friction Figure 9. Because the force is applied at the bracket dur- ing retraction, the canine tips. The archwire deforms elas- tically to apply a moment of the couple, thus minimizing the tip. Note the wire curvature due to its deflection that generates the couple. IV Figure 10. Phases of canine retraction from the facial view. I. Uncontrolled tipping during bracket-wire play phase. II: Controlled tipping with increasing deflection of the wire. III: Translation when the moment of the couple is sufficiently high. IV: Correction of root inclination. The purple arrow represents increasing moment of the couple and thus increasing friction. duced in Phase II as the wire increasingly engages the bracket and tip- ping is being minimized. As the tooth tips more, a sufficiently high angle is produced between the bracket and the wire, and the resultant moment (normal forces) is high enough to produce translation (Phase III). The highest friction forces thus are produced during translation. During Phase Burstone IV as the force is reduced, no more distal sliding occurs and the axial inclination is corrected. Here, of course, there is a high friction force that is acceptable in that sliding is not desired at this stage (Tanne et al., 1987). In short, friction force varies depending on the stage of canine retraction—initially with bracket-wire play none and the highest levels later during translation. Even with rigid edgewise arches, a retracted tooth will go through these four phases; however the angle of tip will be less than with a flexible wire. Clinically it may appear that the tooth has translated in one phase. In reality, it first has tipped, then translated and then finally uprighted. Although the above example demonstrates the effect of moments generated by the bracket-wire interactions from the facial view, the same occurs due to ligation forces and forces in other planes of space, which will be considered separately. How much difference does friction make in the force system? Figure 11 shows different positions of the CR of a typical canine. For the translation phase with the CR at 10 mm from the bracket, 52 g remain from an applied 100 g force. If the distance is 5 mm, 68 g remain. Very narrow brackets like a Begg bracket produce negligible friction forces since they do not prevent tooth tipping. From the facial view, because the CR is apical to the bracket, friction forces are developed as described above. In a similar evaluation from the occlusal view, the bracket is labial to the CR and hence, a distal force will rotate the canine distal-in. The archwire prevents or minimizes canine rotation in four phases (Fig. 12). During Phase I, if play exists between wire and bracket, the canine is free to rotate. No wire restraining of the rotation occurs and, therefore, there is no friction in the occlusal view. During Phase II, the tooth continues to rotate; however, the arch- wire begins to deflect and helps to minimize the rotation by generating a moment of the couple. Because of these archwire moments, friction in- creases and finally, reaches its maximum during the Phase III translation. No sliding occurs in Phase IV when the rotation is being corrected. The amount of friction force from the occlusal view depends on the perpendicular distance of the bracket to the CR. The greater the dis- tance, the larger the moment rotating the canine and the greater the po- tential moment from the archwire preventing this rotation (Fig. 13). A simple calculation of canine retraction friction using a twin bracket (3.5 mm width) and a stainless steel wire (u = 0.16) helps to illustrate this point. The perpendicular distance to CR from the occlusal view is 4 mm and 10 mm to CR from the facial view. Self-ligation and Friction 100g Degradation of 100g Force by Friction .5 mm brack º 68 g 3. F. º Figure 11. Friction significantly reduces force at translation phase. With CR at 10 mm from bracket, only 52 g remain from the 100 g of applied force. II Figure 12. Phases of canine retraction from the occlusal view. I; Rotation with bracket play. II: Rotation with wire bending. III: Translation. IV: Rotation cor- rection. The purple arrow represents increasing moment of the couple and thus increasing friction. A B Figure 13. Canine inclination influences friction. The further labial the bracket is to the CR, the greater the moment of the couple acting on the bracket and there- fore the higher the friction. Tooth A on left has the greatest friction force. 10 Burstone The force loss from friction is shown in Figure 14. The loss is 26% first order (occlusal view) and 48% second order (facial view). Be- cause the friction forces are additive, the total loss of force is 74%. Since a typical canine is flared to the buccal even more than shown here, a greater force loss through friction can be anticipated. This calculation does not include any other friction forces such as the ligature tie. TORQUE, MOMENTS AND FRICTION It has been seen that moments associated with the prevention of tipping and rotation of a canine can lead to high friction forces. In addi- tion, third order moments or torques can lead to particularly high friction forces. Figure 15 compares two activations on a canine. Both have the same moment magnitude of 1000 g-mm; one is in the torque mode and the other in bending or tip mode. Friction Force Loss is Additive 1st order 26% 2nd order 48% Total 74% 10 mm ſo Figure 14. Friction forces are additive in three dimensions. To- tal force loss by friction during translation phase is 74% of the applied force. Figure 15. For the same moments (1000 g-mm), more friction is produced in torque in comparison to a second order tip. | | Self-ligation and Friction The torque produces the largest vertical force for 2000 g (1000 g-mm divided by 0.5 mm) in that the distance is small across the wire. Because the normal forces in torque are the greatest, the friction will be the highest (640 g) in torque as compared to 80 g in tip. For this reason, it is not recommended to use edgewise metal wires that fully engage the brackets because of the potential high friction from torque. The high fric- tion potentially can make for inefficient or unpredictable retraction. Round or undersized wires are preferable to eliminate possible unwanted torque problems. BRACKET DESIGN AND FRICTION Next we consider the effects of two bracket design parameters: self-ligation and bracket width on friction. A wire can be placed pas- sively into a bracket and a ligature or locking mechanism holds it in place. When passive, no force is exerted on the tooth and the tie func- tions purely as a restraint (Fig. 16A). In contrast, the wire in Figure 16B produces an active force potentially producing tooth movement. Displac- ing the wire with more force by the ligature tie will cause the wire to seat more fully in the bracket. After the wire is seated fully, a greater ligature tie force does not increase the force to move the tooth (Fig. 16C). This additional perpendicular force will only produce enhanced friction force that most likely is not required or wanted. The force with which metal ligatures are tied is difficult to con- trol to minimize over seating an orthodontic arch into the bracket. On the other hand, elastomeric “O'” rings can deliver higher forces than a lightly tied metal ligature wire. However, these ties do not necessarily “over- seat” a suitably stiff wire. Furthermore, elastomers will undergo degrada- tion over time, making the ligation force unpredictable. With regard to friction, the so-called “self-ligation” brackets do have the advantage of delivering more predictably lighter restraining forces (forces at 90° to the archwire) and hence, lower friction than other modalities of ligation. Both active and passive self-ligation systems can produce low or no normal forces during ligation. On the other hand, after degradation elastomers also can deliver low tie forces. Some clinicians are adept at forming light metal ties. With both these situations, if fric- tion forces are consistent and known, the forces can be compensated for with appropriate applied forces. It should be remembered that during treatment, the orthodontist must apply forces perpendicular to the arch for tooth movement and it is these forces that produce friction. These treatment forces also are present in “self-ligating” brackets. 12 Burstone Restraint Activation Wedging Figure 16. Increasing ligation forcé. A. Restraint only. B: Active tooth move- ment force. C. Wedging can interfere with tooth movement because of friction. Next we consider whether a wide bracket or a narrow bracket produces the most friction. The answer to this question is that the friction depends on how the bracket is being utilized. If a simple single force is used to bring a tooth to the buccal and close a little space by tipping, it does not make any difference. In the 15th century Leonardo da Vinci correctly stated, “Friction force is proportional to contact load and inde- pendent of surface area.” For the same normal force, the surface of con- tact does not make any difference to the friction generated (Fig. 17). However, if we want to retract a canine mainly by translation, the answer is different. For translation to occur, a moment (couple) that produces vertical forces that generates friction must be present. The formula for friction in this situation is: FF = 2 (u)x M/W where FF = friction force, M = moment at bracket and W = bracket width. In Figure 18 we compare two brackets, a narrow 2 mm and a wide 4 mm. Let us suppose we need a moment of 1000 g-mm for transla- tion (this is an arbitrary number). The narrow bracket requires a 500 g couple (500 g x 2 mm = 1000 g-mm) and the wide bracket a 250 g cou- ple (250 g x 4 mm = 1000 g-mm). Thus, the narrow bracket has twice the friction force during translational movement. IS FRICTION ALWAYS BAD? Orthodontists commonly may think of friction forces as bad. In reality, there is good and bad friction. This concept can be explained us- ing canine retraction as an example in which a 200 g distal force is applied 13 Self-ligation and Friction 50 g 50 g 0.02.2 x 0.016 0.016x0.025 Figure 17. Friction is independent of bracket width with single forces. Moment on both brackets is the same 1000 g-mm 500 * 4 mm width | 250 2mm width ſº F-500x0.15-80g F-1000x0.16=150g Figure 18. For couples, the wider bracket has the lowest friction. Gen- erally, for translational canine retraction wider brackets reduce friction force. together with a reactive moment (root distal-crown mesial) of 1000 g- mm on a canine bracket that is 3 mm wide. Using the applied force sys- tem, a 5:1 moment to force (M/F) ratio is delivered to the bracket of the canine. With this M/F ratio, the expectation is that the canine would tip back with a center of rotation approaching the apex (Fig. 19A). However, when the calculated friction force (FF) is subtracted from the applied force, the effective force is reduced to 94 g (Fig. 19B). Is this good or bad? Perhaps, the original force level of 200 g was too high, but due to friction, the lower force level is more reasonable. Not only has the effec- tive force magnitude changed, but so has the M/F ratio. The new resul- tant M/F ratio of 10:6 would translate the canine instead of tipping it. So the effective force system resulting from friction might be better in this scenario. 14 Burstone |Applied Effective M/F = 5 - M/F = 10.6 Figure 19. Friction during canine retraction reduces the applied force and also changes the M/F ratio. Here the applied force of 200 g would tip the canine, while the effective force of 94 g after subtracting friction force results in tooth translation. The bad aspect of friction is that it makes our appliances less predictable. There is a bigger difference between the applied and the ef- fective force systems. It is likely that friction is so great in some situa- tions that there is no effective force at all. This could be a problem with appliances that deliver the lightest forces. OVER-RIDING FRICTION If the clinician knows the friction forces, additional force can be applied during canine retraction. This is called a friction over-ride. An example is shown in Figure 20. An effective force of 200 g is needed for canine retraction. The M/F of 6 is estimated for the tipping phase and 4:1 to allow some controlled rotation. The ligature tie has a normal force of 500 g. Assuming that u = 0.2, the total sum of the friction forces is 300 g. Therefore, the applied force must be 500 g to produce an effective force of 200 g. Unfortunately, clinically it is not always practical to calculate the friction forces and the over-ride needed. The friction is changing con- tinually during the different phases of retraction. It is difficult to measure ligation force, which also can change (Iwasaki et al., 2003). The coeffi- cient of friction is difficult to determine and other variables can be pre- sent. However, the principal of the over-ride is a useful clinical concept. Thus, Thorstenson and Kusy (2001, 2002) showed that a conventional twin bracket with a metal ligature tie with a 200 g normal load produces about 30 g more friction force during retraction at different bracket wire 15 Self-ligation and Friction M/F = 6 M/F = 4 500g F. 120 g - 80g 100 g 300 Fe 200g FA 500g Figure 20. Over-riding friction. If friction forces are known or calculated, they can be added to the applied force. In this system a force 500 g must be applied to deliver 200 g to over-ride friction generated from the moments and forces of ligation. - angles. If this is known, an over-ride could be easy and practical to apply adding a 30 g overload to the applied load. OCCLUSAL FORCES, VIBRATION AND FRICTION It could be theorized that vibration in the mouth could relieve some frictional forces. This certainly is a commonly observed phenome- non in laboratory friction. In vitro studies by Liew and colleagues (2002) have shown a reduction of friction force using “O'” rings and round wire of 60% to 90% (Liew et al., 2002), while O’Reilly and coworkers (1999) also demonstrated 19% to 85% friction reduction in both rectangular and round wires due to this phenomenon. Different mechanisms may operate to influence the effect of fric- tion. Occlusal forces can produce lateral tooth displacement that can loosen the ligature tie or “O'” ring. Thus, vibration or tooth displacement could be an important factor in eliminating the friction force from the ligation mechanism. However, the friction forces produced during sliding a tooth along an arch wire is an entirely different phenomenon in that it is the elastically bent wire that produces the normal forces (Burstone and Koenig, 1988; Ronay et al., 1989). Occlusal forces may not relieve the force unless the chewing force is placed in a position to reduce the wire- bracket force temporarily. This observation suggests once again that fric- tion from the ligation mechanism may not be as important as friction from tooth-moving forces. 16 Burstone FRICTION AND ANATOMICAL VARIATION Even though two patients may have identical brackets, malocclu- sions and wires, the friction forces could be different due to anatomical variation in root length, alveolar and periodontal support. This phenome- non is demonstrated in the following example (Fig. 21; Tanne et al., 1991) in which canines with different bone or root anatomies are being subjected to translational movement. To translate, a force must be placed through the CR. That force usually is replaced at the bracket level with a force and a couple. The magnitude of the couple is the force times the distance of the bracket to CR. Thus, the greater the moment the higher the vertical normal forces and the greater the friction force. Note that Tooth B with the Shorter root and the Tooth C with root resorption have smaller distances and, hence, require smaller mo- ments and have less friction force during retraction. Tooth D showing alveolar bone loss has the largest distance and would have a greatest fric- tion during translation. Clinically, the tooth might not move so rapidly during translation. Why? Age of patient and biologic response? Maybe. Or perhaps the greater friction force is the answer. ANCHORAGE AND FRICTION The next question to address is whether friction has anything to do with anchorage. For simplicity, two teeth (a canine and a first molar) are used here during space closure to answer this question (Fig. 22). The applied forces are equal and opposite on the molar and canine. Sliding can occur at two possible interfaces either at the molar or the canine. It Figure 21. The greater the distance to the CR, the greater the friction. Root length, alveolar crest height and root morphology are factors in determining the magnitude of friction during translation. 17 Self-ligation and Friction -> -- Fe FA E-TF FE Fa Fe Figure 22. Friction force is reduced equally from the canine and posterior teeth and hence, does not influence anchorage. The effective forces on the anterior and posterior teeth still remain equal. will occur more readily at the interface with the lowest friction force. Assuming for now that this interface is at the canine, the friction force on the canine reduces the effective force on the canine. Similarly, because the arch wire is in equilibrium, the effective force on the molar is reduced by the same amount. Under these conditions, the friction does not influ- ence the anchorage. Next assuming that the sliding interface is at the molar while friction does not allow sliding at the canine, en masse retraction of the incisors and canine still can occur. The forces on the molar and anterior segment still will be equal and opposite. In that forces that are too great commonly are used during space closure, greater anchorage loss may not occur. In the special situation where deep overbite is present, anchorage loss may occur (Fig. 23), because the deep overbite prevents the incisors from retracting and the molar is free to slide anteriorly. REDUCING FRICTION DURING SPACE CLOSURE Space can be closed using sliding mechanics even if there are friction forces. The problem with friction is that it makes the force sys- tem more unpredictable. There are a number of approaches that could be employed that can reduce frictional forces and make the force system more predictable. We already have discussed bracket design and the use of wider brackets and lower ligation forces. Some cases do not require translation 18 Burstone Figure 23. The patient with deep overbite presents a special problem. Even if the forces on the anterior and posterior teeth are equal, anterior teeth cannot retract resulting in anchorage loss. and then tipping or suitable rotation that generate less friction can be al- lowed. If the force is placed closer to the CR, it is not necessary for the archwire to produce the anti-tip and anti-rotation moments and thus the associated friction can be reduced accordingly. Power arms and lingual placement of the force can be utilized to achieve this goal (Figs. 24–26). If an auxiliary spring or loop is used, activations can be placed to minimize tipping or rotation during canine retraction (Fig. 27). The archwire still is present to give positive control with minimum friction. En masse space closure requires sliding of the archwire through the posterior brackets. Because the force is buccal to the CR of the poste- rior teeth, these teeth tend to rotate mesial-in. The archwire can be ad- justed with a toe-in to prevent this side effect, but friction will be pro- duced. Lingual or transpalatal arches can preserve arch form without producing friction (Fig. 28; Burstone, 1989). Finally, space closure can be accomplished without sliding or friction mechanics using canine retraction springs (Fig. 29). All needed anti-tip and anti-rotation moments are bent and twisted into the springs. Since no sliding on an arch is required, this is considered frictionless me- chanics. 19 Self-ligation and Friction CR. Figure 25. Extensions (power arms) place the force closer to the CR, Active springs with helices both deliver forces and place the force apically. Figure 26. Some or all of the force can be applied lingual to the CR. This can eliminate anti-rotation moments and the resultant friction. 20 Burstone Figure 27. Loops can be used as an auxiliary with sliding mechanics. The use of anti-tip moments reduces friction forces from the wire. Figure 28. During en masse space closure, posterior segments tend to rotate me- sial-in. Moments from the archwire prevent this but produce friction forces. Figure 29. An example of frictionless mechanics. All anti-tip and anti-rotation moments are built into the canine retraction springs. 21 Self-ligation and Friction FRICTION DURING INITIAL ALIGNMENT AND FINISHING Friction forces can be present and influence results at all stages of treatment from leveling to finishing. Two effects that occur with lighter alignment arches merit mention. Friction forces are parallel to the arch wire. Sometimes this is good and sometimes bad. The good effect is to open space for tooth alignment (Fig. 30). It is a well-known principle that teeth cannot be aligned or rotated unless there is enough space for them. In that there are limitations in the ability of the main archwire to increase arch length sufficiently, auxiliary or secondary wires can be used to increase arch length such as coil springs, intrusion type arches and bypass arches (Gottlieb and Burstone, 1981). The bad effect of fric- tion during leveling is that the wire may not be free to slide mesially or distally through the brackets and, therefore, the desired forces are not free to express themselves (Fig. 31). If the wire does not slide on its own, it can be removed and retied. Figure 31. An undesirable effect of friction. If wire is unable to slide through brackets, it will not be able to express its effects fully. 22 Burstone FRICTION CAN BE COMPLICATED AND DIFFICULT TO PREDICT This chapter has discussed the role of classic friction in under- standing the biomechanics of an orthodontic appliance. Basic formula- tions have been presented to give the clinician a rational basis on how frictional forces operate so S/he can use any appliance more efficiently. These simple formulas must not be misconstrued to give fully all the re- straining forces to sliding. It is far more complicated. Specialized engi- neers study “friction” in depth and debate its effects. Even at low forces where little permanent deformation or wear occurs, the theory presented may be too limited. Measurement of coefficients of friction is difficult and hence, gives variable and inconsistent values (Kusy and Whitley, 1990). Under oral conditions, the force system is changing continually over time and tooth displacement. Force decay is inherent in our wires and our appliances. Actual loading conditions may be different and many times more complicated. For example, during the four stages of canine retraction, if the arch is not leveled fully before retraction, the described force system will be different from that described in this chapter. Resistance to sliding can involve more than classic engineering formulas if heavier loads are present in the mouth. Wires can perma- nently deform, wear and undergo abrasion. Here prediction or calculation of sliding resistance becomes difficult. Other forces from the cheek, lips and tongue add to the force system and must be considered. We briefly have discussed the importance of cyclic and occlusal forces in friction force reduction. Unfortunately, this topic adds further complexity to the system and makes for poor prediction of results. Nevertheless, an under- standing of classic friction and the formulas that underlie it can go a long way to explain much that is seen clinically and help the clinician in the selection and design of the individualized orthodontic appliance for his/ her patient. REFERENCES Burstone C.J. Biomechanical rationale of orthodontic therapy. In: Melsen B, ed. Current Controversies in Orthodontics. Quintessence Publish- ing Co. Inc., 1991;131-146. Burstone CJ. Precision lingual arches: Active applications. J Clin Orthod 1989:23:101-109. 23 Self-ligation and Friction Burstone CJ. The segmented arch approach to space closure. Am J Or- thod 1982;82:361-378. Burstone CJ, Hanley K.J. Modern edgewise mechanics: Segmented arch technique. Glendora: Ormco Corporation, 1985. Burstone CJ, Koenig HA. Creative wire bending: The force system from step and V bends. Am J Orthod Dentofacial Orthop 1988;93:59-67. Burstone CJ, Koenig HA. Force systems from an ideal arch. Am J Or- thod 1974;65:270–289. Burstone CJ, Koenig HA. Optimizing anterior and canine retraction. Amer J Orthod 1976;70: 1-19. Gottlieb EL, Burstone C.J. JCO interviews Dr. Charles J. Burstone on orthodontic force control. J. Clin Orthod 1981; 15:266-268. Iwasaki LR, Beatty MW, Randall CJ, Nickel JC. Clinical ligation forces and intraoral friction during sliding on a stainless steel archwire. Am J Orthod Dentofacial Orthop 2003;123:408-415. Kusy RP, Whitley JQ. Coefficients of friction for arch wires in stainless steel and polycrystalline alumina bracket slots. Am J Dentofacial Or- thop 1990;98:300-312. Liew CF, Brockhurst P, Freer T.J. Frictional resistance to sliding arch- wires with repeated displacement. Aust Orthod J 2002; 18:71-75. Nagerl H, Burstone CJ, Becker B, Kubein-Meesenburg D. Centers of rotation with transverse forces: An experimental study. Am J Orthod 1991;99:337-345. O’Reilly D, Dowling P, Lagerström L. An investigation into the effect of bracket displacement on the resistance to sliding. Br J Orthod 1999; 26:219–227. Ronay F, Kleinert MW, Melsen B, Burstone C.J. Force system developed by V bends in an elastic orthodontic wire. Am J Orthod Dentofacial Orthop 1989;96:295-301. Smith RJ, Burstone C.J. Mechanics of tooth movement. Am J Orthod 1984;85:294-307. Tanne K, Koenig HA, Burstone C.J. Moment to force ratios and the cen- ter of rotation. Am J Orthod Dentofacial Orthop 1988;94:426-431. Tanne K, Nagataki T, Inoue Y, Sakuda M, Burstone CJ. Patterns of ini- tial tooth displacements associated with various root lengths and alveolar bone heights. Amer J Orthod Dentofacial Orthop 1991; 100: 66–71. 24 Burstone Tanne K, Sakuda M., Burstone C.J. Three-dimensional finite element analysis for stress in the periodontal tissue by orthodontic forces. Amer J Orthod Dentofacial Orthop 1987;92:499-505. Thorstenson GA, Kusy RP. Comparison of resistance to sliding between different self-ligating brackets with second-order angulation in the dry and saliva states. Am J Orthod Dentofacial Orthop 2002; 121:472- 482. Thorstenson GA, Kusy RP. Resistance to sliding of self-ligating brackets versus conventional stainless steel twin brackets with second-order angulation in the dry and wet (saliva) states. Am J Orthod Dentofacial Orthop 2001; 120:361-370. Timoshenko S, Goodier JN. Theory of Elasticity. 2nd ed. New York, McGraw-Hill 1951. 25 SELF-LIGATION: EVIDENCE versus CLAIMS Peter G. Miles ABSTRACT Self-ligating (SL) brackets have existed in one form or another for almost as long as the edgewise bracket itself. Initially they were designed to reduce liga- tion time; now all major orthodontic companies manufacture an SL bracket. Along with these new brackets have come a large number of claims including faster alignment, fewer appointments, faster overall treatment, more rapid space closure, “waking up the tongue” with associated basal arch expansion and re- duced discomfort. In clinical practice, a new technique or material with prom- ises of faster or improved performance can be offered. However, as there is a built-in expectation for an improvement over existing systems, observational bias can result in perceiving an effect when one is not present. Alternatively the Hawthorne Effect can result in an effect being achieved purely because the pro- cedure is under scrutiny, which of itself influences the outcome. This chapter examines the level of evidence for the claims regarding SL brackets and proce- dures for improving treatment efficiency that can confound the results attributed to this type of bracket. KEY WORDS: brackets, self-ligation, friction, archwire, ligature INTRODUCTION Self-ligating (SL) brackets are not new to orthodontics, having been around in one form or another for almost as long as Angle’s edge- wise bracket. These designs even included what we would now call ‘pas- sive’ and ‘active’ brackets, some with a similar appearance to contempo- rary designs. All major orthodontic manufacturing companies now pro- duce a SL bracket. Self-ligating brackets initially were designed to save time during ligation during an era when every archwire was tied in a bracket with ligatures. Apart from saving time for ligation, current adver- tising for SL brackets makes other claims including lower friction, less discomfort, lower forces, faster treatment times, reduced emergencies, 27 Evidence versus Claims less appointments and expansion effects. These claims appeal to the de- sires of both orthodontists and patients — but are they realistic? If true, are these effects a direct result of self-ligation? And what is the evidence to support these claims? This chapter will attempt to evaluate critically some of the statements and claims made regarding SL brackets by exam- ining current evidence. FRICTION: IN VITRO VS. IN VIVO Advertising for SL brackets includes diagrams explaining how these brackets allow free sliding of the arch wire and eliminate undesir- able vectors of force. These simplistic explanations with unbalanced force vectors demonstrate more clearly a blatant disregard for biome- chanical principles. Supporters of self-ligation explain that ligating a bracket with a module applies 50 g of force per tooth, meaning that in a non-extraction case with 20 teeth ligated with modules, we are applying 50 g x 20 = 1000 g (1 kg of force) to the patient’s teeth! Once again, this overly simplistic explanation is incorrect. Although the normal force ap- plied by the module pushes the archwire into the slot with 50 g or ~50 ch of force, the module also pulls under the tie wings, bringing the base of the bracket slot pressing back up into the archwire (also with 50 cM of force). These two forces therefore cancel out, applying no residual force to the tooth, so the amount of ligation force is irrelevant to the force ap- plied to the tooth. This normal force deflects the archwire and, as the archwire re- covers its original shape, this rebound is what applies the pressure to move teeth. The normal force of engagement also is involved in friction when sliding the archwire through the bracket slot. This ‘classical’ fric- tion as described by da Vinci some 500 years ago is proportional directly to the applied normal force provided by the module or other mode of ligation. What often is neglected is that this ‘classical’ friction is only a small component of the resistance to sliding (RS). Resistance to sliding is a combination of three components: 1. Friction (FR), whether static or kinetic, is due to the contact forces between the wire, brackets and liga- tures; 2. Binding (BI) is created as soon as the tooth begins to move and the wire contacts the edge of the bracket; and 28 Miles 3. Notching (NO) occurs when permanent deformation of the wire occurs at the wire-bracket corner interface (Kusy and Whitley, 1999). Therefore RS = FR + BI, or RS = NO because sliding stops when NO begins. Any tip, rotation or torque will engage the edges of the bracket and the arch wire, resulting in binding that increases linearly with the angle of engagement; along with notching, these quickly form the major components of RS. In vitro studies examining friction have con- cluded that passive SL brackets have lower friction than active forms that are lower than conventional methods of ligation (Sims et al., 1993; Shivapuja and Berger, 1994; Pizzoni et al., 1998). As the archwire fills the bracket slot more, however, the RS of the brackets become more comparable (Henao and Kusy, 2004). The assumption by some is that with SL brackets, lower friction in vitro will result in more rapid tooth movement with less discomfort in vivo. But is in vitro research a reliable indicator of in vivo performance? Many in vitro laboratory-bonding studies cannot predict the in vivo clini- cal behavior of the adhesives tested (Swartz, 2007a). Similarly, in pro- spective clinical trials comparing conventional nickel-titanium (NiTi) wires and thermal or heat-activated NiTi wires during initial alignment, no difference was found in their clinical performance (O’Brien et al., 1990; Pandis et al., 2009; Ong et al., 2010). Despite the laboratory- derived advantages of the heat-activated NiTi wires, clinical performance was the same as a conventional NiTi (Pandis et al., 2009). Manufacturer’s claims have focused on friction, but there also is the patient’s biology to consider as a major determinant in the rate of tooth movement. So what is the rate-determining step, the rate of the wire sliding through the bracket or the rate of the supporting tissue re- modeling to allow any movement? The arbitrarily chosen rates of move- ment (0.5 mm per minute to 10 mm per minute) of in vitro research are 21,700 to 435,000 times faster than occurs clinically (1 mm per month = 2.3 x 10° mm per minute). This arbitrary rate cannot take into account tooth movement due to periodontal tissue remodeling that may occur clinically prior to the archwire sliding through the bracket. Even with 100% RS with no archwire sliding occurring, tooth movement still can occur as the wire applies pressure and the supporting tissues remodel. The vast majority of in vitro studies measuring RS use a steady-state laboratory model (Swartz, 2007b). An archwire is pulled through a series of immovable brackets with the archwire and brackets in 29 Evidence versus Claims constant contact while the force is measured. This test design cannot rep- licate the clinical condition accurately as it does not allow for vibration or movement of the brackets that can release binding. Clinically, we are not looking at true friction, but rather a binding and releasing phenome- non. It has been reported that repeated displacement of a bracket, equiva- lent to as little as 0.16 mm of mesiodistal crown movement, could reduce the RS by as much as 85% (O’Reilly et al., 1999). The first clinical data to appear on SL brackets were two retro- spective clinical studies comparing Damon SL brackets with conven- tional brackets and ligation. These studies reported reductions in treat- ment time of four (Harradine, 2001) and six months, respectively (Eberting et al., 2001). It is difficult, however, to control the array of confounding variables in retrospective studies to know exactly what in- fluence each factor has on treatment duration. Altered techniques or me- chanics may have been used (is it the bracket or the system that had the major effect?), bias may be introduced by using a new appliance and sys- tem as the practitioner may unwittingly “test the limits’ or have expecta- tions that treatment will be shorter which in itself influences treatment time. In Eberting and colleagues’ study (2001) with a six-month re- duction in treatment time (from 31 months to 25 months), the reduced treatment time of 25 months still was longer than average treatment times (23.1 months [Fink and Smith, 1992] and 23.5 months [Skidmore et al., 2006]) reported in the literature using conventional brackets. The average of 23.1 months was over six practices, durations that ranged from 19 to 28 months, so variation within and between offices was large (Fink and Smith, 1992). Reasons for these differences could include: 1. Operator experience; The difficulty of the cases treated among offices; Greater time spent in detailing and finishing; Higher extraction rates; Inefficient systems; or Expectations of longer treatment times with longer payment plans. : To determine the specific nature of the effect of SL brackets on treat- ment, we must reduce the impact of such confounders; otherwise im- proved treatment efficiency can be attributed incorrectly to the bracket used rather than other aspects of the treatment mechanics. Research of SL brackets should be designed prospectively with similar treatment sys- 30 Miles tems, archwires and mechanics along with blinding of evaluators where possible to minimize measurement bias. PROSPECTIVE CLINICAL TRIALS OF SL BRACKETS In the first two published prospective studies comparing the Da- mon 2 bracket with conventional twin brackets and the SmartClip bracket with conventional brackets and ligation during initial alignment, no significant difference was found (Miles, 2005; Miles et al., 2006). Another prospective trial found no significant difference overall but when the sample was subdivided, the authors reported that for moderate crowding (irregularity index < 5), the self-ligating group had 2.7 times faster correction (Pandis et al., 2007). The above wording is misleading, however, as the reported 2.7 is a hazard ratio and should be thought of as the odds that a patient will progress more quickly with treatment and not the actual speed of treat- ment. For example, the hazard ratio for the combined overall sample was HR = 1.68. The treatment time for the SL bracket, however, was 91.0 days and the conventional bracket was 114.5 days. Overall, therefore, the rate difference was 114.51 + 91.03 = 1.26 times faster but the hazard ra- tio or odds of that group being faster were 1.68. The Pandis study (Pan- dis et al., 2007) also used different wire sequences for each bracket type and the rectangular second archwire used (0.014” x 0.025” Damon Cop- per NiTi) in the SL cases could explain the more rapid alignment achieved than the round second archwire (0.020” Sentalloy) used in the conventional brackets. - All other prospective clinical trials have found no difference be- tween SL brackets and conventional brackets with conventional modes of ligation (Miles, 2005; Miles et al., 2006; Brock, 2008; Fleming et al., 2008; O'Dwyer et al., 2008; Scott et al., 2008). Another retrospective evaluation also found no difference between an active SL bracket and a conventional bracket in initial alignment, number of visits or the overall treatment time (Hamilton et al., 2008). More recently, studies examining alignment in the upper arch have found no difference between a ‘passive’ and an ‘active’ SL bracket (Pandis et al., 2010) or between a conven- tional porcelain bracket and an “active’ SL porcelain bracket (Miles and Weyant, 2010). The weight of evidence, therefore, currently supports no clinical difference in treatment time during initial alignment (Table 1). 31 Evidence versus Claims Table 1. Research findings comparing self-ligating brackets (SLB) and conven- tional brackets (CB) during initial alignment. Authors Research Type Conclusion Harradine, 2001 Retrospective – case-control SLB more efficient Eberting et al., 2001 Retrospective – case-control SLB more efficient Miles, 2005 Prospective clinical trial CB more efficient Miles et al., 2006 Prospective clinical trial CB more efficient Pandis et al., 2007 Prospective clinical trial SLB more efficient Scott et al., 2008 Prospective clinical trial No difference Fleming et al., 2008 Prospective clinical trial No difference O'Dwyer et al., 2008 Prospective clinical trial No difference Brock, 2008 Prospective clinical trial No difference Hamilton et al., 2008 Retrospective – case-control No difference Miles & Weyant, 2010 Prospective clinical trial No difference An abstract reported at the 2007 IADR meeting found no differ- ence between the total treatment time of a conventional edgewise bracket (27.3 + 6.6 months) and a SL bracket (28.0 + 4.7 months; Yorita and Sameshima, 2007; Kai, 2010). The investigators did record, however, that the self-ligation group had significantly fewer total appointments (16.8 + 3.6 vs. 22.8 + 6.9; P × 0.001). So, if the overall treatment time is the same but there are fewer appointments (excluding emergencies), then there must have been longer appointment intervals used with the SL brackets. This finding suggests that improvements in the area of treatment efficiency other than the bracket potentially are influencing the outcome. TREATMENT EFFICIENCY AND APPOINTMENT INTERVALS During initial alignment using NiTi wires, a longer appointment interval can be used, as the properties of the unloading plateau of a NiTi wire will continue to exert pressure on the teeth without reactivation at an arbitrary five weeks. The ability to use longer appointment intervals, therefore, is not something unique to SL brackets and more dependent upon the reliability of the mode of ligation. A quality module, steel liga- ture or SL bracket can be relied upon in most instances to last for a longer appointment interval such as eight to ten weeks. This approach will achieve the same amount of tooth movement whether the archwires are retied at five weeks or not, but the extended interval saves appoint- ments. This observation also would explain why studies comparing SL brackets with conventional brackets using identical wires and appoint- ment intervals of eight to ten weeks have found no difference during the initial alignment phase. 32 Miles Another potential time saving during treatment could be during space closure in extraction cases. In a split-mouth clinical trial evaluating en-masse space closure in a limited sample, no difference was found be- tween a passive SL bracket and a conventional bracket (Miles, 2007). The conventional bracket side moved at 1.2 mm per month while the SL bracket side moved at 1.1 mm per month (P = 0.86). Another split-mouth study evaluated canine retraction in two types of passive SL brackets and one conventional bracket (Burrow, 2010). This latter study found similar rates of tooth movement to the previous en-masse study of 1.2 mm per month for the conventional bracket and 1.1 mm per month for one of the SL brackets while the third SL bracket moved at 0.9 mm per month. The slightly slower rates of tooth movement in the latter SL bracket were sig- nificant statistically when compared to that of the conventional bracket (P<0.0043 and P × 0.0001). The author attributed this difference in effi- ciency to the dimensions of the brackets. The SL brackets are narrower, resulting in greater elastic binding when the tooth tips, so the RS is much more determined by binding than by friction. It appears, therefore, that the geometry or bracket width is the important factor and not the mode of ligation. Once again, appointment intervals can be modified to take the best advantage of the mechanics used during space closure. Previous re- search has established that the use of NiTi coil springs is at least as or more efficient at space closure as elastic modules or chain (Samuels et al., 1993, 1998; Dixon et al., 2002; Nightingale and Jones, 2003). One such study compared the rates of movement for a stretched module vs. elastic chain and a NiTi spring (Dixon et al., 2002). If the average rates of movement reported in this study are applied to closing a 6 mm extrac- tion space, they result in space closure in 17.1 months for stretched mod- ules, 10.3 months for chain and 7.4 months for the NiTi springs. Al- though more expensive, the NiTi spring appears to be the most efficient in terms of treatment time. If we consider that clinically we may need to reactivate the chain or module more frequently, say every five weeks, whereas the NiTi spring can be relied upon to stay active over a longer period, say eight weeks, then we have an additional saving in the number of appointments. By modifying our appointment intervals to suit the properties of the materials used and applying our knowledge of patient biology and selecting efficient treatment mechanics, we potentially can make signifi- cant savings in the number of appointments required during treatment. Figure 1 shows a hypothetical extraction case where two upper premolars 33 Evidence versus Claims 10/8/5 wits -Align - Space Close - Detail 5 weekly o 2 4. 5 3. 10. 1. 14. Figure 1. The horizontal bar chart represents the appointments required for two hypothetical Class II patients treated with the extraction of two upper premolars over a 16-month period. The lower bar represents appointments conducted every five weeks requiring six appointments to level and align (30 weeks), five ap- pointments to close a 6 mm residual space (using chain at 1.2 mm per month = 25 weeks) and three detailing appointments (15 weeks) for a total of 14 ap- pointments. The upper bar chart represents using extended appointment intervals using three appointments at ten-week intervals during initial alignment (30 weeks), three appointments for space closure using NiTi coil springs (1.2 mm per month) adjusted every eight weeks (24 weeks) and again a final three detail- ing appointments at five week intervals (15 weeks). Using extended appoint- ment intervals has reduced the number of required appointments by five; this can be accomplished regardless of the mode of ligation used. have been removed in a Class II malocclusion. Both treatment times are identical at approximately 16 months, but the appointment intervals dif- fer as discussed above. The lower bar represents five weekly appoint- ment intervals during all stages of treatment. We have an initial round NiTi wire retied at five weeks then possible bracket repositioning at 10 weeks and perhaps a larger round NiTi wire placed at that appointment. Then any further bracket repositioning is performed at 15 or 20 weeks and later a rectangular NiTi engaged so we reach the working wire by 30 weeks. The top bar represents using 10-week intervals during initial alignment so after 10 weeks in the initial round Niſi, we repositioned brackets or engage the rectangular wire and at 20 weeks any further re- positioning and wire change so again by 30 weeks we have reached the working wire but in three less visits. During space closure of a residual 6 mm extraction space at a rate of 1.2 mm per month, we could choose elastomeric chain and reacti- vate at five weekly intervals requiring five appointments or use a NiTi coil spring checked at eight-week intervals requiring only three visits. Finally during detailing, if we have reasonable control of our occlusion 34 Miles and alignment, we can use five-week intervals for both systems as any adjustments for detailing are not expected to remain active over a longer period of time. Both systems, therefore, may require three visits before case completion. Although the treatment times are the same, using a standard five-week appointment interval and less efficient wire se- quences or space closing mechanics that requires more regular reactivation has resulted in five additional appointments. PAIN AND DISCOMFORT WITH SELF-LIGATING BRACKETS One of the claims regarding SL brackets is that they apply less force, resulting in lower pain. Four prospective clinical trials examining discomfort after placement of the initial archwire found no statistically significant difference in perceived discomfort levels between conven- tional and SL brackets (Brock, 2008; Rahman et al., 2008; Scott et al., 2008; Fleming et al., 2009). Another prospective trial found a statistically significant lower mean pain intensity with SL brackets than with the conventional pread- justed appliance patients (P = 0.012; Pringle et al., 2009). This study ex- amined the discomfort during the first week after engaging a 0.014” Cu- NiTi wire. This finding could be due to incomplete engagement in SL brackets of a smaller 0.014” wire whereas modules are engaging the archwire more actively. This observation also may explain why some studies found slightly better reductions in irregularity with the initial round archwires with a conventional bracket and module (Miles, 2005; Miles et al., 2006). Once the rectangular NiTi wire is engaged, however, there is less bracket/archwire play in SL brackets and perhaps a potential for greater discomfort as discovered in the study by Miles and co- workers (2006). The limitation of this study is that it only examined dis- comfort as the archwire was engaged and not over the ensuing days; fur- ther research, therefore, is required to examine this possibility. ARCH EXPANSION Some proponents of self-ligating brackets have imbued these brackets with an ability to expand arches and create or move the support- ing tissues as they do so resulting in less extractions being required and more stable results. There are a limited number of studies on SL brackets assessing the effects on arch form, but we also can gather some informa- tion from other studies to examine this in more detail. One retrospective 35 Evidence versus Claims study evaluated 20 selected cases from a practice using Damon brackets and compared the arch changes with the published literature. When their findings were compared with previously published results on rapid pala- tal expanders followed by fixed appliances, no difference was found in the amount of molar tipping (Mikulencak, 2007). The wording of note here is ‘tipping’ and not basal expansion. More importantly, the cases were selected retrospectively and, therefore, a potential for bias exists. In another study examining the effects of a ‘passive’ ligature meant to mimic a passive SL bracket, Franchi and coworkers (2006) re- ported that the intermolar width increased by 1.7 mm and that the molars also tipped buccally 4°. The first prospective studies to evaluate arch change using SL brackets reported a 1.6 mm expansive effect at the mo- lars but any tipping of the molars was not recorded. It is significant that this study also used different wire sequences, with the Damon bracket group receiving a rectangular 0.014” x 0.025” Damon Cu-NiTi wire while the conventional brackets received a 0.020” round NiTi wire. This difference in the cross-section of the wires used could influence the out- come but even more, the archform of the Damon wires is wider signifi- cantly than other mandibular archforms (Fig. 2). Another study of SL brackets also found a mild expansion of 0.9 mm in the molar region but no changes in any other arch width or incisor position parameters (Fleming et al., 2009). In contrast, two other investi- gations have found no difference in arch width (Brock, 2008; Tecco et al., 2009). Combining these results indicates that any expansive effect from self-ligation either is absent or is restricted to the molars only and in the amount of 0.9 to 1.7 mm. This reduced expansion could be due to the extra play of the archwire in the ‘passive' slot of the premolar brack- ets both buccally and in torsion, allowing more pressure to be exerted on the molar tubes resulting in tipping. Such a small amount contributes little to arch perimeter gain and may be unstable. Some case reports demonstrate more marked expansion most likely due to the much wider Damon archform; so what is the impact of this on the supporting tissues? Two abstracts presented at the 2009 an- nual session of the American Association of Orthodontists in Boston ex- amined this question. One reported pre- and post-treatment CBCT scans of 50 SL patients and assessed the changes in basal alveolar bone (Catta- neo et al., 2009); arch expansion was achieved by buccal tipping and no transverse augmentation of basal bone could be detected. Another ab- stract also examined facial bone changes using CBCT after arch devel- opment using the Damon System (Paventy, 2009). A total of 19 patients 36 Miles Figure 2. Three archwires for the lower arch are overlaid. The longer innermost archwire is a 3M Orthoform III and the adja- cent wire is the GAC Ideal archform. The outer archform is the ORMCO Damon archform, which is wider appreciably than the other two and would be expected to have a significant in- fluence over the arch width irrespective of the bracket used or mode of ligation. with non-extraction treatment of moderate to severe crowding (5+ mm) Were examined. The latter study concluded that although both dental arches were expanded, facial bone did not adapt correspondingly after arch development and the bone actually decreased significantly in height and width for nearly all teeth measured. It seems that when greater expansion is achieved, it is at the ex- pense of the supporting tissues. This loss of basal bone height potentially could result in gingival recession on the buccal aspects. We also must consider the alteration in the tissue forces on these expanded archforms. The equilibrium theory proposed by Weinstein and colleagues (1963) and revisited by Proffit (1978) discusses the delicate balance of pressure applied by the lips, cheeks, tongue, PDL and gingival fiber networks on tooth position. Excessively altering arch form and moving the dentition outside the envelope of balance potentially results in poor long-term sta- bility. 37 Evidence versus Claims FASTER LIGATION The last claim to be examined in this chapter concerns faster ligation. It comes as no real surprise that SL brackets are faster to ligate and untie than conventional modes of ligation, as this reduction in chair time is what self-ligating brackets initially were designed to allow as far back as the 1930s when these modifications in bracket design were first proposed. The amount of time saved varies and when compared with ligatures potentially can reduce up to 10 to 12 minutes of ligation time (Berger and Byloff, 2001). When modules are used, however, the time saving is a more modest one to three minutes depending on the design of the bracket (Berger and Byloff, 2001; Harradine, 2001; Turnbull and Birnie, 2007). Since the advent of elastomeric modules, steel ligatures are used much less with metal brackets except for specific reasons. With cosmetic ceramic and plastic brackets, however, it is more difficult to engage the archwire fully with a module as it cannot be ligated in a figure eight con- figuration due to the bulk of the bracket and tie wings. A ligature likely is to be used more frequently with ceramic and plastic brackets. In a recent prospective randomized clinical trial comparing the effectiveness of SL porcelain brackets with conventional porcelain brackets in the upper arch, no significant difference (P = 0.12) was found in upper incisor irregularity after 10.7 weeks with the initial 0.014” NiTi wire in place (Miles and Weyant, 2010). Discomfort also was recorded; again, no difference between conventional porcelain and self-ligating porcelain brackets was recorded in patient discomfort during the first week of treatment (P = 0.9). From a time perspective, however, the SL bracket saved 22 seconds per bracket that for six anterior porcelain brackets was a time saving of two minutes and ten seconds. This time saving represents only a portion of the actual chair time during an ortho- dontic adjustment. It then is up to the practitioner to determine if this amount of reduced chair time is significant in the day-to-day operation of his/her practice. If, for example, an auxiliary ligates the archwire but the patient cannot be dismissed until the orthodontist has examined the pa- tient, then there is no time saving irrespective of the mode of ligation. The orthodontist must be performing the procedure him/herself or be available immediately for this time saving to be of any benefit. It is, therefore, a practice management decision whether a SL bracket contrib- utes significantly to patient flow within the office. 38 Miles SUMMARY OF THE EVIDENCE In the past, our treatment decisions were based on what we were taught by our teachers, mentors and what we learned over time, as well as on our clinical judgment as a skilled practitioner. Contemporary treat- ment still involves such factors, but these factors need to be balanced with our patient’s values and the best available scientific evidence. Case reports can demonstrate new possibilities but are prone strongly to bias and, along with opinion, form the lowest levels of evidence. Our treatments should be guided by the highest levels of evi- dence, which are considered to be the prospective randomized controlled trials (RCT) and at the very top the meta-analyses and systematic re- views of these prospective RCTs. A systematic review of the literature on SL brackets was published recently and, based on the best available evidence, concluded that there is insufficient evidence to support the use of SL fixed orthodontic appliances over conventional appliance systems or vice versa (Fleming and Johal, 2010). SL brackets did not confer any ad- Vantage concerning pain and treatment was no more or less efficient. The goal of this chapter has been to evaluate some of the claims made regarding SL brackets and examine the current evidence. Based on this evidence regarding SL brackets, it appears that treatment efficiency does not appear to be dependent upon the use of a SL bracket. Apart from modest time saving with ligating SL brackets, no other advantages can be conferred upon them at this time. The decision to use a SL bracket or a conventional bracket, therefore, currently would be either a practice management decision or based on personal preference. REFERENCES Berger J, Byloff FK. The clinical efficiency of self-ligated brackets. J Clin Orthod 2001:35:304-308. Brock J. A comparison of initial alignment and pain with self-ligating and conventionally ligated bracket systems. Unpublished doctoral thesis, University of Queensland, Australia, 2008. Burrow S. Canine retraction rate with self-ligating brackets versus con- ventional edgewise brackets. Angle Orthod 2010;80:626-633. Cattaneo P, Cevidanes L., Treccani M, Myrda A, Melsen B. Transversal expansion and self-ligating brackets: A CBCT study. Boston: Annual session Am Assoc Orthod 2009;12 (abstract). 39 Evidence versus Claims Dixon V, Read MJF, O'Brien KD, Worthington HV, Mandall NA. A randomized clinical trial to compare three methods of orthodontic space closure. J Orthod 2002:29:31-36. Eberting JJ, Straja SR, Tuncay OC. Treatment time, outcome, and patient satisfaction comparisons of Damon and conventional brackets. Clin Orthod Res 2001;4:228–234. Fink DF, Smith R.J. The duration of orthodontic treatment. Am J Orthod Dentofac Orthoped 1992; 102:45-51. Fleming PS, DiBiase AT, Lee RT. Randomised controlled trial of man- dibular alignment with two pre-adjusted appliances. J Orthod 2008; 35:223-224 (abstract). Fleming PS, DiBiase AT, Sarri G, Lee RT. Pain experience during initial alignment with a self-ligating and a conventional fixed orthodontic appliance system: A randomized controlled clinical trial. Angle Or- thod 2009;79:46–50. Fleming PS, Johal A. Self-ligating brackets in orthodontics: A systematic review. Angle Orthod 2010;80:575-584. Franchi L, Baccetti T, Camporesi M, Lupoli M. Maxillary arch changes during leveling and aligning with fixed appliances and low-friction ligatures. Am J Orthod Dentoſac Orthop 2006;130:88-91. Hamilton R, Goonewardene MS, Murray K. Comparison of active self- ligating brackets and conventional pre-adjusted brackets. Aust Orthod J 2008:24:102-109. Harradine NWT. Self-ligating brackets and treatment efficiency. Clin Orthod Res 2001;4:220-227. Henao SP, Kusy RP. Evaluation of the frictional resistance of conven- tional and self-ligating bracket designs using standardized archwires and dental typodonts. Angle Orthod 2004;74:202-211. Kai LM. A comparison of treatment time and number of appointments in active self-ligating and conventionally ligated twin edgewise brack- ets. Los Angeles: Unpublished Master’s thesis, Department of Ortho- dontics, University of Southern California, 2010. Kusy RP, Whitley JC). Influence of archwire and bracket dimensions on sliding mechanics: Derivations and determinations of the critical con- tact angles for binding. Eur J Orthod 1999;21:199-208. Mikulencak DM. A comparison of maxillary arch width and molar tip- ping changes between rapid maxillary expansion and fixed appliance 40 Miles vs. the Damon system. Am J Orthod Dentofac Orthop 2007; 132:562 (abstract). Miles PG. Self-ligating vs. conventional twin brackets during en-masse space closure with sliding mechanics. Am J Orthod Dentofacial Or- thop 2007; 132:223-225. Miles PG. SmartClip versus conventional twin brackets for initial alignment: Is there a difference? Aust Orthod J 2005:21:123-127. Miles PG, Weyant R.J. Porcelain brackets during initial alignment: Are self-ligating cosmetic brackets more efficient? Aust Orthod J 2010; 26:21–26. y Miles PG, Weyant RJ, Rustveld L. A clinical trial of Damon 2 vs. con- ventional twin brackets during initial alignment. Angle Orthod 2006; 76:480–485. Nightingale C, Jones SP. A clinical investigation of force delivery sys- tems for orthodontic space closure. J Orthod 2003:30:229-236. O'Brien K, Lewis D, Shaw W, Combe E. A clinical trial of aligning archwires. Eur J Orthod 1990; 12:380-384. O'Dwyer LA, Littlewood SJ, Rahman S, Spencer R.J. Efficiency of SmartClip self-ligating brackets compared to brackets using conven- tional ligation. J Orthod 2008:35:226 (abstract). Ong E, Ho C, Miles P. Alignment efficiency and discomfort of three or- thodontic archwire sequences: A randomized clinical trial. J Orthod 2010:in press. O'Reilly D, Dowling PA, Lagerström L, Swartz ML. An ex vivo investi- gation into the effect of bracket displacement on the resistance to slid- ing. Br J Orthod 1999:26:219–227. Pandis N, Polychronopoulou A, Eliades T. Active or passive self-ligating brackets? A randomized controlled trial of comparative efficiency in resolving maxillary anterior crowding in adolescents. Am J Orthod Dentofacial Orthop 2010; 137:12.e1-e6. Pandis N, Polychronopoulou A, Eliades T. Alleviation of mandibular anterior crowding with copper-nickel-titanium vs. nickel-titanium wires: A double-blind randomized control trial. Am J Orthod Dento- fac Orthop 2009;136:152.el-e?. Pandis N, Polychronopoulou A, Eliades T. Self-ligating vs. conventional brackets in the treatment of mandibular crowding: A prospective clinical trial of treatment duration and dental effects. Am J Orthod Dentofacial Orthop 2007;132:208-215. 41 Evidence versus Claims Paventy AM. Nonextraction treatment using the Damon System: A CBCT evaluation. Boston: Annual session Am Assoc Orthod 2009: 28 (abstract). Pizzoni L, Raunholt G, Melsen B. Frictional forces related to self- ligating brackets. Eur J Orthod 1998:20:283-291. Pringle AM, Petrie A, Cunningham SJ, McKnight M. Prospective ran- domized clinical trial to compare pain levels associated with 2 ortho- dontic fixed bracket systems. 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A comparative study of conventional ligation and self-ligation bracket systems. Am J Orthod Dentofac Orthop 1994;106:472-480. Sims APT, Waters NE, Birnie DJ, Pethybridge R.J. A comparison of the forces required to produce tooth movement in vitro using two self- ligating brackets and a pre-adjusted bracket employing two types of ligation. Eur J Orthod 1993; 15:377-385. Skidmore KJ, Brook KJ, Thomson WM, Harding WJ. Factors influenc- ing treatment time in orthodontic patients. Am J Orthod Dentofac Or- thop 2006;129:230-238. Swartz ML. Fact or friction: The clinical relevance of in vitro steady- state friction studies. J Clin Orthod 2007b;41:427-432. Swartz ML. Limitations of in vitro orthodontic bond strength testing. J Clin Orthod 2007a;41:207-210. 42 Miles Tecco S, Tetê S, Perillo L, Chimenti C, Festa F. Maxillary arch width changes during orthodontic treatment with fixed self-ligating and tra- ditional straight-wire appliances. World J Orthod 2009; 10:290–294. Turnbull NR, Birnie DJ. Treatment efficiency of conventional vs. self- ligating brackets: Effects of arch wire size and material. Am J Orthod Dentofac Orthop 2007; 131:395-399. Weinstein S, Haack DC, Morris LY, Snyder BB, Attaway HE. On an equilibrium theory of tooth position. Angle Orthod 1963:33:1-26. Yorita R, Sameshima GT. A comparison of self-ligating and conven- tional orthodontic bracket systems. Internat Assoc Dent Res 2007; Program and Abstracts 1918. 43 MECHANICS TO EXPEDITE ORTHODONTIC TREATMENT Ravindra Nanda, Madhur Upadhyay, Flavio Uribe ABSTRACT Orthodontic mechanotherapy often is not planned and managed proactively by the orthodontist but instead is relegated to the inevitable consequences of the cookbook approach being utilized by the clinician. Efficient orthodontic treat- ment requires that sound treatment plans be carried out in conjunction with op- timal mechanic plans. This chapter highlights the importance of employing biomechanics-based appliances in treating various kinds of malocclusions such as open bites, Class II malocclusions and impacted canines. KEY WORDS: biomechanics, one-couple force system, open bite, space closure, Class II correction, canine impaction Efficient orthodontic treatment requires that sound treatment plans be carried out with optimal mechanic plans. Mechanics is a branch of engineering science that describes the effects of forces on an object. When applied to the teeth and bones, the term ‘biomechanics’ is more appropriate as it effects changes at the biological level. It provides a de- fined path for obtaining predicable and stable treatment results and con- trols the inherent side effects of the brackets and wires on tooth move- ment. Biomechanics in orthodontics includes force magnitude, direction and duration of force, M/F ratio and point of force application, among other components. Various orthodontic techniques and appliances either minimize an accurate depiction of force system or completely ignore it. Often the treatment effects are not controlled by the orthodontist but rather by the nature of the cookbook approach of an appliance. Biomechanics-based appliances are user-, patient- and tissue-friendly. The force application is logical and predictable with minimal side effects. Although the basic fundamentals of biomechanics are the same in every clinical situation, the method of its application differs. Let us explore some common mal- 45 Mechanics to Expedite Treatment occlusions where biomechanics-designed appliances can deliver a pre- dictable response. OPEN BITE MECHANICS Two of the most common methods of correcting a dental anterior open bite are an anterior box elastic or a step bend in the arch wire, or a combination of both. Although box elastics extrude the incisors, they also tip them back as the force applied usually is anterior to the center of resistance (CR) of the incisors, which creates a clockwise moment thereby limiting the amount of overbite (overcorrection) that can be ob- tained. On the other hand, a ‘step bend’ being a Class I geometry (Burstone et al., 1974) creates a counterclockwise moment on the poste- rior segment (Mp) that tends to worsen the existing open bite by tipping the posterior teeth forward (Fig. 1). Vertical Forces: Reduces OB Tip Forward Moment: Worsens Posterior OP; Flares Incisors Figure 1. The step bend creates equal and opposite forces on the anterior and posterior segments (green arrows). The moments, however, are in the same di- rection worsening the open bite condition. OP = occlusal plane. OB = open bite. The application of a one-couple force system in the form of an extrusion arch easily can overcome this problem. Instead of inserting the extrusion arch into the bracket slots of the anterior teeth that creates statically indeterminate force systems, a more viable option is to tie the extrusion arch over the anterior segment to have a single point of force application (Fig. 2). Once ligated, the extrusion arch also delivers an un- 46 Nanda et al. Figure 2. An extrusion arch (in blue) tied to a rigid anterior Segment employs a one-couple force system that generates a single force (F) anteriorly (blue arrow). The moments gener- ated are counteracted by an opposite moment (red arrow) that results from using an elastic (orange). desirable moment on the molars or the buccal segments. This unwanted moment can be controlled by using a seating elastic placed from the up- per canines to the lower arch. The force applied passes anterior to the CR of the upper posterior segment, creating a moment that negates the mo- ment created by the extrusion arch. The sum of all forces and moments results in a pure intrusive force on the posterior segment and an opposite and an equal extrusive force on the anterior segment. A case report illus- trates the application of an extrusion arch to treat a dental open bite prob- lem (Figs 3-5). 47 Mechanics to Expedite Treatment Figure 3. Pre-treatment extra-oral and intra-oral photographs of a patient with an anterior open bite. Figure 4. An “extrusion arch” in place to connect the open bite. Elastics are used to control the unfavorable moments. SPACE CLOSURE One popular way of canine retraction is ‘frictional/sliding me- chanics, which employs a continuous arch system. The advantages of this system are minimal wire bending and easier application. When an arch wire with a low load-deflection rate is used, however, it tends to de- form—leading to undesirable side effects on the anterior teeth causing extrusion of the incisors and deepening of the bite. This type of deep bite 48 Nanda et al. Figure 5. Post-treatment photographs showing connection of the open bite. also can be termed as ‘iatrogenic deep bite, which in the present context means deep bite induced inadvertently by the clinician (Fig. 6; Upadhyay and Nanda, 2009). With larger or rigid archwires, the system might de- velop excessive friction leading to delayed tooth movement, anchorage loss or maybe even cessation of canine retraction. With the use of a 0.016’ x 0.022” or 0.017" x 0.025" NiTi intrusion arch (Nanda et al., 1998) as an overlay archwire, however, the biomechanical force system can be optimized for controlled canine retraction with fewer side effects (Fig. 7). The counterclockwise moment (if tied anterior to the center of rotation of the anterior teeth) and the intrusive force on the incisors en- Sure the stability of the anterior segment by counteracting the iatrogenic forces generated by canine retraction which often tend to create a deep bite. Additionally, molar anchorage is reinforced due to the tip-back Mp in cases requiring high anchorage. Differential moment to force (M/F) ratios also can be created for retraction of incisors via a segmental approach. As an example, a mush- room loop (Uribe and Nanda, 2003) with a greater second-order activa- tion of the posterior arm can create this differential moment. The Mp needs to be higher than the moment on the anterior segment (Ma). This differential in moments (Mp Ma) will help reinforce anchorage for ef. ficient group A space closure (Fig. 8). 49 Mechanics to Expedite Treatment Figure 6. Development of deep bite (iatrogenic) during canine retraction using sliding mechanics resulting from the occlusal deflection of the archwire. Figure 7. Application of Connecticut intrusion arch (CTA) to prevent deepening of the bite while simultaneously augment- ing anchorage during canine retraction. Figure 8. Application of ‘mushroom loop to close anterior spaces by creating differential moments in the anterior and posterior segments (Ma and Mp). 50 Nanda et al. MECHANICS FOR DISTALIZATION Most of the distalization appliances obtain a Class I molar rela- tionship after considerable flaring of the anterior teeth. This flaring not only prolongs the treatment time as now the incisors have to be retracted back to their original position, but such ‘round-tripping also can have deleterious effects on the roots and the surrounding tissue. A more efficient and less tedious way of obtaining the same re- sult (a Class I molar and canine relation) is by the application of differen- tial moments, i.e., by using a one-couple force system as discussed in the previous section. This is carried out in two distinct stages. In the first stage, a simple cantilever spring (0.016’ x 0.022” or 0.017" x 0.025” Connecticut new arch wire [CAN]) is used to create a clockwise moment on the molar to tip the crown back. The reactionary force is distributed over the entire arch by the cantilever arm (Fig. 9). Figure 9. A simple cantilever design (intrusion arch, in blue) can be employed to create a one couple force System to tip the molar back. The anterior intrusion can be prevented by using a stiff wire for the entire arch except on the molar that needs to be distalized. 51 Mechanics to Expedite Treatment The second stage uses successive large dimension continuous wires through the molar for root uprighting. The cantilever remains ac- tive through this stage to prevent anterior crown movement. The patient is advised to use Class II elastics in order to maintain the corrected posi- tion of the molar and provide a distal force on the maxillary anterior teeth (Fig. 10). FIXED FUNCTIONAL APPLIANCES An alternative approach for obtaining a Class I molar relation in Class II malocclusions is to use a fixed functional appliance. In principle, such appliances achieve a dentoalveolar correction of the Class II maloc- clusion by applying equal and opposite forces on the upper and lower teeth. Figure 10. Once the molar has been tipped back, a con- tinuous wire (grey) is placed to create a couple that now can tip back the roots of the molar. An open coil spring and/or Class II elastics (orange) usually are em- ployed to prevent mesial drift of the molar crown. 52 Nanda et al. We prefer using the Twin Force Bite Corrector (TFBC; Rothenberg, et al., 2004: Figs. 11-14). It is a bilateral inter-arch push-type appliance that is tied individually to the archwires on each side, thereby distributing the forces on all the teeth. Prior to the placement of TFBC, leveling and aligning is carried out with successive heavier archwires. The appliance is delivered with 0.021” x 0.025” stainless steel (or as heavy wires as possible based on slot size) archwires placed in both arches. Both heavy archwires are bent distal to the molars, thereby creating both upper and lower teeth as two large units. The upper arch also must have a transpalatal arch. Figure 11. Pre-treatment photographs of an 11-year-old patient with Class II Division 2 malocclusion treated with the twin force appliance. Total treatment time was 17 months. A 0.016° x 0.022.” CTA was used to level the upper and lower incisors. TFBC was used for three months on a 0.021” x 0.025” stainless Steel archwire. Figure 12. Progress photographs from patient in Figure 11 with the TFBC. 53 Mechanics to Expedite Treatment Figure 14. The patient from Figure 11 as seen after eleven months of retention. Figure 15 shows the biomechanics of this appliance. The point of force application is mesial to the upper first molars on the maxilla and dis- tal to the canines in the mandible. The direction of force on the maxilla is posterior and apical, with the distal component having the larger magnitude 54 Nanda et al. while the direction of force on the mandible is anterior and apical, with the mesial component having the larger magnitude (Fig. 15). As the appliance generates ‘oscillating force during various jaw movements, it is difficult to quantify its precise magnitude. The appliance forces the patient to bite in an edge-to-edge incisor position. But due to the piston/plunger configuration of the appliance as well as the ball and socket attachments near the teeth, patients can perform almost all the jaw func- tions. The appliance is left in the mouth for approximately three months with one-month intervening visits. After appliance removal, the patient is given seating elastics for three to six months. For retention, a positioner is a good choice for six months with a fixed lower retainer. Later a wrap- around retainer is given for the upper arch. Long-term follow-up of treated cases at our department has shown good retention of the corrected maloc- clusion (Figs. 16-18). Figure 15. The twin force appliance exerts a distal and intrusive force on the maxillary arch along with a clockwise moment (red arrows). In the lower arch, the forces are equal and opposite with a mesial and an intrusive component and an associated moment tending to flare the lower incisors. 55 Mechanics to Expedite Treatment Figure 16. Long-term follow-up of a patient treated with the TFBC. Photos before treatment. Figure 17. Patient shown previously in Figure 16 after treatment. Figure 18. Patient from Figure 16 seven years into retention. EXTRUSION OF IMPACTED CANINES An impacted canine can be defined as a tooth that has failed to erupt even after the complete formation of roots or eruption of contralat- 56 Nanda et al. eral canine with complete root formation. An efficient orthodontic appli- ance should have the ability to bring about a controlled three- dimensional (3D) movement (Yadav et al., 2010) of the impacted teeth within the biological and mechanical realms of tooth movement, in the direction predetermined by the treatment goal. Cantilever-based appliances or springs (one-couple force sys- tems) as demonstrated in Figures 19 to 23 are designed to have a low load deflection rate. The force systems delivered by these appliances tend to stay optimal and consistent in their magnitude, not causing any deleterious effects on the surrounding periodontium through the entire range of tooth movement. Additionally, acceptable magnitude of force is maintained in the appliance during treatment to avoid frequent reactiva- tions. A single force is exerted on the canine for extrusion and alignment. The reactionary force and the moment are dissipated on the molar (Figs. 21 and 22) that can be controlled by using a transpalatal arch and/or ligating the molar to the rest of the arch (Figs. 21 and 22). The biome- chanical design of a cantilever spring to extrude a buccally or labially impacted canine is illustrated in Figure 22. Figure 19. Pre-treatment photographs of a case to illustrate the application of a one-couple force system (cantilever spring) to extrude a palatally impacted ca- Illne. 57 Mechanics to Expedite Treatment Figure 20. Progress photographs of patient in Figure 19 to illustrate the applica- tion of a one-couple force system (cantilever spring) to extrude and produce buccal movement of palatally impacted canines. Figure 21. The force systems and the associated moments generated by the cantilever spring to move the canines labially as seen from an occlusal aspect. Note a transpalatal arch is an effective appliance to counteract all the unwanted side effects generated by such a system. 58 Nanda et al. - - - Passive' CNA Cantilever spring ‘Active' CNA Cantilever spring Figure 22. Illustration depicting the forces and moments generated by a cantile- Ver spring used to extrude a palatally or facially impacted canine from a labial aspect. Figure 23. Post-treatment results of patient shown in Figure 19. 59 Mechanics to Expedite Treatment CONCLUSIONS An understanding of the underlying principles of biomechanics not only ensures a predictable and faster tooth movement while minimiz- ing undesirable side effects, but also makes the clinician less dependent on appliance-driven mechanics. REFERENCES Burstone CJ, Koenig HA. Force systems from an ideal arch. Am J Or- thod 1974;65:270–289. Rothenberg J, Campbell ES, Nanda R. Class II correction with the Twin Force Bite Corrector. J Clin Orthod 2004:38:232–240. Upadhyay M, Nanda R. Etiology, diagnosis and treatment of deep over- bite. In: Nanda R, Kapila S, eds. Current Therapy in Orthodontics. Mosby: Elsevier 2009:186-200. Uribe F, Nanda R. Treatment of Class II, Division 2 malocclusions in adults: Biomechanical considerations. J Clin Orthod 2003:37:599- 606. Yadav S, Chen J, Upadhyay M, Feifei J, Roberts WE. Comparison of the force systems of three different appliances on palatally impacted max- illary canine. Am J Orthod Dentofacial Orthop 2010:in press. 60 EFFICIENCY OF ALIGNMENT OF APICALLY- OR BUCCALLY-MALPOSED TEETH WITH LOW-FRICTION VERSUS CONVENTIONAL SYSTEMS Lorenzo Franchi, Matteo Camporesi, Veronica Giuntini, Tiziano Baccetti ABSTRACT The objective of this chapter is to present the results of an in vitro study that analyzed the forces released by passive stainless steel self-ligating brackets (SLBs) and by a non-conventional elastomeric ligature on conventional brackets (NCLCB) when compared with conventional elastomeric ligatures on conven- tional brackets (CLCB) during the alignment of apically- or buccally-malposed teeth in the maxillary arch. An experimental model consisting of five brackets was used to assess the forces released by the three different bracket-ligature systems with 0.012” super-elastic (SE) nickel-titanium (NiTi) wires in the presence of different amounts of apical or buccal canine misalignments (ranging from 1.5 mm to 6 mm). The forces released by each bracket/wire/ligature combination with the three different magnitudes of apical or buccal canine misalignment were tested 20 times. Comparisons between the different types of bracket/wire/ligature sys- tems were carried out by means of analysis of variance on ranks with Dunnett’s post hoc test (P<0.05). No difference in the amount of force released in presence of a mis- alignment of 1.5 mm was recorded among the three systems. At 3 mm of apical misalignment, a significantly greater amount of orthodontic force was released by SLB or NCLCB when compared with CLCB, while no significant differences were found among the three systems at 3 mm of buccal canine displacement. When correction of a large amount of misalignment (6 mm) was attempted, a noticeable amount of force for alignment still was generated by the passive SLB and NCLCB systems, while no force was released in presence of CLCB. KEY WORDS: friction, super-elastic NiTi wire, conventional brackets, self- ligating bracket, elastomeric ligature 61 Efficiency of Alignment During fixed appliance therapy, the main force that contrasts tooth movement is the frictional force developed between the interface of the bracket slot and the archwire (Frank and Nikolai, 1980). In recent years, a series of methods has been proposed with the aim of reducing the frictional forces that resist tooth movement at the bracket/ wire/ligature interface, such as self-ligating brackets (SLBs; Pizzoni et al., 1998; Thomas et al., 1998; Henao and Kusy, 2005; Franchi et al., 2008; Kim et al., 2008) and non-conventional ligature systems (Thor- stenson and Kusy, 2003; Baccetti and Franchi, 2006; Yeh et al., 2007). In particular, passive SLBs consistently have shown a smaller amount of friction than conventional systems (Pizzoni et al., 1998; Thomas et al., 1998). A significant reduction in friction also has been reported for non- conventional elastomeric ligatures on conventional brackets (NCLCB; Baccetti and Franchi, 2006; Franchi and Baccetti, 2006; Franchi et al., 2008). Classical in vitro studies have been aimed to measure friction in presence of different amounts of tooth displacement. In these studies (Henao and Kusy, 2005; Kim et al., 2008), however, the static and ki- netic frictions were evaluated solely by drawing the orthodontic archwire through a series of aligned/misaligned brackets. A specific testing device has been proposed to re-create clinical conditions for the leveling and aligning phase of the straight-wire technique, i.e., to study the forces re- leased during alignment of a malposed tooth. The tests were conducted with unconventional ligatures on conventional brackets in presence of different amounts of misalignment of one bracket (canine bracket) with regard to four remaining aligned brackets (Franchi and Baccetti, 2006). The aim of the present study was to analyze the forces released by passive stainless steel SLBs and by NCLCB systems when compared with CLCB during the alignment of apically- or buccally-malposed teeth in the maxillary arch at three different levels of tooth misalignment. MATERIALS AND METHODS The study used an experimental model reproducing the right buccal segment of an upper arch to assess the forces released during the alignment of apically- or buccally-malposed canines. The following brackets were tested: passive SLB (Carriere, Ortho Organizers, Carlsbad, CA) and stainless steel brackets (Logic Line brackets, Leone Orthodontic Products, Sesto Fiorentino, Firenze, Italy). The buccal segment model consisted of five brackets of the same type for the second premolar, first 62 Franchi et al. premolar, canine, lateral incisor and central incisor. All brackets tested had a 0.022” slot. The interbracket distance was set at 8.5 mm. The brackets were bonded onto an acrylic block with light-cure orthodontic adhesive (Leone Orthodontic Products), with the exception of the canine bracket that was laser welded to a moveable bar (Fig. 1). A section of 0.021.5” x 0.028” stainless steel wire was used to align the brackets before they were fixed onto the acrylic block. For the ligation systems on the conventional brackets, either non-conventional elastomeric ligatures (Slide, Leone Orthodontic Products) or conven- tional elastomeric ligatures (silver mini modules, Leone Orthodontic Products) were applied on conventional stainless steel brackets. To summarize, three bracket/ligature combinations were tested: passive SLBs (SLB group), conventional stainless steel brackets with low-friction slide ligatures (slide ligatures and conventional brackets, NCLCB group) and conventional stainless steel brackets with conven- tional elastomeric ligatures (conventional ligatures and conventional brackets, CLCB group). Round 0.012” super-elastic (SE) nickel-titanium (NiTi) wires (Memoria wire, Leone Orthodontic Products) were tested. The wires were made of austenitic NiTi alloy with a temperature transitional range below room temperature (Santoro et al., 2001). When used, new elas- tomeric ligatures were placed in a conventional manner (figure-O pat- tern) immediately before each test run to avoid ligature force decay. The upper end of the sliding bar bearing the canine bracket was connected to an Instron 4301 testing machine (Instron Corp., Canton, MA) crosshead. The force recorded by the Instron machine when pulling the sliding bar with the canine bracket in a misaligned position in the absence of any or- thodontic wire was 0 g. The Instron machine with a load cell of 10 N re- corded the forces released by the bracket/wire/ligature combination fol- lowing three different amounts of apical or buccal displacement of the canine bracket (canine misalignment): 1.5, 3 and 6 mm. The moveable bar with the canine bracket then was released, allowing recording of the peak forces produced during 60 seconds of the test run for the different bracket/wire/ligature combinations. These forces could be considered as the forces available for bracket alignment. The forces released by each bracket/wire/ligature combination at the three different amounts of apical or buccal canine misalignment were tested 20 times with new wires and ligatures (when elastomeric ligatures were used) on each occasion. A total of 360 tests (120 tests for each type 63 Efficiency of Alignment Figure 1. Experimental in vitro model with (A) an apically- malposed canine bracket and (B) a buccally-malposed canine bracket. of bracket/wire/ligature combination) were carried out. All tests were performed under dry conditions and at room temperature (20 + 2°C). STATISTICAL ANALYSIS Descriptive statistics were calculated for the amount of force re- leased by the various bracket/wire/ligature combinations in presence of the three different amounts of canine misalignment in the two directions. The data and equality of variance was found not to be distributed nor- 64 Franchi et al. mally (Shapiro-Wilk test and Levene’s test). Therefore, a non-parametric test (analysis of variance on ranks with Dunnett’s post hoc test, P × 0.05) was used (SigmaStat 3.5, Systat Software Inc., Point Richmond, CA) to compare the two low-friction systems (SLB and NCLCB groups) versus the CLCB group that was considered as the control. RESULTS Descriptive statistics and the statistical comparisons between the forces released by the different bracket/wire/ligature combinations in the presence of different amount of canine misalignment are reported in the Table 1 and depicted in Figure 2. Table 1. Descriptive statistics of the forces released by the different bracket/ archwire/ligature systems (measure unit = grams) and statistical comparisons. Significance is set at P × 0.05. SE = super-elastic NiTi archwire; CM = canine misalignment; SLBS = self-ligating brackets (Carriere); NCLCB = non- conventional elastomeric ligatures on conventional bracket; CLCB = conventio- nal elastomeric ligatures on conventional brackets; NS = non-significant compa- T1SOITS. SLB (1) NCLCB (2) CLCB (3) Significant Apical canine Comparisons & º Mean | SD | Mean | SD | Mean | SD misalignment ().012” SE – 1.5 mm CM 74.2 3.9 71.4 5.5 6.3.3 3.6 NS ().012” SE – 3.0 mm CM 96.9 6.5 89.5 4.2 51.4 3.6 1 VS3, 2vs2 ().012” SE – 6.0 mm CM 62.9 7.0 64.2 6.2 0.0 0.0 1 vs.3, 2vs2 Buccal Cà IIIIl e Mean | SD | Mean SD Mean SD misalignment 0.012” SE – 1.5 mm CM 57.7 5.0 47.3 6.8 61.3 3.8 NS 0.012” SE – 3.0 mm CM 89.0 6.5 79.6 4.2 79.9 4.2 NS 0.012” SE – 6.0 mm CM 80.2 7.0 75.9 6.2 0.0 0.0 1 vs.3, 2vs2 65 Efficiency of Alignment 1.5 mm CM 3 mm CM 6 mm CM A • Apical Canine Misalignment —e— SLB - + - NCLCB –a–CLCB 1.5 mm CM 3 mm CM 6 mm CM B Buccal Canine Misalignment Figure 2. Graphic representation of the mean forces released by the low-friction and conventional systems in presence of a malposed canine positioned 1.5, 3 and 6 mm (A) apically and (B) buccally. No significant differences among the three groups were found with 1.5 mm of canine displacement in either direction. Both the SLB and NCLCB groups produced significantly greater orthodontic forces than the CLCB group at both 3 and 6 mm of apical canine displacement. 66 Franchi et al. With 6 mm of apical canine misalignment, the force released dropped to zero in the CLCB group. For buccal displacement of the canine, no significant difference in the amount of force released for tooth movement was found among the three groups either at 1.5 or 3 mm of canine misalignment, while the force generated was significantly greater in the SLB and NCLCB groups when compared with the CLCB group at 6 mm of buccal canine mis- alignment. Once again, at this amount of canine misalignment, the force generated in the presence of CLCB dropped to zero. In presence of the 0.012” SE wire, both the SLB and NCLCB groups showed a tendency for an increase in the amount of force released from 1.5 to 3 mm of api- cal or buccal canine misalignment. DISCUSSION The present investigation compared the forces released by SE NiTi wires during alignment of an apically- or buccally-malposed tooth in presence of two low-friction systems (passive SLBs and conventional stainless steel brackets with slide ligatures) versus a conventional system (conventional elastomeric ligatures on conventional stainless steel brack- ets). Forces Released During Alignment of an Apically-malposed Tooth The forces released by the low-friction and conventional systems in presence of a 1.5 mm apically-malposed canine were similar and ranged from 63.3 g to 74.2 g. At 3 mm of apical canine misalignment, both the SLB and NCLCB groups produced a significantly greater amount of force released for orthodontic alignment with respect to the CLCB group. The average amount of force released by the SLB and NCLCB groups was 96.9 g and 89.5 g, respectively. These forces were greater significantly when compared with the CLCB group (51.4 g). At 6 mm of apical misalignment of the canine the amount of force released by the CLCB group was 0 g, while those produced by the SLB and NCLCB groups still averaged over 60 g. Forces Released During Alignment of a Buccally-malposed Tooth The amount of force released for tooth alignment of buccal tooth displacement was similar for the three systems investigated at 1.5 mm of canine misalignment (ranging from 47.3 g to 61.3 g) and also at 3 mm of canine misalignment (about 80 g to 90 g). At 6 mm of buccal canine dis- 67 Efficiency of Alignment placement, the forces available for tooth movement were still about 75 g to 80 g for the SLB and NCLCB systems, while they dropped to zero for the CLCB system. General Considerations Based on Experimental Data The results of the present study revealed that in presence of both ‘minimal’ or ‘moderate” tooth displacement, either in buccal or apical positions (1.5 mm or 3 mm of misalignment with respect to adjacent teeth), the amount of force released for tooth movement ranged from 55 g to 90 g for both low-friction and conventional bracket-ligature systems. Noteworthy was that the amount of force released by the conventional system at 3 mm of apical canine misalignment was approximately 50% that of the SLB or NCLCB systems (about 50 g versus 90 g, respectively). The greatest differences in performance between the low-friction and conventional systems became apparent at 6 mm of canine misalign- ment in either an apical or buccal position. At 6 mm of canine misalign- ment, while no force was released in the presence of CLCB, the SLB and NCLCB systems were able to produce an amount of force for orthodon- tic movement averaging about 60 g in the case of apical tooth misalign- ment and about 70 g to 80 g in case of buccal tooth misalignment. In general, it can be concluded that a certain amount of ortho- dontic force can be released by any of the investigated systems (either low friction or conventional) when apical or buccal misalignment to be corrected is minimal to moderate. On the other hand, in the presence of severe apical or buccal misalignment (6 mm), the conventional ligatures on conventional brackets did not allow forces to be produced for ortho- dontic movement, while a significant amount of force still was released in the presence of either passive self-ligating systems (Fig. 3) or combi- nations of low-friction ligatures on conventional brackets. Previous in vitro studies (Franchi and Baccetti, 2006; Baccetti et al., 2009) indicated that no amount of force for alignment was released in the presence of the conventional system when the apical misalignment equals 6 mm. The different low-friction systems also showed the greatest amount of force released at 3 mm of apical misalignment, while the force tends to decrease at 6 mm of apical displacement (Baccetti et al., 2009). In agreement with previous studies (Franchi and Baccetti, 2006; Baccetti et al., 2009), the present investigation demonstrated that a NCLCB sys- tem (conventional stainless steel brackets with slide ligatures) is able to produce a significant amount of force for tooth movement, so that this sys- 68 Franchi et al. E. Figure 3. Patient presenting with severe apical displacement of the right maxillary canine. The patient was treated with a pas- sive self-ligating bracket (F-1000, Leone Orthodontic Prod- ucts, Sesto Fiorentino, Firenze, Italy). A. Start of treatment. B: After four months of treatment with 0.012” and 0.014” SE NiTi wires. tem may represent a valid alternative to passive SLBS during leveling and aligning of malposed teeth. Considerations on the Clinical Relevance of the Experimental Findings The findings of the current in vitro experimental study are in line With the results of a recent randomized clinical trial (Scott et al., 2008) in patients with mandibular incisor crowding, where the authors failed to find a significant difference between low-friction and conventional sys- tems in the alignment of dental arches showing a total irregularity index of the lower incisors between 3 mm and 12 mm (that means, on average, from less than 1 mm to less than 3 mm of buccolingual misalignment per single tooth in relation to neighboring teeth in the crowded area). 69 Efficiency of Alignment When analyzing the clinical relevance of the data in the present investigation, it should be emphasized that this in vitro study did not evaluate the behavior of bracket/ligature systems with time. It can be ar- gued that decay of conventional elastomeric ligatures due to their perma- nence in the oral environment along with changes in temperature, pres- ence of saliva and tooth brushing may affect considerably the amount of force released by the conventional systems along with time, before new ligatures are placed at a subsequent appointment. CONCLUSIONS 1. For apical or buccal misalignments of 1.5 mm and 3 mm, both low-friction and conventional systems ap- peared to be effective potentially in releasing an ade- quate amount of force for tooth movement (ranging from approximately 50 g to 100 g); with the low- friction combinations being significantly more effec- tive at 3 mm of apical misalignment. For a large amount of apical or buccal tooth misalignment (6 mm), the low-friction systems presented a significant amount of force released for tooth movement, whereas a null amount of orthodontic force was re- corded for the conventional bracket/ligature combination. 2. The non-conventional elastomeric ligature-bracket system produced levels of force available for tooth movement that were similar to those generated in presence of passive SLBs. REFERENCES Baccetti T, Franchi L. Friction produced by types of elastomeric ligatures in treatment mechanics with the preadjusted appliance. Angle Orthod 2006;76:211-216. Baccetti T, Franchi L, Camporesi M, Defraia E, Barbato E. Forces pro- duced by different nonconventional bracket or ligature systems during alignment of apically displaced teeth. Angle Orthod 2009;79:533–539. Franchi L, Baccetti T. Forces released during alignment with a pre- adjusted appliance with different types of elastomeric ligatures. Am J Orthod Dentofacial Orthop 2006;129:687-690. Franchi L, Baccetti T, Camporesi M, Barbato E. Forces released during sliding mechanics with passive self-ligating brackets or non- 70 Franchi et al. conventional elastomeric ligatures. Am J Orthod Dentofacial Orthop 2008; 133:87–90. Frank CA, Nikolai R.J. A comparative study of frictional resistances be- tween orthodontic bracket and arch wire. Am J Orthod 1980:78:593– 609. Henao SP, Kusy RP. Frictional evaluations of dental typodont models using four self-ligating designs and a conventional design. Angle Or- thod 2005;75:75-85. Kim TK, Kim KD, Baek SH. Comparison of frictional forces during the initial leveling stage in various combinations of self-ligating brackets and archwires with a custom-designed typodont system. Am J Orthod Dentofacial Orthop 2008; 133:187.e 15-e24. Pizzoni L, Ravnholt G, Melsen B. Frictional forces related to self- ligating brackets. Eur J Orthod 1998:20:283-291. Santoro M, Nicolay OF, Cangialosi T.J. Pseudoelasticity and thermoelas- ticity of nickel-titanium alloys: A clinically oriented review. Part I: Temperature transitional ranges. Am J Orthod Dentofacial Orthop 2001; 119:587-593. Scott P, DiBiase AT, Sherriff M, Cobourne MT. Alignment efficiency of Damon3 self-ligating and conventional orthodontic bracket systems: A randomized clinical trial. Am J Orthod Dentofacial Orthop 2008; 134:470.e 1-e&. Thomas S, Sherriff M, Birnie D. A comparative in vitro study of the fric- tional characteristics of two types of self-ligating brackets and two types of pre-adjusted edgewise brackets tied with elastomeric liga- tures. Eur J Orthod 1998:20:589-596. Thorstenson GA, Kusy RP. Effects of ligation type and method on the resistance to sliding of novel orthodontic brackets with second-order angulation in the dry and wet states. Angle Orthod 2003;73:418-430. Yeh CL, Kusnoto B, Viana G, Evans CA, Drummond JL. In vitro evaluation of frictional resistance between brackets with passive- ligation designs. Am J Orthod Dentofacial Orthop 2007;131:704.el 1- e22. 71 THE BIOLOGY OF ORTHODONTIC TOOTH MOVEMENT: CURRENT CONCEPTS ON AND APPLICATIONS TO CLINICAL PRACTICE Nan Hatch ABSTRACT Orthodontic tooth movement requires the conversion of mechanical forces into biological signals by mechanosensitive cells. This mechanotransduction of sig- nals promotes intracellular communication and allows for the coordinated cellu- lar response of alveolar bone modeling that occurs in response to orthodontic force. Orthodontic forces likely are perceived by cells as changes in strain, shear stress and/or oxygen tension. Periodontal ligament (PDL) cells, bone lining cells and osteocytes respond to orthodontic forces by expressing and secreting bio- logic mediators such as tumor necrosis factor-O (TNFO), interleukin-1ſ (IL16), colony stimulating factor-1 (CSF-1), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2). These factors in turn lead to the recruitment, dif- ferentiation and activation of osteoblasts and osteoclasts. Previous studies from the orthodontic literature provide substantial evidence that each of these factors plays a critical role in the bone modeling response to orthodontic force applica- tion. The findings of these studies suggest potential clinical applications of bio- logical mediators to enhance or inhibit orthodontic tooth movement. KEY WORDS: tooth movement, mechanotransduction, biologic mediators, os- teoblasts, osteoclasts ORTHODONTIC FORCES STIMULATE BIOLOGIC RESPONSES The orthodontic profession has known for over a century that changes in the supporting tissues of teeth are necessary for tooth move- ment beyond the constraints of the original tooth socket upon application of an orthodontic force. Theories regarding the biologic response to or- thodontic forces resulting in tooth movement initially were proposed over a century ago. Based upon their clinical observations, Kingsley and 73 Biology of Orthodontic Tooth Movement Walkhoff theorized that tooth movement depends upon the elasticity, compressibility and extensibility of bone while Schwalbe and Flouren theorized that bone resorption occurs in areas of pressure and bone depo- sition occurs in areas of tension, following the application of orthodontic force (reviewed by Stuteville, 1938). The first systematic experimentation investigating local tissue responses to orthodontic force application was performed by Standstedt in the early 1900s. His light microscopic studies following incisor retrac- tion in dogs confirmed the theory of Schwalbe and Flouren and showed for the first time that bone deposition occurs in areas of tension and bone resorption occurs in areas of pressure following the application of ortho- dontic force (Stuteville, 1938). Significantly, Standstedt was the first to show that lighter ortho- dontic compressive forces lead to rapid bone resorption along the alveo- lar wall, while heavier compressive orthodontic forces lead to tissue ne- crosis within the periodontal ligament (PDL) space along the alveolar wall (defined as hyalinized tissue). He also noted that tooth movement in these hyalinized areas occurred only after bone resorption in underlying bone marrow spaces was sufficient to undermine the supporting alveolar bone (defined as undermining resorption). Schwartz (1932) extended the findings of Standstedt by correlating the tissue response to compressive orthodontic forces with PDL capillary blood pressure. He stated that lighter orthodontic forces leading to rapid alveolar bone resorption and tooth movement are those that are below the pressure of PDL blood cap- illaries and that heavier orthodontic forces lead to “suffocation of the peridental membrane” that leads to tissue necrosis and a delay in ortho- dontic tooth movement (Schwarz, 1932). These findings in combination with numerous other studies sug- gested that orthodontic forces move teeth by stimulating a biologic re- sponse involving bone-modeling activity. Importantly, these results also indicated that occlusion of PDL blood vessels with resulting ischemia and necrosis is not required for bone resorption to occur along the alveo- lar wall on the pressure side of orthodontic force application. In other words, light compressive forces can stimulate alveolar bone resorption that allows for tooth movement beyond the original constraints of the tooth socket. We now know that bone modeling requires the differential activ- ity of bone forming cells (osteoblasts) and bone resorbing cells (osteo- clasts). A study by King and colleagues (1991) confirmed that orthodon- 74 Hatch tic force application induces differential osteoclastic and osteoblastic activity. Results of this study showed that orthodontic appliance activa- tion leads primarily to osteoclastic activity along the alveolar bone in the compressed regions of the PDL space and primarily to osteoblastic activ- ity along the alveolar bone in the tensed regions of the PDL space (King et al., 1991). For osteoclastic activity to occur, osteoclast precursor cells, which are of hematopoietic lineage, must be recruited to the PDL space from the bone marrow. For tooth movement to occur, recruited osteoclas- tic precursor cells then must be stimulated to proliferate and differentiate and to develop into fully functional, mature osteoclasts. Similarly, to obtain osteoblastic activity along the alveolar wall of the tooth socket at tension sites, PDL osteoblastic precursor cells and/or bone lining cells, which are of mesenchymal origin, must be stimulated to differentiate into pre-osteoblasts and osteoblasts. King and coworkers’ study (1991), therefore, showed that mechanical orthodontic forces stimulate biological responses involving the recruitment and acti- vation of osteoblasts and osteoclasts. Notably, subsequent studies by the same research group showed that one hour of force activation elicited the same amount of tooth movement as 24 hours of force (Gibson et al., 1992) and that tooth movement continues to occur after orthodontic ap- pliance decay via additional recruitment and differentiation of osteoclas- tic cells (King and Keeling, 1995). Significantly, these latter studies indi- cate that once initiated, the biologic process of tooth movement does not need continued mechanical stimuli to progress to completion. MECHANOTRANSDUCTION MEDIATES THE BONE MODELING RESPONSE TO ORTHODONTIC APPLIANCE ACTIVATION In the years since these studies were completed, significant pro- gress has been made in understanding how mechanical signals can initi- ate biologic cellular responses. This process, known as mechanotrans- duction, requires the application of a mechanical load to tissue, conver- sion of that load into a mechanical signal that can be sensed at the cellu- lar level, and cellular transformation of the mechanical signal into a bio- chemical signal that then is communicated to other cells to elicit a coor- dinated cellular response (Fig. 1). Current research indicates that when mechanical loads are applied to tissue, cells sense these loads as shear stress or strain. Significant evidence exists that mechanical forces applied 75 Biology of Orthodontic Tooth Movement Orthodontic Appliance Activation (mechanical load applied to tissue) Tooth Movement within PDL Space Localized Changes in Oxygen Tension Mechanical Strain in PDL and Alveolar Bone (cell compression, stretch or deformation) + Fluid Flow in PDL and Alveolar Bone (elicits cellular shear stress) Cellular Perception of Changes: PDL Cells, Bone Lining Cells, Osteocytes Mediated by: Integrins Cytokeletal Proteins Cell Membrane lon Channels Cell Membrane Hemichannels Primary Cilia ! Propagation of Signal Mediated by: Gap Junctions IL1ſ, ! Rapid Cellular Release of Ca2+, ATP, NO, PGE2 Downstream Cell Signaling and Release of Biologic Mediators to Elicit Coordinated Cellular Response Involving Bone Resorption and Formation Figure 1. Mechanotransduction of orthodontic forces into bio- logic signals contributes to bone modeling and permits tooth movement beyond the original tooth socket. to bone lead to interstitial fluid flow within the lacunar-canicular network (Riddle et al., 2009). The PDL space also is fluid filled such that the ap- plication of orthodontic force leads to fluid flow changes within the PDL space. Cells sense fluid flow as shear stress; previous studies indicate that shear stress stimulates cellular responses that in terms of frequency and magnitude of applied loads correspond well to in vivo responses of bone to applied forces. Mechanical loads applied to tissues also can be sensed by cells as strain (cell compression, stretch or deformation of shape). While initial studies indicated that physiologic mechanical loads cannot elicit strains at the cellular level of a large enough magnitude to stimulate a cellular response (Rubin et al., 1984; You et al., 2000), more 76 Hatch recent studies have indicated that osteocytes experience significantly amplified strain following mechanical loading of bone due to the struc- tural properties of bone lacunae and/or the close and regular attachment of the lengthy osteocytic cellular processes to the canalicular bone in which they reside (Nicollela et al., 2006; Wang et al., 2008; McNamara et al., 2009). The molecular mechanism by which cells translate these mechanical signals (tissue strain and/or shear stress) into biochemical signals may involve integrins (cell to extracellular matrix adhesion mole- cules), cytokeletal structural proteins, purinergic receptors, connexin 43 hemichannels, stretch sensitive ion channels, Voltage sensitive ion chan- nels and/or primary cilia (microtubular structure extending from the ba- sal body through the cell membrane into the extracellular space; Genetos et al., 2005; Li et al., 2005; Allori et al., 2008; Siller-Jackson et al., 2008; McNamara et al., 2009; Temiyasathit et al., 2010). Once initiated, mechanical signals are propagated intercellularly via gap junctions and/or extracellular cytokines (Salter et al., 2000; Yel- lowley et al., 2000; Jiang et al., 2007). Relevant to orthodontic tooth movement, recent studies have demonstrated that orthodontic force leads to increased connexin 43 expression (the principal molecular component of mechanosensitive hemichannels and gap junctions) in alveolar bone osteocytes and bone lining cells (Su et al., 1997; Gluhak-Heinrich et al., 2006). Currently, it is not known if the mechanotransduction of ortho- dontic force is mediated by integrins, ion channels, primary cilia and/or connexin hemichannels and gap junctions. In the context of orthodontic tooth movement, we should con- sider alveolar bone osteocytes, bone lining cells and PDL mesenchymal precursor cells as the likely initial cellular responders to orthodontic force application (Fig. 2). Osteocytes are dynamic cells that live within the lacunar-canicular spaces within bone. While previously viewed as a rather dormant cell type, osteocytes now are considered to be a primary mechanosensor of bone. Pre-osteoblasts, such as those found within the PDL space, also are responsive to mechanical forces. Mechanical loading stimulates multiple cell signaling pathways. Calcium (Ca"), nitric oxide (NO), interleukin-13 (IL1B) and adenosine triphosphate (ATP), for ex- ample, are secreted by cells within seconds to minutes after exposure to fluid flow induced shear stress (Salter et al., 2000; Genetos et al., 2005; Riddle et al., 2009). Notably, studies indicate that NO synthase (the en- zyme that synthesizes NO) and IL16 also are critical mediators of ortho- dontic tooth movement (Hayashi et al., 2002; Iwasaki et al., 2006, 2009). 77 Biology of Orthodontic Tooth Movement Tooth PDL fibers mononuclear osteocastic precursor cell A Bone - bone lining cells osteocytes Figure 2. Mechanical orthodontic forces induce cellular changes leading to tooth movement. Tooth, PDL space and supporting alveolar bone environment during quiescence are shown. Blood vessels in the PDL space and are contiguous with bone marrow that in turn is located within alveolar bone. Osteoclast precursor cells are located in bone marrow and circulating through blood vessels. Bone lining cells reside along socket wall/alveolar bone surface. PDL cells (mesen- chymal precursor cells) are located within PDL space. During quiescence, OS- teocytes express and secrete sclerostin (small red star within osteocyte), which inhibits pre-osteoblastic (PDL cell and bone lining cell) activity. Once initiated, mechanotransduction leads to the activation of downstream cell signaling pathways and cellular responses that lead to bone resorptive and formative activity. Notably, cell stretching that re- sults from tissue strain induces the osteoblastic differentiation of pre- osteoblasts via integrin/focal adhesion kinase signaling and mechanosen- sitive calcium channels (Robinson et al., 2006; Ward et al., 2007). These mechanisms potentially could explain the differentiation of PDL pre- osteoblasts into osteoblasts and initial mineralization along stretched PDL fibers following orthodontic tooth movement (Stuteville, 1938). Shear stress from fluid flow also can stimulate Caº signaling in mesen- chymal precursor cells within the PDL, which in turn promotes ATP re- lease, the production of prostaglandin E2 (PGE2) and the proliferation of 78 Hatch osteoblastic precursor cells (Genetos et al., 2005; Riddle et al., 2009). Orthodontic forces move a tooth initially within the PDL space. This tooth movement likely results in mechanical strain changes in PDL fibers and in underlying alveolar bone, as well as fluid flow changes within the lacunar-canalicular alveolar bone network and within the PDL space. Tooth movement also can compress PDL blood capillaries resulting in localized hypoxia (Fig. 3). It currently is unknown if the initial cellular responders to orthodontic force are responding to tissue strain, shear stress and/or oxygen levels or a combination of these. - direction of force mechanical strain fluid flow mechanical changesº " - - - Figure 3. Cellular mechanotransduction of applied orthodontic force. Upon ap- plication of an orthodontic force, the tooth moves within the PDL space. This tooth movement results in compression of blood vessels leading to localized hypoxia (diminished oxygen tension). Tooth movement within the PDL space also results in mechanical strain (cell compression, stretch or deformation) and fluid flow changes within the PDL and underlying alveolar bone (which induces cellular shear stress). In response to perception of these changes in the physical *"Vironment, PDL cells, bone lining cells and/or alveolar bone osteocytes rapidly express and secrete local biologic mediators including IL1B, TNFoº, PGE2, CSF-1 and VEGF (yellow, orange and red stars within cells). 79 Biology of Orthodontic Tooth Movement LOCAL BIOLOGIC MEDIATORS OF ORTHODONTIC TOOTH MOVEMENT Despite this gap in our knowledge of the mechanotransduction of orthodontic force, much progress has been made identifying critical downstream biochemical mediators of orthodontic tooth movement. Dur- ing quiescence, osteocytes secrete sclerostin, which inhibits Wnt (a cyto- kine that is involved in bone cell communication) cell signaling, pre- osteoblastic differentiation and bone formation (Robling et al., 2008). During tooth movement, PDL cells, bone lining cells and/or alveolar bone osteocytes secrete inflammatory cytokines such as TNFO and IL13, which function to stimulate autocrine (same cell) and paracrine (neigh- boring cell) cell changes, including the production of additional biologic mediators including colony stimulating factor-1 (CSF-1), vascular endo- thelial growth factor (VEGF) and PGE2 (Fig. 3). PGE2 release is stimu- lated directly by fluid flow induced shear stress (Genetos et al., 2005; Siller-Jackson et al., 2008). Each of these factors in turn elicits multiple cellular reactions. IL13 acts to propagate the opening of connexin hemichannels in re- sponse to mechanical signals (Salter et al., 2000). In this manner, IL15 may act to amplify the cellular response to mechanical load. IL1B, TNFO, and VEGF stimulate angiogenesis, which increases local vascularity. TNFO, CSF-1 and PGE2 stimulate osteoclastogenesis and bone resorp- tion. Of note, PGE2 also stimulates osteoblastogenesis and bone forma- tion. Together, these local biologic mediators elicit changes in cell behavior, resulting in increased blood vessel dilation and permeability, mononuclear osteoclastic precursor cell recruitment and differentiation in regions of compression, as well as pre-osteoblastic proliferation and dif- ferentiation in regions of tension (Fig. 4). Evidence for the early local release of these factors following application of an orthodontic force is provided by the fact that gingival crevicular fluid levels of TNFO, IL13, CSF-1, VEGF and PGE2 all rise significantly following orthodontic tooth movement in humans (Grieve et al., 1994; Uematsu et al., 1996; Lee et al., 2004; Kaku et al., 2008). Each of these mediators previously has been shown to be an essential biologic mediator of orthodontic tooth movement (Table 1). 80 direction of force blood vessel dilation and increased permeability pre-osteoblast º º - - Figure 4. Extracellular biologic mediators induce cellular changes. In response to the secreted factors (small yellow, orange and red stars), cells within the PDL Space undergo changes. Endothelial cells that line the blood vessels respond by proliferating and differentiating, leading to increased blood vessel dilation and increased blood vessel permeability. Mesenchymal precursor cells within the PDL space respond by proliferating and differentiating into pre-osteoblasts. Bone lining cells also can respond by proliferating and differentiating into os- teoblast precursor cells. Pre-osteoblastic cells express RANKL (blue rectangle) that is a mediator of osteoclast differentiation and activity. NEUROPEPTIDES AND ORTHODONTIC TOOTH MOVEMENT PDL and pulpal nociceptors respond to orthodontic tooth move- ment by secreting neuropeptides such as Substance P and CGRP (calci- tonin gene related peptide; Kvinnsland et al., 1990; Nicolay et al., 1990; Norevall et al. 1995; Vandevska-Radunovic et al., 1997; Dudic et al., 2006). These neuropeptides act to enhance the cellular secretion of inflam- Biology of Orthodontic Tooth Movement Extra- cellular GCF Function in Role in Orthodontic Biologic Expression | Bone Modeling/Remodeling Tooth Movement Mediator • Higher IL 1 [3 and lower IL-RA (ILl • Propagate initial response to receptor antagonist) levels in GCF Within one mechanical signal are associated with faster orthodontic - tooth movement in humans IL1B hour post * Stimulate angiogenesis appliance • Homozygosity for IL-1ſ polymor- activatl On • Stimulate production/secretion phism (A1, Al at position +3954) is of additional biologic factors associated with faster orthodontic tooth movement in humans * , 3 º' • Stimulate angiogenesis Within 24 e * * * * * * TNF receptor knockout mice exhibit hours post- • Stimulate production/secretion a º º - TNFO: - - - - - diminished osteoclastogenesis and appliance of additional biologic factors tooth movement activation * * s * Stimulates osteoclastogenesis • Stimulates inflammatory cyto- kine expression e - • & e • Prostaglandin receptor EP4 agonist • Bimodal function: important for enhances tooth movement in rats - - - bone resorption and bone for- Within 24 mation • PGE2 but not PGE1 enhances tooth hours post- - PGE2 li - * movement in monkeys appliance • Stimulates RANKL expression - - - - - * * act1 Vation and inhibits OPG expression by • NSAIDs (inhibit COX2 activity) pre-osteoblasts and osteoblasts inhibit osteoclastogenesis and ortho- & - dontic tooth movement in rodents • Stimulates RANK expression by pre-osteoclasts and osteoclasts • Stimulate angiogenesis e * Neutralizing antibodies against • Promote recruitment of mono- - g gainst - Within 24 * VEGF inhibit osteoclastogenesis and nuclear osteoclastic precursor tooth movement VEGF hours post- cells from bone marrow appliance • P diff iation of • Local delivery of VEGF enhances activation romote differentiation o osteoclastogenesis and tooth move- osteoclastic precursor cells ment • Promote osteoclast Survival * Stimulate angiogenesis • Promote recruitment of mono- .º : nuclear osteoclastic precursor Neutralizing antibodies against CSF-1 CSF-1 º cells from bone marrow receptor inhibit osteoclastogenesis and activation • Promote differentiation of tooth movement osteoclastic precursor cells • Promote osteoclast survival matory cytokines and to increase vasodilation and vasopermeability of blood vessels (Hall et al., 2001; Yamaguchi et al., 2004). That sensory nerve responses are critical for orthodontic tooth movement is evidenced by studies showing that transection of the inferior alveolar nerve in rats inhibits vascular and tooth movement responses to applied loads (Vandevska- 82 Hatch <- Table 1. Local biologic mediators of orthodontic tooth movement. This table includes information on inflammatory cytokines, growth factors and prostagland- ins that are expressed rapidly following orthodontic appliance application and are established as essential for orthodontic tooth movement. Additional mediators of tooth movement include but are not limited to neuropeptides, leukotrienes and chemokines. Abbreviations: GCF = gingival crevicular fluid; IL1B = interleukin 1 beta; TNFoº = tumor necrosis factor alpha; PGE2 = prostaglandin E2; VEGF = vascular endothelial growth factor; CSF-1 = colony stimulation factor. Radunovic et al., 1998, 1999; Yamashiro et al., 2000). While it is tempt- ing to consider utilizing local delivery of neuropeptides to enhance or- thodontic tooth movement in humans, the fact that neuropeptides also mediate pain makes this proposition less promising. RANK/RANKL/OPG SYSTEM FOR CONTROLLING OSTEOCLASTOGENESIS No discussion of the biology of orthodontic tooth movement would be complete without a review of the RANK/RANKL/OPG sys- tem. This biologic system controls osteoclastogenesis, which is required for alveolar bone resorption and orthodontic tooth movement (Fig. 5; reviewed in Yamaguchi, 2009). Receptor Activator for Nuclear Factor k B (RANK) is a cell membrane protein that is expressed on osteoclastic precursors cells, pre-osteoclasts and osteoclasts. Receptor Activator for Nuclear Factor k B Ligand (RANKL) is a cell membrane protein that is expressed on pre-osteoblasts and osteoblasts. Osteoprotegerin (OPG) is a soluble extracellular factor that is secreted by pre-osteoblasts and os- teoblasts. The association of RANK with RANKL stimulates the fusion of mononuclear osteoclastic precursor cells into multinuclear pre- osteoclasts and the differentiation of pre-osteoclasts into mature osteo- clasts. OPG competes with RANKL for RANK and therefore acts to di- minish osteoclastogenesis. OPG can inhibit osteoclast differentiation, activity and survival. OPG expression increases in tensed regions of the PDL and alveolar bone while RANKL expression increases in com- pressed regions of the PDL and alveolar bone following orthodontic tooth movement (Shiotani et al., 2001; Nishijima et al., 2006; Garlet et al., 2007, 2008; Brooks et al., 2009; Tan et al., 2009). 83 Biology of Orthodontic Tooth Movement activated PDL cell --- Cathepsin K MMP9 Figure 5. Recruitment, differentiation and activation of osteoclast precursor cells leads to alveolar bone resorption and tooth movement. Endothelial cells, OS- teoblastic precursor cells, bone lining cells and/or osteocytes that have been ac- tivated by changes in oxygen tension, mechanical strain and/or shear stress pro- duce and release biologic factors such as TNFO, CSF-1, VEGF and PGE2 (small grey circles). Once released, these factors act to recruit mononuclear osteoclastic precursors cells (yellow/orange cells) from the adjacent bone marrow via local permeabilized blood vessels. These osteoclastic precursor cells express receptors for the secreted extracellular factors and, once recruited, are stimulated further by these factors. This stimulation leads to cellular changes including expression of the transmembrane protein, RANK. RANK binds RANKL, a transmembrane protein that is expressed on pre-osteoblasts (blue cell). Binding of RANK with RANKL, in addition to continued stimulation by the other secreted factors, leads to fusion of the mononuclear osteoclastic precursor cells into a multinucleated pre-osteoclast (brown cell). Stimulation of this pre-osteoclast via the RANK RANKL interaction promotes differentiation of the pre-osteoclast into a mature osteoclast (purple cell). The mature osteoclast adheres tightly to bone via the integrin ovſ53. Once adherent, the osteoclast secretes acid and enzymes that demineralize the bone and degrade the bone matrix (bone resorption). That this system controls osteoclastogenesis, bone resorption and orthodontic tooth movement is evidenced by numerous studies. Alveolar bone resorption is enhanced dramatically following orthodontic tooth 84 Hatch movement in OPG null mice (Oshiro et al., 2002). Local delivery of OPG through gene transfer or injection of a recombinant protein inhibits osteoclastogenesis and orthodontic tooth movement, while local delivery of RANKL enhances osteoclastogenesis and tooth movement (Kanzaki et al., 2004, 2006; Dunn et al., 2007). Should current clinical trials on re- combinant OPG protein for the treatment of osteoporosis prove effective and safe, as a profession we could consider translating a more local de- livery of this protein into orthodontic practice. TRANSLATION OF BIOLOGIC APPROACHES INTO CLINICAL ORTHODONTIC PRACTICE: THE FUTURE OF OUR PROFESSION? Throughout the past century, many orthodontic academics have advocated theories that include an individualized tissue response to or- thodontic force application. With more recent advances in biomedicine, We Soon may see an incorporation of new technologies into private prac- tice that allow for enhanced and predictable response of a given patient to orthodontic force application. In understanding the true potential for translation of this knowledge into clinical practice, it is important to re- member that each individual patient is likely to have subtle differences in expression levels and/or function of these mediators. Because the biologic mediators of orthodontic tooth movement are encoded by genes and because the genetic sequence of each gene dif- fers between individuals (existence of polymorphisms or normal varia- tions in the genetic code that result in subtle differences in protein ex- pression and/or function), it is likely that the individual variation seen following orthodontic appliance activation is due, at least in part, to these differences. Gingival crevicular fluid expression of biologic mediators following orthodontic appliance activation also can diminish with age (Kawasaki et al., 2006). In addition, bone modeling, as mediated by os- teoblastic and osteoclastic cell function, can be influenced by hormones, medications and diet. Significant advances in protein bone biomarkers of osteoclast and osteoblast activity have been accomplished within the past decade. Proteomic analysis of known orthodontic biologic mediators and/or bone biomarkers, therefore, could provide novel and relevant information for all of our patients. Given the dramatic advances that have been made in the fields of genetic testing and proteomics, it is possible that the ortho- dontic records for a given patient could include genetic polymorphic test- 85 Biology of Orthodontic Tooth Movement ing (DNA accessed via a buccal Swab) and gingival crevicular fluid pro- teomic analysis. With this information, we could predict tooth movement and relapse better for each patient and could provide better- individualized orthodontic treatment recommendations for each patient. 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J Bone Miner Res 2000; 15:209-217. 90 Hatch You J, Yellowley CE, Donahue HJ, Zhang Y, Chen Q, Jacobs CR. Sub- strate deformation levels associated with routine physical activity are less stimulatory to bone cells relative to loading-induced oscillatory fluid flow. J Biomech Eng 2000;122:387-393. 91 IL-1 GENETIC POLYMORPHISMS AND IL-1 PROTEIN SECRETION IN GINGIVAL CREVICULAR FLUID PREDICT THE SPEED OF HUMAN ORTHODONTIC TOOTH MOVEMENT Laura R. Iwasaki, Jeffrey R. Chandler, David B. Marx, Janardan P. Pandey, Jeffrey C. Nickel ABSTRACT To investigate genetic, biological and mechanical factors that affect the speed of human orthodontic tooth movement, 66 maxillary canines in 33 subjects were translated distally for 84 days. Distal compressive stresses of 4, 13, 26, 52 or 78 kPa were applied via segmental mechanics. Dental casts and gingival crevicular fluid (GCF) samples were collected nine to ten times/subject over 84 days, at one- to fourteen-day intervals. Three-dimensional tooth movements were meas- ured using a microscope and dental casts. GCF samples were analyzed for total protein, Interleukin-13 (IL-13) and Interleukin-1 Receptor Antagonist (IL-1RA). Cheek-wipe samples from 18 subjects were typed for IL-1 gene cluster poly- morphisms. Results demonstrate that average speeds of distal translation were 0.028 + 0.012, 0.043 + 0.019, 0.057 = 0.024, 0.062 + 0.015 and 0.067 + 0.024 mm/day for 4, 13, 26, 52 and 78 kPa, respectively. Notably, most teeth showed no lag phase following force application (63/66). Three factors significantly affected speed of tooth movement (P = 0.0391) and provided the best predictive model (R* = 0.691). Activity Index (AI = Experimental [IL-1B/IL-1RA]/Control [IL-1B/IL-1RA]), IL-1RA in GCF and genotype at IL-1B. Conclusions: In- creased AI and decreased IL-1RA in GCF plus having > 1 copy of allele 2 at IL- 1B (+ 3954) were associated with faster orthodontic tooth movement in humans. KEY WORDS: human, tooth movement, IL-1beta, IL-1RA, genetic polymor- phism, gingival crevicular fluid CLINICAL RELEVANCE Factors that maximize the speed of orthodontic tooth movement and explain inter-individual variability remain unknown. Research re- ported herein examines mechanical, biological and genetic factors that may account for differences in rates of bone remodeling and tooth 93 IL-1 Genetic Polymorphisms movement between patients. The results provide a basis for improved future clinical efficiency through measurement of applied forces com- bined with diagnostic and therapeutic predictors of patient-response. INTRODUCTION Over 100 years of orthodontic research and practice has yielded no conclusive evidenced-based information regarding ideal biomechani- cal prescriptions to optimize the speed of human tooth movement. That is, factors that affect bone remodeling and tooth movement, such as ap- plied force or stress magnitude, age-related characteristics, cell biology and genetics have not been established or quantified yet. This lack of in- formation is a barrier to improving the efficiency of orthodontic treatment. Previously conducted surveys of the literature concerning opti- mum force magnitudes for orthodontic tooth movement reveal a remark- able paucity of experimentally based studies (Quinn and Yoshikawa, 1985; Ren et al., 2003a). Uncontrolled force systems acting on teeth were a common limitation of previously conducted studies (Quinn and Yoshikawa, 1985). Just 17 animal and 12 human studies were found (Ren et al., 2003a) in which reasonable criteria for study design were applied. Of the 12 human studies, only four involved controlled tooth movement (Storey and Smith, 1952; Lee, 1965, 1995; Iwasaki et al., 2000) and only one (Iwasaki et al., 2000) quantified the magnitude of applied stress (force/area). Needless to say, a meta-analysis was not pos- sible due to insufficient data for analysis; therefore, optimum force mag- nitudes for human orthodontic tooth movement currently remain un- known. Previously published studies on controlled tooth movement in humans by our research group demonstrated clinically important and sta- tistically significant results (Iwasaki et al., 2000, 2005, 2006). Combined data from these studies offer information from 50 maxillary canines moved using 4 to 52 kPa of force for 84 days and suggest 26 kPa as op- timal and 0.063 mm/day as the associated maximum mean speed of tooth movement. However, these data also demonstrate mean speeds for the same stress were about two times higher in subjects who showed growth compared to subjects who showed no growth and were over five times faster in some subjects compared to others. Review of the orthodontic literature also indicates that inter- individual differences exist that can influence a patient’s response to or- thodontic forces dramatically, including age, biology and genetics. Ex- 94 Iwasaki et al. perimental studies that compared rates of tooth movement in adolescents versus adults demonstrated consistently faster rates in younger individu- als (Darendeliler et al., 1997; Iwasaki et al., 2005). Studies of age effects on tooth movement in rodents also have shown generally higher rates in younger animals (Bridges et al., 1988; Takano-Yamamoto et al., 1992; Kyomen and Tanne, 1997: Ren et al., 2003b; Misawa-Kageyama et al., 2007). Most of these latter studies, however, were of short duration and the stress magnitudes used were relatively high. In addition, the physiol- ogy of rodents in terms of their teeth and aging is different from that of humans. Variability in the rate of tooth movement between individuals of similar age for the same applied force has been noted in multiple studies involving humans (Owman-Moll et al., 1995, 1996a,b; Iwasaki et al., 2000, 2005, 2006) and animals (Mitchell et al., 1973; Pilon et al., 1996). Together these findings strongly suggest that individual-specific charac- teristics play a significant role in the biological responses that result in bone remodeling and tooth movement when orthodontic forces are applied. The rate of orthodontic tooth movement depends on the rate of bone modeling activity. Induction of bone modeling in response to or- thodontic forces involves a complex cascade of events and release of multiple biochemical agents that can act synergistically or antagonisti- cally in a highly redundant system. Interleukin-1 (IL-13), a pro- inflammatory cytokine and its competitive antagonist, IL-Receptor An- tagonist (IL-1RA) are just one pair of these agents. We previously showed that the ratio of IL-13/IL-1RA measured in gingival crevicular fluid (GCF) during tooth movement at control versus experimental sites accounted for 60% of the variation shown for speed of movement among the 50 teeth studied (Iwasaki et al., 2005, 2006). Because expression lev- els of IL-13 are associated with distinct IL-1 gene cluster polymor- phisms, we also previously have investigated the relationship between IL-13 genotype of orthodontic patients and the speed of orthodontic tooth movement. Initial results demonstrated that subjects with specific IL-1 gene cluster polymorphisms showed significantly faster tooth movement (Iwasaki et al., 2006). Data from a fourth, previously unpublished study (Chandler, 2006) using a similar protocol was combined with those from the three previous studies and are reported herein. These data were used to inves- tigate biochemical, genetic and mechanical factors that may account for differences in rates of human bone modeling and tooth movement. 95 IL-1 Genetic Polymorphisms MATERIALS AND METHODS Thirty-four generally healthy subjects gave informed consent to participate in accordance with ethical standards of the appropriate institu- tional review board. All subjects had orthodontic treatment plans involv- ing extraction of maxillary first premolars and distal movement of maxil- lary canines. Subjects were instructed to maintain excellent oral hygiene and avoid medications during the study. One subject (4M 1) violated the latter criterion and was withdrawn. Therefore, data were based on 21 fe- males and 12 males with starting mean age 14.8 + 3.9 years (Table 1). Detailed protocols were reported previously (Iwasaki et al., 2000, 2005, 2006) and will be re-presented in brief. Table 1. Demographics of subjects: side, stress, speed of distal movement of maxillary canine; R of distal movement versus time; and average Activity Index (AI). Subjects are identified by Study #, Sex (F = Female, M = Male), Subject #. ND = not determined. subject| 6...) || “..." | side . . ...) | R' | *.* 4F1 13.3 Grower R 52 0.079 0.973 0.70 L 78 0.090 0.988 ().53 AF2 | 12.8 || Grower Hº-Hº-Hº-Hº 4F3 12.2 Grower ; ; # # § 4F4 11.8 Grower ; É # #. § 4Fs 179 | . Hº-Hº-H; AF6 108 || Grower H.-H...-H...-H. 4M2 14.2 Grower ; É # #. § 4M3 16.1 Grower ; #. # # § 3F | 16.1 || Grower H.-H...-H...-H.; 3F2 13.2 Grower ; # # #. }; 3F3 246 | d. Hº-Hº-Hº-H. * | * | * H-Hº-Hº-Hº-Hº * | ** | * H-Hº-Hº-HºHº 3M | 12.5 || Grower Hº-Hº-Hº-H; 96 Iwasaki et al. Table 1 (Continued). ę Age Growth gº Stress Speed 2 Average Subiect Side R up] (years) || Status (kPa) (mm/day) AI 3M2 13.8 Grower L 26 ().097 ().988 2.43 R 52 ().084 ().990 0.95 R 26 ().09() ().984 2.02 2 ) * Yº 3M3 | 2.2 Grower L 52 0.080 ().989 2.34 -- R 26 0.054 ().957 0.69 3M4 | 6.3 Grower L 52 0.034 ().99 | 0.41 L | 3 0.046 ().990 0.43 3M5 14.1 Grower R 26 ().058 0.993 0.39 Non- R 13 ().0 12 0.659 0.21 2F | 30.9 Grower L 26' 0.013 0.729 0.46 2F2 15.1 Non- L 13 0.021 0.881 1.54 Grower R 26 0.022 0.926 0.90 2F3 16.1 Non- R 13 0.033 0.957 ().75 e Grower L 52 0.052 ().884 1.08 L 13 0.052 ().901 1.33 2F4 12.8 Grower R 26 0.053 0.841 1.23 R 13 0.045 0.864 0.72 2F5 10.4 Grower L 52 0.056 0.948 0.83 Non- L 13 ().015 0.881 0.77 .9 2M1 17 Grower R 52 0.037 0.760 0.98 R 13 0.057 0.905 2.59 | 2. 2M2 2.9 Grower L 26 0.043 0.933 0.97 L 13 0.068 0.963 0.79 14.2 2M3 Grower R 52 0.063 0.924 1.01 R 4 0.029 0.968 0.50 1F1 2.2 1 Grower L 13 ().046 0.970 1.62 R 4 0.020 0.970 1.01 |F2 14.8 Grower L 13 0.018 0.913 0.99 R 4 0.048 0.985 1.09 | F3 13.2 Grower L 13 0.049 0.941 0.86 L 4 0.019 0.857 0.84 1 F4 13.3 Grower R 13 0.052 0.970 0.74 L 4 0.022 0.903 3.62 1F5 14.4 Grower R 13 0.026 0.990 7.59 L 4 0.016 0.725 0.93 1 M1 16.2 Grower R 13 0.024 0.903 1.12 L 4 0.042 0.868 0.26 1 M2 13.9 Grower R 13 0.066 0.929 0.62 Segmental mechanics were used to translate distally 66 maxillary canines from Day 0 to 84, while the mandibular teeth were without ap- pliances. To provide passive anchorage, the maxillary first molars were linked to a Nance appliance and the posterior teeth of each maxillary quadrant were connected via buccal stainless-steel segment archwires (of rectangular cross-section > 0.016” x 0.018”) and linked with figure-eight ligation (Fig. 1A,B). At one month prior to canine retraction (Day 0), each subject received anchorage appliances and began twice-daily 97 IL-1 Genetic Polymorphisms chorhexidine gluconate oral rinses. At two weeks prior to canine retrac- tion, the maxillary first premolars were removed. Forces and counter- moments were delivered to each maxillary canine starting on Day 0 us- ing a stainless steel vertical loop auxiliary wire of rectangular cross- section (> 0.016” x 0.018”) ligated to the canine bracket and extending through the auxiliary tube on the first molar band in the same quadrant (Fig. 1A, B). Each loop was activated by a nickel-titanium (NiTi) spring calibrated at mouth-temperature and selected to apply 4, 13, 26, 52 or 78 kPa to a given canine. Corresponding forces were approximately 18, 60, 120, 240 and 360 ch, respectively. Two different stresses per subject were assigned systematically via a balanced incomplete block design, with stresses assigned randomly to right or left sides. Subjects. made nine to ten visits on Day 0, 1, 3, #7, 14, 28, 42, 56, 70 and 84. At each visit, oral hygiene and gingival inflammation were evaluated using the Modified Gingival Index (MGI; Lobene et al., 1986). GCF samples were collected, a supragingival prophylaxis was performed and a maxillary dental impression was made in polyvinylsi- loxane using a custom tray. Established techniques were used for collection, storage and analysis of GCF (Iwasaki et al., 2005, 2006). At each visit, two GCF samples were obtained from the two experimental sites (distal of each maxillary canine) and for one control site (interproximal of a mandibular canine or adjacent tooth). The two samples/site were combined and as- sayed using commercial kits and a spectrophotometric microplate reader to quantify IL-13 (Cayman Chemical, Ann Arbor, MI) and IL-1RA (R&D Systems, Minneapolis, MN). GCF samples from 25 of 33 subjects were assayed similarly to quantify total protein (BCA Protein Assay, Pierce Biotechnology, Rockford, IL). Results of duplicate enzyme-linked immunosorbent assays (ELISAs) for each cytokine and total protein were → Figure 1. A: Subject 4M2: Occlusal view showing appliances including verti- cal loops activated by calibrated springs selected to deliver a prescribed force (F) for a specified stress (o) to each maxillary canine, according to: O = F/Aa, where A-La (1-[bºſa'])” was the distal root surface area of the canine adjusted for root curvature and labiolingual (2a) and mesiodistal (2b) widths at the ce- mentoenamel junction plus the root length (L.) were measured from a periapical 98 Iwasaki et al. radiograph of the tooth corrected for magnification (Iwasaki et al., 2000). B. Subject 4M2: Left buccal view showing heights matched for the center of the vertical loop and center of resistance of the maxillary canine (CR), estimated using CR = 0.24L (Tanne et al., 1988). 99 IL-1 Genetic Polymorphisms averaged for each time-point. Readings below the detectable limit were not used. IL-13 and IL-1RA levels at each visit were expressed as ratios of experimental versus control sites (E/C) relative to total protein (where able) and via a modified Activity Index (AI) as previously described (Iwasaki et al., 2005, 2006), where: * IL Experimental . . . . AI = IL – 1 RA gº Il – 1/3 Control Overall average values for IL-13 and IL-1RA levels and the AI for each maxillary canine were calculated from Day 0 to 84 or until re- traction was complete according to the following: initial averages and standard deviations (SDs) for all GCF measures were calculated over all time-points for each tooth; any data >2 SDs above or below the initial average for a given site or tooth were defined as outlier data; averages and SDS for measures, sites and teeth were recalculated excluding outlier data; and average values were determined based on remaining data from four to nine time-points, where average number of time-points was 7+ 1. Tooth movements were quantified using a microscope (MM-11 Measurescope, Nikon Inc., Melville, NY), the series of nine to ten maxil- lary dental casts/subject derived from impressions made at each visit, and a set of three custom acrylic templates for each subject (Fig. 2). Repeated measurement errors for this technique were a maximum of 0.05 mm and ().28°. Cheek-wipe samples were collected from 18 of 33 subjects for genotyping (Kimball Genetics, Denver, CO or Medical University of South Carolina) of IL-1 gene cluster polymorphisms at loci: IL-1A(+ 4845), IL-1B(+ 3954), and IL-1RN (variable number of tandem repeats of 86 base pairs [VNTR86]), using previously described techniques (Chandler, 2006; Iwasaki et al., 2006). The growth status for each subject was established as positive (Grower) or negative (Non-grower) by presence or absence of demon- strated height change and craniofacial growth via serial lateral cephalo- metric superimpositions during orthodontic treatment. To determine if distal tooth translation was the predominant movement, three linear (distal, lateral and extrusion) and three angular (distal crown tip, lateral crown torque and distopalatal rotation) movements 100 Iwasaki et al. ZExtrusion Y Lateral R2/fº-C/CŞTorque 1 time-point in this period was equal to or less than that at Day 1 and after which the speed of tooth movement was linear and markedly increased from Days 42 to 84 (data not shown). Speeds of distal tooth movement ranged between 0.016 to 0.109 mm/day in Growers and 0.012 to 0.066 mm/day in Non-growers. Maxi- mum difference in speed between all teeth in the study was 9.1:1.0. For the same stress and growth status, maximum differences in speed were 4.2:1.0 for 13 kPa in Growers and 4.8:1.0 for 26 kPa in Non-growers. Average speeds of distal movement (+ SD) were 0.028 (+ 0.012), 0.043 (+ 0.019), 0.057 (+ 0.024), 0.062 (+ 0.015) and 0.067 (+ 0.024) mm/day for 4, 13, 26, 52 and 78 kPa, respectively (Fig. 4). On average, speed in- creased approximately linearly with stress over this range. However, the effect of stress was not significant statistically (P × 0.05). Average speeds of distal movement in Growers were faster than in Non-growers at each stress (Fig. 5) but this effect also was not significant statistically (P - 0.05). - 102 Iwasaki et al. 8 7- 4 kPa X 52 kPa 6- © 13 kPa O 78 kPa I º 5- A 26 kPa F ) E - 4: 5 E 3: I g C 2- > ; ſº 1- º # 14, -1- –2- –3 o 10 20 30 40 50 60 70 30 go ApproximateTime-point (day) Figure 3. Average amount of distal movement of maxillary canines for the five applied stresses at indicated time points. Vertical lines indicate 1 SD about aver- age. 0.10- 0.09- 0.08– 0.07- 0.06- 0.05- | 0.04- 0.03- | | 0.02- | 0.01 - 0 4. 13 26 52 78 Stress (kPa) Figure 4. Average speed of distal movement of maxillary canines versus applied stress. Vertical lines indicate 1 SD about average. 103 IL-1 Genetic Polymorphisms 0.10- 0.09– 0.08– 0.07 - 0.06– 0.05– 0.04- 0.03- 0.02– 0.01 - 0 D Growers T | Non-growers F- ; 4. 13 26 52 78 Stress (kPa) Figure 5. Average speed of distal movement of maxillary canines versus applied stress and growth status of subjects. Vertical lines indicate 1 SD about average. Extrusion and angular movements tended to fluctuate with time (Fig. 6). These movements generally were small for applied stresses from 4 to 52 kPa where absolute values of averages were s 0.71 mm for extru- sion and < 5.34° for all three angular movements. Movements generally were larger for 78 kPa where absolute averages were s 1.05 mm for ex- trusion (Fig. 6A), s 5.38° for distal crown tip (Fig. 6B), sº 6.38° for lateral crown torque (Fig. 6G) and < 13.75° for distopalatal rotation (Fig. 6D). Lateral movements tended to increase steadily with time (Fig. 6E), simi- lar to but lesser than distal movements and were highest for 78 kPa where absolute averages were s 2.79 mm, whereas these were s 1.81 mm for 4 to 52 kPa. In general, as reported previously (Iwasaki et al., 2005, 2006), the levels of IL-13 and IL-RA in GCF fluctuated over time for all sub- jects and amounts of cytokines collected in GCF samples generally were low (Table 2). Malfunction of an assay for IL-13 for Subject 4F6 and the screening protocol for outlier data resulted in average AI calculations for 27 of 33 subjects (Table 1). 104 Iwasaki et al. 8 F 7- 4 kPa X 52 kPa E. • 13 kPa O 78 kPa -- 6- 5 A 26 kPa F 5- Q1) 3 4. E 5 3- 3 a 2- P. É 1- § 0. TTT QD § -1. 35 * -2- –3 I I i I i i i i i 0 10 20 30 40 50 60 70 80 90 A ApproximateTime-point (day) 25 20 4 kPa X 52 kPa § • 13 kPa O 78 kPa § 15. A 26 kPa S. c. 10- H. 5 5. S $º o º º * I C -5- QD § § -10- > < -15- –20-l- i t i i t i I I 0 10 20 30 40 50 60 70 80 90 B Approximate Time-point (day) Figure 6. Average movement of maxillary canines for the five applied stresses at indicated time points. A: Extrusive. B: Distal crown tip. Vertical lines indicate | SD about average. 105 IL-1 Genetic Polymorphisms 2 5 4 kPa X 52 kPa • 13 kPa O 78 kPa A 26 kPa 2 0 1 5 - 1 0 5 - -10 : o 10 20 30 40 50 60 70 30 go ApproximateTime-point (day) C 4 kPa X 52 kPa • 13 kPa O 78 kPa A 26 kPa 2 0 1 5 1 0 5 1- 05 15-0 : –2 0 0 10 20 30 40 50 60 70 30 90 D Approximate Time-point (day) Figure 6 (Continued). Average movement of maxillary canines for the five ap- plied stresses at indicated time points. C. Lateral crown torque. D: Distopalatal rotation. Vertical lines indicate 1 SD about average. 106 Iwasaki et al. 8 – 7 || || 4 kPa × 52 kPa = • 13 kPa O 78 kPa st 6- E A 26 kPa Q1) 5- 8- Q1) 3 4- s 5 3. O S 2. º - § 1. - co º alsº oo S -1- Q1) > < -2. –3 I I i I i i t 0 10 20 30 40 50 60 70 30 90 E Approximate Time-point (day) Figure 6 (Continued). Average movement of maxillary canines for the five ap- plied stresses at indicated time points. E. Lateral. Vertical lines indicate 1 SD about average. Table 2. Subjects; side, stress, average IL-13 and IL-1RA in GCF at experimen- tal site (E) relative to protein and relative to control site (C); and genotype (al- lele numbers). Subjects are identified by Study #, Sex (F = Female, M = Male), Subject, E = experimental site: C = control site; VNTRs6 = variable number of tandem repeats of 86 base pairs; ND = not determined. É # Stress IL-1ſ IL-1RA Genotype # ° (*) | pºſſ. pg/ug IL-1A | IL-1B | IL-1RN protein E/C protein E/C (+4858) (+3953) (VNTRs6) 4F1 || R. 52 1.11 | 1.30 | 16.16 | 1.80 1.2 12 1.1 L 78 0.85 0.67 17.24 1.63 - * - AF2 || R. 78 0.48 0.54 21.22 0.96 1.2 1.1 1.3 L 52 0.53 0.89 17.72 0.84 - - - 4P3 || R. 26 0.31 2.06 6.40 1.63 1,1 1.2 1,1 L 78 0.44 3.95 7.57 2.38 4F4 # 78 0.68 2.34 31.50 0.99 1,2 1,2 1,1 - 13 0.73 2.75 27.38 1.38 | | L 78 ND ND ND ND AF6 || R. 78 ND ND 12.83 0.86 1,1 1,1 1,1 | | L 52 ND ND 19.68 0.83 4M2 || R. 78 1.66 1.29 39.49 0.55 1,2 1,2 1,1 | | L 13 2.58 2.94 66.14 0.96 107 IL-1 Genetic Polymorphisms Table 2 (Continued). # | 3 || stress IL-13 IL-1RA Genotype # % (kPa) Tºñº, pg/ug IL-1A | IL-1B | IL-1RN protein E/C protein E/C *-i-º-º-º- 4M3 R 13 ().20 ND 23.86 1. 8 |, | 1, 1 |, | L 78 ().52 4.9 | 21.39 1.3() C 3F Hº-Hº-H 12 || || || 2.2 3F2 Hº-Hº- L| | | | 12 3Fs Hº-Hº-Hº-Hº- L| | | | 1.2 3f4 Hº-Hº-H;-H 1, 1.2 | 1. 3Fs Hº-Hº-Hº- 22 2.2 | 1.2 3M. H.-H...-H...-H...-H...— . . . . 12 3M2 Hº-Hº-Hº-H 12 | 1.2 | 1. 3M, Hº-Hº-Hº-Hº- 12 | 1.2 | 1. 3M, Hº-Hº-Hº- L| | | | 2.2 3Ms Hº-Hº-Hº-Hº- 12 | 1.2 | 1. 2F H ND | ND | ND 2F2 HHH ND | ND | ND 2F3 H ND | ND | ND 2F4 H ND | ND | ND 2Fs Hº-Hº-Hº- ND | ND | ND 2M Hà–H ND | ND | ND 2M2 Hº-Hº-Hº- ND | ND | ND 2M H-H ND | ND | ND IFI Hº-Hº-Hº-Hº-Hº- ND | ND | ND IF. H.; H ND | ND | ND IF3 Hº-Hº-Hº-Hº- ND | ND | ND IF4 Hº-Hº-H...-H.H ND | ND | ND 108 Iwasaki et al. Table 2 (Continued). # # . IL-13 IL-1RA Genotype 2 (kPa) peſº pg/ug IL-1A | IL-1B | IL-1RN protein E/C protein E/C (+4858) (+3953) (VNTRs) |F5 L 4 3.46 4.37 67.13 | .03 ND ND ND R | 3 4. | 6 7.6() 91.00 1.45 L 4 1.04 1.79 144.82 3.19 |M|| R 13 ().9() 1.66 | | ()().35 | 2.23 ND ND ND L 4 ().29 ().23 || 69.31 2.14 | M2 ND ND ND R | 3 | .22 1.63 | 0 || 49 2.58 Genotypes for IL-1A (+4858), IL-1B (+3954) and IL-1RN (VNTR86) loci for 18 subjects (Table 2) were grouped according to: genotype l = homozygous for allele 1 (1,1); genotype 2 = heterozygous (1,2) or homozygous for allele 2 (2,2); and genotype 3 = having alleles 1 and 3. For the IL-1A (+4858) locus, eight subjects were genotype 1 while ten subjects were genotype 2. For the IL-1B (+3954) locus, nine subjects each were genotype 1 and 2. For the IL-1RN locus, ten subjects were genotype 1, seven subjects were genotype 2 and one subject was geno- type 3. A stepwise regression analysis using speed of distal tooth movement as the dependent variable showed three significant factors affected speed at the 15% level: IL-1B (+ 3954) genotype (P = 0.039), AI (P = 0.0005) and IL-1RA in GCF at the experimental site (P = 0.005). That is, higher speeds were associated significantly with genotype 2 at IL-1B (+ 3954), higher AI and lower IL-1RA in GCF at the experimental site. Combined, these three factors provided a model that explained 69% of the variability found in the speed of distal tooth movement (Fig. 7). DISCUSSION Sixty-six maxillary canines in 33 human subjects were retracted into edentulous spaces by continuous stresses of 4, 13, 26, 52 or 78 kPa for 84 days. Tooth movement was distal predominantly (Fig. 3). The relatively large amount of distal tooth movement seen at Day 1 likely represented initial squeezing of the periodontal ligament in response to the applied retraction force. Generally steady distal tooth movement was demonstrated in 95% of the teeth from Day 3 to 84 or until retraction was complete. Only three teeth, one each moved by 4, 52 and 78 kPa, showed a so-called “lag phase” from Days 3 to 28, after which time these teeth also showed a linear relationship between distal movement and time. 109 IL-1 Genetic Polymorphisms Contrary to previous suggestion based on preliminary data (Iwa- saki et al., 2005), current evidence does not support the theory that pres- ence of a lag phase is related to higher stresses. Average lateral tooth movement also showed a steady but smaller increase with respect to time (Fig. 6E) and could be accounted for by cases in which initial dental arch form and position of the maxillary canine necessitated some lateral as well as distal movement in order to approximate contact points on the distal of the canine and mesial of the second premolar in the same quad- rant (e.g., Fig. 1A). Tracking tooth movement relative to an orthogonal axis system, as in the current protocol, tends to underestimate the total amount of dis- tal movement during canine retraction. The subtle fluctuations with respect Genotype at IL-1B (+3954) O A2+ e A1,A1 O 0.40 C/? Q, o O O O % 0.08 O º CO £2. O O - O 3. 6 O O , % 0.0 O (P Q 23. %3 O 3 92. 3 * a 04 a #" • % a 0% 7~ # 0. «TV, sº *…? 2: 3. %22r. 2.3" 62 Q Figure 7. Quasi-three-dimensional graph showing effects of IL-1B genotype (O = subjects homozygous for allele 1 [A1, A1]; e = subjects with > 1 copy of allele 2 [A2+]), Activity Index (AI) and IL-1RA in GCF at experimental sites on speed of distal movement of maxillary Ca111116S. 110 Iwasaki et al. to time and relatively small amounts of extrusion and angular movements suggest that predictable tooth translation was generated via the applied mechanics. Average tooth movements in all aspects were larger for 78 kPa than lower stresses. Furthermore, average speed of distal movement showed a positive linear relationship with stress for 4 to 78 kPa. How- ever, the effect of stress on speed of distal movement was not significant for these combined data. Overall, teeth in Growers moved faster than teeth in Non-growers. However, the effect of growth status on speed also was not significant for these combined, data. Three factors that were shown to have a significant effect on speed of distal movement were: IL- 1B (+ 3954) genotype, average activity index (AI) and IL-1RA in GCF at the experimental site during the tooth movement. These results in general are in agreement with previous findings on smaller sub-samples (Iwasaki et al., 2005, 2006; Chandler, 2006). The results also are consistent with reports that individuals with genotype 2 compared to genotype 1 at IL- 1B (+ 3954) secrete more IL-13 for the same stimulus (Cork et al., 1995). Such individuals might be expected to have higher average AI values and relatively lower average IL-1RA levels in GCF at experimen- tal sites as found in the current study and associated with increased rela- tive bone resorption and faster speeds of tooth movement. Limitations of the study protocol were discussed previously (Iwasaki et al., 2000, 2005, 2006) and include the indirect assessment of bone turnover agents by measuring GCF, limited focus on only two of many such agents and genes responsible for bone modeling and ortho- dontic tooth movement, potential for unmeasured effects on appliances such as binding of active components and challenges in obtaining consis- tent results from ELISAs. It should be noted further that evidence from studies of single nucleotide polymorphisms (SNPs), such as those of the IL-1 gene cluster, demonstrate regional and ethnic differences in allelic frequencies (Armitage et al., 2000) and the interplay between SNPs (Chen et al., 2006). Genes do not act in isolation; there is a growing body of evidence that epistasis—modification of the action of a gene by one or more other genes—plays a significant role (Phillips, 2008) in human de- velopment and metabolism. Future investigations include larger samples and investigating interacting genes, therefore, are needed. Of additional note, genetics associated with normal physiological processes such as bone modeling/remodeling in generally healthy indi- viduals, like most orthodontic patients, has received limited study. Fur- thermore, unlike genetically complex diseases, many of the candidate 111 IL-1 Genetic Polymorphisms environmental factors associated with the phenotype speed of bone turn- over and orthodontic tooth movement can be identified and measured (Iwasaki et al., 2008). Thus, orthodontic tooth movement could provide a well-controlled human model for the study of the molecular biology and genetics of bone. CONCLUSIONS Combined data from 66 teeth moved over 84 days demonstrated that predominant translation is possible and that a number of factors af- fect the speed of bone modeling and tooth movement in humans. Specifi- cally, having at least one copy of allele 2 at IL-1B (+3954), high average activity index and low average IL-1RA in GCF at experimental sites are associated with faster distal tooth movement. Higher stresses in the range 4-78 kPa and evidence of growth also may be associated with faster tooth movement. ACKNOWLEDGEMENTS Copyright 2009 Wiley. Used with permission from: Iwasaki LR, Chandler JC, Marx DB, Pandey JP, Nickel JC. IL-1 gene polymor- phisms, secretion in gingival crevicular fluid, and speed of human ortho- dontic tooth movement. Orthodontics and Craniofacial Research. John Wiley and Sons Inc., 2009; 12:129-140. Participation by Marian Schmidt, Bobby Simetich, former stu- dents and subjects in these studies; donations of supplies, in particular, from G&H Wire Co. 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The biology of OTM is characterized by a cascade of events, triggered by the strain of the periodontal ligament fibers, leading to an inflammatory process that allows appropriate tissue remodeling. However, this inflammatory process may evoke side effects, such as pain, for which the use of non-steroidal anti- inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) has been ad- vocated. In vitro and in vivo studies have demonstrated that the arachidonic acid (AA) pathway represents a main step of the molecular events governing tissue remodeling during OTM. Through this pathway, important pro-inflammatory prostaglandins (PGs) are synthesized by three isoforms of a key enzyme referred as cyclooxygenase (COX), which catalyzes the conversion of AA into prosta- glandin G2 (PGG2), the precursor of all of the other PGs. Interestingly, among the downstream effects of these PGs also are the main side effects of OTM, pain and root resorption. The NSAIDs thus act by non-specifically blocking either all of the COX isoforms or the isoform 2 (COX-2), while paracetamol specifically blocks the isoform 3 (COX-3). The different tissue distribution and action of these COX isoforms likely would be responsible for some differences in the clinical effects produced by NSAIDs and paracetamol. Current animal and hu- man studies show that all NSAIDs, including paracetamol, generally are useful in controlling pain associated to OTM while not affecting root resorption. How- ever, only paracetamol does not appear to inhibit OTM and, therefore, may rep- resent the drug of choice to control pain during OTM. Moreover, specific inhibi- tors for the COX-2 have not been reported to have significantly different effect on OTM as compared to all the non-specific inhibitors. The choice between these two classes of drugs, therefore, should be made on the basis of whether the patient has other systemic conditions, such as gastric or cardiovascular diseases. Although general indications for the use of these NSAIDs during OTM now are available, future investigations on both the basic biology underlying OTM and on the mechanisms of action of these drugs are warranted to further optimize orthodontic treatments. KEY WORDS: orthodontic, tooth movement, drug, inflammation, pain 117 Impact of Anti-inflammatory Drugs INTRODUCTION Orthodontic tooth movement (OTM) involves a complex combi- nation of biological mechanisms that still are not understood fully. Past and present studies on the biology of OTM have been performed with the aim of optimizing orthodontic treatment. In this regard, rapid and bio- logically compatible tooth movement is desirable, along with good pain control, which can represent a major problem for some patients. Modula- tion of the force is necessary but not sufficient to achieve these goals; therefore, the use of anti-inflammatory drugs has been advocated. The optimal use of the anti-inflammatory drugs requires knowl- edge of the basic underlying biology of OTM, with emphasis on the mo- lecular mechanisms that are triggered by the orthodontic force and that govern tissue remodeling. Modifications induced by orthodontic forces have been described extensively at the tissue and cellular levels, and our knowledge of the molecular level of the response (i.e., the intracellular signaling cascades) continues to grow. Although many aspects of the molecular machineries involved still have to be defined, combining our present knowledge with results from clinical trials now enables the selec- tive use of anti-inflammatories in orthodontic patients, with a potential of increasingly individualized treatments. Thus the effects of anti-inflam- matories and their indications for use now need to take into account not only the patients’ symptoms (e.g., pain), but also side effects on tissue remodeling (e.g., root resorption) and rate of OTM. THE BASIC BIOLOGY OF OTM Main Models of OTM Orthodontic tooth movement occurs as a consequence of a series of biological responses that can be triggered within the periodontal liga- ment following application of a force. In particular, these orthodontic forces induce mechanical deformation that can alter the vascularity and blood flow of the periodontal ligament. This, in turn, can result in the lo- cal synthesis and release of various key signaling molecules including neurotransmitters, cytokines, growth factors, colony-stimulating factors (CSFs) and arachidonic acid metabolites. These signaling molecules can evoke the tissue, cellular and molecular mechanisms that then promote the tissue remodeling necessary for OTM. Four extensive reviews have been published recently on this topic (Vandevska-Radunovic, 1999; Krishnan and Davidovitch, 2006; 118 Perinetti et al. Masella and Meister, 2006; Meikle, 2006); the focus herein, therefore, will be to summarize and discuss critically the main models that have been proposed since the beginning of the biological studies of OTM over a century ago (Sandstedt, 1904). Pressure-tension Model The pressure-tension model was the first proposed for OTM and was derived from the combined observations of Sandstedt (1904), Schwarz (1932) and Oppenheim (1935; Fig. 1). These studies relied on animal models, in which a force of a given direction was applied to a tooth, with the periodontal tissues in the tension and compression areas investigated histologically. As a result, bone was deposited with both light and heavy forces on the alveolar wall on the tension side of the tooth, with newly formed bone spicules following the orientation of the periodontal fiber bundles. On the compression side, two distinct behav- iors were seen for light and heavy forces. With light forces, alveolar bone was resorbed directly by numerous multinucleate osteoclasts in How- ship’s lacunae (frontal resorption). In contrast, for heavy forces, the periodontal tissues were compressed, leading to capillary thrombosis, cell death and the production of localized cell-free areas known as hya- line zones. The presence of hyaline zones was demonstrated further in other studies (Reitan, 1967: Rygh, 1972a,b). At these sites, the osteoclast re- Sorption of the adjacent alveolar wall does not take place directly, but in- stead is initiated by the neighboring marrow spaces from macrophagic cells that are recruited to these areas (undermining resorption). The re- sorption of the hyaline zones and the corresponding bone in the com- pressed areas (by either frontal or undermining mechanisms) is a prereq- uisite for OTM to occur. Bone Bending/Piezoelectric Current Model The bone bendingſpiezoelectric current model was derived from the observation that when an external load is applied to a long bone, the deformation that occurs produces electrical phenomena in the surface curvature of the bone (Fig. 2). Thus, the external surface of the cortex is under tension, promoting elongation, while the internal surface is under compression, promoting shortening (Epker and Frost, 1965). This in- creased bone concavity was shown to be associated with electronegativ- ity and bone formation, while the increased convexity was associated with electropositivity and bone resorption (Bassett and Becker, 1962). 119 Impact of Anti-inflammatory Drugs Orthodontic Force - Compression of PDL Stretching of PDL (solid tissue) (solid tissue) * - * - - ºf | light forces | Heavy forces | | Strain of PDL fibers - Z. Hyaline zones | Bone deposition Recruitment of macrophagic cells Bone resorption (undermining resorption) | KEY - 7 - Tissue modifications OTM - - Cellular modifications Figure 1. The pressure-tension model. Bone resorption (frontal resorption) Electrical potentials were recorded in a dog mandible following application of a mechanical force to the teeth that was able to bend the alveolar bone (Gillooly et al., 1968). Subsequently, experiments in hu- mans showed that the interseptal bone also can be bent (Grimm, 1972). According to these observations, electrical potentials were proposed to be responsible for the regulation of osteogenesis and bone resorption that takes place during OTM (Zengo et al., 1973). Therefore, OTM was ex- plained here by the same histological findings reported for the pressure- tension models, with the addition of the generation of piezoelectric cur- rents that trigger the cell replication and differentiation, and the cell re- cruitment that is necessary to resorb the hyaline zone (Fig. 2). Despite the considerable interest in piezoelectric currents as a stimulus for bone remodeling (which occurred prior to the discovery of growth factors and other important biochemical mediators), this model had major drawbacks. Indeed, physically distorting a dry bone also pro- duces piezoelectric currents that can develop as a consequence of the dis- tortion of any crystalline structure (McDonald, 1993). The magnitude of 120 Perinetti et al. | Orthodontic Force - RC Tissue modifications — ` - - - ſ Cellular modifications | Movement of PDL fluids Gradual distortion of PDL (viscoelastic tissue) - - Hyalinization of Bending of PDL the alveolar bone T- | Piezoelectric effects Recruitment of . Cell replication macrophagic cells and differentiation U. Hyaline zone resorption Undermining resorption . Figure 2. The bone bendingſpiezoelectric current model. Molecular modifications these charges also is small and there was some doubt whether they are sufficient to induce cellular changes (McDonald, 1993). Moreover, pie- Zoelectric currents would not be sufficiently discriminatory for the regu- lation of the metabolic activities of such diverse cell types as osteoblasts and osteoclasts, which also need to function in close proximity (Meikle, 2006). Therefore, while these bone-bending observations still remain Valid, along with new evidence for osteocyte response to mechanical load (Gluhak-Heinrich et al. 2003), these piezoelectric currents no longer are considered to have a primary role in OTM. Neurogenic Inflammation Model The neurogenic inflammation model was proposed just over a decade ago (Vandevska-Radunovic, 1999: Fig. 3). It is based on the as- Sumption that OTM is the result of an inflammatory process triggered by the peripheral nerve fibers. This neuronal contribution, referred to as *urogenic inflammation, is characterized by the release of neuropeptides 121 Impact of Anti-inflammatory Drugs Orthodontic Force * - - Movement of PDL fluids Gradual distortion of PDL - Neuropeptides release (solid-viscoelastic tissue) from afferent nerve endings º – - Z- | Hyalinization of Bending of | | 1. Capillary vasodilatation PDL the alveolar bone 2. Migration of leukocytes - i. - into extravascular areas -- _ Piezoelectric effects / . Nº. Y - - Synthesis and release of Recruitment of Cell replication | . dins macrophagic cells N and differentiation Nº f 3. 3. Leukotrienes - - - KEY Hyaline zone resorption issue modifications Undermining resorption Tissue modifications | - - - P. Cellular modifications OTM Molecular modifications Figure 3. The neurogenic inflammation model. / | upon stimulation of afferent nerve endings, which then initiate the cas- cade of events leading to an inflammatory reaction (Brain, 1997). After the periodontal ligament has been strained by the force applied to the tooth, the nerve endings within it release the neuropeptides. These periodontal nerve endings consist of pressure receptors (mechanoceptors; Maeda et al., 1989) and pain receptors (nociceptors. Jyvasjarvi et al., 1988). The mechanoceptors show low-threshold activa- tion that is responsive to stretch (Linden, 1990), while the nociceptors show high-threshold activation that is responsive to heavy forces or tis- Sue injury (Jyvasjarvi et al., 1988). The nociceptors contain various neuropeptides including calciº tonin gene-related peptide (CGRP) and substance P that are released upon nociceptor activation (Hokfelt et al., 1975). Interestingly, both traumatic occlusion (Kvinnsland and Heyeraas, 1992) and OTM (Kvinn- sland and Kvinnsland, 1990) have been shown to induce the release of CGRP 122 Perinetti et al. and substance P from the nociceptor endings within the periodontal ligament. Thus, according to the neurogenic inflammation model, upon application of an orthodontic force, the CGRP and substance P released within the periodontal ligament initiate the initial events leading to OTM. Among these there are capillary Vasodilatation and leukocyte migration into extravascular areas, with the release of a series of inflammatory me- diators that finally recruit the macrophagic cells that are necessary for hyaline-zone resorption. Further Models Very recently, some further models for tissue remodeling under- lying OTM have been proposed. As with the bone bending/piezoelectric current model, the focus indeed has returned to alveolar bone as one of the main tissues in the initiation of the remodeling necessary for OTM. Here, the concept is that periodontal ligament alterations with strain can provide only a partial explanation for the mechanisms involved in dento- alveolar remodeling (Melsen, 1999, 2001; Verna et al., 1999; Pavlin et al., 2001; Milne et al., 2009). These recent models are based on the assumption that mechani- cal function is an important determinant of bone mass and architecture. The increases in bone strain above a certain threshold that arise from physical activity have a positive effect on bone mass (Nilsson and Wes- tlin, 1971; Jacobson et al., 1984) and does not require a prior episode of bone resorption (Lanyon and Baggott, 1976). On the other hand, the re- duced bone strain that results from weightlessness or prolonged bed rest leads to bone loss and osteopenia (Donaldson et al., 1970). For instance, it has been proposed that orthodontic loading can trigger bone remodeling by producing ‘microdamage” (Verna et al., 2006), or alternatively, by stimulating the induction of a regional accel- eratory phenomenon: a reaction to trauma in which the rate of bone re- modeling exceeds its normal tissue activity (Melsen, 1999). The very re- cent modification of the original mechanostat model (Milne et al., 2009) proposes that an orthodontic force creates a particular constant loading condition in which some areas are shielded from mechanical stress. Moreover, areas of low mechanical stimulation are coincident with his- tologically observed sites of bone loss, while bone mass is preserved in areas with higher levels of loading. However, all of these models still re- quire further investigation and definition. 123 Impact of Anti-inflammatory Drugs MOLECULAR MECHANISMS GOVERNING OTM A dramatic growth in our knowledge of the mechanisms behind OTM has been seen over the last three decades. This increase in knowl- edge has been driven mainly by the advent of a spectrum of molecular analysis techniques that allow more direct investigations of the molecular machinery underlying OTM. A thorough knowledge of these molecular mechanisms will be essential if OTM and the related side effect are to be modulated or controlled. Irrespective of the model considered for OTM, a common and general molecular mechanism can be postulated. According to the neurogenic inflammation model, one of the first events to trigger tissue remodeling is the release of CGRP and substance P from the nerve endings within the strained periodontal ligament (Vandevska-Radunovic, 1999). How these nerve endings are stimulated to produce and release these neuropeptides is still under investigation. One of the most interesting hypotheses proposes a role for the cell adhesion receptors: the integrins (Sastry and Burridge, 2000; Meikle, 2006). The integrins are transmembrane proteins that are responsible for adhesion of the plasma membrane of the cell with the surrounding struc- ture, the extracellular matrix. With the cytoplasmic tail of the integrins linked to the intracellular cytoskeleton, recent evidence has indicated that the strain applied to the integrin molecules can activate several intracel- lular signaling cascades through activation of the cytoskeleton (Sastry and Burridge, 2000). Combining the large pool of evidence collected to date (for re- views, see Vandevska-Radunovic, 1999; Krishnan and Davidovitch, 2006; Meikle, 2006), the general signal transduction network that func- tions downstream of this cytoskeleton activation is summarized in Figure 4. Thus, following integrin activation, the intracellular signaling cascades believed to be involved are the cyclic adenosine-monophosphate (cAMP), the phosphatidylinositol (PI) and the arachidonic acid (AA) pathway, along with calcium ion (Ca") channel activation (Fig. 4). All of these phenomena thus would lead to activation and tran- scription of the genes for CGRP and substance P. These neuropeptides then can have two major activities, one autocrine and one paracrine. Through the former, they can reactivate the same signaling cascade (positive feedback) and through the latter, they induce the synthesis and release of several pro-inflammatory mediators in leukocytes, including in- 124 Perinetti et al. Integrin activation by strain - 2. - — — CAMP pathway Pipathway AA pathway Caº channel . . . . Gene transcription substance 5 and carp - - | In leukocytes, synthesis of: * In osteoblasts, synthesis of: Cytokines (e.g. IL-1, TNF INF) || RANK-RANKL, CPG, colony-stimulating factor Osteoclast differentiation Bone resorption Figure 4. The molecular mechanisms governing OTM. cAMP = cyclic adeno- Sine-monophosphate; PI = phosphatidylinositol; AA = arachidonic acid; CGRP = calcitonin gene-related peptide; IL-1 = interleukin-1; TNF = tumor necrosis factor: INF = interferon; RANK receptor activator of nuclear factor-KB; RANKL = receptor activator of nuclear factor-KB ligand; OPG = osteoprotegerin. terleukin-1 (IL-1), tumor necrosis factor (TNF) and interferon (INF). In turn, these pro-inflammatory mediators can activate osteoblastic cells to the synthesis and release of other important signaling molecules, such as the receptor activator of nuclear factor-kB ligand (RANKL), osteoprote- gerin (OPG) and CSFs. These mediators finally promote osteoclastic dif- ferentiation and bone resorption. The same pro-inflammatory mediators also would be responsible for the macrophage differentiation and activation that is necessary to re- Sorb the hyaline zone. Of note, the AA pathway has a primary role in this Cascade of events. ORTHODONTIC TOOTH MOVEMENT: AN INFLAMMATORY PROCESS2 Despite our knowledge of the intimate molecular mechanisms underlying OTM, there still is open debate relating to the concept that these phenomena can be classified as inflammatory processes (Sandy et al., 1993; Vandevska-Radunovic, 1999; Krishnan and Davidovitch. 2006) or not (Meikle, 2006; Milne et al., 2009; Maclaine et al., 2010). Evidence has been provided in favor of both of these hypotheses (Table 1). 125 Impact of Anti-inflammatory Drugs Table 1. The main arguments for and against orthodontic tooth movement as an inflammatory process. FOR (Sandy et al., 1993; Vandevska-Radunovic, 1999; Krishanan and Davidovitch, 2006) 1. Increases in the synthesis of cytokines are an index of inflammation 2. The use of NSAIDS reduces the rate of OTM 3. Presence of pain 4. Tissue damage always present, although minimal AGAINST (Meikle, 2006; Milne et al., 2009; Maclaine et al., 2010) 1. Cytokines also are synthesized under physiological conditions in connective tissue cells (i.e., fibroblasts, osteoblasts) 2. The redness, swelling and heat typical of inflamed tissues are ab- sent during OTM º 3. OTM has no effects on the systemic levels of C-reactive protein, TNF-0 and IL-6 Analyzing this evidence, it is reasonable to assume that an inflammatory process takes place upon the application of a force to the teeth and that this inflammatory process would be responsible for OTM. Inflammation, however, is not likely to be the only phenomenon leading to OTM; other non-inflammatory mechanisms also have been shown to contribute to tissue remodeling (e.g., osteocyte activation through bone bending or the mechanostat mechanisms). Interestingly, this inflammation might occur only at a sub- clinical (i.e., molecular) level and might be limited to the alveolar bone, with no systemic consequences (Maclaine et al., 2010). Future investiga- tions are warranted to cast further light on these aspects. SIDE EFFECTS OF OTM: PAIN AND ROOT RESORPTION Two common side effects of OTM are pain and root resorption. Although the clinical manifestations of these phenomena have been de- scribed extensively, several aspects relating to the molecular mechanisms behind them remain to be defined. 126 Perinetti et al. Painful sensations associated with OTM usually begin a few hours after the activation of an orthodontic appliance and can last up to one week (Jones, 1984; Kvam et al., 1987). As this pain leads to im- paired function, biting and chewing are reported to be sources of discom- fort during orthodontic treatment (Scheurer et al., 1996), making the management of this side effect a relevant aspect in clinical practice. This pain arises from stretching and distortion of the periodontal tissues (Ste- phenson, 1992), which is a secondary effect of the force, with the pain itself resulting mainly from the multiple molecular mediators that are re- leased locally (including PGs and substance P), through their binding to and activation of the nociceptors (Davies and MacIntyre, 1992; Har- graves et al., 1995). Other findings indicate that the nociceptive informa- tion triggered by OTM is transmitted to and modulated by several re- gions of the brain (Roberts et al., 2004). The ability to move teeth through bone is dependent on bone be- ing resorbed and the tooth roots remaining intact. From the tooth root side, the cementum does not undergo appreciable resorption. It appears to be excluded from the remodeling activities associated with the main- tenance of calcium homeostasis. However, the application of an ortho- dontic force sometimes can evoke excessive resorption of root cemen- tum, which then can proceed into the dentin. Previous evidence has shown that even with an applied force as low as 30 g, some degree of hyalinization and root resorption appears in- evitable (Reitan, 1951). The reasons for this root resorption appear to be related to the activation of the macrophagic and osteoclastic cells that are needed to resorb the hyaline zone and the bone, respectively. These cells release a series of proteolytic enzymes known as the metalloproteases (Takahashi et al., 2003), which also can have deleterious effects on the cementum and the tooth root. Thus, excessive root resorption is found in 3% to 5% of ortho- dontic patients (Roberts-Harry and Sandy, 2004). Some teeth are more susceptible than others; for instance, the upper lateral incisors that can lose 2 mm of root length during the course of fixed orthodontic treatment (Roberts-Harry and Sandy, 2004). The precise reasons why tooth roots generally are not resorbed is not known, although without this property, it would impossible to move teeth orthodontically. 127 Impact of Anti-inflammatory Drugs THE ANTI-INFLAMMATORIES AND THEIR EFFECTS ON TOOTH MOVEMENT The Arachidonic-acid Pathway and the Effects of Anti-inflammatory Drugs Among the molecular mechanisms governing OTM, the AA pathway is of primary importance (Khanapure et al., 2007; Fig. 5). AA is itself the main product of a phospholipase A2 enzymatic action on the cell-membrane phospholipids that is activated by several stimuli, includ- ing integrin activation via mechanical strain (Vandevska-Radunovic, 1999; Krishanan and Davidovitch, 2006). Subsequently, this arachidonic acid can be converted into a series of important intracellular messengers that then can trigger an inflammatory response. The key enzymes here are lipoxygenase, with the production of the leukotrienes and cyclooxygenase (COX), which produces PGs and further inflammatory mediators. COX has two catalytic sites, the first of which has the COX activity itself, which converts arachidonic acid into the endoperoxide prostaglandin G2 (PGG2). The second catalytic site has a peroxidase activity, which then converts the PGG2 into another endop- eroxide, PGH2. This PGH2 is processed further by specific prostacyclin synthase to form the other PGs (e.g., PGE2) and prostacyclin and throm- boxane A2. PGE2 and prostacyclin are the main inflammatory mediators. As a further complication, there are two distinct isoforms of COX, known as COX-1 and COX-2. COX-1 represents a constitutive isoform that has various physiological functions. Activation of COX-1 leads to the production of prostacyclin, which has an anti-thrombogenic activity when released by the vascular endothelium (Woo et al., 2005), while it is cytoprotective when released by the gastric mucosa (Gramke et al., 2006). In platelets, it is COX-1 that leads to thromboxane A2 pro- duction, causing aggregation of platelets to prevent inappropriate bleed- ing (Ong et al., 2005). In contrast, COX-2 is not expressed constitutively in tissues (with some exceptions); rather, it only appears in response to certain stimuli (as an inducible isoenzyme). Indeed, COX-2 is induced during inflammatory reactions, thereby mediating the synthesis of the PGs that are responsible for pain (Laudano et al., 2001). More recent evidence, however, has shown that COX-2 also is responsible for the main production of prostacyclin (Botting, 2005). COX-2 is upregulated when orthodontic forces are applied (de Carlos et al., 2006, 2007). Of interest, a further COX isoform, COX-3, recently has 128 Perinetti et al. Memºrane phospholipids Stimuli (chemical, physical, º PLA2 Corticosteroids inflammation) Arachidonic acid Lipoxygenase Tºrº, - - NSAIDs Cycloxygenases Leukotrienes - - Prostaglandin G2 | Prostaglandin H2 * Prostacyclin PGE, and others PGs Patelet aggregation (++) Platelet aggregation (-) Tissue inflammation vºnstan vºodºon Figure 5. The arachidonic acid cascade and the anti-inflammatories. PLA2 = phospholipase A2; NSAIDs = non-steroidal anti-inflammatory drugs; PGE2 prostaglandin E2; PGs = other prostaglandins. been reported to be expressed in the brain and in spinal cord tissues (Bot- ting and Ayoub, 2005). Non-steroidal Anti-inflammatory Drugs These groups of drugs are known as the non-steroidal anti- inflammatory drugs (NSAIDs) and are characterized by their blocking actions against the COX isoforms (Botting, 2005; Poveda Roda et al., 2007). NSAIDs are used widely in medicine; the main categories com- monly administered in dental practice are shown in Table 2. It should be noted that side effects of NSAIDs have been re- Ported, which include: gastrointestinal alterations (due to reduction of PGs synthesis), inhibition of platelet aggregation (due to reduction of thromboxane A, synthesis); and arterial hypertension and kidney toxicity (although only in patients with diminished kidney perfusion; Poveda Roda et al. 2007). With the discovery of COX-2, a search for their spe- cific drug inhibitors, the coxibs (Table 2) was initiated on the assumption that selective COX-2 inhibition would reduce the adverse gastric effects Caused by the other non-specific NSAIDs. 129 Impact of Anti-inflammatory Drugs Table 2. The main classification groups of non-steroidal anti-inflammatory drugs (modified from Bartzela et al., 2009). Group Subgroup Brand Names Salicylates Aspirin Aspirin, Acetal, Acetophen, Acetosal, Aspro Arylalkanoic Diflunisal Dolobid acids Voltaren, Voltarol, Diclon, Dicloflex, Diclofenac Difen, Difene, Cataflam, Pennsaid, Rhumalgan, Abitren Arylp ropion1c Indometacin Indocin, Indocid, Indochron acids Ibuprofen Nurofen, Advil, Brufen, Dorival, p Panafen, Ibumetin, Ibuprom Flurbiprofen ANSAID Naproxen Aleve, Anaprox, Naprogesic, Naprosyn, Naprelan Oxicams Piroxicam Feldene Meloxicam Movalis, Melox, Recoxa, Mobic Coxibs Celexocib Celebrex, Celebra Rofecoxib Vioxx (withdrawn), Ceoxx Valdecoxib Bextra Paracetamol tº-, - Tylenol, Gelocatil, Apiretal, Efferalgán However, serious cardiovascular complications have been asso- ciated with the COX-2 inhibitors including acute myocardial infarction, ischemic stroke or peripheral arterial disease. In the context of NSAIDs, a particularly well-known agent is paracetamol, also known as aceta- minophen or Tylenol (Anderson, 2008). Paracetamol is a commonly used analgesic with weak anti-inflammatory properties. Therefore, it should not be considered as a “genuine” NSAID, although the chemical structure of paracetamol is comparable with that of NSAIDs. Paracetamol also has almost no effects on blood clotting and no detrimental effects on the stomach lining. The lack of these side effects probably is related to the mode of action of paracetamol: while NSAIDs block COX-1 and/or COX-2, paracetamol is believed to block COX-3 (Botting, 2006). As COX-3 appears to be expressed only in the central 130 Perinetti et al. nervous system, a consequence of paracetamol is minimal effects on pe- ripheral PG synthesis (Botting, 2006). Corticosteroids The corticosteroids represent a second class of potent anti- inflammatory drugs. These are steroid hormones that are produced in the adrenal cortex. They are involved in many physiologic systems such as stress responses, inflammatory and immune responses, carbohydrate me- tabolism, protein catabolism and control of blood electrolyte levels (Chrousos and Kino, 2009). Osteoblasts and osteoclasts express a class of corticosteroid receptor – the glucocorticoid receptor – the expression of which is influenced by pro-inflammatory mediators such as IL-6 and IL-11 (Angeli et al., 2002). Corticosteroid administration can induce os- teoporosis (Silverman and Lane, 2009). The main anti-inflammatory mechanisms of action of the corti- costeroids arise from their indirect block of PLA2-mediated AA produc- tion. As indicated in Figure 5, this blockage leads to inhibition of the synthesis of PGs along with that of leukotrienes (Chrousos and Kino, 2009). These anti-inflammatories also show potent immunosuppressive actions due to their inhibition of ILs and interferon-Y synthesis. THE EFFECTS OF ANTI-INFLAMMATORY DRUGS ON PAIN, THE RATE OF ORTHODONTIC MOVEMENT AND ROOT RESORPTION Knowledge of the effects of the anti-inflammatories on both pain and the rate of OTM are of importance in clinical practice. Similarly, knowledge of the different uses and side effects of NSAIDs and the cor- ticosteroids is useful to the clinician. In orthodontics, NSAIDs (including paracetamol) can be administered to control OTM-associated pain. In contrast, the corticosteroids are prescribed for serious inflammatory and autoimmune conditions (i.e., rheumatoid arthritis, dermatitis, allergies and asthma) and also are used as immunosuppressive medications after organ transplantation. Therefore, the knowledge of the effects of these drugs on the rate of OTM is of importance, particularly in orthodontic patients who are under chronic corticosteroids treatment for specific sys- temic conditions. It also is useful to compare the effects of NSAIDs and corticosteroids on the rate of OTM, pain and root resorption. However, few such studies have been performed to date, and most of the available data of the effects on the rate of OTM and root resorption are derived from animal models (Table 3). 131 Impact of Anti-inflammatory Drugs Table 3. The main controlled animal studies on the effects of the anti- inflammatories on the rate of OTM and on root resorption. Stud Model Dru Administration in the Test Comparative º ; y g Groups Rate of OTM oo: Resorption NSAIDs Sandy and ol-1- . S 1 -kº i r r \ {i, 10 mg/kg/day for 3, 10 and 14 ... fºx, , t , , ... fºr , t , , Harris, 1984 Rabbit Flurbiprofen days Unaffected Unaffected Chumbley and Mongrel st , , , , , 5 mg/kg/dav for 21 davs * f | | | * * * * * * * * * * | * * * * * * * Tuncay, 1986 Cats Indometacin 5 mg/kg/day for 21 days Reduced Not evaluated Yº et al., Guinea pig Acetylsalicylic acid 100 mg/kg/day for 28 days Unaffected Not evaluated * et al., Rabbit Paracetamol 1 g/kg/day for 21 days Unaffected Not evaluated Zhou et al., - - * 1997 Rat Indometacin 4 mg/kg single dose Reduced Increased Arias and Marquez- Rat Acetylsalicylic acid 65 mg/kg/day for 10 days Reduced Not evaluated Orozco, 2006 Ibuprofen 30 mg/kg/day for 10 days Reduced Not evaluated º Paracetamol 200 mg/kg/day for 10 days Unaffected Not evaluated º et al., Rat Diclofenac 10 mg/kg for 2 injections Reduced Not evaluated Rofecoxib 1 mg/kg for 2 injections Reduced Not evaluated Hauber - Gameiro et al., Rat Celecoxib 10 mg/kg/day for 3 days Not evaluated Unaffected 2008a 10 mg/kg/day for 14 days Not evaluated Unaffected Hauber Gameiro et al., Rat Celecoxib 10 mg/kg/day for 3 days Reduced Not evaluated 2008b 10 mg/kg/day for 14 days Reduced Not evaluated º et al., Rat Acetylsalicylic acid 300 mg/kg/day for 2 weeks Unaffected Unaffected 60 mg/kg/day for 2 weeks Unaffected Unaffected Meloxicam 67 mg/kg/day for 2 weeks Unaffected Unaffected 13 mg/kg/day for 2 weeks Unaffected Unaffected Celecoxib 16 mg/kg/day 2 weeks Unaffected Unaffected 22 mg/kg/day 2 weeks Reduced Reduced Stabile et al., Rat Paracetamol 200 mg/kg, 4 times over 48 Unaffected Not evaluated 2009 hours Celecoxib 50 mg/kg, 4 times over 48 Unaffected Not evaluated hours • * > - Corticosteroids º et al., Rabbit Cortisone acetate 15 mg/kg/day for 4 days Increased Not evaluated .." al., Rat Prednisolone 1 mg/kg/day for 12 days Unaffected Reduced : et al., Rat Methylprednisolone 8 mg/kg/day for 7 weeks Increased Not evaluated 8 mg/kg/day for 3 weeks Reduced Not evaluated Verna et al., º Poorly 2006 | Rat | Methylprednisolone 8 mg/kg/day for 7 weeks Not evaluated affected 8 mg/kg/day for 3 weeks Not evaluated Increased ºles et al., | Rat | Prednisolone 0.67 mg/kg/day for 2 weeks Reduced Reduced 0.13 mg/kg/day for 2 weeks Unaffected Unaffected Reviews relating to the rate of OTM and to root resorption have been published previously (Tyrovola and Spyropoulos, 2001; Walker and Buring, 2001; Bartzela et al., 2009; Gonzales et al., 2009). The key stud- ies, along with their corresponding outcomes, are summarized in Tables 3 and 4. As can be seen from the present evidence, the effects of the anti- 132 Perinetti et al. Table 4. The main controlled human studies on the effects of various non- steroidal anti-inflammatory drugs on pain associated with OTM. Administration in the Test Study Drug Groups Effects on Pain (up to 4 times a day) Polat et al., Ibunrofen 400 mg. once pre-operative Naproxen sodium was more effec- 2005 p 8, pre-op tive than ibuprofen in controlling Naproxen sodium 550 mg, once pre-operative pain Ngan et al., Both ibuprofen and acetylsalicylic 1994 Ibuprofen 400 mg acid were effective in controlling Acetylsalicylic acid 650 mg pain, with the former more efficient Young et al., Valdecoxib 40 mg, once pre-operative Both Valdecoxib treatments were 2006 C. 4 and for 2 days , more effective in controlling pain as compared to the placebo treat- ment, although not statistically significant 40 mg, once post-operative and for 2 days Arantes et al., Tenoxicam 20 m Paracetamol was the only drug able 2009 8 to control pain (both Tenoxicam and paracetamol did not reduce the Paracetamol 750 mg rate of OTM) Minor et al., • Ibuprofen was effective in control- 2009 Ibuprofen 400 mg ling pain Salmassian et * Ibuprofen, paracetamol and pla- al., 2009 Ibuprofen 400 mg cebo were similarly effective in Paracetamol 600 mg controlling pain inflammatories on the outcomes examined here are not always com- pletely clear, with some contrasting results reported. While these dis- crepancies also are due to the differing protocols that have been used, an overview of the main controlled animal and human studies provides us with the following: 1. NSAIDs may reduce the rate of OTM depending on 2. the dosage, while the corticosteroids may increase it. NSAIDs for specific inhibition of COX-2 appear to reduce OTM at similar rates to those of other non- specific inhibitors. Paracetamol appears not to affect the rate of OTM. . All NSAIDs, including paracetamol, are effective in controlling the pain associated with OTM. 4. NSAIDs generally show no effects on the degree of root resorption, while more evidence is needed to de- fine the effects of corticosteroids on this side effect. CONCLUSIONS In this review, we have presented up-to-date evidence of the ef- fects of the anti-inflammatory drugs on various aspects related to OTM. 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The authors describe comparatively the effectiveness of several interceptive treatment approaches to PDC in order to avoid the unfavorable outcome of PIC. In particular, the extraction of the deciduous canine, alone or in combination with orthodontic forces aimed to prevent the physiological mesial movement of the upper permanent teeth posterior to the canine, appears to increase the eruption rate of PDCs by two to three times when compared to PDCs that remain untreated. These interventions are indicated in the late mixed dentition, during pre-pubertal or pubertal stages of skeletal development and before the apex of the displaced canine is formed completely. The extraction of the deciduous canine corresponding to the PDC in combination with a transpalatal arch (and rapid maxillary expansion in cases requiring expansion) can prevent canine impaction in over 80% of PDC cases. KEY WORDS: canine, impaction, palatal displacement, orthodontic treatment Intercept: To seize or halt something on the way from one place to another; to cut off from an intended destination. PALATAL DISPLACEMENT OF THE CANINE vs. PALATAL IMPACTION OF THE CANINE Natural history studies of the prevalence of impacted maxillary canine teeth have estimated that 0.2% to 2.3% of the orthodontic population have at least one impacted maxillary canine (Peck et al., 1994). In Caucasian populations, approximately 85% of maxillary canine impactions are orientated palatally (Hurme, 1949; Peck et al., 1994). 141 Interceptive Treatment Procedures Palatal maxillary canine impaction is thought to have a genetic etiology (Pirinen et al., 1996), yet the pathogenesis of palatal canine impaction is characterized by an early developmental stage that can be reversed with treatment. At this stage, the canine is considered to be a palatally displaced canine (PDC) when it presents with an intraosseous palatal displacement prior to the expected time of eruption. If left untreated, PDCs generally progress to impaction after the pubertal growth spurt and will require surgical intervention (Becker and Chaushu, 2000; Baccetti et al., 2005, 2008a). Recent studies reported prevalence rates for impaction of PDCs ranging from 75% to 85% (Baccetti et al., 2009; Sigler et al., 2010). Failure to recognize and treat maxillary canine displacement may result in root resorption of adjacent teeth (Buchner, 1936; Hoffmeister, 1985; Ericson and Kurol, 1987) and/or the formation of cysts (Ericson and Kurol, 1988; Alling et al., 1993; Hyomoto et al., 2003). Furthermore, patients with PDCs that progress to impaction will incur higher treatment costs, more complex treatment plans and delayed treatment timetables. Palatal impaction of the permanent maxillary canine (PIC), therefore, is the final outcome of a developmental anomaly that has been defined as palatal displacement of the canine (PDC). While in the past the expected time for canine eruption was correlated to chronologic age (12 years three months in females, 13 years one month in males; Hurme, 1949), attention has been given recently to the skeletal maturation of the patient. The permanent upper canine can erupt at any pre-pubertal or pubertal stage of skeletal development until CS5 in cervical vertebral maturation (CVM; Baccetti et al., 2008a; Figs. 1 and 2). Beyond this stage, which occurs on average one year after the end of the adolescent growth spurt, a PDC can be defined as a PIC. When the development of the dentition is used to determine the time of emergence of the maxillary permanent canine, delayed dental age is found in association with PDCs (Becker and Chaushu, 2000). The early diagnosis of dental abnormalities that share a common genetic origin with PDC and PIC can lead to the identification of risk indicators for PDC. The etiology of PDC, and subsequent PIC, is associated with a multi-factorial genetic complex that controls the expression of other, potentially concurrent, tooth anomalies (Bjerklin, 1992; Baccetti, 1993; Peck et al., 1994; Leifert and Jonas, 2003; Sacerdoti and Baccetti, 2004; Shalish et al., 2009). While the gene loci that dictate these anomalies are not yet known, Peck and colleagues (1994) have indicated multiple evidential categories for the genetic origin 142 (MMVAſ). D|D|D [...] [I]|| || D. D. D. D. [T][] . . CS 1 CS 2 CS 3 CS 4 CS 5 CS 6 Figure 1. Schematic representation of the CVM method. Stages CS1 and CS2 are pre-pubertal, the pubertal growth spurt occurs between stages CS3 and CS4, and stages CS5 and CS6 are post-pubertal. º º Figure 2. A. Panoramic radiograph of 12 year, four-month-old male. The permanent maxillary left canine is impacted. B: Diagnosis of impaction is corroborated by the presence of CS5 in the assessment of skeletal maturation by means of the CVM method. 143 Interceptive Treatment Procedures of PDC (i.e., familial occurrence, bilateral occurrence [17% to 45%], sex differences, differences in prevalence rates among different populations and increased occurrence of other concomitant dental anomalies). Table 1 reports the list of dental anomalies that present with a significant association with PDC and those that can be used as risk indicators for the eruption anomaly of the maxillary canine (Baccetti, 1998). Once a patient is diagnosed with PDC (in most instances during the late mixed dentition phase), interceptive measures can be implemented to avoid the final establishment of a PIC. These interceptive measures classically tend to facilitate eruption of the canine by acting on local/mechanical factors that may affect the evolution from PDC to PIC. ALTERNATIVE TREATMENT OPTIONS TO INTERCEPT PDCS As mentioned above, while the etiology of PDC (and subsequently to PIC) has been linked to a genetic component, the evolution from PDC to PIC can be affected by local/mechanical factors that have become the targets of “interceptive treatment” of PDC in order to prevent the final occurrence of PIC, as well as to allow the canine to erupt without surgical intervention. Extraction of the Deciduous Canine The procedure of reducing the prevalence of PDCs from becoming impacted by extracting the corresponding deciduous canine has been present in the dental literature for many years (Buchner, 1936). The outcomes in several individual cases during the subsequent 50 years have corroborated the clinical recommendation for this interceptive measure, as reviewed by Jacobs (1998). A prospective study by Ericson and Kurol (1988) analyzed the effects of the extraction of the deciduous canine on PDC in terms of rate and time of “spontaneous” eruption. A total of 36 out of 46 PDC canines (78%) presented with an improvement in the eruption pathway after removal of the deciduous canines, after a time interval of six to twelve months. In a longitudinal two-year investigation, Power and Short (1993) described the achievement of a normal eruptive position of PDC in 62% of patients following the extraction of the deciduous canines. It should be emphasized that both of these studies were conducted before the establishment of a genetic basis for PDC. Both studies 144 Baccetti and Sigler Table 1. Dental anomalies associated to PDCs as early risk indicators for the palatal displacement of the canine (the associated dental anomalies become clinically evident before PDC). Dental anomalies associated significantly with PDC • Small size of upper permanent incisors (unilateral or bilateral) • Aplasia of upper lateral incisors • Aplasia of second premolars • Infraocclusion of primary molars • Distal angulation of lower second premolars (before their eruption) • Enamel hypoplasia (upper central incisors and first permanent molars) Dental anomalies not associated significantly with PDC • Supernumerary teeth • Ectopic eruption of first permanent molars • Aplasia of third permanent molars calculated the prevalence rates of canine eruption by using the number of erupting individual teeth, which is not recommended due to the genetic etiology of the tooth developmental disorder. In fact, cases with bilateral PDCs should not count as two independent statistical units, because the same etiologic factors act on both sides of the maxillary arch. Therefore, when analyzing data pertaining to PDCs or PICs, it is recommended to use individual subjects and not individual teeth as statistical units in order to avoid “inflated” prevalence rates. Also, the prevalence rate for successful outcomes indicated by Ericson and Kurol (1988) included both PDCs that improved their pathway and PDCs that erupted. A study by Leonardi and associates (2004) failed to find extraction of the deciduous canine to be an effective treatment for PDC. The power of the Leonardi study was limited, however, as stated in a more recent investigation that was characterized by a randomized prospective approach to interceptive treatment of PDC with the incorporation of untreated controls and a statistically appropriate number of subjects (Baccetti et al., 2008b). In this recent investigation, the removal of the deciduous canine as an isolated measure to intercept 145 Interceptive Treatment Procedures palatal displacement of maxillary canines showed a 65% prevalence rate of success, which was significantly greater (almost double) than the success rate in untreated controls (36%). The prevalence rate of canine eruption here was calculated on individual subjects and eruption of the tooth was defined when a bracket could be placed on the crown of the canine. Interceptive Therapies Including the Use of Orthodontic/Orthopedic Devices: Randomized and Prospective Controlled Clinical Trials Two randomized clinical trials and one prospective controlled clinical study have evaluated the role of alternative interceptive approaches to PDC that consisted of either extraction of the deciduous canine in association with the use of a headgear appliance (Leonardi et al., 2004) or a rapid maxillary expander (RME: Baccetti et al., 2009, 2010; Sigler et al., 2010). The randomized clinical trial (RCT) by Baccetti and associates (2008b) evaluated the effectiveness of deciduous canine extraction in combination with the part-time use of a cervical pull headgear (patients wore the headgear only at night). The randomized prospective design of the investigation comprised of 75 subjects with PDCs (92 maxillary canines) who were assigned to three groups: 1. EG: extraction of the deciduous canine only; 2. EHG: extraction of the deciduous canine and cervical pull headgear; and 3. CG: untreated control group. Panoramic radiographs were evaluated at the time of initial observation (average age of 11.7 years) and 18 months later. An evaluation of the relative success of canine eruption was performed at the second time point, with a statistical comparison between the groups. A superimposition study on the serial lateral cephalograms evaluated the changes in the Sagittal position of the upper molars in the three groups. As mentioned before, the extraction of the deciduous canine as an isolated measure to intercept palatal displacement of maxillary canines showed 65% prevalence rate of success, which was significantly greater than the success rate in untreated controls (36%). The nighttime use of a headgear in addition to the extraction of the deciduous canine was able to induce successful eruption in 88% of the cases, with a significant improvement in the measures for intraosseous canine position. No 146 Baccetti and Sigler significant difference was noted between the two interceptive approaches regarding time for canine eruption. The cephalometric superimposition study showed a significant mesial movement of the upper first molars in CG and EG when compared with EHG. It appears, therefore, that the main effect of the headgear is to prevent the mesial movement of the posterior segments of the maxillary arch, thus facilitating the maintenance of an eruption pathway for the canine. It should be remembered that a non-randomized retrospective study by Olive (2002) previously had reported the significantly favorable effects of a clinical protocol including the extraction of the deciduous canine followed by fixed appliance therapy to increase the maxillary arch perimeter. A second prospective randomized clinical study (Baccetti et al., 2009) assessed the prevalence rate of eruption of PDCs when diagnosed at an early developmental stage by means of posteroanterior headfilms and consequently treated by RME. A sample of 60 subjects in the early mixed dentition with PDC diagnosed on PA radiographs according to the method by Sambataro and coworkers (2005) was enrolled in the trial. The age range of the subjects at first observation was 7.6 to 9.6 years, with a pre-pubertal stage of skeletal maturity (cervical stage CS1 or CS2). The diagnosis of PDC was performed on posteroanterior cephalograms as the assessment of PDC on panoramic films is not reliable at these early ages. The 60 subjects were allocated randomly to the treatment group (TG; 35 cases) or the no-treatment group (NTG; 25 cases). The TG was treated with a banded RME; at the end of expansion all patients were retained with the expander in place for six months; thereafter, the expander was removed and patients wore a retention plate at night for one year. The NTG did not receive any treatment. At the second observation (early permanent dentition, post-pubertal, CS5) all cases were re-evaluated. No statistically significant differences were found for any variable at the initial observation. It should be noted that subjects with PDCs in the early mixed dentition did not exhibit transverse deficiency of the maxillary arch. Therefore, the transverse features of the maxilla were not related to the etiology of the eruption disorder of the canine, as indicated already by Langberg and Peck (2000). In fact, the indication for RME in the cases enrolled in the clinical study was the presence of mild-to-moderate tooth-size/arch-size discrepancy and/or Class II or Class III tendency and not a transverse maxillary deficiency. 147 Interceptive Treatment Procedures RME assisted in preventing final impaction of PDC during the developmental stages from PDC to PIC. Once again, while a genetic etiology has been postulated for initial palatal displacement of maxillary canines, the pathogenesis of the displacement and of final impaction is related especially to the anatomical complexity of the eruption pathway of this tooth (Peck et al., 1996) that can be affected by environmental alterations. The prevalence rate of successful eruption of the maxillary canines was 66% in the group treated with RME, while it was only 14% in the untreated control group. The comparison obviously was significant statistically and led to the conclusion that the use of a rapid maxillary expander as an early interceptive approach is an effective procedure to increase the rate of eruption of PDCs. The low prevalence rate for spontaneous eruption of canines in the controls is due to methodological aspects of the study, which included subjects not only with a PDC diagnosis, but also with a prognosis of PIC as derived by the analysis of PA films according to the method by Sambataro and colleagues (2005). Finally, a prospective controlled clinical trial was aimed to investigate the effect of RME and transpalatal arch (TPA) therapy in combination with deciduous canine extraction on the eruption rate of PDCs in late mixed dentition patients by means of a two-center prospective study. Seventy subjects were enrolled based on PDCs diagnosed on panoramic radiographs (Sigler et al., 2010). The treatment group (TG; 40 subjects) underwent RME followed by TPA therapy plus extraction of deciduous canines. The control group (CG; 30 subjects) received no orthodontic treatment. At the second observation (CVM stage CS5 or CS6), all cases were re-evaluated and the eruption of the permanent maxillary canines was assessed. Initially, panoramic radiographs and dental casts were compared between the TG and CG by means of the Mann-Whitney U test (P - 0.05). The prevalence rates of successful cases in the TG were compared with those in the CG by means of chi-squared tests (P º 0.05). The association of PDCs with other dental anomalies was evaluated. The results showed that no statistically significant difference initially was found for any measurement between the two groups. The prevalence rate of eruption of the maxillary canines was 80% for the TG vs. 28% in the CG, a statistically significant difference (chi^ = 1626, P × 0.001). The prevalence rate initially for pubertal stages of CVM (63%) was greater significantly in unsuccessfully treated cases than in successfully treated cases (16%). 148 Baccetti and Sigler In the controls, all successful cases presented PDCs that overlapped the corresponding deciduous canine or the distal aspect of the lateral incisor. Eruption of PDCs in both the TG and the CG was associated significantly with the presence of an open root apex. The conclusions of the study were that RME therapy followed by a TPA combined with extraction of the deciduous canine is effective in treating late mixed dentition PDC patients. Predictive pre-treatment variables for the success of treatment on the eruption of PDCs were less severe sectors of displacement, pre-pubertal stages of skeletal maturity and an open root apex of PDCs. Several dental anomalies were associated significantly with PDCs, thus confirming the genetic etiology of this eruption disturbance. The comparison of the prevalence rate for successful outcomes of the early use of RME as an interceptive procedure in PDC subjects in the early mixed dentition with those reported by previous studies on alternative treatment approaches to potentially impacted canines reveals that RME treatment shows a rate of effectiveness (66%) similar to the one described for extraction of the deciduous canines alone (78%) according to Ericson and Kurol (1988), including improvement of eruption path (62%) according to Power and Short (1993), 65% according to Baccetti and colleagues (2008b) or in combination with fixed appliances (75%) according to Olive (2002). The prevalence rate for the early use of RME, however, was smaller than the prevalence rate for eruption of the canines following the night-time use of a cervical-pull headgear (88%) according to Baccetti and coworkers (2005) or the use of RME and TPA therapy in the late mixed dentition (80%). Recent unpublished data suggest that the use of a TPA in combination with the extraction of the deciduous canine may provide similar results (79% canine eruption) in patients who do not require maxillary expansion (Baccetti et al., 2010; Table 2). Clinical Considerations and Critical Approach Several considerations should be mentioned when evaluating the outcomes of the alternative interceptive treatment approaches to PDCs. The extraction of the deciduous canine alone, though less effective than the same procedure in combination with headgear or RME appliances, requires also a significantly smaller “burden of treatment” for the patient. The same can be said for the use of a TPA in conjunction with the extraction of the deciduous canine. Also, the extraction of the deciduous canine alone presents with same effectiveness in preventing PIC than RME 149 Interceptive Treatment Procedures Table 2. Comparative tabulation of the outcomes of studies on interceptive treatment of PDCs. PREVALENCE PREVALENCE RATE OF RATE OF SUCCESSFUL SUCCESSFUL CAN INF CANINE ERUPTION IN AGE AT TIME OF ERUPTION IN UNTREATED INTERCEPTIVE INTERCEPTIVE TREATED CONTROL STUDY TREATMENT TREATMENT SUBJECTS SUBJECTS 78% e e * * {~ ājň - -- *"..." | Extraction of º deciduous canine 10 to 13 years prove No controls Kurol, alone eruption pathway; 1988 % calculated on # of teeth) Power & Extraction of 62% (eruption; % Short, deciduous canine 11.2 + 1.43 years calculated on # of No controls 1993 alone teeth) g Extraction of 75% (eruption; % Olive, deciduous canine + * - | 1.4 to 16.1 years calculated on # of No controls 2002 fixed appliances to & s teeth) gain arch perimeter Baccetti Extraction of 65.2% (eruption; % et al., deciduous canine 11.7 ± 0.8 years calculated on # of 36% 2008b alone subjects) Extraction of Baccetti deciduous canine + 87.5% (eruption; et al., headgear on 11.9 + 0.9 years percentage calculated 36% 2008b maxillary molars on # of subjects) (at night) Baccetti Rapid maxillar 65.7% (eruption; % 13.6% (severe PDCs et al., º: ansion y 7 to 9 years calculated on # of with prediction of 2009 p subjects) impaction) & Rapid maxillary 0 * r * - 0 Sigler expansion + TPA 10.6+ 0.9 years 80% (eruption; % O et al., e s * , e. calculated on # of 28% +/- extraction of (late mixed dentition) g 2010 - - subjects) deciduous canine & 0 e • 0 Baccetti TPA + extraction of 10/8 + 0.9 years 79% (eruption; % 0 et al., & e e - - - calculated on # of 28% deciduous canine (late mixed dentition) e 2010 subjects) therapy performed in the early mixed dentition (when the diagnosis of PDC is less reliable). Obviously, patients showing an indication for the use of orthodontic forces to distalize maxillary molars (Class II or end- to-end patients, or patients with a tendency to crowding of the upper arch) will benefit from the combined treatment (extraction of the deciduous canine and headgear) both in terms of correction of their malocclusions and of improvement in the probability of canine eruption. Further, when tested at an early developmental age (e.g., seven to nine years), the RME approach resulted in less favorable results than when used in the late mixed dentition. This dentitional stage in combination 150 Baccetti and Sigler with a pre-pubertal stage of skeletal maturation and an open apex of the PDC appears to be the most effective time to perform either of these interceptive treatments. Moreover, before 10 years of age (in the early mixed dentition), the diagnosis of PDC on PA films can be carried out effectively only in cases with severe displacement of the canine toward the midfacial structures, while PDCs can be diagnosed more accurately in the late mixed dentition. CONCLUSION Palatal displacement of the canine (PDC) is the developmental antecedent of palatal impaction of the canine (PIC). Skeletal maturation (by means of the CVM method) can assist in the determination of the evolution from PDC to PIC: the canine is impacted when it is still in an intraosseous position at CS5 or beyond this stage (two or more years after the adolescent growth spurt). If not intercepted with early treatment modalities, PDCs become PICS in two out of three cases. Different interceptive approaches to PDCs are able to promote eruption of the displaced canine with a success rate that ranges from two to three times the rate shown by untreated controls, as assessed in several evidence-based literature reports. Interceptive treatment of PDC to avoid PIC, therefore, is recommended clinically. The extraction of the deciduous canine corresponding to the PDC in combination with simple devices to avoid mesialization of the posterior teeth (like a TPA) avoids canine impaction in about 80% of PDC cases. A similar favorable outcome can be reached with the addition of RME in subjects requiring maxillary expansion. All these interventions are indicated in the late mixed dentition, before CS4, and before the apex of the displaced canine is completely formed. REFERENCES Alling CC, Helfrick JF, Alling RD. Impacted maxillary teeth. In: Impacted Teeth. Philadelphia: WB Saunders 1993:247-269. Baccetti T. A controlled study of associated dental anomalies. 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Am J Orthod Dentofacial Orthop 2009:136:657-661. Baccetti T, Sigler LM, Masucci C, McNamara JA Jr. A RCT on treatment of palatally-displaced canines with RME and/or a transpalatal arch. Eur J. Orthod 2010:in press. Becker A, Chaushu S. Dental age in maxillary canine ectopia. Am J Orthod Dentofacial Orthop 2000;1 17:657-662. Bjerklin K, Kurol J, Valentin J. Ectopic eruption of maxillary first permanent molars and association with other tooth and developmental disturbances. Eur J Orthod 1992; 14:369-375. Buchner H.J. Root resorption caused by ectopic eruption of maxillary cuspid. Int J Orthod 1936:22:1236-1237. Ericson S, Kurol J. Early treatment of palatally erupting maxillary canines by extraction of the primary canines. Eur J Orthod 1988; 10. 283–295. Ericson S, Kurol J. Radiographic examination of ectopically erupting maxillary canines. Am J Orthod Dentofacial Orthop 1987;91:483- 492. Ericson S, Kurol J. Resorption of maxillary lateral incisors caused by ectopic eruption of the canines: A clinical and radiographic analysis of predisposing factors. Am J Orthod Dentofacial Orthop 1988;94: 503–513. Hoffmeister H. Undermining resorption of the 2nd deciduous molar by the permanent molars as a microsymptom of hereditary dentition disorders. [In German.] Schweiz Mschr Zahnmed 1985;G5:151-154. 152 Baccetti and Sigler Hurme V. Range of normalcy in the eruption of permanent teeth. J Dent Child 1949; 16:11-15. Hyomoto M, Kawakami M, Inoue M, Kirita T. Clinical conditions for eruption of maxillary canines and mandibular premolars associated with dentigerous cysts. Am J Orthod Dentofacial Orthop 2003; 124: 515–520. Jacobs SG. Reducing the incidence of unerupted palatally displaced canines by extraction of primary canines: The history and application of this procedure with some case reports. Austr Dent J 1998:43:20-27. Langberg BJ, Peck S. 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An investigation into the response of palatally displaced canines to the removal of primary canines and an assessment of factors contributing to favourable eruption. Brit J Orthod 1993:20:215-223. Sacerdoti R, Baccetti T. Dentoskeletal features associated with unilateral or bilateral palatal displacement of maxillary canines. Angle Orthod 2004;74:725-732. Sambataro S, Baccetti T, Franchi L, Antonini F. Early predictive variables for upper canine impaction as derived from posteroanterior cephalograms. Angle Orthod 2005;75:28-34. 153 Interceptive Treatment Procedures Shalish M, Chaushu S, Wasserstein A. Malposition of unerupted mandibular second premolar in children with palatally displaced canines. Angle Orthod 2009;79:796-799. Sigler LM, Baccetti T, McNamara JA Jr. Effect of RME/TPA treatment associated with deciduous canine extraction on the eruption of palatally-displaced canines: A two-center prospective study. Am J Orthod Dentofacial Orthop 2010:in press. 154 FACTORS BEYOND THE CONTROL OF THE CLINICIAN: UNDERSTANDING THE GENETICS UNDERLYING ORTHODONTIC TREATMENT James K. Hartsfield Jr. ABSTRACT The interface of genetics and orthodontics has focused primarily on two main areas: 1) the understanding and treatment of craniofacial anomalies; and 2) the prediction of growth and putative limitations of stable treatment in the remain- ing majority of patients. Research on the influence of genetics on developmental variation relevant to standard orthodontic treatment previously has been inferred from familial correlations and heritability studies. Unfortunately, these types of studies are inadequate and inappropriate, respectively, to be of significant use in every day clinical practice. The greatest contribution of genetics to the practice of orthodontics ulti- mately may be a better understanding and accounting for individual growth and development as well as variable responses to treatment. If the component of Variation associated with genetic differences could be accounted for, then the effect of environmental (treatment) factors and the effect of their interaction with genetic factors could be determined more precisely. Studies of linkage or association of specific DNA polymorphisms with the trait in multiple families and/or in large population samples are needed not only to demonstrate a genetic influence, but also to determine ultimately what those genetic influences are and how they interact with environmental factors. It is time for large clinical studies of individuals undergoing orthodontic treatment using modern genotyping techniques to determine definitively which specific genetic factors influence growth, development and the response to treatment, so as to understand better the etiology and treatment prognosis for malocclusion. KEY WORDS: orthodontics, genetics, facial growth, malocclusion, root resorp- tion, heritability Future orthodontic practice may include scenarios such as the following. Your first patient of the day presents for an initial evaluation. The case is Class I with “borderline” crowding and good positioning of incisors. Evaluation of polymorphic variations in the major and modify- 155 Understanding Genetics ing susceptibility for external apical root resorption genes indicates that this patient has a relatively high risk of this type of root resorption. Be- cause you recognize that tooth extraction will involve significantly greater tooth movement and a longer anticipated time in fixed appliances (risk factors for orthodontics-associated root resorption), you use the ge- netic diagnostic data to decide upon a treatment plan. Your next patient, a seven-year-old, comes in with a negative an- terior overjet. Cephalometric analysis indicates a relative retrusion of the maxilla involving certain anatomical structures. Evaluation of the poly- morphic variations of the major and modifying Class III malocclusion genes, your examination and radiographic evaluation indicate a diagnosis of “Class III malocclusion, type 3.” Based on this subclassification, you know what type of treatment provided at what stage of development will result in the greatest likelihood of success. Your next young patient comes in with a Class II malocclusion. Cephalometric analysis indicates a relatively retruded mandible. Know- ing that although Class II early treatment studies were equivocal about the average benefit of functional appliances, or headgear treatment ver- sus non-treated control patients, you also know that there was notable variation in growth among all three of the experimental groups in those studies. Now you evaluate the polymorphic variations of the major and modifying genes to see if this patient might be one who likely will expe- rience “catch-up” mandibular growth without treatment, or perhaps one who would respond more with a functional appliance. You use this diag- nostic information to devise your treatment plan for the patient on an evidence-based foundation. You review the screening genetic variants report on your next new patient before starting your initial exam to see if s/he may be more likely than most people to be particularly responsive to painful stimuli or to develop neurogenic pain. If so, you explain this to the patient and fac- tor the information into your assessment and treatment plan. Your next patient has hypodontia, prompting a question about family members who might be affected and/or if there is a history of cancer, especially of the colon or ovaries. If the family history is positive for the co-occurrence of hypodontia and cancer, you refer the family to a medical clinic for evaluation and genetic counseling (Hartsfield, 2011). What is the current status of research that could lead to this type of future practice? What needs to be understood before this type of data can be a part of everyday care? Even as progress is made, care must be 156 Hartsfield taken to manage the expectations of practitioners and the public set by promises, press release hyperbole and the repeated exposure to headlines about genetic discoveries in general (Roses, 2001). GENETICS AND ORTHODONTICS HISTORICALLY The “rediscovery” of Mendel’s laws of inheritance in the early 20th century led to the mistaken belief that development and behavior were controlled by genetic factors and that abnormalities in development or behavior could be eliminated from the population through the practice of eugenics. Gradually the fallacy of this line of thought was realized, particularly when the environmental teratogenic (i.e., increasing the inci- dence of birth defects) potential of rubella and thalidomide was recog- nized. Increases in malocclusion when populations move to another area and/or mix with other populations more likely are due to changes in environmental rather than to genetic factors (Corruccini, 1984). The ge- netic background of the individual, however, can influence the response to environmental factors, particularly those that are more likely to de- lineate different individual responses. This observation is supported by the finding that the differences in shape of the mandibular condyles was “slightly greater” among four different inbred strains of mice on a hard diet than on a soft diet for six weeks. When the environment changed sufficiently, the response was different among animals with different genotypes that were not different before the environmental change (Lav- elle, 1983). In response to the presumption of the genome being the prede- termining force for facial development and by inference skeletal maloc- clusion, the Functional Matrix Hypothesis by Moss (1997a) theorized the primary role of function in craniofacial growth and development. Still, Moss did conclude that both genomic and environmental/epigenetic fac- tors are necessary causes, that neither alone is a sufficient cause and that only the two interacting together furnish both the necessary and suffi- cient cause(s) of growth and development (Moss, 1997b). Experimentally, Petrovic and colleagues (1986) demonstrated that mandibular condylar growth is adaptive highly and responsive to extrinsic systemic factors and to local biomechanical and functional fac- tors (Carlson, 2005). The next step after investigations as those of Moss and Petrovic is to study how individuals respond differently to extrinsic systemic factors and local biomechanical and functional factors, and to 157 Understanding Genetics determine how this inter-individual response variation corresponds to genetic variation. The interface of genetics and orthodontics has been in two areas: 1. The understanding and treatment of craniofacial anomalies; and 2. The prediction of growth and putative limitations of stable treatment in the remaining majority of patients. Basic to both was the admonishment attributed to Angle (1907) that, “In studying a case of malocclusion give no thought to methods of treatment or appliances until the case shall have been classified and all peculiarities and variations from the normal in type, occlusion, and facial lines have been thoroughly comprehended. Then the requirements and proper plan of treatment becomes apparent.” Focusing on the latter area, the influ- ence of genetics on developmental variation up to now has been inferred from familial correlations and heritability studies. Unfortunately, these are inadequate and inappropriate, respectively, to be of significant use in clinical orthodontic practice. FAMILIAL CORRELATIONS Harris and associates (1975) showed that the craniofacial skeletal patterns of children with Class II malocclusions are heritable and have a high resemblance to the skeletal patterns of their siblings with normal occlusion. From this research, it was concluded that the genetic basis for the resemblance likely is polygenic. Family skeletal patterns thus were used as predictors for the treatment prognosis of the child with a Class II malocclusion, although it was acknowledged that the current morphology of the patient is the primary source of information about future growth (Harris and Kowalski, 1976). Siblings often have been noted to show similar types of maloc- clusion. Examination of parents and older siblings has been suggested as a way to gain information regarding the treatment need for a child, in- cluding early treatment of malocclusion (Litton et al., 1970; Niswander, 1975; Harris and Kowalski, 1976; Saunders et al., 1980). Niswander (1975) noted that the frequency of malocclusion is decreased among sib- lings of index cases with normal occlusion, whereas the siblings of index cases with malocclusion tend to have the same type of malocclusion more often. 158 Hartsfield Each child receives half of his/her genes from each parent, but not the same combination of genes as a sibling, unless the children are monozygotic twins. When looking at parents with differing skeletal and/or occlusal morphologies, knowing the combinatorial influence of the parental developmental genes from each parent present in the child is difficult until the child’s phenotype matures under the continuing influence of environmental factors. The highest phenotypic correlation that can be expected for polygenic traits based on genes in common by inheritance from one parent to a child, or between siblings, is 0.5 (Hunter, 1990). Because the child’s phenotype likely is to be influenced by the interaction of genes from both parents, the “mid-parent” value may increase the correlation with their children to 0.7 because of the regression to the mean of parental dimensions in their children. Squaring the correlation between two variables derives the amount of variation predicted for one variable in correlation with the other variable. Therefore, at best, using mid-parent values (0.7), only 49% of the variability of any facial dimension in an adult offspring can be predicted by consideration of the average of the same dimension in the parents. Because environmental factors interact with genetic factors to a varying degree, the usual correlation for facial dimensions between parents and their offspring is about 30%, yielding even less predictive power (Hunter, 1990). Only 25% of the variability of a facial dimension in an adult offspring can be predicted by considering the same dimension in one sibling or in one parent. Family patterns of resemblance frequently seem obvious, but predictions must be made cautiously because of the multiple genetic and environmental variables, and their interaction, which are unknown and difficult to evaluate (Hartsfield and Bixler, 2010). HERITABILITY ESTIMATES There exists in our profession a common misperception that knowing a trait’s heritability can guide how a patient should be treated (e.g., for malocclusion), that maybe knowing the heritability will guide us among treatment options or that it will define the limits of tooth movement or the manipulation of jaw growth. Nothing could be farther from the truth. The ability of the patient to respond to changes in the en- Vironment (including treatment), which has nothing to do with heritabil- ity, will define these limits. Heritability estimates, in fact, imply nothing about trait size or treatment limits based upon some presumed genetic “predetermination” (Harris, 2008). Still, the estimation of heritability can 159 Understanding Genetics provide an indication of the relative importance of genetic factors for a trait under a specific circumstance. Confirming that there is a certain de- gree of genetic influence on a trait is a preliminary step to performing further specific genetic linkage studies (using DNA markers), to deter- mine areas of the genome that appear to be associated with the character- istics of a given trait (LaBuda et al., 1993). Unfortunately the results of estimation of heritability studies on the genetic and environmental factors that influence the development of malocclusion are representative of the samples studied, not necessarily of any particular individual. In addition, the extent that a particular trait is influenced by genetic factors may have little, if any, effect on the success of environmental (treatment) intervention. Still, it may be that genetic factors that influenced a trait also will influence the response to intervention to alter that trait, or other genetic factors may be involved in the response. Therefore, the possibility of altering the environment to gain a more favorable occlusion theoretically exists even in individuals in whom the malocclusion does have a high estimation of heritability. However, the question of how environmental and genetic factors interact is most relevant to clinical practice because it may explain why a particular alteration of the environment (treatment) may be successful in one patient and not in another (Hartsfield, 2002). In summary, we are interested in knowing if there are genetic factors that will affect or limit the results of our treatments. These are defined most clearly for those traits whose genetic influence exhibits a clear pattern of Mendelian (autosomal or X-linked dominant or recessive) inheritance. These patterns of inheritance (not to be confused with the previously mentioned estimates of heritability) are secondary to the primary effect of single genes, or more accurately, the effect of the variations of the gene at the same chromosomal location (locus). However, most traits, including almost all of the developmental variation we deal with clinically, do not follow a Mendelian pattern of inheritance. Instead, they are the result of some combination of multiple genetic and envrionmental factors that now commonly is referred to as complex inheritance. For these complex traits, we do not have sufficient information to make accurate predictions about the development of facial morphology or occlusion simply by studying its correlation, the frequency of its occurrence or the estimation of heritability in family members. 160 Hartsfield PERSONALIZED ORTHODONTICS Personalized medicine refers to the realization and practice that individual variation in normal traits, development, disease or response to treatments can be influenced by individual genetic variants. This concept has been applied to oral-facial growth, oral-facial development and the response to orthodontic treatment, and is referred to as “Personalized Orthodontics.” The understanding of the combination and interaction of genetic and environmental (including treatment) factors that influence oral-facial growth and development, and the treatment response of our patients is fundamental to the evidence-based practice of orthodontics (Hartsfield, 2008a,b). The completion of the Human Genome Project almost ten years ago pointed out the genomic areas of variation present in humans (Lander et al., 2001). Investigating the ethnic geographic distribution of these areas of DNA variation in the HapMap project has increased the knowledge of DNA markers that may be used in genetic studies either to link or associate genetic markers with particular traits (International HapMap Consortium, 2005). The differences between genetic linkage and association studies are reviewed elsewhere (Abass and Hartsfield, 2008), but for our purpose, both of their outcomes help to explain how specific individual genetic variation, not the general sharing of half or fewer of one’s genes as used in heritability estimations, may be used to understand better the affect of genetic factors on specific traits. GENETIC FACTORS The genome contains the entire genetic content of a set of chro- mosomes present within a cell or an organism. On the chromosomes are genes comprised of specific DNA sequences that represent the Smallest physical and functional units of inheritance. Each gene resides at a spe- cific site or locus in the genome. A gene can be defined as the entire DNA sequence necessary for the synthesis of a functional polypeptide (production of a protein via messenger RNA or an mRNA intermediate) or RNA (transfer or ribosomal RNA) molecule (Everett and Hartsfield, 2000). Genotype generally refers to the set of genes that an individual carries and, in particular, refers to the particular pair of alleles (alterna- tive forms of a particular gene) that a person has at a given region of the genome (Baltimore, 2001). 161 Understanding Genetics The genetic background (genome) and environmental (non- genetic) factors are the two main aspects that determine phenotype. Al- though there long has been a tendency to separate these two influences (nature versus nurture), for essentially all traits and disorders (besides those secondary to trauma), genetic and environmental factors interact to develop the phenotype (nature and nurture; Hartsfield, 2002). Traits (dis- eases) can be divided into two broad categories based on their genetic components’ pattern of transmission. The first category is the simple or Mendelian traits that generally follow the two laws of heredity: the law of segregation and the law of independent assortment originally identified by Mendel in the middle of the 19" century. These traits have a “simple” pattern of inheritance (autosomal dominant, autosomal recessive or X-linked) and in most of the cases they result from a mutation of a single gene (Abass and Harts- field, 2008). A relationship between a particular genotype and a phenotype is relatively easy to establish in Mendelian traits or diseases because a sin- gle gene mutation usually results in a recognizable phenotype. Environ- mental factors and other genes may modify the clinical expression of the disease (Chanock and Wacholder, 2002), but are not of crucial impor- tance for disease development (Fig. 1). Still, even in traits that have auto- somal dominant inheritance, there are other factors that result in pheno- typic variation. When a person with a given genotype fails to demon- strate any aspect of the phenotype characteristic for the genotype, the gene is said to show reduced penetrance, or in lay terms, skip a genera- tion. In contrast, if a single gene trait can show variable phenotypes among those affected, it is said to show variable expressivity (Abass and Hartsfield, 2008). The second category includes genetically complex disease. These traits are more common than Mendelian traits. They do not follow a clear pattern of inheritance, although they do tend to run in families. Relatives of an affected individual or one who has the trait have an in- creased risk of developing the disease or having the trait. The genetic determinants of such traits are difficult to identify because the trait or disease results from a set of genetic variations (polymorphisms) that may be common within the population, both affected and non-affected. The interplay of these polymorphisms in different genes with environmental factors leads to the manifestation of such complex traits. Unlike Men- delian traits, environmental factors and multiple genes are critical to the development of such complex traits (Fig. 2; Abass and Hartsfield, 2008). 162 Hartsfield Mendelian (Monogenic) Traits Gene Environment ....... • vs. Modifying Gene(s) Factors - - - - " * > J . - Protein * ~ J ... Protein(s) a p _----' Phenotype * Figure 1. Mendelian (monogenic) traits or diseases result because a single gene polymorphism or mutation usually results in a recognizable phenotype. Envi- ronmental factors and other genes may modify the clinical expression of the disease or other type of trait, but are not of crucial importance for its develop- ment. Complex (Polygenic) Traits Gene 1 Gene 2 Gene 3 Gene 4 Environmental Ö. EF , EF , EF , – >< |Sº Protein 1 Protein 2 Protein 3 Protein 4 lºgº __NEFNFF/FF, Phenotype Figure 2. Unlike Mendelian traits, environmental factors and multiple genes are critical to the development of complex (polygenic) traits. The Human Genome Project resulted not only in definition of a single human genome sequence composed of overlapping parts from many humans, but also in an expanding catalogue of over one million sites of variation in the human genome sequence as further investigated in the before-mentioned HapMap project. These variations (or polymor- phisms) may be used as markers to perform genetic analysis (including 163 Understanding Genetics analysis of genetic-environmental interaction) in human beings (Pem- berton et al., 2006). The genome varies from one individual to the next, most often in terms of single base changes of the DNA, called single nu- cleotide polymorphisms (SNPs, pronounced “snips”). The main use of this human SNP map will be to determine the contributions of genes to diseases (or non-disease phenotypes) that have a complex basis (Chakravarti, 2001). Another type of marker referred to as short tandem repeats (STRs or “microsatellites”) also may be used in family genetic linkage studies. Although they are not as common as SNPs, because they potentially have more than two forms, they can be more informative statistically (Payseur et al., 2008). The type of marker used depends on the type of genetic study. CLASS III MALOCCLUSION The futility of expecting genetic factors to explain growth and development precisely can be highlighted by what is meant by the terms variable expressivity and incomplete penetrance. These concepts typi- cally are applied to phenotypes (traits or syndromes) that have an auto- somal dominant mode of inheritance. Although the name includes the word dominant, implying it supersedes the effect of all other factors, this is not always the case. Simplistically it may be expected that if someone has the genetic mutation for the phenotype, then s/he will show the phe- notype in the same manner or extent as someone else with the same mu- tation. If in this group of individuals, the manner or extent of the pheno- type varies but is observable, then the phenotype has variable expressiv- ity. If there are individuals with the same mutation who show no indica- tion of having the phenotype, then it is incomplete penetrance, the same as when a trait or syndrome is said to skip a generation (Everett et al., 1999). Both of these concepts are seen in Class III malocclusion and this complicates not only its treatment, but also the investigation of its genetic origins. As every orthodontist knows, not everyone in a family with segregating Class III malocclusion necessarily is affected to the same degree; sometimes Class III malocclusion exhibits incomplete penetrance in that it skips a generation or more in some families (Cruz et al., 2008). Thus, even if genetic testing indicated that an individual will develop a Class III malocclusion, there still could be variation in the se- verity of the malocclusion and possibly, but not likely, the malocclusion would not occur at all. Even for traits with an autosomal dominant mode of inheritance, genetic testing may be able to tell us the likelihood that 164 Hartsfield Something will happen qualitatively, but with the quantitative detail that we would like to know clinically. Class III malocclusion morphology is heterogeneous (i.e., the mandible or maxilla is affected, or both), with varying incidence among different ethnic groups and various underlying facial patterns that may result as a composite in the condition (Singh, 1999: Bui et al., 2006). There is a strong heritable component in Class III malocclusion in general, with modes of inheritance being reported to be polygenic (Litton et al., 1970), autosomal dominant in a Libyan sample (El-Gheriani et al., 2003) and autosomal dominant with incomplete penetrance with a multifactorial component in a Brazilian sample (Cruz et al., 2008). With the variation seen in Class III malocclusion morphology, it is not surprising that it also appears to have genetic heterogeneity. The Variation in ethinic incidence may reflect different genes involved in these groups as indicated by the finding of linkage to chromosomes |p36, 6q25 and 19p 13.2 in Korean and Japanese patients primarily with mandibular prognathism (Yamaguchi et al., 2005), to 1p22.1, 3426.2, 11q22, 12q13.13 and 12q23 in Colombian patients primarily with maxillary hypoplasia (Frazier-Bowers et al., 2009a) and to chromosome 7p21.3 in Colombian and Brazilian patients primarily with mandibular prognathism (Falcão-Alencar et al., 2010). HYPODONTIA Hypodontia may occur without a family history of hypodontia, although often it is familial. Hypodontia also may occur as part of a syndrome, especially in one of the many types of ectodermal dysplasia, although it usually occurs alone (isolated). Note that “isolated” in this use of the word means not a part of a syndrome, although it still has a familial pattern of inheritance. Genetic factors are believed to play a major role in most hypodontia cases; with autosomal dominant, autosomal recessive, X-linked and multifactorial inheritance patterns of transmittion reported (Mostowska et al., 2003). Still, only a few genes (MSX1, PAX9 and AXIN2) so far have been found to be involved in Some families with non-syndromic autosomal dominant hypodontia. In that there are families with non-syndromic hypodontia that do not appear to have a mutation in one of these genes, it is presumed that there are other genes that could be important, including KROX-26 and candidate genes in the region of chromosome 10q11.2 (Liu et al., 2001; Gao et al., 2003; Mostowska et al., 2003). 1.65 Understanding Genetics There also are genes involved with hypodontia as part of a syndrome, such as the EDA gene in which mutations result in the most common type of X-linked hypohydrotic ectodermal dysplasia and the LTBP3 gene, which also may involve short stature and increased bone density in autosomal recessive hypodontia (Vastardis et al., 1996; Monreal et al., 1998; Stockton et al., 2000; Noor et al., 2009). A unique but potentially significant type of hypodontia, the presence of a single primary and permanent maxillary incisor, at first may appear to be a product of fusion. However, if the single tooth is in the midline and symmetric with normal crown and root shape and size, then it can be an isolated finding or can be part of the solitary median maxillary central incisor syndrome. This heterogeneous condition may include other midline developmental abnormalities of the brain and other structures that can be due to mutation in the sonic hedgehog (SHH) gene, the SIX3 gene or other genetic abnormality (Nanni et al., 2001). Although rare, the development of only one maxillary central incisor is an indication for review of the family medical history and evaluation for other anomalies. A general trend in patients with hypodontia is for the mesio- distal size of tooth crowns present to be relatively small (especially if multiple teeth are missing). The mesio-distal size of the permanent maxillary incisor and canine crowns tend to be large in cases with supernumerary teeth (Brook et al., 2002). Relatives who do not have hypodontia still may manifest teeth that are small, which may result in a Bolton discrepancy. This observation suggests a polygenic influence on the size and patterning of the dentition, with a multifactorial threshold for actual hypodontia and/or Bolton discrepancies in some families. As the following discussion will indicate, what we consider to be non-syndromic hypodontia still may be associated with an increased likelihood of other findings such as cancer, palatally displaced canines (PDCs) and Class II, division 2 (II/2) malocclusion. Further consideration and investigation into this area may require us to redefine hypodontia occuring with these other findings as syndromes, or at least as an example of a pleiotropic effect from the interaction of genetic and environmental factors. HYPODONTIA AND CANCER Recently it has been realized that hypodontia may be an indicator of susceptibility for developing cancer. A striking example of this was reported in a Finnish family in which oligodontia and colorectal cancer 166 Hartsfield were associated with each other with autosomal dominant inheritance. The oligodontia and cancer predisposition were caused by a nonsense mutation in the AXIN2 gene. Colorectal cancer or precancerous lesions in the family were found only in association with oligodontia and the AXIN2 mutation and affected all those of the oldest generation who had the mutation. A different type of de novo mutation (frameshift) in the same gene was found in an unrelated young patient with oligodontia. Both mutations are expected to inactivate the AXIN2 protein function, leading to an increase in Wnt signaling, which may lead to cancer development. This change in AXIN2 protein function also clearly changes the network signaling involved in dental development (Lammi et al., 2004). Further support for the proposition that hypodontia can be associated developmentally with cancer comes from a University of Kentucky report (Chalothorn et al., 2008) that women with epithelial ovarian cancer (EOC) are 8.1 times more likely to have hypodontia than are women without EOC. In contrast to the oligodontia reported with the specific mutations in the AXIN2 gene, the severity of hypodontia was similar between the two groups (affected and nonaffected) in this study, with usually one or two teeth not developing. Maxillary lateral incisors followed by second premolars were the teeth most frequently affected in the cancer and control groups (Chalothorn et al., 2008). These findings are an example of how changes in the protein products of genes can have pleiotropic effects on different parts of the body at different times. At this time, it is not known what the real individual risk for cancer is in the individual with hypodontia. Future studies into the family history and genotypes of individuals with hypodontia will help illustrate what the risk may be of individuals or family members developing cancer associated with hypodontia in the general population. At this time, the prudent action maybe to inquire about a history of cancer in the families or older individuals with hypodontia and make referral to their physician/medial clinical geneticist for appropriate monitoring based on family cancer history (Hartsfield, in preparation 2011). HYPODONTIA AND PALATAL CANINE DISPLACEMENT Palatally displaced canines (PDCs) are associated with other dental anomalies more often than would be expected by chance. 167 Understanding Genetics Associated anomalies include small, peg-shaped or agenesis of lateral incisors, second premolar agenesis, infraocclusion of primary molars, generalized maxillary crown size reductions, enamel hypoplasia and third molar agenesis (Peck et al., 1994, 1996; Baccetti, 1998; Hartsfield, 2005). Langberg and Peck (2000) showed that mesiodistal measurements of maxillary and mandibular central and lateral incisors were smaller in patients with PDCs compared to controls. Patients with unilateral and bilateral PDCs were included. The article states that all measurements were taken on the patients’ left side regardless of PDC location on the basis of “strong right-left metrical concordance between homologous human teeth.” This is true, although the measurement of corresponding teeth on the right and left of the maxillary arch might have disclosed some information on PDCs and developmental fluctuating asymmetry, which often is taken as an indicator of developmental instability (Cassidy et al., 1998; Sprowls et al., 2008). Sacerdoti and Baccetti (2004) found that most (75%) of PDC cases associated with small lateral incisors were those in which unilateral PDCs were associated with bilateral small lateral incisors. In contrast, 9% of unilateral PDCs were associated with contralateral (opposite side) small lateral incisors and 8.6% were associated with ipsilateral small incisors. Extending this thought is the finding by Paschos and colleagues (2005) that in patients with unilateral PDCs, both central and lateral incisors were smaller significantly buccolingually on the affected side. In addition to the majority of reports indicating an increased incidence of dental anomalies associated with PDCs, the etiology of PDCs can be influenced by studying who most often presents with canine displacement. While unilateral displacement is said to occur twice as often as bilateral displacement, female to male occurrence is reported among unilateral PDCs as 1.65:1 and among bilateral PDCs as 4:1 (Sacerdoti and Baccetti, 2004). Interestingly, anomalous laterals also present more often in females than males (2-3:1; Becker, 2007), although these data do not prove cause and effect. Data indicating a greater female prevalence supports the idea of a genetic influence, possibly secondary to the earlier development of the dentition in females compared to males (Demirjian et al., 1973), although other specific dental development factors also may be involved. Overall these studies suggests that PDCs were correlated less with the small size of the ipsilateral lateral incisor than an influence on maxillary lateral incisor size in general. 168 Hartsfield Pirinen and coworkers (1996) constructed 35 family trees (pedigrees) after examining 77 female and 29 male orthodontic patients (probands) treated for PDCs, 110 first-degree relatives (sharing on average one out of two of their genes with the probands) and 93 second- degree relatives (who share on average one out of four genes with the probands). They found PDCs within eight families, with a total of ten first- or second-degree relatives expressing the phenotype, representing a 4.9% prevalence in these relatives of patients with PDCs (Pirinen et al., 1996), 2.5 times the population prevalence (Thilander and Jakobsson, 1968). However, it should always be kept in mind that traits that occur more often in some families are not due necessarily to intrafamilial genetic factors, although these factors may influence how the family members tend to react to the environmental factors that they also will share (King et al., 1993). Segregation analysis of affected families found that ectopic canines most likely are an autosomal dominant trait in most of the families in the study, with incomplete penetrance (sometimes referred to as “skipping generations”). More specifically, 85% of the three- generation families studied showed instances where someone presumed to have the genetic factor(s) involved showed a normal phenotype (no canine impaction), although the condition occurred in their children. Interestingly, although there was, as reported before, a predilection toward females being affected, there was no evidence in the segregation analysis of sex-linked inheritance. The dominant inheritance with a relatively low penetrance of 36% indicates that although a dominant gene likely is involved, other factors (environmental, epigenetic or perhaps additional genes) influence and account for the varying phenotypes (Camilleri et al., 2008). Unfortunately, the conclusions from this study are clouded by the lumping of buccally- and palatally-positioned canines that did not erupt into the classification of fully ectopic canines. Mossey (1999) pointed out that since PDCs occur with other anomalies such as reduced tooth size and tooth agenesis, and that these types of genes influence dental patterning and development, then perhaps genes such as these also may effect canine development/displacement/ impaction. Although much yet is to be learned regarding the etiology of palatal canine displacement, evidence gathered to date points to the etiology of PDCs fitting more than one pathogenic model. Both genetic and environmental factors contribute to a possible complex etiology, in 169 Understanding Genetics which each case could be influenced by both factors to varying degrees (Hartsfield, 2005; Rutledge and Hartsfield, 2010). HYPODONTIA AND CLASS II, DIVISION 2 MALOCCLUSION The Class II, division 2 (II/2) malocclusion is a relatively rare type of malocclusion, representing between 2.3% and 5% of all malocclusions in the western white population (Ast et al., 1965; Mills, 1966). Class II/2 malocclusion has been shown to be one of the most difficult malocclusions to treat to a good scored outcome (Knierim et al., 2006). Markovic studied the role of genetic factors in the etiology of Class II/2 malocclusions. While 100% of the 20 monozygotic (MZ) twin pairs were concordant for Class II/2 malocclusion, only 10.7% of the 28 (dizygotic) DZ twin pairs demonstrated concordance for the Class II/2 malocclusion. Based on these data, it would appear likely that Class II/2 malocclusion is unlikely to be due to the action of a single gene, but rather more likely is due to multiple genetic and environmental factors (Markovic, 1992; Morrison et al., unpublished data). Basdra and coworkers (2000, 2001) estimated the prevalence of dental developmental anomalies in patients with Class II/2 maloclusion. When comparing the percentage of tooth agenesis in Class II/2 subjects with that reported in the literature, they found an increased association of Class II/2 malocclusion with agenesis of teeth. It was determined that, excluding third molars, agenesis of other teeth was at least three times more common in Class II/2 subjects than in the general population. In addition, there were a significantly greater number of dental developmental anomalies present in Class II/2 subjects as compared to the general population. Peck and colleagues (1998) showed a statistically significant reduction in permanent maxillary incisor mesial-distal width associated with Class II/2. In a subsequent report, Basdra and associates (2001) found that the occurrence of various tooth anomalies was similar between Class II, division 1 (II/1) malocclusions and the general population, while Class II/2 malocclusions showed at least a three-fold increased frequency compared with data from general populations. The results of these studies revealed that the Class II/2 malocclusion is associated closely with dental developmental anomalies. 170 Hartsfield In addition, Morrison and coworkers (unpublished data) found first-degree relatives of family members with a Class II/2 malocclusion may be at an increased risk of having hypodontia and/or microdontia over the general population. The association of hypodontia and other dental anomalies with Class II/2 malocclusion suggests that one or more of the genetic factors involved in hypodontia may be ones involved in Class II/2 malocclusion as well. Supporting this is preliminary data from Morford and associates (2010a,b) indicating that the PAX9 and or RUNX2 genes may play a role in Class II/2 malocclusion. PRIMARY FAILURE OF ERUPTION (PFE) In addition to hypodontia and its primary or secondary relationship to tooth size, maxillary canine eruption, Class II/2 malocclusion and cancer, there is emerging data regarding the influence of genetics on dental eruption. Presently this relationship is most clear in cases of Primary Failure of Eruption (PFE), in which all teeth distal to the most mesial involved tooth do not erupt or respond to orthodontic force. The familial occurrence of this phenomenon in approximately 25% of cases facilitated the investigation and discovery of the PTHR1 gene being involved (Frazier-Bowers et al., 2007, 2009b; Decker et al., 2008; Proffit and Frazier-Bowers, 2009). Advancements in this area could help not only to define patients who likely are to develop or have PFE, but also potentially to result in the molecular manipulation of selective tooth eruption rates to enhance treatment protocols on an individual basis (Wise et al., 2002). DIFFERENCES IN FACIAL GROWTH DURING PUBERTY Research and discussion of facial growth and treatment in the lit- erature has focused primarily on either the timing of the greatest amount of facial growth (mandibular growth in particular; Gu and McNamara, 2007; Hunter et al., 2007; Verma et al., 2009) or the estimated extent of facial growth to be attained (Chvatal et al., 2005; Turchetta et al., 2007). In order to diagnose and treat the child or adolescent patient optimally, the orthodontist needs to know as much as possible about the patient’s growth potential. Predictions based upon expected growth models start- ing from an earlier point in life can be useful; however, they must incor- porate and account for the variation associated with individual genetic factors, especially those that come to the forefront during the pubertal growth spurt. 171 Understanding Genetics The CYP19A1 (aromatase) gene has an effect on the amount of Sagittal growth of the mandible and maxilla on average during puberty in boys, yet only accounts for part of the growth variation (Hartsfield et al., 2010). Regulation of this gene’s transcription is critical for the testoster- one/estrogen (T/E) ratio in the body since aromatase plays an important role in the conversion of androgens to estrogens. Some studies have shown that the T/E ratio is critical in the development of sex-indexed facial characteristics (Schaefer et al., 2005, 2006) such as the growth of cheekbones, mandible and chin, prominence of eyebrow ridges and lengthening of the lower face. As variation in the aromatase gene ac- counts for some, but clearly only a part, of all the variation in male Sagit- tal jaw growth at puberty, further investigation of this and other genetic factors, their interaction and interaction with environmental factors will help to explain'individual components of facial growth. Another study explored a genetic association with the Pro561Thr (P56IT) variant in the growth hormone receptor (GHR) gene with cranio- facial growth attained in adulthood in both men and women. Those who did not have the GHR P56IT allele had a significantly greater mandibular ramus length (condylion-gonion) than did those with the GHR P56IT allele in a normal Japanese sample of 50 men and 50 women (Yamagu- chi et al., 2001). The average mandibular ramus height in those with the GHR P56IT allele was 4.65 mm shorter than the average for those with- out the GHR P56IT allele. This significant correlation between the GHR P56IT variant and shorter mandibular ramus height was confirmed in an additional 80 women. Further investigation yielded similar results with more GHR ge- netic variants, almost all of which are not common in non-Asian groups (Tomoyasu et al., 2009b). Although 15% of the Japanese population car- ries at least one P561T variant, it is rare in non-Asian populations, re- quiring other variants present in non-Asian populations to be explored for their relationship with ramus height. Other studies in Chinese and Korean populations found other GHR variants to be associated with variation in ramus height (Zhou, 2005; Kang et al., 2009). Together, these findings demonstrate that genetic polymorphisms predictive of a specific physical characteristic in one population may not be present in another population. 172 Hartsfield TEMPOROMANDIBULAR DYSFUNCTION (TMD) Temporomandibular dysfunction (TMD) can be classified broadly as somatic and neuropathic, although the individual etiologies within each category are heterogeneous and probably often complex. Genetic factors may play a role in TMD by influencing variation in individual pain perception, sex and ethnicity, production of proinflammatory cytokines, the breakdown of extracellular matrix by other proteins from genes expressed in the TMJ and as a part of some genetic syndromes (Oakey and Vieira, 2008). Relationships between genetic variants and disease can be investigated using family aggregation studies where clusters of disease within genetically related family members are analyzed. To date, family-aggregation studies have failed to identify a genetic influence on TMD (Slade et al., 2008). These types of studies, however, may have been “underpowered,” meaning that they did not have a sufficient number of subjects to be effective in this type of analysis. Interestingly, Zubieta and colleagues (2003) reported that a common variant of the gene that codes for the enzyme catechol-O-methyl-transferase (COMT) was associated in humans with diminished activity of pain regulatory mechanisms in the central nervous system. Slade and associates (2008) pursued a three-year prospective study of 202 healthy females (18 to 34 years old) who did not have TMD when examined at baseline (none of whom were in orthodontic treatment at the time, although 99 had a history of orthodontic treatment). They found that TMD onset was 2.3-fold greater for subjects who had high pain sensitivity (HPS) and/or average pain sensitivity (APS) haplotypes, based on COMT genetic variation, compared with subjects who had low pain sensitivity (LPS) haplotypes. Out of 174 subjects in the study available for analysis, there were 15 (8.6%) new cases of TMD during the three years of the study. Although the risk of TMD was threefold greater among subjects who reported a history of orthodontic treatment compared with those who did not, the associated relative risk was not significant statistically (95% confidence interval 0.89-10.35). In subjects who developed TMD and who had COMT pain resistant haplotypes, there was no difference in having a history of orthodontics or not. Of the subjects with pain-sensitive haplotypes, there were significantly (P=0.04) more individuals with a his- 173 Understanding Genetics tory of orthodontic treatment who developed TMD than those who developed TMD and had no history of orthodontics (Slade et al., 2008). Although interesting, further study is needed to know if pain- sensitive COMT haplotypes are really a marker for individuals who may be more likely to develop TMD given a history of orthodontic treatment. A statistically significant elevation in risk in a small sample is not sufficient evidence that an attribute (in this case, orthodontic treatment) is causal, although it does raise the question: do patients with pain- sensitive haplotypes experience relatively greater discomfort or pain when undergoing procedures used during fixed orthodontic treatment? It also should be noted that the experience of orthodontic treatment was assessed in this study merely by asking subjects a single question. No attempt was made to determine if the treatment involved fixed or removable appliances, the duration of the treatment and if any additional treatments such as surgery also were involved. Any etiological role of orthodontic treatment in this study would require that the putative causal effect of orthodontic treatment was one that persisted after completion of treatment, yet which did not cause the person to develop TMD at the time of recruitment. This association of a history of orthodontic treatment with later development of TMD, but not during the time of the orthodontic treatment, raises the possibility that another environmental interaction occurred in the time between completion of orthodontic treatment and enrollment in the study. Still, the association of a history of orthodontic treatment and pain-sensitive COMT haplotypes with later development of TMD is an intriguing outcome that needs to be investigated further. EXTERNAL APICAL ROOT RESORPTION Analysis of the genetic basis for variable response to treatment has been applied to the specific adverse outcome sometimes associated with orthodontic treatment called external apical root resorption (EARR). Although often associated with orthodontic treatment, EARR does occur in those who have not received orthodontic treatment, with missing teeth, increased periodontal probing depths and reduced crestal bone heights (Harris et al., 1993). Individuals with bruxism, chronic nail biting and anterior open bites with concomitant tongue thrust also may show an in- creased extent of EARR before orthodontic treatment (Harris and Butler, 1992). 174 Hartsfield Some patients have a relationship between EARR and orthodon- tic mechanical loading (Brezniak and Wasserstein, 1993a,b). The amount of orthodontic movement is associated positively with the resulting ex- tent of EARR (DeShields, 1969; Sharpe et al., 1987; Parker and Harris, 1998). Orthodontic tooth movement or “biomechanics” has been found to account for approximately 10% to 33% of the total variation in EARR (Linge and Linge, 1991; Baumrind et al., 1996; Horiuchi et al., 1998). Owman-Moll and coworkers (1995) showed that individual variation overshadowed the force magnitude and the force type in defining the susceptibility to histological root resorption associated with orthodontic force. Individual variations were considerable regarding both extension and depth of histological root resorption within individuals; these were not correlated to the magnitude of tooth movement achieved (Kurol et al., 1996). This individual variation in EARR associated with orthodontic treatment indicates an individual predisposition and a multifactorial (complex) etiology (Massler and Malone, 1954; Massler and Perreault, 1954; Reitan, 1957; Newman, 1975; Harris et al., 1997; Sameshima and Sinclair, 2001). Heritability estimates have shown approximately 50% of EARR variation concurrent with orthodontic treatment and almost 66% of maxillary central incisor EARR specifically can be attributed to ge- netic variation (Harris et al., 1997; Hartsfield et al., 2004). A retrospec- tive twin study on EARR found evidence for both genetic and environ- mental factors influencing EARR (Ngan et al., 2004). In addition, studies in different inbred mice also supported a genetic component involving multiple genes in histological root resorption (Al-Qawasmi et al., 2006; Abass and Hartsfield, 2008). - While there is a relationship between orthodontic force and root resorption, it is against the backdrop of previously undefined individual susceptibility. Because mechanical forces and other environmental fac- tors do not explain adequately the variation seen among individual ex- pressions of EARR, interest has increased on genetic factors influencing the susceptibility to EARR. The reaction to orthodontic force, including rate of tooth movement, can differ depending on the individual’s genetic background (Abass and Hartsfield, 2007; Iwasaki et al., 2008). Variation in the interleukin-13 gene (IL-1B) in orthodontically treated individuals accounted for 15% of the variation in EARR in one study of Caucasian subjects in the state of Indiana. Persons in the orthodon- 175 Understanding Genetics tically treated sample who were homozygous for IL-1B +3953 (previously designated as +3954) SNP rs1143634 allele “1” were estimated to be 5.6 times (955 CI 1.89–21.20) more likely to experience EARR of 2 mm or more than those who were heterozygous or homozygous for allele “2” (P=0.004; Al-Qawasmi et al., 2003a). Investigators in Brazil followed essentially the same protocol except that they used periapical instead of lateral cephalometric radiographs to measure pre- and post-treatment EARR. Similar to the findings of the above study, they also found that IL-1B polymorphisms are associated significantly with EARR concurrent with orthodontic treatment (Bastos Lages et al., 2009). Figure 3 combines the data from the Indiana and Brazilian samples. In interpreting these results, it is important to note that EARR likely is to be a multifactorial or complex trait. Because EARR has multiple contributing etiologies, the IL-1B will associate with EARR most, but not all of the time. As a result, the “predictive” value of this single marker is limited when provided without information regarding other DNA (gene) markers and other variables that may be involved. These findings illustrate the complexity of genetic association studies and the challenge of genetic counseling based upon a marker that accounts for only a portion of clinical (phenotypic) variation (Schenkein, 1998; Kinane et al., 2005). This caveat is emphasized further by the fact that a group in Germany failed to find the same association with IL-1B and EARR, although they did find an association with IL-1A and EARR (Gulden et al., 2009). Reminescent of the GHR variants associated with differences in ramus height that are not common in non-Asian groups, the relative lack of the IL-1B +3953 variant in a Japanese study made its evaluation with EARR and orthodontia difficult (Tomoyasu et al., 2009a). It is noteworthy that Iwasaki and colleagues (2001) found individual differences in a ratio of IL-13 to IL-1RA (receptor antagonist) cytokines in crevicular fluid that correlated with individual differences in canine retraction using identical force. Although the relation to genetic markers was not undertaken, this study indicates a variable individual response to orthodontic force that may be mediated at least in part by IL- 13 and IL-1RA cytokines. This variation in rates of tooth movement in different individuals associated with different levels of IL-1B and IL-1RA cytokines supports the hypothesis that bone modeling as an individual response to orthodontic force is mediated to some extent by IL-13. 176 Hartsfield Figure 3. Percentage of orthodontic patients with 2 mm or more of EARR by IL-1B +3953 (previously designated as +3954) SNP rs1143634 genotype combining the data from in- dependent investigations in Indiana and Brazil following es- sentially the same protocol, except the Indiana measurements were from lateral cephalometric radiographs and the Brazilian measurements were made from periapical radiographs. A large number of other genes that affect bone physiology also could be involved in the rate of tooth movement as well as in orthodontics- associated EARR (Iwasaki et al., 2008). Further testing of additional candidate genes using nonparametric sibling pair linkage analysis with the DNA microsatellite marker D18S64 (tightly linked to the gene TNFRSF11A) identified evidence of linkage (LOD = 2.5: P = 0.02) of EARR affecting the maxillary central incisor (Al-Qawasmi et al., 2003b). This evidence of genetic linkage indicates that the TNFRSF11A locus, or another tightly linked gene, is associated with EARR. The TNFRSF11A gene codes for the protein RANK, part of the osteoclast activation pathway (Boyle et al., 2003). Data so far implicate this and one other interactive pathway involved in the variation seen in EARR concurrent with orthodontic treatment: 1. Activation control of osteoclasts through the ATP / P2XR7 / IL-1B inflammation modulation pathway; and 2. The RANK / RANKL / OPG Osteoclast activation control. 177 Understanding Genetics Histological root resorption occurs with or without orthodontic treatment and typically is healed. If resorption outpaces healing, then EARR develops. Normal and parafunctional forces, as well as orthodontic forces, may add to or interact with the individual’s susceptibility to pass the threshold of developing EARR. Future estimation of susceptibility to EARR likely will require the analysis of Several genes as mentioned previously, root morphology, skeletodental values and the treatment method to be used, or essentially the amount of tooth movement planned for treatment (Hartsfield et al., 2004; Hartsfield, 2009). CONCLUSION The greatest contribution of genetics to the practice of orthodon- tics ultimately may be a better understanding and accounting for variable responses to treatment. If the component of variation associated with ge- netic differences could be accounted for, then the effect of environmental (treatment) factors and the effect of their interaction with genetic factors could be determined more precisely. Comparing early treatment, re- sponse to functional appliances, development of TMD or the effect of different forces on tooth movement or root resorption when there are marked inter-individual differences (and each treatment/control group has major variation) may not show statistically significant differences if any actual difference due to treatment factors are washed out by the in- ter-individual variation (Hartsfield, 2008a,b). There is a tendency in the specialty of orthodontics for one type or system of treatment (e.g., brackets and other associated appliances) to be touted as the best fit for all patients. Promotion of these appliances by the companies and their proponents should be accepted readily by practi- tioners only if these appliances, their applications and outcomes, are ana- lyzed independently and systematically. Unfortunately this rarely is the case. In addition, regardless of the treatment philosophy, technique or appliances employed, there will be individual patient variation in re- sponse to their use. As knowledge and technology moves ahead with ma- terials and imaging, there also is an increase in the understanding of the biology involved in all aspects of medical, including dental, diagnosis and treatment. Studies of linkage, or association of specific DNA polymorphisms with the trait in multiple families and/or in large population samples, are needed not only to demonstrate a genetic influence, but also to determine what those genetic influences are and how 178 Hartsfield they interact with environmental factors (Abass and Hartsfield, 2008; Hartsfield, 2008a,b). 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Frazier-Bowers ABSTRACT Tooth eruption is highly variable, ranging from a normally timed and sequenced process to one that results in partially or completely unerupted teeth. Molecular studies in rodent models have improved our understanding of dental eruption mechanisms significantly; defects in the differential apposition/resorption mechanism in alveolar bone cause eruption failure in rat molars. Our under- standing of the molecular basis of tooth eruption is strengthened further by the finding that one gene, parathyroid hormone receptor 1 (PTHIR), is causative for familial cases of Primary Failure of Eruption (PFE). Although PFE is a rela- tively rare condition, knowledge of a biological mechanism underlying the de- velopment of PFE illuminates: 1) the influence of genetics on orthodontic tooth movement in general; 2) the differential diagnosis of clinical eruption disorders; and 3) the clinical management of eruption failure. In this chapter, we evaluate what is known about normal tooth eruption and eruption disorders from biological and clinical perspectives. Further, we consider a recent finding that some individuals previously diagnosed with anky- losis subsequently were found to have alterations in the PTHIR gene. This find- ing indicates the initial misdiagnosis of ankylosis and the necessary reclassifica- tion of PFE, and also suggests that other disturbances in tooth eruption may have a genetic etiology. Thus, recent advances in our understanding of normal and abnormal tooth eruption will allow for a refined clinical diagnostic regime based on the genetic cause versus the clinical appearance of an eruption disorder, shift- ing the focus in orthodontics from ‘how to move teeth’ to ‘how teeth move.” KEY WORDS: ankylosis, eruption failure, genetic, tooth eruption Eruption disorders may present as part of a syndromic condition (i.e., cleidocranial dysplasia; CCD) or occur as an isolated dental defect. Primary Failure of Eruption (PFE), originally described by Proffit and Vig 191 Primary Failure of Eruption (1981), is characterized eruption failure of permanent teeth in the ab- sence of mechanical obstruction or syndrome. The hallmark features of this condition are: 1. Infra-occlusion of affected teeth; 2. Significant posterior openbite malocclusion accom- panying normal vertical facial growth; and 3. The inability to move affected teeth orthodontically. Although many prior studies noted the heritable basis of this dental phe- notype (Bosker et al., 1978; Brady, 1990; Ireland, 1991; Raghoebar et al., 1992; DiBiase and Leggat, 2000; Frazier-Bowers et al., 2007, 2009), until the recent reports of mutations in the parathyroid hormone receptor 1 (PTHIR) gene (Decker et al., 2008; Frazier-Bowers et al., 2010a), non- syndromic eruption disturbances (i.e., ankylosis, secondary retention, primary retention and PFE) proved difficult to distinguish from one an- other. Moreover, in that the orthodontic management of mechanical fail- ure of eruption (MFE; Frazier-Bowers et al., 2007) is different from that of PFE, it is critically important to distinguish between eruption failure due to local or mechanical causes (e.g., cysts, interference of adjacent tooth, lateral pressure from tongue, secondary to syndrome such as clei- docranial dysplasia) and a failure of the eruption mechanism completely. The recent reports of PTHIR mutations associated with PFE also provide confirmation of a genetic etiology for eruption failure; previ- ously, it generally was thought to be an isolated event. Accordingly, it is reasonable to suspect a genetic etiology for other eruption disturbances (i.e., delayed eruption, impaction) that do not involve a mechanical bar- rier. Viewing eruption disorders from a genetic perspective necessarily shifts the focus in diagnosis from one based on a clinical description to one based on the biologic defect. Eruption disturbances should be thought of in broad etiologic categories rather than narrowly defined morphological characteristics (Proffit and Frazier-Bowers, 2009). These categories should include biologic dysfunction (e.g., primary failure of eruption and primary retention) and physical obstruction (e.g., mechani- cal failure, cysts and lateral tongue pressure; Fig. 1). Impacted teeth might belong to either category, depending upon the location of the im- pacted tooth (i.e., palatal or buccal canine impaction). While palatally impacted canines are hypothesized to be both multifactorial and genetic in origin (Zilberman et al., 1990; Peck et al., 1994; Pirinen et al., 1996; Baccetti et al., 1998), teeth also can become im- 192 Frazier-Bowers NORMAL ERUPTION ERUPTION FAILURE MECHANICAL FAILURE lateral tongue pressure cysts supernumerary teeth DELAYED SECONDARY ERUPTION MPACTED RETENTion TEETH DEAL ERUPTION PRIMARY FAILURE PFE Figure 1. Diagrammatic representation of the spectrum of tooth eruption, rang- ing from normal eruption to mechanical or primary failure of eruption. Delayed eruption is at the far end of the normal eruption sequence. Mechanical failure of eruption can be due, for instance, to local causes such as a cyst, Supernumerary teeth and lateral pressure from the tongue. On the other hand, impactions (espe- cially canine), secondary retention and ankylosis represent either a defect in the primary eruption mechanism or a mechanical obstruction. PFE is, by definition, primary failure of eruption. pacted secondary to an obstruction of the eruption pathway, such as crowded dental arches. Likewise, though “secondary retention’ – defined as a cessation of tooth eruption after its emergence into the oral cavity in the absence of a physical barrier – has an unknown etiology, it has been Suggested that this condition could be due to a physiologic, mechanical or genetic disturbance (Andersson et al., 1984; Raghoebar et al., 1991). In this chapter, we examine the relationship between the clinical eruption disorder, PFE, and the genetic mechanisms underlying its de- Velopment. The implications of a genetic etiology for PFE aids to sim- plify the diagnosis of PFE and also suggests a genetic cause for other eruption disturbances. For the clinical Orthodontist, the utilization of bio- logic information may facilitate the accurate and timely diagnosis of an eruption disorder and therefore appropriate management of the orthodon- tic problem (Kurol, 2006; Loriato et al., 2009). THE BIOLOGY OF TOOTH ERUPTION It is important to consider what is known about normal tooth eruption in order to gain a true appreciation for the biologic basis (i.e., genetic etiology) of abnormal tooth eruption. In its simplest form, human 193 Primary Failure of Eruption dental eruption can de defined as the axial movement of a tooth from its non-functional, developmental position in alveolar bone to a functional position of occlusion (Ten Cate and Nanci, 2003). Recent molecular studies have revealed more precisely that eruption is a tightly coordi- nated process, regulated by a series of signaling events between the den- tal follicle and the osteoblast and osteoclast cells found in the alveolar bone (Wise and King, 2008). Over the past two decades, advances in cellular and molecular biology have improved our understanding of the biological events sur- rounding tooth eruption (Wise and King, 2008). Several studies confirm the role of the dental follicle as a central mediator of tooth eruption (Ca- hill and Marks, 1980; Marks and Cahill, 1987; Wise et al., 2002); the dental follicle provides the environment and chemo-attractants for mono- cytes to differentiate into osteoclasts, facilitating the bone resorption necessary for normal tooth eruption. Historical experiments by Cahill and Marks (1980) demonstrated the critical role of the follicle in experi- ments where a metal object was substituted for a tooth in the dental folli- cle. Evidenced by the successful eruption of the follicle containing a metal object, it was concluded that the follicle was necessary and suffi- cient for eruption. Studies over the past decade using the rat molar illustrate the im- portance of key cytokines and diffusible growth factors in tooth eruption. Yao and collaborators (2007) suggest that specific growth factors and cytokines produce a ‘motive force’ that propels the tooth into the oral cavity. The evidence of this ‘motive force’ is the following chain of events: 1. Stellate reticulum cells found in the dental follicle are observed to secrete parathyroid hormone related pep- tide (PTHrP); 2. PTHrP induces expression of colony stimulating fac- tor-1 (CSF1) and receptor activator of NF-kappaB ligand (RANKL), which are primary factors involved in osteoclastogenesis (Yao et al., 2007); 3. At the apical end of the dental follicle, concomitant expression of bone morphogenic protein (BMP) pro- motes osteogenesis (Yao et al., 2007) in a temporally and spatially coordinated fashion (Wise, 2009). While these experiments in rats reveal that the amount and dura- tion of bone growth occurring at the apical base of the tooth is necessary and sufficient to propel the tooth into the occlusal cavity (Wise et al., 194 Frazier-Bowers 2007), it remains unclear what role, if any, root development or crown mineralization plays in the eruption process. For instance, it is known that genes involved in mineralization, e.g., amelogenin (AMELX) and ameloblastin (AMBN) may act in concert with those involved in osteo- clastogenesis, such as RANKL, CSF1 and C-Fos (Hatakeyama et al., 2006). While an analysis of two genes involved in tooth mineralization (AMLEX and AMBN) did not reveal any functional mutations in a small PFE cohort, it is possible that defects in genes primarily responsible for mineralization may act to suppress RANKL and prevent tooth eruption (Frazier-Bowers et al., 2009). The respective roles of these genes in PFE and their connection to each other warrant further investigation. The recent identification of a gene associated with PFE also cor- relates well with the studies using the rat molar described above, enhanc- ing our understanding of the specific biologic mechanism underlying tooth eruption. The apparent connection between PTHIR and PTHrP. which is secreted in the stellate reticulum and responsible for the induc- tion of CSF1 and RANKL, was confirmed in a simple network pathway analysis (Frazier-Bowers et al., 2010b). The established link between PTHIR and PTHrP provides significant evidence of the relationship be- tween PFE, PTHrP signaling and the mediators of eruption necessary for normal bone remodeling. The relationship of PFE with PTHIR and PTHrP also provides clues to the possible mechanism of tooth eruption. Because PTHIR and PTHrP act in the vitamin D receptor – retinoid X receptor (VDR/RXR) activation pathway – it is plausible that a critical target of the genetic defect in PFE is the alveolar bone. The VDR/RXR pathway primarily af- fects cell signaling, molecular transport and vitamin and mineral metabo- lism (Christakos et al., 1996; Kim et al., 2005). Yet WDR/RXR signaling also plays a key role in balancing bone formation with bone resorption such as that seen in bone remodeling (Lanske et al., 1998, 1999). In addi- tion to influencing calcium homeostasis in general, the focal genes, PTHIR and PTHrP, and the pathway in which they belong, have been shown to affect the number, quality and function both of osteoclasts and osteoblasts (Yoneda et al., 1993; Chiusaroli et al., 2003) as well as the Volume, thickness and density of trabecular bone (Miao et al., 2002, 2004). Consequently, one might hypothesize that some variants in one of these two focal genes (e.g., PTHIR) could disrupt the balance between bone resorption, necessary to establish the passageway for an erupting tooth, and bone formation, necessary to rebuild bone through which the tooth has transited, thus contributing to PFE. 195 Primary Failure of Eruption The association of PTH 1 R and PFE provides a significant con- tribution to the understanding of the eruption process; however, there are many additional genes (van't Hof et al., 2000), WDR/RXR activation and other pathways that interact with PTH 1 R. Moreover, the role of “envi- ronmental” factors still must be considered. It is likely that cell-, tissue- and developmental stage-specific effects influence the contributions of these genes to PFE. Accordingly, studies that evaluate additional candi- date genes and investigate the role of environmental factors (e.g., trauma or orthodontic forces) will be essential to understand the normal eruption process completely. DIAGNOSIS OF ERUPTION PROBLEMS * The identification of mutations in the PTH 1 R gene as the cause of PFE provides clarity to the current terminology used to describe erup- tion disorders. For instance, clinical cases in question now can be evalu- ated for a link to a specific biologic cause (i.e., PTHIR mutation) and therefore rule out MFE or ankylosis. Although PFE is relatively rare (es- timated incidence of 0.6%), the occurrence of eruption problems in the dental/orthodontic setting is not uncommon. Other eruption disorders include secondary retention, ankylosis, reimpaction, reinclusion, MFE and delayed eruption (Raghoebar et al., 1991; Bondemark and Tsiopa, 2007). Ankylosis, the most commonly diagnosed of this group, refers to the fusion of a tooth to bone in the ab- sence of a periodontal ligament. It can be thought of as a mechanical eruption failure, primarily because it can develop secondary to trauma (Biederman, 1962) or from lateral tongue pressure (Kapoor et al., 1998). It also is true that ankylosis can occur secondarily from orthodontic forces applied to a tooth with a defective eruption mechanism as in PFE (Proffit and Vig, 1981). Whether the etiology of ankylosis is environmental (i.e., trauma) or genetic, the diagnosis is subjective. Ankylosis is diagnosed largely by the absence of a periodontal ligament space radiographically, the absence of physiologic mobility and the sharp solid sound on percussion of the tooth (Biederman, 1962). However, the determination of an absent periodontal ligament space often can be misinterpreted on a radiograph. In this case, an- kylosis and/or secondary retention can be difficult to distinguish from PFE. This condition is exemplified in one family in which five mem- bers carried the same mutation in PTHIR. Two affected individuals were diagnosed previously with ankylosis as determined by bone sounding, 196 Frazier-Bowers and the other two affected members were diagnosed with PFE (Fig. 2). The fact that all family members carried the same mutation causative for PFE, but only two were diagnosed with PFE, reveals a need to establish better diagnostic tools to distinguish between ankylosis and PFE. The consequence of the misdiagnosis in this family led to unsuccessful at- tempts to correct the malocclusion orthodontically that instead worsened the severity of the posterior openbite and intruded teeth anterior to af- fected teeth (Frazier-Bowers et al., 2010). The diagnostic distinction between isolated ankylosis, secondary retention and PFE is important in the context of whether teeth distal to the more commonly unerupted first molar are normal or abnormal. A positive family history of PFE and/or positive identification of a muta- tion in the PTH 1 R gene (likely additional genes in the not-so-distant fu- ture) should alert the clinician that affected teeth would be abnormal and unresponsive to orthodontic treatment. However, if a diagnosis of anky- losis is accurate then the remaining teeth will be responsive to orthodon- tic treatment following extraction of the ankylosed tooth. Given the diffi- culty in diagnosing ankylosis accurately, if a physical or mechanical cause cannot be documented and a genetic etiology is discovered, then PFE more likely is the diagnosis. The diagnostic approach above will allow the clinician to follow two different treatment courses including: 1. If PFE can be confirmed, orthodontic treatment to move affected teeth will be avoided. This diagnosis prevents a waste of effort by doctor and patient be- cause the teeth will not respond; and 2. If a first molar fails to erupt, early extraction of the first molar will allow the second molar to drift me- sially if the second molar is normal and does no harm if the second molar exhibits abnormal eruption. PHENOTYPIC FEATURES OF PFE A significant challenge in the accurate diagnoses of PFE is the high degree of clinical variability observed in familial and isolated cases (Frazier-Bowers et al., 2007; Proffit and Frazier-Bowers, 2009). Specifi- cally, our phenotypic evaluation of eruption failure in a large cohort re- Vealed that there are distinguishable types of PFE related to the extent of eruption potential in the anteroposterior and vertical gradient. With respect to the pattern viewed from an anteroposterior gradi- ent, there are two types. Type I is marked by a progressive openbite from 197 Primary Failure of Eruption Figure 2. A-B. Type II PFE is observed in pretreatment photos of two siblings. This mild presentation of a unilateral openbite initially was mistaken for isolated ankylosis. Both siblings have a unilateral pattern of PFE with a Class I relation- ship on the unaffected side. Another affected sibling (C) and the mother of all three children (D) show Type I PFE, with the distal most teeth affected more severely. Despite disparate diagnoses, all of the family members carried the same mutation in the PTH 1 R gene. the anterior to the posterior of the dental arches. For Type I, we speculate that the eruption defect, which we now know is controlled genetically, Was expressed at the same developmental time for all affected teeth. The second type (Type II) also presents as a progressive open- bite from the anterior to the posterior; however, there also is a more Var- ied expression of eruption failure in more than one quadrant and greater although inadequate eruption of a second molar. It originally was hy- pothesized that in Type II, the timing of onset might be related to the stage of root development. While the exact reason for this clinical varia- tion is unknown, in light of the recent PTHIR finding, we speculate that the predominant molar phenotype that we observe may be the result of a coordinated series of molecular events that act in a temporally- and spatially-specific manner such that posterior rather than anterior alveolar 198 Frazier-Bowers bone is affected. Future molecular genetic studies using human and ro- dent models offer great potential for discerning the clinical variation and establishing a phenotype: genotype correlation. The eruption potential of affected teeth in PFE also can be viewed with respect to the extent of eruption (i.e., whether the tooth is intra-osseous or supra-Osseous). This range of clinical variability ob- served in PFE is evident in affected individuals who present with a fail- ure in both intra-Osseous and supra-osseous eruption (Fig. 3A-B). The ultimate position of affected teeth in the alveolar bone may be related to whether the most likely site of the molecular defect is in the bone (i.e., intraosseous eruption failure) or in the PDL (i.e., supraosseous failure), or can be explained by a combination of both. However, an important observation is that the pathway for the erupting tooth appears to be cleared by bone resorption in PFE (Fig. 3B); this observation raises the question of how a genetic defect in PTHIR acts to cause eruption failure. The fact that the bone has been cleared in affected (unerupted teeth) sug- gests that the function of osteoclasts is normal, although one might sus- pect that a mutation in PTHIR would cause a defect in osteoclastogene- sis since the gene belongs to a pathway critical for osteoclast production. Moreover, the co-existence of both intra-Osseous and supra-osseous eruption failure in PFE (Fig. 3) suggests that the eruption failure ob- served may be caused by a defect in bone formation at the apices of af- fected teeth. This does not rule out the possibility that a defect can origi- nate from the PDL or from vascular pressure variation at the root apices (Cheek et al., 2002). CONCLUSION Taken together, the collective advances in our understanding of the cellular and genetic control of tooth eruption provides the important perspective for orthodontists to reconsider our current clinically- and morphologically-based nomenclature of eruption disorders for one that is more biologically and genetically based. This understanding is important particularly since currently there are no mechanotherapeutic means for orthodontic or orthopedic modification of dentoalveolar growth in PFE; a misdiagnosis and attempt at early orthodontic intervention for these pa- tients is futile. Once growth is complete, however, several multidisciplinary treatment strategies can improve the severe posterior openbite malocclu- 199 Primary Failure of Eruption Figure 3. A: Radiographic evidence of PFE in an individual with bilat- eral posterior openbite, characterized by supra-osseous eruption failure in both right and left posterior quadrants at the first molars juxtaposed with intra-Osseous eruption failure both of the second and third molars. B: A panoramic radiograph of a different individual with PFE also demonstrates Supra- and intra-Osseous eruption failure of the right Sec- ond molar to erupt, despite a clear eruption pathway. 200 Frazier-Bowers sions that are characteristic of this disorder. Specifically, single tooth or multiple tooth osteotomies and/or selective extractions followed by im- plants often can lead to a functioning occlusion. Distraction osteogenesis also may provide a reasonable alternative to orthodontic tooth move- ment, but this approach first must be tested for its clinical effectiveness in modifying PFE-affected teeth. The advantage of being able to make an early diagnosis of PFE is that it provides a definitive diagnosis for the patient and peace of mind for the clinician, while saving time and money for both parties. The disadvantage of utilizing a therapeutic diagnosis (early orthodontic intervention particularly with a continuous archwire) is that it actually can make the situation worse. In summary, the best treatment for an accurately established early diagnosis of PFE is the initial avoidance of a continuous archwire mechanics. Anterior segments that would benefit from orthodontics still can be treated. Following the completion of growth, the selection of a more definitive multidisciplinary option will depend entirely on the ex- tent of the eruption failure and on the individual’s accompanying sagittal relationship. 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Kišnisci ABSTRACT Dentolaveolar distraction osteogenesis (DAD) for rapid orthodontic tooth movement (OTM) is a new and promising technique based on the principles of distraction osteogenesis. The DAD technique shortens the duration of overall orthodontic treatment time in extraction cases. Rapid canine retraction by DAD is based on four sequential periods of distraction osteogenesis: osteotomy, la- tency, distraction and consolidation. After DAD surgery, distraction is initiated within three days. The distractor is activated twice per day for a total of ap- proximately 0.8 mm per day. The canine is moved in its surrounding alveolar bone as an alveolar bony transport disk including the tooth. Using the DAD technique, canines can be retracted fully into extraction spaces of the premolars in eight to fourteen days. With the DAD technique, anchorage teeth can with- stand the retraction forces with no anchorage loss and teeth moved rapidly with- out any clinical or radiographic evidence of complications such as root resorp- tion, root fracture, ankylosis, periodontal problems and soft tissue problems. Therefore, DAD technique reduces overall orthodontic treatment time signifi- cantly (by about 50%). Possible orthodontic treatment duration would be nine to twelve months in moderate to severe malocclusion cases, with no unfavorable long-term effects. Moreover, by using the DAD technique, there is no need for extra- or intraoral anchorage mechanics, even in maximum anchorage cases. KEY WORDS: distraction osteogenesis, canine retraction, transport disc, alveolar Surgery DISTRACTION OSTEOGENESIS ON HUMAN FACIAL SKELETON A modified version of the Ilizarov method of bone lengthening known as distraction osteogenesis (DO) opened a new chapter in the treatment of craniofacial anomalies and various malocclusions (Ilizarov, 1988). In 1860, Angell described an expansion procedure by using a 207 Distraction Osteogenesis differentially threaded jackscrew and claimed that the maxillary bones had separated. Goddard (1893) further standardized the maxillary expan- sion procedure and described a retention period to allow the deposition of osseous material in the created gap. DO is a procedure that was used as early as 1905 by Codivilla and later popularized by the clinical and research studies of Ilizarov in Russia. The Ilizarov concept of long bone elongation by distraction applied to the craniofacial skeleton stands for a new chapter in the treatment of various malformations (Ilizarov, 1988, 1989). The first report demonstrating the application of Ilizarov’s prin- ciples to the dog mandible was published by Snyder and colleagues (1973). In this experimental study, the device was activated at a rate of l mm per day for fourteen days after a seven-day latency period. Reestab- lishment of the mandibular cortex and medullar canal across the distrac- tion gap was noted following six weeks of fixation. Another important experimental study was published by Michieli and Miotti (1977). The authors demonstrated the feasibility of intraoral mandibular lengthening by using the Ilizarov’s principles and distraction protocol without any damage to the mandible. Lengthening of the man- dibular body in two dogs was achieved with a technique that involved osteotomies and the use of an experimental orthodontic appliance with- out any damage to the mandibular nerve and no conspicuous alterations of the nerve fibers. Therefore, this technique has been proposed for use in correction of large discrepancies in length in persons with excessive mandibular retrusion. Distraction osteogenesis first was used in the human mandible by Guerrero (1990) and McCarthy and associates (1992). Since then, this technique has been applied to various bones of the craniofacial skeleton. In 1996, iseri and coworkers first used DO in a patient with hemifacial microsomia and published ten-year follow-up findings of the same case (Iseri et al., 2008). The first use of maxillary distraction was reported by Rachmiel and colleagues (1993) who performed gradual advancement of the mid- face in sheep. Block and coworkers (1996) demonstrated anterior maxil- lary advancement in dogs. The first clinical application of maxillary dis- traction was reported by Polley and associates (1998) using a rigid exter- nal distraction device (RED). **. Constantino and associates (1990, 1991) introduced the bone transport technique for segmental mandibular regeneration experimen- 208 Iseri and Kisnisci tally. The first application of bone transport in the human mandible was reported by Constantino and Friedman a year later (1991). In 1996, Block and colleagues indicated the validity of alveolar ridge distraction in dog experiments and Chin and Toth (1996) presented the first clinical application of vertical mandibular alveolar DO on a 17- year-old patient. A modification of bone transport technique for rapid tooth movement based on the principles of DO has been used clinically by Íseri and Kisnisci since 1999 and was reported in 2001. BIOLOGICAL PRINCIPLES OF DISTRACTION OSTEOGENESIS Distraction osteogenesis (DO) is a biologic process of new bone formation between the surfaces of bone segments that are separated gradually by incremental traction. The traction generates tension that stimulates new bone formation parallel to the vector of distraction. Spe- cifically, this process is initiated when distraction forces are applied to the callus tissues that connect the divided bone segments and continues as long as these tissues are stretched. DO begins with the development of a reparative callus. The callus is placed under tension by stretching, which generated new bone. DO consist of four sequential periods: 1. Osteotomy or a corticotomy to fracture the bone into two segments. Discontinuity of a skeletal segment triggers an evolutionary process of bone repair known as fracture healing. A reparative callus is formed within and around the ends of fractured bone seg- ments. The callus undergoes gradual replacement by lamellar bone. 2. The latency period is the period from bone division to the onset of traction and is the time required for re- parative callus formation. As a result of vascular dis- ruption, a hematoma forms around the bone segments and a tremendous amount of cellular proliferation oc- curs. This stage of inflammation and fracture healing continues for about three days. Following inflamma- tion is the soft tissue callus stage, during which - granulation tissue is converted to fibrous tissue and cartilage. On the fifth day after osteotomy, a minicel- lular network of growing capillary loops is formed in the medullary canal of both proximal and distal seg- 209 Distraction Osteogenesis ments in the areas adjacent to the fracture line (Iri- anov, 1996a,b; Cope and Samchukov, 2001). Callus formation serves as a solid base on which new bone tissue is deposited. The latency period usually lasts five to seven days. 3. Distraction is characterized by the application of gradual traction to osteotomized bone segments; new bone or distraction regenerate is formed within the progressively increasing intersegmentary gap. During DO, the normal process of fracture healing is inter- rupted by the application of gradual traction to the soft tissue callus. Gradually stretched tissues with tension stress cause changes at the cellular and sub- cellular levels and stimulate changes that can be de- fined as growth stimulating and shape forming effect (Kallio et al., 1994; Holbein et al., 1995). The regen- erate within the distraction gap always is formed along the axis of applied traction or vector of tension. The distraction regenerate functions as a growth zone, providing osteogenesis throughout the period of elon- gation. 4. Consolidation is the time that allows healing, matura- tion and corticolization of the new bone after traction forces are discontinued. In this period, mineralization of the distraction regenerate is completed. Ilizarov (1988) introduced two biological principles of DO known as the Ilizarov effects. These are: 1. The tension stress effect on the genesis and growth of tissues. This principle postulates that gradual traction creates stress that can stimulate and maintain regen- eration of living tissues. The newly formed bone re- models rapidly to conform to the bone’s natural struc- ture. 2. The influence of blood supply and loading on the shape of bones and joints. The second Ilizarov princi- ple theorizes that the shape and mass of bones and joints are dependent on an interaction between me- chanical loading and blood supply. Blood supply and mechanical loading have a significant influence on the 210 Iseri and Kisnisci shape and mass of the resulting bone. If the blood supply is inadequate to support normal and increased mechanical loading, then the bone cannot respond fa- vorably, leading to degenerative changes. In contrast, if the blood supply is adequate to support increased mechanical loading, the bone will demonstrate com- pensatory hypertrophic changes. The following are the principles of distraction osteogenesis: 1. Preservation of osteogenic tissues during osteotomy is necessary. The periosteum, bone marrow and the nu- trient arteries are equally important for new bone formation. 2. Direction of distraction. The regenerate within dis- traction gap always is oriented along the axis of the applied traction. 3. Rate and rhythm. Successful distraction depends on the rate and rhythm of the applied distraction force. The optimal rate of distraction is 1 mm per day. More frequent rhythms of distraction lead to more favorable regenerate formation and cause less soft tissue prob- lems. If the rate of distraction is less than 0.5 mm per day, the bone may consolidate prematurely. If the rate of distraction is more than 1.5 mm per day, local ischemia in the interzone and delayed ossification or pseudo arthrosis may result. BIOLOGY OF ORTHODONTIC TOOTH MOVEMENT Orthodontic tooth movement (OTM) is a process in which the application of a force induces bone resorption on the pressure side and bone apposition on the tension side (Reitan, 1967; Rygh, 1974). Thus, conventional tooth movement is a result of biologic cascades of resorp- tion and apposition due to the mechanical forces. The term physiologic tooth movement refers primarily to the slight tipping of the tooth in its Socket and, secondarily, to the changes in tooth position that occur dur- ing and after tooth eruption (Reitan, 1974). In general, there is no signifi- cant difference between the tissue reactions observed in physiologic tooth movement and those observed in OTM. However, because the teeth are moved more rapidly during treatment, the tissue changes elicited by orthodontic forces are more marked and extensive. 211 Distraction Osteogenesis Classically the typical rate of OTM depends on magnitude and duration of force applied (Reitan, 1967), number and shape of roots, quality of bony trabeculae, individual response to treatment and patient compliance. It has been assumed that application of force will result in hyalinization, caused partly by anatomic and partly by mechanical fac- tors (Reitan, 1985), with the hyalinization period usually lasting two or three weeks (Reitan, 1974). The rate of biologic tooth movement with optimum mechanical force is about 1.0 to 1.5 mm in four to five weeks (Pilon, 1996). Accord- ing to previously published clinical studies, the rate of OTM varies be- tween 0.03 and 0.08 mm per day (Pilon et al., 1996; Kuhlberg and Priebe, 2003; Hayashi et el., 2004). Therefore, in maximum anchorage premolar extraction cases, canine distalization phase usually takes about six to nine months, with an average overall treatment time of two years. DURATION OF ORTHODONTIC TREATMENT AND ATTEMPTS TO SHORTEN THE ORTHODONTIC TREATMENT TIME Most orthodontic cases involve a shortage of space and some crowding. Non-extraction treatment has become increasingly popular during the last decade; however, the proper management of a substantial number of patients requires the removal of permanent teeth as part of the treatment plan. The first phase of the treatment in a premolar extraction case is distalization of the canines. Using conventional orthodontic treatment techniques, biological tooth movement can be achieved with a limited rate (Reitan, 1967; Rygh, 1974). The canine retraction phase usually lasts about six to eight months. In addition, extraoral or intraoral anchorage mechanics typically are required to maintain the obtained space during canine distalization, particularly in cases where maximum or moderate anchorage is required. Therefore, under normal circumstances conven- tional treatment with fixed appliances is likely to last about 20 to 24 months—with the duration of orthodontic treatment the most complained about issue, especially for adult and young adult subjects. Many attempts have been made to shorten the time for OTM and overall orthodontic treatment time. In 1959, Köle reported combining orthodontics with corticotomy surgery in order to increase the rate of OTM, 212 Iseri and Kisnisci Köle’s corticotomy-facilitated orthodontics technique (1959) was used and reported by several authors since (Anholm et al., 1986; Gantes et al., 1990; Suya, 1991; Wilcko et al., 2001). In the 1980s, an increase in the rate of tooth movement and periodontal cyclic nucleotide levels by combined force and electric cur- rents was studied by Davidovitch and coworkers (1980a,b). Liou and Huang (1998) introduced the technique of distraction of periodontal ligament for rapid tooth movement. In 1999, a new technique of rapid tooth movement by using the principles of DO has been described and used by Iseri and Kisnisci; namely dentoalveolar distraction (DAD, iseri et al., 2001, 2005; Kišnisci et al., 2002; Gürgan et al., 2005). This tech- nique is in the section below. PRINCIPLES OF RAPID TOOTH MOVEMENT BY DENTOALVEOLAR DISTRACTION OSTEOGENESIS (DAD) Beginning in 1999 and taking the principles of DO into consid- eration, our team introduced a new technique for rapid tooth movement, namely dentoalveolar distraction osteogenesis, known by the acronym DAD (Iseri et al., 2001, 2005). A detailed description of DAD is pre- sented below. DAD Appliance Design A custom-made rigid, tooth-borne intraoral distraction device has been designed and used in patients undergoing DAD (Fig. 1). The device is made of stainless steel with one distraction screw, two guidance bars and a special apparatus to activate the distractor by turning the screw in a clockwise direction. As the first step of the DAD procedure, the canines and the first molars are banded with 0.006” x 0.180” (0.15 x 4.55 mm) band material and an impression is made with the bands placed on the teeth (Fig. 2A, B). In the second step, the distractor is soldered to the canine and first molar bands on the dental cast after taking the biomechanical prin- ciples of tooth movement into consideration. The buccal location and angulation of distractor is adjusted according to the position of the canine (Fig. 2C). In order to minimize tipping, the distractor is positioned as high as possible buccally (Fig. 2C, D). 213 Distraction Osteogenesis Figure 1. DAD distractor. A custom-made, rigid, tooth-borne intraoral distraction device is designed for DAD and rapid tooth movement. The device is made of stain- less steel and has one distraction screw and two guidance bars. The patient or parent turns the screw clockwise with a special apparatus to produce rapid tooth movement. Figure 2. Fabrication of dentoalveolar distraction device. The canine and molar bands are fabricated and the distractor is soldered to the bands on the cast. A and B. Intraoral views of molar and canine bands. C. The DAD device is positioned and then soldered to the bands on the cast. D. Custom-made DAD distractor is cemented on the canine and the first molar immediately after the surgical procedure. 214 Iseri and Kisnisci DAD Surgical Procedure Surgical procedure has been described previously by Kišnisci and colleagues (2002) and iseri and coworkers (2009). Surgery is per- formed under local anesthesia, supplemented with nitrous oxide sedation if necessary. A horizontal mucosal incision that is 2.0 to 2.5 cm in length is made parallel to the gingival margins of the canine and premolar, be- yond the depth of the vestibule (Fig. 3). On the medial aspect of the ca- nine tooth to be distracted posteriorly, multiple cortical holes are created in the alveolar bone between the canine and the lateral incisor and the holes around the canine root are connected by way of a thin and tapered fissure bur (Fig. 4A-C). The same procedure is applied to the distal aspect of the canine close to the extraction area. The osteotomy curves apically at a distance of 3 to 5 mm from the apex. Then the fine osteotomes are advanced in the coronal direction. The first premolar is extracted at this stage and the buccal bone is removed between the outlined bone cut at the distal canine region anteriorly and the second premolar posteriorly using a large round bur (Fig. 4C). Larger osteotomes of appropriate sizes are used to mobilize the alveolar segment that includes the canine by fracturing the spongy bone of the lingual/palatal cortex around the canine root (Fig. 3). The buccal and apical bone adjacent to the extraction socket as well as any bony interferences that might be encountered during the distraction process are eliminated or smoothed between the canine and the second premolar, preserving the palatal or lingual cortical shelves (Fig. 3). The palatal shelf is preserved, but the apical bone near the sinus wall is removed (leaving the sinus membrane intact) to avoid interferences during the active distraction process. Osteotomes along the anterior aspect of the canine are used to split the bone surrounding its root from the palatal or lingual cortex and neighboring teeth (Fig. 3). The transport dentoalveolar segment that in- cludes the canine also incorporates the buccal and palatal cortex and the underlying spongy bone that envelopes the canine root, leaving an intact lingual/palatal cortical plate and the bone around the apex of the canine (Fig. 4C). Finally, the DAD device is cemented on the canine and the first molar (Fig. 4D). The incision is closed with absorbable sutures and an antibiotic and non-steroidal anti-inflammatory drug are prescribed for five 215 Distraction Osteogenesis Figure 3. Illustration of the surgical procedure. The first premolar is extracted and any bony interferences in the extraction socket are eliminated. Osteotomies are used to mobilize fully the alveolar segment that includes the canine. Figure 4. A: Intraoral view of the operative site. B. Multiple cortical holes are made on the alveolar bone with a small round carbide bur. C. View of the corti- cotomy of the cortical bone and extraction socket of the first premolar. D. The DAD distractor is cemented immediately after the surgical procedure and the dentoalveolar segment including the tooth is used as a transport disc to carry the maxillary canine posteriorly. 216 Iseri and Kisnisci days. The patients also are instructed to discontinue tooth brushing to avoid trauma around the surgical site for three days. A 0.2% chlorhexi- dine gluconate (Klorhexº, Drogsan, Ankara, Turkey) solution rinse is prescribed twice per day during the distraction period (Kišnisci et al., 2002, iseri et al., 2005). DAD Protocol Distraction is initiated within three days after surgery. The dis- tractor is activated twice per day, in the morning and in the evening, for a total of approximately 0.8 mm per day (Fig. 5). This type of distraction is termed bifocal osteosynthesis and consists of gradual movement of a Vascularized bony segment or transport disc separated previously from the residual bone segment (Fig. 6). New bone is formed during move- ment of the transport disk through the distraction site with simultaneous closing of the bony defect. In our cases, the alveolar bony transport disc includes the canine. C D Figure 5. Illustration of the rapid canine movement by means of grad- ual movement of a vascularized bony segment or transport disc sepa- rated previously from the residual bone segment (bifocal osteosynthe- sis). The transport dentoalveolar segment containing the canine also in- cludes the buccal cortex and the underlying spongy bone that surrounds the canine root, leaving an intact palatal/lingual cortical plate and the bone around the apex of the canine. 217 Distraction Osteogenesis Figure 6. Rapid movement of the maxillary canines in eleven days by means of dentolaveolar distraction, periapical views. Arrows represent the movement of the canine in its surrounding alveolar bone as an alveolar bony transport disc according to the principles of DO. DAD is discontinued when the canine has moved posteriorly into the desired position or makes contact with the second premolar. The DAD device (distractor) then is removed and fixed orthodontic appliance treatment immediately is initiated by leveling of both dental arches. Ligatures are placed under the archwire between the distracted canine and the first molar; the ligatures are kept in place for at least three months after the DAD procedure to avoid mesial movement of the ca- 11111CS. All patients are included in a meticulous oral hygiene program, which is initiated before and after the DAD procedure and reinforced monthly, together with professional tooth cleaning, during fixed appli- ance orthodontic therapy. Rapid Tooth Movement by DAD The idea of rapid tooth movement by using the principles of DO is to shorten the duration of orthodontic treatment time, iseri and col- leagues (2005) published data on the duration of canine retraction and the effects of DAD on dentofacial structures. The study sample consisted of 20 maxillary canines in ten growing or adult subjects (mean age ºf 16.5 years; range = 13.1 to 25.7 years). The distraction procedure Was completed in eight to fourteen days, with a screw turning rate of 0.8 mm per day (Figs. 6 and 7). Full retraction of the canines was achieved in a mean time of 10 (+ 2) days. This rate of tooth movement is the most rapid ever demonstrated in the literature, compared to previously pub- lished studies (Pilon, 1996; Liou and Huang, 1998). The distal displace: ment of the canines was mainly a combination of tipping and translation. with a mean change in canine inclination of 13.2° (+4.7°) at the end of the distraction period (iseri et al., 2005). 218 Iseri and Kisnisci Rate of Tooth Movement 0.2 0.03 + 0.035 0.01 ISERI et al. ISERI et al. DAD - elastic Figure 7. Rapid movement of the maxillary canines by den- toalveolar distraction, occlusal views. Full distraction of the canines was completed in eleven days with a rate of 0.67 mm per day. Posterior Anchorage Maintenance with DAD No posterior anchorage loss was observed in any of the DAD cases, iseri and coworkers (2005) demonstrated the mean Sagittal and Vertical anchorage loss in molar teeth as 0.2 + 0.3 mm and 0.5 + 0.9 mm. *Spectively, during ten days rapid distraction of the canines, values that Were insignificant statistically and clinically. During OTM, hyalinized tissue neighboring the tooth on the movement side must be undermined 219 Distraction Osteogenesis with indirect resorption. This period usually lasts two or three weeks (Reitan, 1974). In the current study, rapid canine retraction with DAD was achieved in eight to fourteen days, which is a short period for molars to move mesially (Fig. 8). Root Resorption and Periodontal Status Periapical radiographs of the canines and first molars and pano- ramic films were taken at the start and end of the distraction procedure to evaluate root structure. Root resorption scores were detected according to the root resorption scale modified from Sharpe and associates (1987) as follows: S0 = No apical root resorption. S1 = Widening of PDL space at the root apex. S2 = Moderate blunting of the root apex up to one third of the root length. S3 = Severe blunting of the root apex beyond one third of the root length. No clinical or radiographic evidence of complications such as root fracture, root resorption, ankylosis and soft tissue dehiscence was observed in the DAD cases (iseri et al., 2005). Gürgan and colleagues (2005) evaluated the alterations that occurred in the gingival dimensions of canine teeth following DAD during a twelve-month follow-up period. Before surgery (pre-DAD), immediately after removal of the device (post-DAD) and at one, six and twelve months post-DAD, the plaque index (PI), gingival index (GI), pocket depth (PD) and width of kerati- nized gingiva were recorded and the width of attached gingiva was cal- culated. There were significant differences between pre- and post-DAD for PD measurements for all sites, with the highest at the distal site. The palatal sites likewise showed significant differences at one-, six- and twelve-month follow-up periods compared with the post-DAD period. The buccal sites showed no significant changes at any time point. The width of keratinized gingiva also showed no significant change during the follow-up period, while the width of attached gingiva was significant different only between the pre- and post-DAD periods (P<0.01). Periodontal status was normal in all cases at the end of the one- year orthodontic treatment time following the DAD. The plaque and gingival index values increased following the surgery and then gradually decreased through the one-, six- and twelve-month periods. The pocket depth 220 Iseri and Kisnisci Figure 8. The anchorage teeth were able to withstand the retraction forces with no anchorage lost and with no need for extraoral or intraoral anchorage devices. Arrows indicate no structural changes in the periodontal ligament. measurements on three sites other than the buccal site increased by DAD, but decreased significantly during the follow-up period. Therefore, the DAD technique was found to be viable innovative method to reduce the Orthodontic treatment time without any unfavorable long-term effects on the gingival tissues. Tooth Vitality Pulp vitality was evaluated and recorded with an electronic digi- tal pulp tester and a thermal pulp tester (iseri et al., 2005). All teeth sub- Jºcted to pulp vitality test (canines, incisors, second premolars, first mo- 221 Distraction Osteogenesis lars) were cleaned and tested on the buccal surfaces. Before the start of treatment, pulp vitality was tested with an electronic pulp tester. All teeth reacted positively, with the exception of a right maxillary central incisor in a patient who previously had had root canal therapy. At the end of the dentoalveolar distraction procedure and during the fixed appliance ortho- dontic treatment, no reliable reactions to the pulp test were achieved in the study subjects. However, all teeth tested positively for vitality at the sixth month evaluation following the end of orthodontic treatment. Fixed Appliance Orthodontic Treatment Stages and Mechanics in DAD Cases Stages of fixed appliance orthodontic treatment: 1. End of DAD. 2. Placement of 0.010” ligature between canine and first molar before removal of the distractor (Fig. 6, day 11). 3. Initiation of fixed appliance orthodontic treatment on the upper and lower dental arches. 4. Removal of the 0.010” ligature and placement of a new 0.008” ligature between the first molar tube and the canine brace. 5. Placement of 0.014” NiTi arch wire for leveling (three to six weeks). - 6. Placement of 0.016.” NiTi arch for wire for leveling (if necessary for three weeks). 7. Placement of the 0.016” x 0.016” archwire with re- verse closing loops for incisor retraction and/or torque control (three to four months). 8. Placement Of the 0.017° x 0.025” and 0.018” x 0.025” finishing phase archwires (three months). 9. End of orthodontic treatment (nine to twelve months). CASE REPORT The patient was an 18-year-old female. Her chief complaint was crowding in upper maxillary dental arch and unaesthetic appearance of her anterior teeth (Fig. 9). She had Class II molar and canine relationship with 2 mm overjet and 3 mm overbite. At the start of treatment, she had 11 mm and 4 mm crowding in the maxilla and mandible, respectively. Her maxillary left lateral incisor was blocked out palatally whereas the right 222 Iseri and Kisnisci Figure 9. Class II patient with severe maxillary crowding and unaesthetic ap- pearance of the anterior teeth. Her maxillary left second lateral incisor was blocked out palatally whereas the right maxillary lateral incisor and canine were located palatally and buccally, respectively. maxillary lateral incisor and canine were located palatally and buccally, respectively. Intraoral evaluation showed that the maxillary midline was shifted 1 mm to the left. Treatment Plan Bilateral maxillary first premolar extraction was the treatment of choice after taking her severe maxillary crowding into consideration. Conventional and rapid treatment options were explained to the patient. Therapy based on extraction of the maxillary first premolars and use of extraoral anchorage appliances for retraction of the maxillary canines and alignment of the maxillary incisors was explained to the patient as the conventional type of treatment modality. Because of 11 mm maxil- lary crowding, the patient was informed about use of cervical headgear for maximum anchorage reasons for retraction of the canines and align- ment of the maxillary incisors. Detailed information about different op- tions to maintain adequate posterior anchorage during the canine retrac- tion including extraoral (i.e., headgear) and intraoral (i.e., TPA and mini of Zygomatic implants) anchorage mechanics was provided to the patient. The patient preferred to be treated by rapid orthodontic treatment that would be completed within one year without using any extraoral anchorage appliance. DAD surgery, distraction protocol and orthodontic Procedures were described in detail and an inform consent was signed by the patient. The treatment plan, therefore, was bilateral maxillary first 223 Distraction Osteogenesis premolar extraction followed by rapid canine retraction with DAD and then fixed appliance orthodontic treatment, with no use of extra- or in- traoral anchorage. Treatment Progress DAD surgery was performed and the distractor was cemented on the canine and the first molar immediately after the surgical procedure. Distraction was initiated within three days after the surgery. The distrac- tor was activated twice per day, in the morning and in the evening, about 0.8 mm per day. Rapid canine movement was completed in twelve days (Figs. 10–13) and the distractors were removed when the canine teeth came into contact with the second premolars. A mild amount of edema was observed following the DAD Sur- gery and no significant soft tissue change was seen at the end of twelve days DAD procedure (Fig. 14). month 6 - month 11 Figure 10. Dentoalveolar distraction of maxillary canines from start to end of distraction, occlusal views. Full distraction of the canines was completed in twelve days. month 6 - month 11 224 Iseri and Kisnisci Figure 14. Facial photographs of the patient at start of DAD, end of DAD and end of orthodontic treatment. No significant soft tissue change (e.g., edema) was observed following the surgery. - * Figure 11. Intraoral photographs of the patient from start of DAD to end of Orthodontic treatment, which was completed in eleven months. DAD was com- pleted in twelve days and a ligature was placed between the canine and first molar before removal of the distractor. Fixed appliances were placed immedi- ately after the removal of the distractor and ligatures then were inserted under the archwire between the distracted canine brackets and the first molar tubes and kept in place for three months. 225 Distraction Osteogenesis After removal of the distractors, fixed appliance orthodontic treatment was initiated immediately. First a 0.014” and then a 0.016” NiTi arch wire was placed to the upper and lower dental arches for level- ing. In the next appointment, a 0.016” x 0.016” stainless steel arch wire with reverse closing loops was used to close the remaining extraction spaces. Following closure of the extraction space, 0.017" x 0.025” stain- less steel archwires were used for maintaining adequate torque in both dental arches (Figs. 10-13). Treatment Outcome Class I canine and Class II molar relationship were achieved at the end of orthodontic treatment. Cephalometric analysis showed no sagittal and vertical posterior anchorage loss at the upper first molar re- gion during DAD and fixed appliance orthodontic treatment. The canines were retracted into the extraction site completely in twelve days. Class I canine and Class II molar relationships and ideal overbite and overjet were achieved after orthodontic treatment in eleven months. No posterior anchorage loss was seen even though no extraoral or intraoral anchorage device was used during the DAD and fixed appliance orthodontic treat- ment. Periapical films of maxillary canines before and after DAD, after orthodontic treatment and at one-year follow-up indicated no evidence of complications such as root resorption, root fracture, ankylosis and soft tissue dehiscence (Fig. 15). CLINICAL IMPLICATIONS AND CONCLUSIONS The following patients would be suitable candidates for rapid tooth movement by using DAD: 1. Patients with compliance problems for social and professional reasons. 2. Older adolescent and adult patients with moderate or severe crowding. Adult Class II division 1 cases. Bimaxillary dental protrusion cases. 5. Orthognathic surgery cases needed dental decomposi- tion. 6. Cases having root shape malformations, short roots and periodontal problems. 7. Patients with ankylosed teeth. : 226 Iseri and Kišnisci 1 year follow up Figure 15. Radiographic appearance of maxillary canines before, during and after DAD, after orthodontic treatment of eleven months and one year follow- up. There was no radiographic evidence of complications such as root resorp- tion, root fracture or ankylosis. In conclusion, the DAD technique is a viable innovative method to reduce orthodontic treatment time in extraction cases. 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Rapid orthodontics with alveolar reshaping: Two case reports of decrowding. Int J Perio- dontics Restorative Dent 2001:21:9-19. 231 CORTICOTOMIES AND OTHER ADJUNCTS TO ENHANCE ORTHODONTIC TOOTH MOVEMENT Flavio Uribe, Alice Cutrera, Carlos Villegas, Ravindra Nanda ABSTRACT Multiple surgical procedures now are available as orthodontic adjuncts to en- hance tooth movement and improve treatment efficiency. These procedures all rely on the basic combination of two elements: surgical technique and applied force. The two predominant surgical procedures are corticotomy and osteotomy. The two primary types of force are heavy or orthopedic (commonly delivered by distraction devices) and light (delivered by traditional orthodontic appliances). Different names have been given to the combination of these procedures includ- ing periodontally accelerated osteogenic orthodontics (PAOO) and speedy or- thodontics, dental distraction and dentoalveolar distraction (DAD). We find that elimination of the pre-surgical phase of treatment in combined orthodon- tic/orthognathic surgery approaches (surgery first) has reduced treatment times in these patients by approximately 50%. This chapter will discuss all of these techniques and the differences between them. KEY WORDS: corticotomies, osteotomies, regional acceleratory phenomenon, Surgery first Orthodontics, as any other field in the health sciences, is in con- tinuous search of innovation and new clinical approaches. It is important that these new approaches are evaluated in light of two important factors: effectiveness and efficiency. Effectiveness pertains to achieving the de- sired outcome with treatment. Efficiency requires achieving the desired outcome with special consideration to the time and resources required for treatment. Efficiency has become a mainstream topic in orthodontics, with the prime intent of reducing treatment time. This interest has Surged as patients appear to have a desire for instant change without ex- tended treatment times. Furthermore, clinicians also are interested in ex- pediting treatment to prevent certain sequelae of orthodontic therapy such 233 Corticotomies and Other Adjuncts as root resorption, periodontal disease and white spot lesions, all of which are associated with prolonged treatment times. In order to enhance the speed of tooth movement, two areas need to be targeted: biology and mechanics. A significant amount of basic Sci- ence research has been devoted to study of osteoclast mediated bone re- sorption, the rate-limiting process of tooth movement. Published results demonstrate that relevant molecules may have promising effects for gen- erating faster tooth movement, including cytokines IL-1, TNF and RANKL (Iwasaki et al., 2006; Andrade et al., 2007; Yamaguchi, 2009). Unfortunately, the profession still is far from delivering these biological substances to enhance tooth movement in a clinical setting. A better un- derstanding of these substances is needed to assure that when delivered specific cells are targeted and that their effects are controlled temporarily and regionally once activated (King, 2009). With regard to the mechanics of orthodontic treatment, many dif- ferent approaches to enhance the speed of tooth movement have been attempted. Varying magnitudes and frequencies of force application have been explored. Despite numerous previous studies, the definition of an optimal force magnitude for tooth movement still is elusive (Luther et al., 2003). Overall, it is believed that a constant low magnitude force is the most efficient protocol for moving teeth with orthodontic appliances. The effects of orthodontically applied mechanical forces can be modulated by the simultaneous mechanical or physical perturbation of the bone, whether applied directly or indirectly. Perturbations of bone that show some degree of success in enhancing the speed of tooth movement are vibration, low energy lasers and direct surgical insults to the alveolar bone in the form of osteotomies or corticotomies (Wilcko et al., 2001; Nishimura et al., 2008; Yoshida et al., 2009). Surgical insults such as corticotomies and osteotomies have been demonstrated to generate a significant physical bone perturbation and to induce what is known as a Regional Acceleratory Phenomenon (RAP). Frost (1989) was the first to describe this phenomenon in the process of bone fracture healing. He described it as a “cascade of physiological healing events” characterized by an initial increase of cortical bone po- rosity, due to an increase of osteoclastic activity, followed by osseous and soft tissue reorganization and remodeling. Yaffe and coworkers (1994) suggested that the peak of human RAP ensues one to two months after the perturbation, with effects evident up to 24 months. Ferguson and colleagues (2006) described this healing process as “transient os- 234 Uribe et al. teopenia” due to a sterile inflammation, which increases the speed of or- thodontic tooth movement without compromising the periodontal health. SURGICAL PROCEDURES TO ENHANCE EFFICIENCY IN ORTHODONTIC TREATMENT Different ancillary dentoalveolar surgical procedures are avail- able to enhance the speed of tooth movement. It is necessary to define these different techniques as there has been widespread confusion on the mechanisms of action behind each procedure. The majority of the dento- alveolar surgeries require a mucoperiosteal flap reflection on the buccal and/or lingual aspects of the teeth beyond the apices. Following the flap elevation, the surgeon may perform a corticotomy, osteotomy or an ostectomy. A corticotomy is defined as the selective split of bone only through the cortex, leaving the medullary bone intact. An osteotomy is a full-thickness bone cut which includes not only the buccal cortex, but also the medullary bone; thus, the bone is free to move and it is possible to change its alignment. Finally, an ostectomy is a procedure where a Segment of a bone is removed to reduce its length or make it narrower. An ostectomy in periodontics also is defined as the removal of tooth- Supporting bone. The use of accessory dentoalveolar surgery to accelerate the speed of tooth movement was first reported more than 60 years ago. Köle (1959) described a combined interradicular corticotomy in the lingual and buccal aspects of the alveolar bone with a 10 mm supra-apical os- teotomy technique. He believed that the denser layer of cortical bone created the resistance of tooth movement and, using the crown of the teeth as handles, the “block of bone” could be moved easily if connected only by the medullary bone. The author reported orthodontic correction in six to twelve weeks without root resorption. Presently, significant scientific interest has emerged in these sur- gical approaches for accelerating tooth movement. The techniques pro- posed in the last twelve years are dental distraction, dentoalveolar dis- traction (DAD), periodontally accelerated osteogenic orthodontics (PAOO) and speedy orthodontics. All these techniques use corticotomies or osteotomies as basic procedures to modulate tooth movement. These different procedures have created some degree of confusion among clini- cians. To summarize the different techniques, Figure 1 illustrates the three options available to expedite tooth movement based upon the type of surgical procedure and the type of orthodontic force. 235 Corticotomies and Other Adjuncts + Force Orthopedic Forceſ + Distraction +º, + Figure 1. Osseous surgical procedures and types of forces to expedite tooth movement. DENTAL DISTRACTION (PERIODONTAL DISTRACTION) Periodontal distraction, also known as desmodental distraction, is based on the process of rapid osteogenesis wherein the periodontal ligament on the mesial side of the distracted tooth changes its morphol- ogy in four weeks from stretched and wide with active striated bone for- mation to a normal width. The periodontal ligament (PDL) attachment to new alveolar bone and lamina dura once the movement is completed also is evident. In 1998, Liou and Huang proposed the periodontal ligament dis- traction technique for technique for rapid canine retraction. In their re- port, the surgery consisted of a first premolar extraction in combination with simultaneous undermining of the interseptal bone distal to the ca- nine. More specifically, vertical grooves were made inside the extraction socket on the lingual and buccal sides, from the crestal bone to the socket base. However, the surgical cuts did not penetrate the lingual or buccal cortical plates (Fig. 2). Immediately after surgery, a tooth-borne intraoral distractor was cemented on the canine and on the first molar and actic vated. According to the authors, the interseptal bone distal to the canine followed the tooth closely during the distraction until contacting the me: sial interseptal bone of the second premolar. After three months, the ra: diographic characteristics of the region are similar to those of normal interseptal bone. This technique has been employed not only for mesio- distal tooth movements, but also for vertical movement of ankylosed and displaced teeth (Wilmes and Drescher, 2009). 236 Uribe et al. º Figure 2. Lateral and occlusal view of periodontal distraction surgical procedure. The black lines depict the surgical cuts in the interseptal bone distal to the ca- nine after the extraction of the first premolar. Note that the buccal and lingual cortical plates are left untouched, thereby creating a trough for the distal move- ment of the canine. Immediately after the surgery, a dentoalveolar distractor is Cemented to the canine and the molar. PERIODONTALLY ACCELERATED OSTEOGENIC ORTHODONTICS (PAOO) Wilcko and colleagues (2001) proposed a selective decortica- tion-facilitated orthodontic technique combined with periodontal alveolar augmentation (bone grafting) to reduced treatment time and to increase the volume of alveolar bone. The surgical procedure consists of interproximal vertical and horizontal circumscribing decortications in the buccal and lingual aspects of the root of all the teeth undergoing move- ment. In addition to the decortications, numerous perforations are drilled into the cortical layer (Fig. 3) and resorbable grafting material is applied to the perturbated bone and any exposed root surfaces. No luxation is performed after the selective decortication. Orthodontic forces are applied immediately after the surgical Procedure and orthodontic adjustments are performed every two weeks. 237 Corticotomies and Other Adjuncts Figure 3. Interproximal and circular groove corticotomies in PAOO surgical procedure. Wilcko and coworkers reported that this technique allowed for the reso- lution of severe crowding in two patients within six months without periodontal sequelae. The authors explained the enhanced speed of Or- thodontic treatment to be the result of the regional acceleratory phe- nomenon, which causes transient osteopenia and increases bone turnover. In the literature, the use of PAOO has been applied to correct crowding (Wilcko et al., 2001, 2003; Nowzari et al., 2008), molar intru- sion (Hwang and Lee, 2001; Oliveira et al., 2008), molar uprighting and protraction (Kim et al., 2009a) and molar distalization (Spena et al., 2007). A less invasive procedure called corticision has been tested in a cat animal model with positive results related to the speed of tooth movement (Kim et al., 2009b). This application was taken to the clinical arena and applied as a method called piezoincision. Piezoincision is a technique in which the corticotomy is approached interdentally with a piezotome, after a small interproximal incision is made. This technique 238 Uribe et al. mimics PAOO in that a grafting material also is tunneled through the incisions to build up alveolar ridge width (Dibart et al., 2009). SPEEDY ORTHODONTICS Speedy orthodontics is a type of corticotomy-assisted orthodon- tic treatment that provides for rapid movement of dental segments with application of orthopedic forces using temporary anchorage devices. Chung and coworkers (2009) described this procedure for treating adult patients with dentoalveolar bimaxillary protrusion. The Speedy ortho- dontic technique was used in combination with a mandibular subapical Segmental osteotomy to set back the canine-to-canine segment immedi- ately. The surgery procedure consisted of extraction of first premolars followed by vertical and horizontal corticotomies at the first premolars sites and removal of cortical bone. After two weeks (to allow sufficient healing of palatal soft tis- Sue), a buccal corticotomy was performed and the buccal cortical plate was removed. A C-plate then was placed on the midpalatal bone area and a force heavier than 500 grams per side was applied to retract the anterior bony segment (Fig. 4). In four months, the retraction was complete with no evidence of root resorption. With this osteoplastic technique, the al- Veolar bone, depleted of the cortical plates and subjected to heavy forces, is compressed and can be repositioned easily. The substantial difference in the speedy orthodontics and corti- cotomies techniques is the presumed mechanism of tooth movement ac- celeration. In speedy orthodontics, the faster tooth movement is through the reduction of mechanical bone resistance, while in corticotomies the enhanced speed is attributed to a biological effect on the dentoalveolar complex. Indeed, Wilcko and coworkers (2008) contend that the cortico- tomies increase the biological bone turnover using orthodontic forces, thereby enhancing the rapidity of tooth movement, while Chung and col- leagues (2009) believe that the mechanical repositioning of a dentoalveo- lar segment through the application of orthopedic forces is responsible primarily for the enhanced tooth movement. DENTOALVEOLAR DISTRACTION Anteroposterior Distraction In 2002, Kišnisci and colleagues introduced the dentoalveolar distraction technique (DAD) to achieve rapid canine retraction. This tech- 239 Corticotomies and Other Adjuncts Figure 4. Speedy orthodontics procedure. The red line indicates the flap needed to access the bone for corticotomies. Black indicates corticotomies and extrac- tion of the first premolars. Note a horizontal palatal corticotomy connecting the extraction sites is performed as an initial surgery (A). Horizontal and vertical corticotomies on the labial side are performed two weeks later to preserve vital- ity of the dentoalveolar segment (B and C). After surgery, a C-plate (yellow) is placed in the midpalate to retract the anterior segment that has been splinted with a lingual bonded appliance. nique applies the principles of bifocal distraction osteogenesis where a vascularized dentoalveolar segment is moved progressively, after being separated from the adjacent alveolar bone. This technique differs from the monofocal distraction as a transport disk (vascularized dentoalvolar segment) is created to be displaced along the adjacent bone to fill a de- fect. Mobilization of the “transport dentoalveolar segment” then Was carried out (Fig. 5). At the end of the procedure, a tooth-borne intraoral distraction device was cemented onto the canine and first molar. DistraC- tion started three days after surgery and the device was activated twice per day (0.8 mm per day) to achieve the desired amount of movement. The procedure was completed in approximately ten days. The authors claimed the distal displacement of the canine was a combination of tip- ping and translation due to the lower position of the distractor compared to the center of resistance of the canine. Fixed orthodontic appliances were bonded immediately after the completion of canine distraction to ſº 240 Uribe et al. U \, Figure 5. Layout of DAD surgical procedure. The black lines represent the os- teotomy of the dentoalveolar segment of the canine that will become a transport Segment (bifocal distraction). A dentoalveolar distractor is cemented to the mo- lar and canine at the end of the surgery. The dentoalveloar transport segment Will dock with the mesial bone of the second premolar. tract the incisors and refine the occlusion. No apical root resorption, an- kylosis, soft tissue dehiscence or loss of anchorage was detected. Vertical Distraction Many authors have described the vertical repositioning of a dento-osseous segment by a distraction osteogenesis technique. Kofod and collaborators (2005) and Alcan (2006) detailed the repositioning of an infra-erupted ankylosed central incisor by combining osteotomy pro- cedures with a tooth-borne distractor that was attached to the incisor brackets and the arch wire or to an acrylic splint (Fig. 6A). Both proce- dures required ten days of distraction to erupt the incisor into the ade- Quate vertical position in the arch. In 2003, Kinzinger and colleagues used a bone-borne intraoral distractor for the same purpose (Fig. 6B). After eighteen days the distraction was completed without any complica- tions. 241 Corticotomies and Other Adjuncts A B Figure 6. DAD procedure to reposition ankylosed central incisor utilizing (A) tooth-borne distractor. Black lines represent horizontal and vertical osteotomies creating a “floating tooth.” The tooth had root canal therapy previously and the apex was amputated with the horizontal osteotomy. A: Tooth-borne distractor was bonded to the ankylosed tooth and anchored to an acrylic splint covering the other maxillary teeth. B. A bone-borne distractor where the moving segment (ankylosed incisor) and anchor segment are secured with bone screws. When comparing a bone-borne to a tooth-borne distractor, the former has more drawbacks than the latter; namely, a greater chance of infection due to the temporary projection of the appliance into the vesti- bule and the need for a second surgery to remove the distractor. In an effort to avoid these disadvantages of bone borne distractors, Dolanma/ and coworkers (2010) described the repositioning of an ankylosed central incisor osteotomy segment using continuous distraction forces produced by conventional orthodontic mechanics, instead of a distractor. This pro- cedure used “light” orthodontic force and lasted about two weeks without any soft tissue or alveolar bone compromise. Most of the osteotomies performed in conjunction with an ortho- dontic force have been reported with respect to ankylosed maxillary Cell: tral incisors. The anatomic location of this tooth allows adequate access 242 Uribe et al. to perform the subapical osteotomy needed to mobilize the dentoalveolar segment. For this reason, this procedure is not applicable to teeth close to the mandibular dental nerve or in areas limited by crucial anatomic struc- tures, such as the roots of mandibular molars or high impacted, anky- losed canines. Recently at the University of Connecticut, a vertical DAD tech- nique was used to reposition an impacted ankylosed canine. A maxillary left canine that was erupting ectopically between the central and lateral incisors was resorbing the roots of these teeth (Fig. 7A). The canine was exposed from the labial aspect and a force was applied by means of a lever arm from the maxillary left molar. The canine was moved success- fully to a position just distal to the canine region (Fig. 7B) and an occlu- sal force then was applied with a cantilever from the molar. After no movement was evident in a five-month period, the tooth was re-exposed and subluxated to achieve noticeable movement during the surgical in- tervention. Additionally, the crestal bone occlusal to the tooth was re- moved to decrease the resistance to eruption. Orthodontic forces were applied for an additional ten months to no avail. The options at this point were extracting this tooth or attempting an osteotomy to bring the entire dento-Osseous complex incisally. After discussing the options with the patient, it was decided to attempt the osteotomy of the canine with the application of a heavy orthodontic force. The procedure consisted of the elevation of a muco-periosteal flap on the labial side of the alveolar bone with a piezotome to prevent injury to the canine and the adjacent anatomical structures. Initially two shallow vertical corticotomies were extended interproximally to the apex of the canine. A periapical radiograph was taken with surgical blades used as radiopaque markers inserted in the corticotomy lines, allowing for verification of the surgical cuts. After confirmation of an adequate path, the corticotomies were converted into two vertical osteotomies. One horizontal osteotomy was performed above the apex of the canine through the buccal cortex and the medullary bone, leaving the palatal cortex intact. The dentoalveolar segment was mobilized to ensure no re- sistance (Fig. 7C). A base archwire was placed bypassing the canine and a 0.014” NiTi wire was overlayed to start delivering an incisal force. Two weeks later, the canine tip was observed clinically and a cantilever (150 grams) was added extending from the molar to increase the amount of force delivered (Fig. 7D). The tooth was displaced approximately 6 mm from its impacted location into the arch in one month (Fig. 7E). The Satisfactory results achieved in this patient suggest that DAD is a promis- 243 Corticotomies and Other Adjuncts Figure 7 (this page and next). Vertical dentoalveolar osteot- omy of ankylosed canine. A. Maxillary right canine resorbing the central and lateral incisors roots. B. Canine brought dis- tally above the lateral incisor root into the canine region with orthodontic force. C. Osteotomy of the ankylosed canine. ing technique for moving infrapositioned ankylosed canines to the occlu- sal plane. The magnitude of force needed to obtain tooth movement after the osteotomy and mobilization procedure in a vertical DAD is uncertain. Since the resistance to eruption primarily is the soft tissues, a distraction appliance that generates a heavy force may not be necessary. 244 Uribe et al. Figure 7 (continued). D. Overlay NiTi archwire to bony seg- ment containing canine. E. Bony segment containing canine successfully repositioned with orthodontic force. “SURGERY FIRST’” TO EXPEDITE ORTHOGNATHIC SURGERY A final procedure that has yielded significant promising results With a possible paradigm shift for expedited tooth movement is the con- Cept of “surgery first.” The combined treatment of orthodontics and or- thognathic surgery usually is lengthy. Recently, O’Brien and colleagues (2009) reported on the effectiveness and efficiency of orthognathic sur- gery combined with orthodontics in a prospective clinical trial. They found that on average, the total treatment time from the insertion of fixed appliances to the removal of appliances was 32 months. Moreover, the Pre-Surgical time spent optimizing the dental arches prior to surgery was 25 months. This lengthy treatment time was similar to findings of an- other study where the median duration of pre-surgical orthodontics was 17 months (Luther et al., 2003). 245 Corticotomies and Other Adjuncts Considering these findings, it seems reasonable that eliminating the pre-surgical phase and performing orthognathic surgery without the alignment of the arches could expedite the treatment time. The feasibility of this approach has been facilitated by skeletal anchorage. The place- ment of four plates, one in each quadrant, would allow control following any inaccuracies in Surgical outcomes or post-Surgical relapse tendencies. Other advantages of the “surgery first” approach are elimination of the decompensation of the malocclusion with pre-surgical orthodon- tics, preventing the accentuation of the dentofacial deformity (Fig. 8) and the elimination of the soft tissue imbalance after surgery, which may fa- cilitate the orthodontic movement. Finally, because osteotomies consti- tute a significant surgical insult, there may be a RAP phenomenon gener- ated that could enhance the speed of tooth movement. In fact, Mueller and colleagues (1991) described a Systemic Acceleratory Phenomenon (SAP) with a distant surgical bone insult. Although this phenomenon may be a factor influencing the significant reduction in treatment times, more research is needed to understand the biology behind the perceived accelerated tooth movement after orthognathic surgery. Case Report A 21-year-old female presented with chief complaint: “I don’t like how my lower jaw protrudes.” The patient had a previous orthodon- tic consult and was aware that she needed orthognathic surgery to achieve a more harmonious soft tissue balance concurrent with orthodon- tics to address the malocclusion. Of great concern to the patient, how- ever, was the extensive treatment time associated with orthodontic appli- ances and the accentuation of the dentofacial deformity prior to surgery. When informed about a new approach that does not involve pre-surgical orthodontics and the possibility of finishing treatment in less than a year, the patient was excited to explore this option. The patient exhibited a slightly concave skeletal and soft tissue profile with a mildly retrusive maxilla and a mildly protrusive mandible. No gross asymmetry was noted from the frontal plane. The malar promi- nences were deficient, the mentolabial sulcus was absent and the lower lip was protrusive (Fig. 9A-E). Occlusally, the patient had almost a full cusp Class III molar and canine occlusion. However, the central incisors had positive overjet in that the lower incisors were retroclined and crowded. The maxillary lateral incisors were in anterior crossbite with the mandibular canines and a unilateral dental cross bite was evident dis- tal to the right maxillary second premolar (Fig. 9F-K). 246 Uribe et al. Figure 8. Decompensation of a Class III malocclusion with significant accentua- tion of the dentofacial deformity. Figure 9 (this page and next). Initial photos and x-rays of a patient with a mild dentofacial deformity and Class III malocclusion. 247 Corticotomies and Other Adjuncts The maxillary arch had minimal amount of crowding with an adequate arch form with the exception of the right first molar, which was positioned lingually. Additionally, the lateral incisors previously had been contoured labially with composite veneers to compensate for their lingual alignment. The surgical plan consisted of a 3 mm maxillary advancement and a 3 mm mandibular setback. Immediately post-surgery, the patient was expected to have a 5 mm overjet in order to align the lower incisors through flaring, achieving an appropriate incisor inclination (Fig. 10). Fixed appliances were placed one week before surgery. No arch wires were inserted and surgical stents were fabricated at this time. On the day of Surgery, the patient was brought to the operating room and given general anesthesia. At this point, a maxillary 0.016° x 0.022.” Niſ archwire and a mandibular 0.016.” NiTi arch wire were tied in and the Osteotomies were started thereafter. 248 Uribe et al. Figure 10. Surgical prediction. The patient presented one month after surgery with minimal SWelling and what could be considered a Class I malocclusion (Fig. 11). The bracket of the maxillary left lateral incisor, which had becomes debonded during surgery, was rebonded and the archwires retied. The patient wore short Class III elastics full time to maintain the occlusal re- lationship. The alignment phase continued for three months (Fig. 12) until both arches were aligned almost fully, although the lower arch was Skewed slightly. In order to resolve this issue, several stops were placed mesial to the left first premolar and mesial to the right central incisor and ºtra wire was added in this region. After five months, the patient was fitted with a 0.019° x 0.025” maxillary stainless steel arch wire and a mandibular 0.017" x 0.025” [3- tanium archwire. Finishing bends were placed and box elastics with a Class II vector to achieve perfect anterior contacts were prescribed. 249 Corticotomies and Other Adjuncts Figure 11. Extraoral and intraoral photos one month after surgery. After six months the patient was debonded (Fig. 13), and an ex- cellent aesthetic and occlusal outcome was evident. A maxillary vacuum- formed retainer was delivered and a mandibular 0.01.75” stainless steel braided wire was bonded between the mandibular canines including all the incisors. 250 Uribe et al. Figure 12. Intraoral photos three months after Surgery. CONCLUSIONS Different ancillary surgical procedures are available to enhance the speed of orthodontic tooth movement. Although these techniques *PDear promising, more research is needed to evaluate their efficiency and define clear indications for their use. 251 Corticotomies and Other Adjuncts Figure 13 (this page and next). Extraoral and intraoral photos and x-rays at the end of treatment, six months after surgery. “Surgery first’ is an attractive alternative approach for orthog- nathic surgery cases. Radical reductions in treatment times have been shown for patients with this approach. 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RANK/RANKL/OPG during orthodontic tooth move- ment. Orthod Craniofac Res 2009; 12:113-119. Yoshida T, Yamaguchi M, Utsunomiya T, Kato M, Arai Y, Kaneda T, Yamamoto H, Kasai K. Low-energy laser irradiation accelerates the velocity of tooth movement via stimulation of the alveolar bone re- modeling. Orthod Craniofac Res 2009;12:289-298. 256 EXPERIMENTAL EVIDENCE SUPPORTING THE USE OF MINISCREW IMPLANTS IN ORTHODONTIC PRACTICE Peter H. Buschang, P. Emile Rossouw, Rolf G. Behrents ABSTRACT This review summarizes recently conducted experimental studies pertaining to the use of miniscrew implants (MSIs). Studies focusing on MSI characteristics have shown that shorter length (3 mm) MSIs hold great potential for future use in orthodontics, that reductions in pitch and the incorporation of longitudinal flutes may be effective ways of increasing the holding strength of MSIs placed in immature or thin cortical bone and that sandblasted and acid-etched surfaced MSIs promote incorporation of greater amounts of cortical and non-cortical bone around the implant than machine surfaced MSIs. Our studies evaluating placement site characteristics have shown that up to 34 kg of force are required to pull an MSI out of mandibular bone, that MSI orientations have substantial effects on the resistance-to-failure, that increases in bone density have greater potential to cause damage than to increase the holding strength of MSIs, that optimal pilot holes sizes create the least amount of damage and provide maximal holding strength and that there are clinically significant differences in cortical bone thickness between and within placement sites. Studies evaluating loading characteristics have shown that significantly more failures are associated with higher than lower loads, but that there is less bone formed around unloaded than loaded MSIs. Studies specifically designed to evaluate potential root damage have shown that MSIs can damage all aspects of the tooth as well as surrounding bone and periodontal ligament. While most (64%) damaged teeth heal normally, lack of normal PDL and bone regeneration, bone degeneration in the furcation area, ankylosis and inflammatory responses are not uncommon. Using MSIs to control the forces, our studies also demonstrate that there is no relationship be- tween the amounts of force applied to a tooth and the amounts of movements (intrusive or anteroposterior) or root resorption that occurs. Using MSIs to ex- pand the Sagittal suture, we have shown that continuous forces produce substan- tially more sutural bone than intermittent forces, that there is a specific rate of Sutural separation that produces the maximum amount of bone and that rhEMP- 2 may enhance sutural bone formation upon expansion. KEY WORDS: miniscrew implants, tooth movement, beagle dogs, pitch 257 Experimental Evidence Over the past 10 years, miniscrew implants (MSIs) have become one of the most popular devices used by orthodontists because, if used appropriately, they can improve the quality of treatment. A recent survey showed that the vast majority (79%) of the American Association of Or- thodontists membership felt that MSIs have made their treatment more effective (Buschang et al., 2008); MSIs do not appear to improve treat- ment efficiency (Fig. 1). MSIs are the smallest skeletal anchorage de- vices available, which makes them extremely versatile. They can be placed easily in multiple locations, removal is fast and typically unevent- ful, they are affordable and do not require a healing period prior to force activation. Unfortunately, there currently is no consensus concerning the terminology used for MSIs. The prefix micro-, as in micro-implant and microscrew implant, is inappropriate because micro denotes a factor of one millionth, which is far too small for MSIs. The terms bone screws and miniature implants are not descriptive sufficiently: the first set of terms provides no indication of size or osseointegration; the second set does not specify the shape of the device. Temporary anchorage devices (TADs) do not indicate size or shape. More importantly, the acronym TAD is not specific enough; MSIs, headgears, lip-bumpers, lingual arches and numerous other orthodontic appliances also qualify as TADS. Miniscrew implants indicate size, shape and Osseointegration. While variation is substantial, the majority of practicing ortho- dontists (approximately 67%) reports that MSIs fail less than 25% of the time (Buschang et al., 2008). Those with greater failure rates also had the least experience with MSIs and expressed the greatest dissatisfaction with MSIs (Fig. 2). Less experience leads to increased failure, which in turn results in decreased usage. A recent systematic review found that most studies report suc- cess rates greater than 80% when mobile or displaced MSIs are included (Reynders et al., 2009). Importantly, this review showed that, despite all of the work that had been performed, there is a definite lack of under- standing pertaining to patient acceptance of MSIs, the severity of adverse events associated with their use and the factors that influence MSI suc- cess. Retrospective cross-sectional clinical studies, which are subject to various sources of uncontrolled variation and bias, cannot be expected to clarify these issues. Future improvements depend on well-controlled clinical and experimental studies. Experimental studies provide the best means for determining the causal factors necessary to optimize the use of MSIs in orthodontics. 258 Buschang et al. 00 Have MSls made treatment faster? Have MSls made treatment better? 100 DYes - No ºn Don't Know 9 0 90 | TYes | No I.Don't Know 8 o 80 7 0. 70 6 0. 60 5 0 50 4. 0. 40 i i 3. 0. 30 2 0. 20 10 10 0. o Figure 1. Survey results of 564 AAO members (65% US and 35% non-US: 58% had practiced more than 15 years) evaluating whether MSIs have made ortho- dontic treatment faster or better (Buschang et al., 2008). Previous studies have shown that MSIs osseointegrate, as de- fined by Bränemark and colleagues (1969) and that the amount of inte- gration that occurs is variable highly among screws. Melsen and Costa (2000) showed that osseointegration ranged from approximately 10% to 58%, depending on the duration of time after insertion; Büchter and co- Workers (2006) reported osseointegration ranging from approximately 50% + 15% after 22 days to 83% + 13% after 70 days. Our histological investigations also have shown variation in bone-to-implant contact ranging from 2% to 100% for 6 mm long MSIs after 110 days post-insertion (Woods et al., 2009). There also were dis- tinct differences in osseointegration between stable and mobile MSIs; the latter showed no evidence of bone-to-implant contact, whereas the for- mer always showed some osseointegration (Fig. 3). Mobile MSIs were Surrounded by fibrous tissue—the more fibrous tissue around the screw, the greater the mobility. While the available studies indicate that only limited amounts of osseointegration are necessary for MSI stability, the high degrees of variability observed for smooth machined MSIs could Prove to be problematic for certain applications (e.g., young children and older patients with thin, less dense cortices). The purpose of this review is to summarize recent experimental Studies conducted at Baylor College of Dentistry (BCD) and Saint Louis University (SLU). Each institution brings its own strengths: BCD pro- Vides excellent animal facilities and bone biologists focused on the cranio- 259 Experimental Evidence [] Less than 1 year || 1-3 years [] 3-5 years L. More than 5 years 7 0. px.001 0 0 - : 0 1 : - i i None Less than 10% 10-25% More than 25% A Percentage of Failures 5 0. p3.001 4. 0 3. 0. 2 0. 1 0. - 0 | i T None Less than 10% 10–25% More than 25% Percentage of Failures Figure 2. A. Percentages of failures of MSIs related to years of use. B. Percent- ages of satisfaction with the use of MSIs. (Adapted from Buschang et al., 2008.) facial complex, SLU provides unique mechanical testing apparatus and bioengineering expertise. This review covers studies that experimentally evaluate: MSI characteristics that improve stability; Placement site characteristics that improve stability; Loading characteristics that influence stability; Potential root injuries; and Clinical applications of MSIs. 260 Buschang et al. Figure 3. Representative photomicrographs of the coronal (Cor), middle (Mid) and apical (Api) sections of stable (A, B and C) and mobile (D, E and F) MSIs. (Adapted from Woods et al., 2009.) MSI CHARACTERISTICS Miniscrew implants should be designed to maximize primary Stability (initial mechanical retention in pre-existing bone) and secondary Stability (healing; mechanical retention in new bone). Theoretically, the Overall stability of MSIs can be enhanced by either delaying the decel- eration in primary stability that occurs over time after insertion, or accel- erating the increases in secondary stability that occur with healing (Fig. 4). Unfortunately, increases in primary stability often damage the Surrounding bone. In fact, the insertion of most MSIs damages the sur- rounding bone. Finite element analyses have shown that the insertion of MSIS produces bone strains above physiologic limits (Nam et al., 2008) that could cause damage, increase remodeling requirements and have a negative impact on both primary and secondary stability. Ideally, MSIs should require only minimum insertion torque (i.e., producing less bone Strain, heat and damage), provide maximal holding strength immediately after insertion and establish a local environment that accelerates the heal- ing process. Primary stability of an MSI depends on its interaction with the bone at the time of placement. As MSIs are inserted into bone and meet resistance, shear stresses develop along the length of the screw. While these stresses increase primary stability initially and temporarily, their effects on insertion torque and pullout force should not be expected to be equivalent. Consequently, both measures need to be evaluated in order to understand how changes in the physical characteristics of MSIs influence 261 Experimental Evidence 100 …~ ----- 80 * E 60 º Overal # 40 . Seconoia s ſy 20 0 100 8 0 Overal - Primary Secondary - º I I I i i I 0 1. 2 3 4. 5 6 7 8 Time (weeks) Figure 4. Increases in overall MSI stability associated with (A) decelerating the primary stability (old bone) curve and (B) accelerating the secondary stability (new bone) curve. primary stability. Increasing the shear forces that develop along the screw increases the strain and microfractures, which might be expected to affect the healing process and lead to degeneration or necrosis at the interface. Bone damaged during MSI insertion requires repair, too much of which can result in screw loosening. As such, primary stability has a direct and important effect on secondary stability. Because the primary and secondary stability of MSI remain un- derstood poorly, we recently conducted a prospective study evaluating changes in MSI stability over time (Ure et al., 2011). This study is unique because it measures stability in vivo in beagle dogs over time us: ing the Osstell Mentor (Osstell AB, Göteborg, Sweden). The Mentor produces an electromagnetic signal that causes the MSI to vibrate via an attached magnetic peg. The results showed significantly greater de- 262 Buschang et al. creases in the primary stability during the first three weeks for MSIs that failed than for those that remained stable (Fig. 5A). MSIs placed in non- keratinized tissue – most of which eventually failed – also exhibited sig- nificantly greater decreases in MSI stability during the first three weeks than MSIs placed in keratinized tissue (Fig. 5B). The stability of the MSIs placed in keratinized tissue also decreased during the first three weeks and increased significantly thereafter, indicated healing and in- creased secondary stability (Fig. 6). Interestingly, the Mentor appeared to be sensitive enough to identify a disruption of the healing process after the fifth week associated with the administration of NSAIDs, which are known to inhibit bone résorption and therefore, bone remodeling. This study is important because it shows that MSI failures can be predicted and that the primary and secondary stability curves of MSIs are similar to the curves demonstrated previously for endosseous implants. Effects of MSI Length One of the easiest ways to increase the surface area and, there- fore, the primary stability of MSIs is to increase their length. The ortho- pedic literature has shown that implant length is one of the most impor- tant factors determining mechanical holding strength (Hitchon et al., 2003). Increases in strength might be expected because it long has been known that the holding power of a screw is proportional to the amount of thread engagement (Lyon et al., 1941). The problem is that longer screws limit where MSIs can be inserted. The question is: how short can MSIs be and still remain stable? We recently compared 6 mm long commercially available (Den- tos, Inc., Daegu, Korea) MSIs to identical 3 mm long MSIs (Mortensen et al., 2009). Success rates six weeks after immediately loading were higher significantly for the 6 mm (100%) than the 3 mm (67%) MSIs (Table 1). The differences in success were due to the fact that the tips of Some of the 3 mm MSIs sheared off during insertion, which might be expected to ream out bone around the screw during insertion and de- crease stability. Moreover, dog #3, which was described in the veterinar- ian notes as “unusually active and prone to chewing on the run bars and food bowls,” accounted for 60% of the failures. Excluding all (those that failed and did not fail) of the MSIs from that dog, as well as the sheared MSIs, a success rate of 91% was produced. Importantly, neither the 3 nor the 6 mm MSIs were inserted completely into bone; postmortem evalua- tions showed that the average thread depths were 3.9 mm for the 6 mm MSIs and 1.6 mm for the 3 mm MSIs (Caraway, 2007). Three recent exper- 263 Experimental Evidence 3. -6 is - Failed MSls - Stable MSIs -10 - Time (weeks) º: () –2 –4 8 – Non-keratinized - Keratinized Ti e (weeks) - Figure 5. A. Differences (* = P × 0.05) in implant stability quotient (ISQ) of MSI that failed vs. those that did not fail. B. MSIs placed in non-keratinized vs. keratinized tissues. (Adapted from Ure et al., 2011.) B -12 264 Buschang et al. Stability=P-S Stability=S-P 3. 0 1 2 3 4. 5 6 7 8 Time (weeks) Figure 6. Changes in the implant stability quotient (ISQ) over time, with hypo- thetical primary (P) and secondary (S) stability curves. (Adapted from Ure et al., 2011.) Table 1. Overall and net (excluded sheared MSIs and all MSIs of dog #3) suc- cess rates of 3 mm and 6 mm MSIs. (Adapted from Mortensen et al., 2009.) overall success Rate Net success rate Experimental MSIs 75% (30/40) 97% (28/29) 3 mm 68% (20/30) 95% (20/21) 6 mm 100% (10/10) 100% (8/8) P º 0.05 P & 0.05 iments using a total of 162 loaded and unloaded 3 mm MSIs showed an Overall Success rate of 91.4% (Liu et al., 2009, 2010, 2011). While de- Sign changes are required to enhance their stability further, shorter MSI hold great future potential for providing orthodontists even greater versa- tility in terms of placement sites. 265 Experimental Evidence Effects of Pitch and Fluting Another way to increase the surface area and primary stability of MSIs is to decrease the pitch (i.e., the distance between the threads). It is well established that pitch increases the purchase strength of screws in porous materials. Decreases in pitch previously have been shown to in- crease pullout strength of bone screws (DeCoster et al., 1990; Chapman et al., 1996). Because there had been no previous studies evaluating the ef- fects of MSI pitch on both insertion torque and pullout strength, we compared MSIs that differed only in terms of pitch. All of the MSIs were made of surgical grade titanium, were 6 mm long and were self-drilling and self-tapping (Brinley et al., 2009). In addition, the miniscrews had major and minor diameters of 1.8 mm and 1.6 mm, respectively, the threads had a 90° asymmetric buttress design and the apical 3 mm of the MSIs were tapered. The control MSIs, which had 1.0 mm pitch, were compared to MSIs with 0.75 mm and 1.25 mm pitch MSIs using syn- thetic bone. While insertion torque increased with decreases in pitch, the differences were small and not significant statistically (P = 0.275). Com- pared to the 1.0 mm pitch screws, the insertion torque of the 0.75 and 1.25 mm pitch MSIs were only 7.2% greater and 3.6% less, respectively (Fig. 7). In contrast, pullout strength was over 105% greater with the 0.75 mm than 1.0 mm pitch MSIs; the pullout strength of 1.25 mm pitch MSIs was approximately 18% greater than the 1.0 mm MSI. The effects of pitch on pullout were associated clearly with bone density. When the MSI were inserted in denser human cadaver bone, the differences in pullout strength were only 7.1% greater for the 0.75 mm than for the 1.0 mm pitch MSIs. Together, these results suggest that changes in pitch might be an effective approach for increasing stability in patients with immature or thin cortical bone. The same study also evaluated the effects of fluting (Brinley et al., 2009). Three longitudinal flutes, extending the full length of the threaded portion, were added to the control MSI design. The depth of each flute extended through the threads to the core; each flute was 0.25 mm wide and the surfaces of the flutes were beveled, giving them a cut- ting edge to facilitate placement and removal. Results showed even more pronounced differences between synthetic and cadaver bone for fluting than for pitch. In the softer synthetic bone, insertion torque and pullout were 15% and 400% larger, respectively, for the fluted MSIs (Fig. 8). In the denser cadaver bone, insertion torque increased by 120%, while pull-out 266 Buschang et al. 9.5 p = .275 7.1% # =#H#Pºs 25 20 - 105.2% f 15 - B 0.75 mm 1.0 mm 1.25 mm Figure 7. The effects of MSI pitch on (A) insertion torque and (B) pullout strength testing using synthetic bone with percent changes based on the 1.0 mm pitch MSI. (Adapted from Brinley et al., 2009.) increased only 65%. This research suggests that fluting also could be used to enhance the primary stability of screws placed in thinner, less dense bone, which might be expected to better adapt to the flutes. SLA Coating Surface modification of endosseous implants has proven to be ºne of the best ways to increase surface area, accelerate secondary stabil- ity and enhance osseointegration. Sand blasted large-grit and acid-etched (SLA) titanium surfaces on endosseous implants exhibit significantly greater shear strength than machined surfaces (Buser et al., 1999). SLA surfaces also increase the rate of osseointegration (Abrahamsson et al., 2004; Chang et al., 2009). The effects that SLA surfaces have on MSIs are controversial and studies remain limited. Kim and coworkers (2009) 267 Experimental Evidence 25 - Insertion (Ncm) 20 p“.001 A 15 p“.001 10 5 - I i t Fluted Control Fluted Control Synthetic Bone Cadaver Bone Pullout (N) Fluted Control Fluted Control Figure 8. The effects of MSI longitudinal fluting on (A) insertion torque and (B) pullout strength testing using (A) synthetic and (B) cadaver bone, with percent changes based on the 1.0 mm pitch MSI. (Adapted from Brinley et al., 2009.) reported significantly lower insertion torque and significantly higher total removal energy (energy [J) required to remove MSI from maximum torque through time of removal) for SLA than machined MSIs, but no differences in removal torque. More recently, Mo and coworkers (2010) showed that SLA- coated MSIs (9.5 x 1.8 mm) produced significantly greater removal torque than machined MSIs (8.2 vs. 5.8 Ncm, respectively) during the first six weeks after placement, but no differences in removal torque were evident after 10 weeks. The actual effects of SLA modification On the bone in the vicinity of the MSI remain understood poorly. Using a split-mouth design to determine the effects of SLA coat- ing on secondary stability, 21 SLA coated MSIs were compared to 21 machine-surfaced MSIs (Ikeda et al., 2011). The MSIs were placed in seven mature foxhounds and loaded immediately with a 200 g force. 268 Buschang et al. which was maintained for an average of 9.2 weeks. Micro-CT (u0T) was used to determine the absolute and relative amounts of bone surrounding the MSI. Two very thin layers of bone surrounding the MSI were evalu- ated; one layer included bone located 6 to 24 plm from the MSI surface; the other layer included bone 24 to 42 um from the MSI. For each specimen, separate ratios of bone volume to total volume (BV/TV) were calculated for both the superior cortical and the more inferior non- cortical portions of the MSI. The results showed significantly (P º 0.05) greater amount of bone (5% to 21%) around the SLA coated than ma- chined miniscrews (Fig. 9). SLA coating had the greatest effects in the most coronal aspects of both the cortical and non-cortical sections evalu- ated (Fig. 10), which were also the regions exhibiting the greatest BV/TV. PLACEMENT SITE CHARACTERISTICS As indicated previously, the ability of an implant to provide an- chorage depends on its interaction with the bone into which it is inserted. Difference in the quality and quantity of bone into which MSI are placed might be expected, therefore, to influence both their primary and secon- dary stability. - Figure 9. A. Micro-CT (uCT) of bone block and peri-bone to implant contact (PBIC) 6 to 24 um thick surrounding the MSI (green). B: PBIC of machine Sur- faced. C. PBIC of sand blasted large-grit and acid-etched (SLA) MSIs. (Adapted from Ikeda ef al., 2011.) 269 Experimental Evidence -Machined - -SLA 1.2 1.2 1.0 -Machined - -SLA 1-0 0.8 . 0.8 Apical i 24.6. i 2.4.º Apical A d d - - B o 0. - 0. 100 200 300 400 -00 600 d 100 200 add 400 500 600 slice number slice Number 1.2 1.2 1.0 -Machined --SLA - -Machined --SLA # 0.8 - * 0.6 S. ºn 0.4 0.2 C. o.o. coronal Apical D on coronal - Apal d 100 200 300 400 500 600 º 100 200 300 400 500 600 Slice Number slicenumber Figure 10. SLA vs. machined surfaces peri-bone-implant contact. A Cortical section 6 to 24 um. B. Cortical section 24 to 42 um. C. Non-cortical section 6 to 24 um. D. Non-cortical 24 to 42 um. (Adapted from Ikeda et al., 2011.) MSI Orientation One of our earliest studies was designed to evaluate the effects of MSI orientation on the stability and resistance to failure at the bone- to-implant interface (Pickard et al., 2010). We also wanted to determine the maximum amount of force that a MSI (6 mm long and 1.8 mm Outer diameter) placed in the human mandible might be expected to withstand. Ninety MSIs were allocated into nine groups of 10 each and placed in nine fresh human cadaver mandibles. A 1.1 mm pilot hole was drilled using a guide and the MSIs were inserted at either 90° angles to the bone surface, angled at 45° along the maximum axis of stiffness or angled at 45° along the minimum axis of bone stiffness (Fig. 11). Pullout forces were oriented at 90° to the bone surface; shear forces were applied paral- lel to the bone surface along either the maximum and minimum axes of bone stiffness. The pullout tests showed that the implants aligned at 90 to the bone surface required significantly greater amounts of force before failing (34.2 kg) than those oriented at 45° (10.8 and 14.1 kg). The diſ- ferences in force reflected differences in the amount of bone that re- mained in contact with the MSI after failure. The bone that remained in contact after failure with the 90° MSI surrounded the implant more of less symmetrically and had an elliptical shape. MSIs oriented at 45° to the bone surface produced a smaller wedge of bone on only one side of the screw, oriented at approximately 135° to the MSI. The shear tests showed 270 Buschang et al. MSI Orientation Direction of Force 25.3 kg 10.2 kg §s -N-N-N-N-N-N-N-N-N-N-N-N-N-N-N -vº-º-º-º-º- - --~~~~~ º 26.4 kg 8.8 kg Nº. Prºvºsºrºrº ºSSSSSSSSSSSSSSSSSS: & Shear- - wºman, bonestiffness 90° 45° towards shear force 45° opposing shear force Figure 11. Maximum pullout and shear forces at failure of 6 mm MSI placed perpendicular and at 45° toward shear force. (Adapted from Pickard et al., 2010.) that the MSIs that were angled at 45° in the same direction as the line of force required significantly more force before failing (25.3 and 26.4 kg) than the MSIs oriented at 90° (12.4 and 13.8 kg); the MSIs oriented at 45° away from the line of force (tent-peg) displayed the lowest forces at failure (8.8 and 10.2 kg). The tent-peg orientations had stresses that con- Centrated near the cortical surface at 135° between the MSI and bone. which decreased their stability. Bone Density/Quality It has been suggested that cortical bone quantity and quality are two of the most important determinants of primary stability (Costa et al., 1998; Miyawaki et al., 2003). As indicated previously, secondary stabil- ity also should be expected to be affected by the initial quality and quan- tify of bone. Greater numbers of MSI failures might be expected for denser bone due to increases in microfractures. In addition, greater MSI failures in the mandible than maxilla might be due to ischemia and ne- crosis associated with overheating when drilling into denser bone (Eriks- Son and Albrektsson, 1983; Tehemar, 1999). 271 Experimental Evidence Because the same MSIs were placed in the maxillas and mandi- bles of the same animals, several of our experimental studies made it possible to evaluate jaw differences in stability. A total of 106 immedi- ately loaded MSIs (6 mm long and 1.8 mm wide) were placed and fol- lowed for either 98 days (Carillo et al., 2007a,b) or 105 days (Owens et al., 2007). Of the 53 that were placed in the maxilla, 52 (98%) remained stable, compared to 49 (93%) of their counterparts placed in the mandi- ble (Table 2). These findings suggest that failures may be higher in the mandible, but the differences between jaws were small and not signifi- cant statistically (P=0.119). Another study (Fig. 12) comparing 3 mm MSI loaded with 600 g also showed significantly greater stability (P º 0.001) over a six-week observation period for MSI placed in the maxillas than for those placed in the mandibles of the same dogs (Mortensen et al., 2009). Also, We demonstrated recently that there were no significant differences in the amount of bone-to-implant contact (BIC) after 110 days between MSIS placed in the maxilla and mandible (Woods et al., 2009). The coronal and apical aspects of the screws showed greater BIC for MSIs placed in the mandible, whereas the middle aspects showed greater BIC for MSIS placed in the maxilla (Fig. 13). In order to understand better how bone density affects the pri- mary stability of MSIs, we recently compared the insertion torque and pullout strength of MSI placed in synthetic cortical bone (Hung et al., 2010). Bone with cortical densities of 0.8 g/cc and 0.64 g/cc were com- pared (the density of the human mandible has been reported to be 0.66 g/cc; Fig. 14). While the MSIs placed in more dense bone exhibited Sig- nificantly greater insertion torque and pullout strength than the MSIs placed in less dense bone, the effects were greater on insertion torque (156% increase) than on pullout strength (135% increase). Table 2. Differences in the stability of immediately loaded MSIs (6 mm long X 1.8 mm wide) placed in the maxilla and mandible. (Adapted from Owens et al. 2007 and Carrillo et al., 2007.) Study Maxilla Stability (%) | Mandible Stabili 1 Control 14/14 (100%) Control 13/14 (93%) 1 25 g 7/7 (100%) 25 g 5/7 (71%) 2 25 g 16/16 (100%) 25 g 16/16/ (100% 2 100 g 15/16 (94%) 100 g 15/16 (94%) Total 52/53 (98%) 49/53 (93%) 272 Buschang et al. - Maxilla - Mandible p > .001 100 p > .001 80 - > :- o 60 — (U -- C/D 40 – S. 20 – O - Overall Net Figure 12. Overall and net stability of MSIs placed without pilot holes in the maxillas and mandibles of mature beagle dogs and immediately loaded with 600 g. (Adapted from Mortensen et al., 2009.) - Cor-max º Cor-mand |Mid-max ºn Mid-mand Api-max & Api-mand 100 # Figure 13. Histological comparisons and graphical representation of bone-to- Implant contact (BIC) around MSIs placed in the maxillas and mandibles. (Adapted from Woods et al., 2009.) 273 Experimental Evidence 14 Insertion Torque 12 | Low 10 - High ; : 40 Pullout Strength 35 30 25 on 20 * 15 10 5 0. Figure 14. Effects of synthetic cortical bone density (high [0.8 g/cc vs. low |0.64 g/cc]) on the insertion torque and pullout strength of 6 mm long MSIs (Adapted from Hung et al., 2010.) Pilot Hole Size Decreases in insertion torque previously have been reported in association with increasing the size of pilot holes used for inserting bones screws (Daftari et al., 1994; Heidemann et al., 1998) and MSls (Gantous and Phillips, 1995; Wilmes et al., 2006). Insertion torque de- creases with pilot holes due to the decreased amounts of bone that needs to be displaced during insertion. Larger pilot holes require less bone 10 274 Buschang et al. be displaced during MSI insertion, resulting in less compression of the adjacent bone. Pullout strength also has been reported to decrease with increas- ing pilot hole size (Gantous and Phillips 1995; Heidemann et al., 1998). While pilot holes are associated with decreases in both insertion torque and pullout strength, there have been no studies evaluating the interac- tion between pilot hole size and bone density. Understanding this asso- ciation is essential for individualizing the size of pilot holes. Moreover, the ideal pilot hole should provide the greatest decreases in insertion torque and smallest decreases in pullout strength. None of the previous studies evaluating pilot holes have examined both of these parameters in the same specimens. A recent study evaluated the effects of pilot holes on the inser- tion torque and pullout strength (Hung et al., 2010). The MSI were 6 mm long with inner and outer diameters of 0.9 and 1.6 mm, respectively. As expected, insertion torque and pullout strength were lower significantly with, rather than without, pilot holes (Fig. 15). Importantly, the relative reductions in insertion torque associated with increasing pilot hole size were greater consistently than the observed relative reductions in pullout strength, indicating that pilot holes may reduce the initial trauma associ- ated with MSI insertion without significantly compromising stability. In comparison with no pilot hole, the 1 mm pilot holes produced substan- tially greater relative reductions in insertion torque than pullout strength; the relative reductions also were greater for insertion torque with 1.4 mm pilot holes, but the differences between insertion torque and pullout strength were smaller substantially. These findings strongly suggest that – depending on the MSI characteristics – there is an optimal pilot hole size, which substantially reduces the stresses caused during insertion but maintains the holding power of the screw. Moreover, these effects are most pronounced in more dense bone, the type of bone that might be ex- pected to benefit most from pilot holes. Cortical Bone Thickness The thicker the cortical bone, the higher the insertion torque and pullout strength (Huja et al., 2005; Cleek et al., 2007), indicating greater primary stability. However, cortical bone that is too thick could lead to greater MSI failures; clinical failures of MSIs commonly are attributed to thick cortical bone (Miyawaki et al., 2003; Park et al., 2004; Wilmes et al., 2006; Motoyoshi et al., 2007). On the other hand, thin cortical bone 275 Experimental Evidence 30 —- 25 20 15 10 5 - 0- IT POS IT POS Low Density High Density Figure 15. Insertion torque (Ncm) and pullout strength (POS) of miniscrew im- plants (MSIs) placed in lower (0.64 g/cc) versus and higher (0.8 g/cc) density cortical bone, with no pilot hole (0 mm), a 1.0 mm pilot hole and a 1.4 mm pilot hole. (Adapted from Hung et al., 2010.) could explain the higher failure rates that have been attributed to younger patients (Park et al., 2004; Chen et al., 2007; Motoyoshi et al., 2007. Garfinkle et al., 2008). There also are differences in cortical bone thick- ness between and within regions of the jaws and these differences may have important clinical implications (Schwartz-Dabney and Dechow. 2003; Deguchi et al., 2006; Petersen et al., 2006; Katranji et al., 2007; Ono et al., 2008). Because there had been no comprehensive comparisons of corti- cal bone thickness at common placement sites of the maxilla and mandi- ble, we quantified cortical bone thickness at 16 commonly used sites (Farnsworth et al., 2011). Cone-beam computed tomography (CBCT) images taken at 0.39 mm voxel size of 26 adolescents (11 to 16 years of age) and 26 adults (20 to 45 years of age) were used to evaluate three paramedian sites, one site on the infrazygomatic crest, four buccal inter radicular sites on the mandible and four buccal and four lingual interra- dicular sites of the maxilla. Cortical bone of adults was thicker signifi- cantly (0.12 to 0.56 mm) than the cortical bone of adolescents at all sites except at the infrazygomatic crest, the most posterior palatal site and the mandibular buccal 6–7 site. Cortical bone at the buccal mandibular sites was thicker significantly in the posterior than anterior regions; the cortº was more than twice as thick between the first and second molar (2.4 to 276 Buschang et al. 2.5 mm) than between the lateral incisors and canines (0.9 to 1.2 mm; Fig. 16). Cortical bone in the buccal aspect of the maxilla tended to be thinner than in the mandible. Also, differences between sites were much smaller in the maxilla; the cortex was only slightly thicker between 5-6 (1.0 to 1.5 mm) and 4-5 (1.1 to 1.3 mm) than between 2-3 (1.0 to 1.2 mm) and 6-7 (0.9 to 1.2 mm). Cortical bone thickness and differences between sites in the lingual region of the maxilla were similar to the buc- cal region of the maxilla (Fig. 17). Paramedian palatal cortical thickness decreased anteroposteriorly; it was thickest 3 mm behind the incisive foramen (1.3 to 1.4 mm) and thinnest 9 mm behind the foramen (1.0 to 1.2 mm). The cortical bone in the infrazygomatic crest (1.4 to 1.6 mm) more closely approximated cortical thickness of the mandible than max- illa. Importantly, variability in cortical thickness among individuals was Substantial; it would not be unusual for an adolescent patient to present with maxſſlary cortices less than 1.0 mm thick, which could be problem- atic for MSI retention. Conversely, it is not uncommon for mandibular cortices between the first and second molars to be more than 2.5 mm thick, which also could be problematic when the bone is dense. LOADING CHARACTERISTICS The way in which loading characteristics affect the primary and secondary stability of MSIs remains understood poorly. While the influ- ence of heavy forces on the peri-implant tissue has been established for endosseous implant applications (Duyck et al., 2001; Berglundh et al., 2005), the effects of force on MSIs is unknown. Orthodontic forces placed on MSI, which are lower considerably than the occlusal forces placed on dental implants, might be expected to produce less strain and have lesser effects. While excessive loads could affect MSI stability, no clear pattern of association between the amount of load (ranging from 100 ch to 500 cM) and bone-to-implant contact (Büchter et al., 2005) is apparent. Most of the available literature comparing loaded vs. unloaded MSIs demonstrates that little to no relationship between MSI loading and Osseointegration or failure (Freire et al., 2007; Vande Vannet et al., 2007), even though Garfinkle and colleagues (2008) have reported a higher success rate for loaded than for unloaded MSIs. 277 Experimental Evidence 3.5 - 3 - 2.5 Site 6–7 Site 5-6 Site 4-5 Site 2–3 A Mandibular Buccal Sites Adolescents Adults Pal 3 mm Pal 6 mm Pal 9 mm |Z B Palatal and Infrazygomatic Crest Sites Figure 16. Cortical bone thickness (means and ranges) for (A) mandibular buccal sites between the first and second molars (site 6-7), the first molar and second premolar (site 5-6), the first and second premolars (site 4-5), and between the canine and lateral incisor (site 2-3) and (B) three palatal sites (located 3, 6 and 9 mm behind the incisive foramen) and an infrazygomatic crest (IZ) site. (Adapted from Farnsworth et al., 2011.) 278 Buschang et al. Site 6-7 Site 5-6 Site 4-5 Site 2-3 Maxillary Buccal | D. Adolescents Adults Site 6-7 Site 5-6 Site 4–5 Site 2–3 Maxillary Lingual Figure 17. Cortical bone thickness (means and ranges) for maxillary buccal and maxillary lingual sites between the first and second mo- lars (site 6-7), the first molar and second premolar (site 5-6), the first and second premolars (site 4-5) and between the canine and lateral incisor (site 2-3; adapted from Farnsworth et al., 2011). 279 Experimental Evidence The Effects of Force Using split-mouth designs, we evaluated the effects of force on the stability of 142, 6 mm long MSIs placed in the maxillas and mandibles of 15 beagle dogs (Carrillo et al., 2007a,b; Owens et al., 2007). The overall stability of the miniscrews was 97% (Table 3); the MSI on the side of the mouth subjected to lighter forces showed slightly higher sta- bility (100% stable) than those subjected to heavier forces (94% stable). Chi-square analyses showed that these differences were significant statis- tically (P = 0.015), indicating that heavier forces lead to a slightly higher number of failures than lighter forces. Interestingly, we obtained the opposite results in another split- mouth design using the 3 mm long MSIs described previously (Mort- ensen et al., 2009). While there were no differences in stability associ- ated with load when all of the MSIs were included, the MSIs loaded with 900 g exhibited greater stability (100%) than those loaded with 600 g (86%), after the sheared MSIs and those belonging to dog #3 were ex- cluded. Sample sizes were small, however, and the differences were not significant statistically. Most recently (Fig. 18), we showed significantly higher (100%) success for 3 mm long MSIs loaded with 100 g and 200 g, than for the same MSI placed in different animals and loaded with 50 g (77%). Success rates also were lower significantly for unloaded MSIs (75%) than those loaded with 100 g or 200 g (Liu et al., 2011). These conflicting results suggest that other factors could have been responsible for the different success rates observed (i.e., it is possible that the amount of force – within limits – does not matter). We also have performed histological and pu-CT evaluations to de- termine the effects of force levels on bone-to-implant contact and peri- bone-to-implant (i.e., bone close to, but not in direct contact with, the MSI) contact. Our histological evaluations of the coronal, middle and apical aspects of 6 mm screws showed no consistent pattern or signifi- cant differences in percent BIC between MSIs loaded with 25 g on one side of the mouth and those loaded with 50 g on the other side (Woods et al., 2009). The same study also showed no significant differences and no clear pattern of difference between MSIs that were loaded and control MSI that remained unloaded throughout the course (110 days) of the study (Fig. 19). Based on pu-CT evaluations, we recently demonstrated significantly greater peri-bone-to-implant contact for loaded (200 g), 6 mm long sandblasted and acid-etched surfaced MSIs than for the unloaded controls (Ikeda et al., 2011). Again, the differences were greatest in regions 280 Buschang et al. Table 3. Split-mouth comparisons of the stability of 6 mm long MSIs loaded immediately with lighter or heavier immediate forces (chi-square = 4.23; P = 0.039; data from Carrillo et al., 2007a,b; Owens et al., 2007). Overall stability = 138/142 (97.2%). - Study Lighter Stability (%) Heavier Stability Md 25 g 7/7 (100%) Md 50 g 5/7 (7.1%) 2 Md 25 g 16/16 (100%) Md 50 g 16/16 (100%) 2 Md 50 g 16/16 (100%) Md 100 g 15/16 (94%) 2 Md 25 g 16/16 (100%) Md 100 g 16/16 (100%) 2 Mx 50 g 16/16 (100%) Mx 100 g 15/16 (94%) 2 71/71 (100%) 67/71 (94%) 120 | Econtrol isog stoog -200g 100 - - 80 60 | 40 20 0 Force Levels Figure 18. Percent stability of 3 mm control and immediately loaded MSIs over a 42-day experimental period, showing significantly (P<0.001) greater stability for MSI loaded with 100 g or 200 g (*), than for unloaded controls or MSIs loaded with 50 g (*: adapted from Liu et al., 2010). showing the greatest bone-volume-to-total-volume (i.e., the more coronal *Spects of the cortical and non-cortical regions) for which the loaded MSIs showed 3% to 13% more peri-bone-to-implant contact than the unloaded MSIs (Fig. 20). POTENTIAL ROOT INJURIES While there are a variety of reasons why orthodontists do not place their own MSIs (Fig. 21), the most frequently cited reason for hav- "g someone else place them is the risk of root damage (Buschang et al., 2008). Risk of root damage was deemed to be more important than time, 281 Experimental Evidence - MD - MD – Cnt - MX - MX - Cnt 100 # Figure 19. Bone-to-implant contact (BIC) of loaded and unloaded control (Cnt) 6 mm long MSIs. (Adapted from Woods et al., 2009.) control MSI Loaded MSl 282 Buschang et al. Il Training Il Time I Too Invasive - No kit D Pain ºn Root Damage % Figure 21. Responses to a survey of 451 orthodontists to the question, “Why don’t you place your own MSIs?” (Adapted from Buschang et al., 2008.) training, pain or the availability of a kit. Potential damage to the roots of teeth has been well documented for dental implants and fixation screws. Implant placements have resulted in loss of tooth vitality (Margelos and Verdelis, 1995) and transection of root apices (Rubenstein and Taylor, 1997). Fixation screws have been shown to damage tooth roots in up to 43% of the cases (Farr and Whear, 2002; Fabbroni et al., 2004). Impor- tantly, the periodontal literature shows that repair can occur following root and PDL damage (Hellden, 1972). Until recently, our understanding of the healing effects on structures damaged with MSIs was limited. Chen and coworkers (2008) reported increased failure rates when MSIs Contact roots. They also showed that roots repair by cementum deposi- tion and that bone regenerates if the MSIs are removed and the sites are allowed to heal. In order to evaluate the immediate, short-term (six weeks) and long-term (twelve weeks) damage caused by MSIs that were left in situ, intentional damage was inflicted to the roots of the maxillary second, third and fourth premolars of seven mature beagle dogs with self-tapping MSI (8 mm x 1.8 mm, Hembree et al., 2009). Undecalcified histological Sections were used to determine the extent of damage; fluorescence la- bels (alternating tetracycline and calcein) were used to evaluate formation - Figure 20. Micro CT (u-CT) image of bone 6 to 24 um thick surrounding the MSI of unloaded control and loaded SLA surfaced MSIs. (Adapted from Ikeda et al., 2011.) 283 Experimental Evidence of dentin, cementum and bone. The results showed that the placement of MSIs can produce immediate and extensive damage of the teeth, perio- dontium and bone; the short- and long-term damage was similar to the immediate damage caused. Importantly, we showed that tactile resistance felt by the opera- tor increases suddenly when the MSI contacts the tooth. Resistance was approximately twice as great when the MSI contacts the tooth than when it goes through the adjacent bone. The change in resistance felt during insertion may be a better indication of root contact than radiographs. His- tology showed that approximately 75% of the teeth had been damaged by the MSIs (Fig. 22). Damage varied from the displacement of bone and periodontal ligament (7%) to invasion of the pulp chamber (14%) – den- tinal damage was the most common (26%), followed by cementum dam- age (19%). Immediate damage usually produced clean cuts through both the cementum and dentinal layers. Remarkably, there was evidence of short- and long-term healing even though the MSIs remained in place throughout the experiment. Placement of MSIs into the pulp produced detrimental and irreversible damage, which usually warrants either root canal therapy or extraction of the tooth (Mehlman, 2000). Based on the extent of damage that is possible when placing MSI, orthodontists should have a thorough knowledge of the underlying structures before place- ment and obtain informed consent from their patients. A companion study evaluated healing of the roots and surround- ing structures after damage with MSIs (Brisceno et al., 2009). The ex- periment was based on 56 MSIs placed in the mandibles of beagle dogs. Radiographs and insertion torque values were used to verify root contact. After root contact had been confirmed, the MSIs were removed immedi- ately and the sites were allowed to heal for either six or twelve weeks. As shown previously, insertion torque doubled when the MSI made contact with the roots. Approximately 68% of the teeth showed damage of the dentin, 20% showed damage of the cementum and 13% showed damage of the pulp. Most of the damaged teeth (64%) displayed normal healing (Fig. 23). Healing was evident by six weeks and continued through twelve weeks. New cementum approximately doubled between six and twelve weeks of healing. After twelve weeks of healing, the new bone, PDL and cementum appeared similar to the adjacent, undamaged struc- tures. Abnormal healing, including lack of PDL, lack of bone regenera- tion, bone degeneration in the furcation area, ankylosis and the lack of healing due to inflammatory infiltrate or pulpal invasion was evident in 36% of the damaged teeth. The observed lack of healing further empha- 284 Buschang et al. Figure 22. Short- and long-term damage caused by MSI placement to the (A) PDL, (B) cementum [Cel, (C) dentine [Den] and (D) furcation causing inflam- mation [I], necrotic tissue [NT and loss of bone [Bol (Hembree et al., 2009). Den V No PDL | - - |cº Dº Figure 23. A. Normal healing after damage caused by MSI inserted into the den- in Den] with a new cementum [Cel layer, PDL restored to functional width and bone [Bol regeneration in the area of damage. B: New cementum but no PDL or bone regeneration around the dentin defect (arrows). C. Degeneration in the furcation area. D. Lack of a layer of cementum and PDL with direct contact between the bone and dentin. Note the inflammatory infiltrate [I] in both B and C. (Adapted from Brisceno et al. 2009.) sizes the importance of obtaining informed consent from patients prior to MSI placement. 285 Experimental Evidence CLINICAL APPLICATIONS OF MISIS MSI anchorage provides an excellent means for evaluating tooth movement, sutural separation and root formation because the forces ap- plied can be estimated and controlled more accurately. While it often has been assumed that different force levels produce differences in the de- gree of tooth movement, sutural separation and root resorption, the actual relationships remain understood poorly. We used a randomized split-mouth design to evaluate whether horizontal tooth movement is related to the timing of force application and/or the amount of force applied (Owens et al., 2007). Eight MSIs (6 mm long and 1.8 mm in diameter) were placed in the maxillae and man- dibles of seven adult beagle dogs after the third premolars had been ex- tracted; the MSIs were loaded for 105 days. The results showed no sig- nificant differences in tooth movement at the end of the experiment asso- ciated with the timing of force application (immediate vs. delayed) or the amount of force applied (25 g vs. 50 g). The 25 g force produced increas- ingly greater tooth movements initially, but the differences decreased after approximately 60 days. Rates of tooth movement increased during the study, from approximately 0.4 mm over the first 19 days to 1.0 mm over the last 19 days of the study (Fig. 24). Peri-implant inflammation, which peaked 20 days post-operatively and decreased thereafter, did not predispose the MSIs to failure. Our group also used skeletal anchorage to evaluate how different forces affect lower premolar intrusion (Carrillo et al., 2007a). Twelve MSIs (two per tooth) were placed in the lingual and buccal cortical plates of eight mature beagle dogs. Intrusive forces were assigned randomly between bilateral pairs of teeth: second premolars were loaded with ei- ther 50 g or 100 g; the third premolars were loaded with 100 g or 200 g, and the fourth premolars were loaded with 50 g or 200 g. The forces were delivered immediately after MSI placement and continued uninter- rupted for 98 days. While 100 g of force produced slightly more intru- sion than 50 g, 200 g resulted in slightly more intrusion than 100 g and 50 g produced more intrusion than 200 g, none of the differences relating to the amount of force applied were significant statistically (Fig. 25). In- stead, the amounts of intrusion appeared to be related to the size of the teeth being intruded (approximately 2.5 mm for the second and third premolar; 1.75 mm for the fourth premolar). 286 Buschang et al. 40 60 80 100 120 140 Days Figure 24. Split-mouth design evaluating differences in the AP movement of Second premolars subjected to 25 g or 50 g. (Adapted from Owens et al., 2007.) MSIS also were used to evaluate segmental intrusion of the pre- molars (Carrillo et al., 2007b). A cast vitallium appliance was attached to the maxillary first, second and third premolars, and intrusive forces were applied to the segment via four MSIs (two per side) inserted buccally at the level of the first and third premolars. A sample of eight mature beagle dogs were divided randomly so that one group had intrusive forces of 50 g applied anteriorly and 100 g applied posteriorly; the other group had 100 g applied anteriorly and 50 g applied posteriorly. The amounts of intrusion that occurred again were independent of the magnitudes of force delivered. The group loaded with the heavier posterior forces showed 2.0 mm of first premolar intrusion and 1.5 mm of third premolar intrusion; intrusion again was related to the surface area of the tooth rather than the amounts of force applied. The group with the heavier an- terior forces showed 0.9 mm of intrusion of the first premolars and no significant intrusion of the third premolars. Lack of intrusion of the larger posterior teeth appears to have limited the intrusion of the anterior teeth. More recently, we used 3 mm MSIs to expand the sagittal Su- tures of growing rabbits. Our aim was to evaluate the effects of: 1. Continuous vs. intermittent forces: 2. Different amounts of force; and 3. Bone morphic protein (BMP) on sutural growth. 287 Experimental Evidence 3.5 3 2.5 E 2 1.5 E 1 0.5 0. 10 20 30 40 50 60 70 80 90 100 Days Figure 25. Split-mouth design evaluating the effects of different forces on lower premolar intrusion. (Adapted from Carrillo et al., 2007a.) The MSIs made it possible to control the amounts of force delivered and therefore, the amounts of sutural expansion that occurred. Longitudinal biometric and histomorphometric analyses showed that intermittent forces produced only 61% as much sutural separation, 59% as much mineral apposition and 6.1% as much bone formation (BF) as continuous forces (Liu et al., 2011). In terms of BF, the results clearly showed that continuous forces provide a much more efficient approach for separating sutures than intermittent forces (Fig. 26). 288 Buschang et al. 300 - - Continuous Intermittent Control 100 50 Figure 26. Bone formation rates (BFR) between seven to 27 days with fluores- cent labeled sections below (note that distances between green and orange fluorescent labels are greater in the continuous than the intermittent and control groups). The green scale bars represent 1 mm. (Adapted from Liu et al., 2010.) Since sutural separation stimulates BF and increases in sutural Separation are related to higher expansive forces, increases in the force used to separate sutures might be expected to increase BF. However, Parr and coworkers (1997) reported no differences in sutural BF between 1N and 3N expansion forces in rabbits. To investigate these relationships more fully, we randomly assigned rabbits to four groups and again used 3 mm MSIs to apply continuous forces (50 g, 100 g and 200 g) across the Sagittal suture for 42 days (Liu et al., 2010). The biometric results showed a decelerating pattern of sutural separation; the largest increases Occurred during the first week, while the smallest increases in sutural Width occurred during the final week (Fig. 27). Overall, sutural widths increased 0.6 mm in the controls and 3.2 mm, 5.1 mm and 6.2 mm in the 50 g, 100 g and 200 g force groups, respectively. Sutural BF also in- °reased with increasing force for all group except the 200 g group for Which the amount of bone produced was not different significantly than the 100 g force group. These results demonstrate that there is an optimal Fate of sutural separation that maximizes the rate of BF. 289 Experimental Evidence 1600 1400 1200 - # 1000 || – 800 - 600 400 200 - 0 In Sutural gap - BF Days 28-38 L BF Days 18-28 0 50 100 200 Force (g) Figure 27. Bone formation (BF) assessed using fluorescent labels (control suture inset) and sutural gap increases associated with the amount of force used to separate the sagittal suture. (Adapted from Liu et al., 2011.) # Having determined that continuous forces produce greater amounts of bone than intermittent forces and that a 100 g force was the optimal force for the rabbit sagittal suture, we then sought to determine whether rhEMP-2 could be used to enhance BF further (Liu et al., 2009). Growing rabbits were assigned randomly to receive 0 (control), 0.1 mg/mL or 0.4 mg/mL of rhEMP-2 delivered via an absorbable collagen sponge placed over the suture. All of the sutures were expanded with a 100 g force. Because rh BMP-2 caused premature fusion of the ectocra- nial aspect of almost all of the sutures, the control groups showed sig- nificantly greater BF after 30 days than the rhEMP-2 groups (Fig. 28). However, BF between days 10 to 20 was greater significantly (58%) in the 0.4 mg/mL than in the 0.1 mg/mL group, suggesting that the rhEMP- 2 may have a stimulatory effect. While rhEMP-2 may accelerate BF temporarily, premature fusion prevented the actual effects to be determined. We also evaluated whether increasing amounts of intrusive force cause greater amount apical root resorption (Carrillo et al., 2007a). Long- tudinal perapical radiographs showed less than 0.1 mm of resorption of the root apices and furcation (Fig. 29A). There was no consistent patterſ and no statistically significant differences in the amounts of root resorp. tion observed. In other words, applying 200 g of intrusive force to a tooth had no more effect on root resorption than applying 50 g. 290 Buschang et al. 1800 D BF days 10-20 1500 IBF days 20-30 - D Sutural gap £ 1200 9 3 900 E 600 0 || |_ _ Control 0.1 0.4 rhEMP-2 (mg/mL) Figure 28. Bone formation (BF) as assessed with fluorescent labels and sutural gap measurements for control and experimental animals that re- ceived 0.1 or 0.4 rh BMP-2. (Adapted from Liu et al., 2009.) *-LPM2-FLT (100g) --LPM3-FLT (200g) --LPM4-MRLT (200g) º LPM4-MRLT (50g) --LPM4-DRLT (50g) y Figure 29, Root resorption assessed (A) radiographically, showing little or no Foot resorption and no association between resorption and force (adapted from Carrillo et al. 2007a); (B) histology section, showing resorptive lacunae; and º Same section with healing outlined. (Adapted from Ramirez-Echave et al., 1.) We evaluated the same sample histologically and found root re- Sorption in all of the teeth evaluated (Ramirez-Echave et al., 2011). The apices and interradicular regions of the teeth showed the greatest amounts of resorption with dental involvement at the furcation. The amounts of resorption again were independent of the amounts of force applied to the tooth. Interestingly, almost 25% of the lacunae exhibited °mentum repair, demonstrating that resorption and repair are ongoing 291 Experimental Evidence processes during intrusion (Fig. 29B,C). Segmental intrusions also pro- duced small (0.6 mm or less) but statistically insignificant amounts of root resorption (Carrillo et al., 2007b). Once again, the amounts of root resorp- tion observed were not related to the amounts of force applied to the seg- ment. CONCLUSION Because MSIs have proven to be so popular among orthodon- tists, it is more important than ever to continue conducting well- controlled experimental and clinical studies. Unfortunately, much of the knowledge that orthodontists have about MSIs comes from anecdotal clinical case reports or from people who have economic interests in providing limited or even misleading information. Weak studies produce conflicting information that often is used to support untenable positions. Progress only can be made based on evidence that can only come from the strongest of study designs. Progress is vitally important because it will allow future orthodontists to individualize the use of MSIs, depending on the mechanics they want to use, as well as the patients’ characteristics. CBCTs, or a similarly less invasive approach, will be used to determine where to place MSIs and to indicate the quantity and quality of bone at the insertion sites. To reduce the likelihood of damage and increase the number of potential insertion sites, MSIs will be smaller substantially than those currently in use. MSI coating should enhance healing and improve retention. MSIs of the future also could be coated with compounds that inhibit bone resorption and/or enhance BF. In the future, MSIs will be designed according to patient and implant site characteristics. For example, flutes and reduced pitch could be used for children with thin, less dense, cortical bone. Pilot holes will be tailored specifically for adults with thick dense bone. 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Wilmes B, Rademacher C, Olthoff G, Drescher D. Parameters affecting primary stability of orthodontic mini-implants. J Orofac Orthop 2006; 67: 162-174. Woods PW, Buschang PH, Owens SE, Rossouw PE, Opperman LA. Bone to implant contact of miniscrew implants used as orthodontic anchors: Experimental evaluation of the effects of force, timing and location. Eur J Orthod 2009; 31:232–240. 298 IMMEDIATE AND DELAYED ORTHODONTIC LOADING OF OSSEOINTEGRATED IMPLANTS: A PROSPECTIVE CLINICAL STUDY José Augusto M. Miguel, Lisiane Meira Palagi, Carlos Eduardo Sabrosa, Eveline Gava, Tiziano Baccetti ABSTRACT This study clinically and radiographically evaluated the success rate following application of immediate orthodontic loading to implants as compared to ortho- dontic loading delayed classically by four months. Twenty implant sites were allocated randomly to two groups: immediate orthodontic loading (group A) and delayed orthodontic loading (group B) on provisional crowns. The sample was evaluated at two different time points, before and after orthodontic forces were applied to the restored implants of each group. The results indicated that ten out of the eleven implants evaluated under immediate orthodontic loading were suc- cessful six months after the start of orthodontic treatment, resulting in a success rate of 91%, while eight out of the nine implants that received orthodontic load- ing after four months of healing were successful, resulting in a success rate of 89% for this group. Therefore, the findings of the present randomized prospec- tive clinical trial revealed that the reduction in waiting time for application of orthodontic load may not diminish the success of osseointegrated implants bear- ing provisional crown restorations. KEY WORDS: dental implantation, orthodontics, orthodontic anchorage proce- dures, tooth movement, osseointegration In contemporary dentistry, the number of adults and aging per- Sons who are seeking esthetic oral rehabilitation is increasing. Both the input of the media and the fact that life is becoming on average longer creates a population of older patients who need orthodontic treatment. Many of these adult subjects require an integrated interdisciplinary treatment due to tooth loss, which leads to difficulties or even impair- ments in solving biomechanical problems related to orthodontic anchor- age. The use of osseointegrated implants has been proposed as a valid alternative in these cases. Besides promoting absolute anchorage during 299 Orthodontic and Prosthetic Load orthodontic movement, implants also are employed with little difficulty as a base for posterior prosthetic restorations, as they can be considered a secure, predictable and durable method of rehabilitation (Skeggs et al., 2007). Although high success rates have been reported for both imme- diate loading applied to implants and for implants used for orthodontic anchorage, few studies join these two purposes to evaluate the possible utilization of immediate orthodontic loading on osseointegrated implants used for orthodontic purposes (Roberts et al., 1984; Karaman et al., 2002; Trisi and Rebaudi, 2002, 2005). These investigations analyzed few cases and were not prospective in nature. The aim of the present study was to: 1. Evaluate clinically and radiographically the success rate following application of immediate orthodontic loading to Osseointegrated implants; 2. Evaluate the success rate of application of orthodontic loading after a period of four months of healing; and therefore, 3. Determine if decreasing the waiting time for ortho- dontic load application diminishes the success of os- Seointegrated implants. SUBJECTS AND METHODS In this prospective clinical study, 20 implant sites were allocated randomly to two groups: immediate orthodontic loading on provisional crowns (group A) and delayed orthodontic loading on provisional crowns (group B). The sample was evaluated at two different time points: before and after application of orthodontic force to prosthodontic restorations on the implants of each group. Adult patients who were in need of corrective orthodontic ther- apy and prosthodontic rehabilitation including one or more single os- Seointegrated implants were selected prospectively for this study at the Clinic for Orthodontic Graduate and Postgraduate Studies at the State University of Rio de Janeiro, Brazil. The enrollment criteria for patients in the sample were: 1. Partial edentulous areas on posterior sites of the man- dible; 2. Necessity of orthodontic treatment; 300 Miguel et al. Adequate oral hygiene; Absence of local inflammation; Absence of diseases of the oral mucosa; Absence of history of local radiation therapy; and Bone height and width appropriate to accommodate an implant 4 mm in diameter and 13 mm in height, determined by panoramic radiographs and computed tomography. i The exclusion criteria for patients in the sample (according to in- dications reported by Chiapasco and Gatti, 2003) were: . Severe bruxism; . Drugs and alcohol abuse; . Smoking habits (more than ten cigarettes a day); . History of radiation therapy of the neck and head ar- eaS; . Recent chemotherapeutic treatment; . Severe chronic renal disease; . Severe chronic hepatic disease; . Non-controlled diabetes; 9. Hemophilia or blood disorders; 10. Immunosuppression; 11. Treatment with Steroids; 12. Pregnancy; and 13. General contraindication for surgical procedures. : After exclusion criteria, thirteen patients (seven males and six females) were enrolled in the randomized clinical trial (RCT). Patient age ranged from 22 to 56 years with an average value of 35.7 years. A total of 20 edentulous areas in these patients were considered as adequate sites for ultra self-tapping titanium implants (SIN, São Paulo, Brazil; Figs. 1-4), which would further receive orthodontic loading through the application of a bracket on a provisional crown restorations. The 20 implant sites were assigned randomly to group A and group B. The group for each implant was determined at the day of sur- gery. The random assignment was carried out using Microsoft Office Excel" 2003 software with the “rand” function. In group A, the implants Were used immediately as orthodontic anchorage under load ranging from 60 g to 200 g, as assessed with a dynamometer. Only implants as- sessed as presenting primary stability (i.e., that could support load of 40N; 301 Orthodontic and Prosthetic Load º ſº ---, ºr sº ºn ſº º Figure 2. Visualization of the surgical guide at CT evaluation. Hruska et al., 2002; Calandriello et al., 2003; Lorenzoni et al., 2003) were considered suitable to receive immediate loading. In group B, the traditional protocol consisting of four months waiting time before any Orthodontic loading of the implants (Shapiro and Kokich, 1988) was em: ployed, although the provisional crown restorations had been placed pre- viously. As the primary purpose of implant positioning in the patients ob: served in the present study was related to the function of implants as Orº thodontic anchorage, the surgical guide filled with gutta-percha was built from a correctly made set-up diagnosis (Fig. 1). That guide also was used by the patients during the computed tomography examination (Fig. 2). As 302 Miguel et al. Figure 3. A Guide adapted to original cast. B. Guide adapted to patient’s mouth. C: Preparation of the implant site. D. Insertion of the implant. E. Check for im- plant final position. F. Evaluation of primary stability of the implant. 3utta-percha is a radiopaque material, the precise location for future Implant placement can be determined, thus allowing for a quantitative and qualitative evaluation of the alveolar bone of the site. Group A comprised eleven implants, placed in five female and six male patients aging from 22 to 56 years (mean age of 35.9 years). Group B consisted of nine implants, placed in three female and six male patients aging from 22 to 52 years (mean age of 35.3 years). The implants were evaluated clinically after six months of ortho- dontic loading. At this time, the following criteria for clinical success Were employed (Chiapasco and Gatti, 2003): 303 Orthodontic and Prosthetic Load Figure 4. A. Manufacturing of the provisional crown. B and C: Provisional crown cemented on the implant and bonded to a bracket used for orthodontic treatment. 1. Absence of signs and symptoms of pain, infection or discomfort; 2. Absence of implant mobility, determined with the aid of the handles of two dental mirrors; and 3. Absence of peri-implant radiolucency shown on peri- apical radiographs, indicating bone resorption. 304 Miguel et al. RESULTS No patient dropouts were recorded. In the total sample, out of the twenty implants evaluated after a period of six months from the initial orthodontic load application on provisional crown restorations, eighteen implants were not associated with any signs or symptoms of pain, infec- tion or neuropathy. Two implants were lost due to excess of mobility and lack of osseointegration during the first two weeks after implant inser- tion, one in group A and the other one in group B. Out of the eleven implants in group A, ten were successful and only one failed (success rate of 91%). Out of the nine implants in group B, eight were successful and one failed (success rate of 89%). The final results are summarized in Table I. As for the radiographic evaluation, none of the successful cases in either group showed any radiolucent area indicating peri-implant re- Sorption. Bone ridge level appeared located above the second spiral ridge of the implant screw in all the successful implants of both groups, thus indicating an excellent relationship between the implant and the bone at a radiographic evaluation (Fig. 5). DISCUSSION Previous literature reports investigating orthodontic loading of Osseointegrated implants are limited to case reports and case series with a limited number of subjects/implants and without an adequate control group. Table I. Results of immediate orthodontic load and control groups after six months of orthodontic load application. RESULT GROUP SUCCESS | FAILURE | TOTAL A: Immediate orthodontic * 10 1 11 loading B: Orthodontic loading 8 1 9 delayed by four months TOTAL 18 2 20 305 Orthodontic and Prosthetic Load Figure 5. The 11 implant sites of the subjects in group A (immediate orthodontic loading on provisional prosthetic crowns). The arrow indicates the implant Se- lected for evaluation in that subject. In an extensive systematic review on the reinforcement of anchorage dur- ing orthodontic treatment using implants and other surgical methods, Skeggs and colleagues (2007) reported that evidence regarding the favor- able outcomes of immediate orthodontic load in osseointegrated implants is reasonable, although they recommended further studies in adult human patients. The present RCT in 13 patients and 20 osseointegrated implants contributed to data about this issue in human subjects instead of animal or laboratory studies (Roberts et al., 1984); it compared immediate ver- sus delayed orthodontic load in single mandibular implants. The posterior segments of the mandible were chosen as sites for the placement of single implants in this study. A recent systematic re- View revealed that those areas are the most well suited alveolar regions to receive immediately loaded implants (Nkenke and Fenner, 2006). Fur- ther, the posterior mandibular region is the area in which edentulism is more frequent due to caries (Carlos and Gittelsohn, 1965) or periodontal disease (Wood et al., 1989). Further, the placement of restoration in this region is less demanding esthetically when compared with the anterior dentoalveolar regions. Also, a greater success rate of immediate occlusal loading (Balleri et al., 2002; Finne et al., 2007) has been reported for implants placed in the mandibular posterior area with respect to the post terior area of maxilla, which is more susceptible to failure (Jaffin and Berman, 1991; Glauser et al., 2001; Weng et al., 2003). 306 Miguel et al. No difference was found with regard to the success rate of im- plants immediately loaded with orthodontic forces versus implants where the application of the orthodontic force was delayed for the canonical four months (91% versus 89%, respectively). Both clinical and radio- graphic assessments of successful implants in both groups revealed fa- vorable outcomes. Therefore, the results of the present RCT confirm the observations reported in the systematic review by Skeggs and coworkers (2007) with the aid of stronger evidence due to the methodological de- sign of the present study in human subjects. Roberts and colleagues (1984) published the first observations of immediate orthodontic load effects on osseointegrated implants. The success rate in that study was 0% within the four evaluated implants that were placed in rabbit femurs. The comparison of that investigation with the present study is not possible, because Roberts and coworkers (1984) evaluated the implants in animals and not in humans. Moreover, the es- tablishment of initial stability of implants of any magnitude was not de- termined, which could have interfered with the results. The comparison of the outcomes of the present study with those of previous investigations that used immediate orthodontic load in os- Seointegrated implants placed in human subjects is challenging due to different employed methodologies. The number of implants receiving immediate orthodontic load in the present study is greater than in previ- ously reported studies (Roberts et al., 1984; Karaman et al., 2002; Trisi and Rebaudi, 2002, 2005) and the present trial was conceived as a pro- spective randomized investigation. The utilization of implants not only for orthodontic anchorage, but also as support for future prosthetic crowns represents another variable that distinguishes the present study from others that evaluated immediate orthodontic load. As a conse- quence, the treatment plan for each of the patients enrolled in the present study did not include implant removal at the time the orthodontic treat- ment was accomplished. FINAL REMARKS This randomized prospective clinical trial found that: 1. Ten out of the eleven evaluated implants under im- mediate orthodontic load were successful six months after the start of orthodontic treatment, resulting in a success rate of 91%; 307 Orthodontic and Prosthetic Load 2. Out of the nine implants which received orthodontic load after four months of healing, eight were success- ful, resulting in a success rate of 89%; and 3. The reduction in waiting time for application of or- thodontic load may not influence negatively the suc- cess of Osseointegrated implants bearing provisional crown restorations. Although the results from this study are encouraging, the long- term outcomes require further investigation. A follow-up evaluation of the samples investigated here will provide useful insights on the effects of continued orthodontic treatment including immediately loaded im- plants. REFERENCES Balleri P, Cozzolino A, Ghelli L, Momicchioli G, Varriale A. Stability measurements of osteointegrated implants using Osstell in partially edentulous jaws after one year of loading: A pilot study. Clin Implant Dent Relat Res 2002:4: 128-132. Calandriello R, Tomatis M, Vallone R, Rangert B, Gottlow J. Immediate occlusal loading of single lower molars using Brânemark System Wide-Platform Tiunite implants: An interim report of a prospective open-ended clinical multicenter study. Clin Implant Dent Relat Res 2003 S1:74–80. Carlos JP, Gittelsohn A.M. Longitudinal studies of the natural history of caries II: A life-table studies of caries incidence in the permanent teeth. Arch Oral Biol 1965; 10:739–751. Chiapasco M, Gatti C. Implant-retained mandibular overdentures with immediate loading: A 3- to 8-year prospective study on 328 implants. Clin Oral Implants Res 2003;5:29-38. Finne K, Rompen E, Toljanic J. Clinical evaluation of a prospective mul- ticenter study on 1-piece implants: Part 1. Marginal bone level evaluation after 1 year of follow-up. Int J Oral Maxillofac Implants 2007:22:226-234. Glauser R, Rée A, Lundgren A, Gottlow J, Hämmerle CH, Schärer P. Immediate occlusal loading of Brânemark implants applied in various jawbone regions: A prospective, 1-year clinical study. Clin Implant Dent Relat Res 2001;3:204-213. 308 Miguel et al. Hruska A, Borelli P, Bordanaro AC, Marzaduri E, Hruska KL. Immedi- ate loading implants: A clinical report of 1301 implants. J Oral Im- plantol 2002:28:200-209. Jaffin RA, Berman CL. The excessive loss of Bränemark fixtures in type IV bone: A 5-year analysis. J Periodontol 1991;62:2-4. Karaman AI, Basciftci FA, Polat O. Unilateral distal molar movement with an implant-supported distal jet appliance. Angle Orthod 2002; 72; 167–174. Lorenzoni M, Pertl C, Zhang K, Wimmer G, Wegscheider WA. Immedi- ate loading of single-tooth implants in the anterior maxilla: Prelimi- nary results after one year. Clin Oral Implants Res 2003; 14:180-187. Nkenke E, Fenner M. Indications for immediate loading of implants and implant success. Clin Oral Implants Res 2006; 17 S2:19-34. Roberts WE, Smith RK, Zilberman Y, Mozsary PG, Smith RS. Osseous adaptation to continuous loading of rigid endosseous implants. Am J Orthod 1984;86:95-111. Shapiro PA, Kokich VG. Uses of implants in orthodontics. Dent Clin North Am 1988:32:539-550. Skeggs RM, Benson PE, Dyer F. Reinforcement of anchorage during orthodontic brace treatment with implants or other surgical methods. Cochrane Database Syst Rev 2007, Issue 3. Art. No.: CD005098. DOI: 10.1002/14651858.CD005098.pub’. Trisi P, Rebaudi A. Peri-implant bone reaction to immediate, early, and delayed orthodontic loading in humans. Int J Periodontics Restorative Dent 2005:25:317-329. - Trisi P, Rebaudi A. Progressive bone adaptation of titanium implants during and after orthodontic load in humans. Int J Periodontics Re- storative Dent 2002:22:31-43. Weng D, Jacobson Z, Tarnow D, Hürzeler MB, Faehn O, Sanavi F, Barkvoll P, Stach RM. A prospective multicenter clinical trial of 3i machined-surface implants: Results after 6 years of follow-up. Int J Oral Maxillofac Implants 2003;18:417-423. Wood WR, Greco GW, McFall WT. Tooth loss in patients with moderate periodontitis after treatment and long-term maintenance care. J Perio- dontol 1989;60:516–520. 309 UTILIZATION OF MINISCREW IMPLANTS FOR EFFECTIVE ORTHODONTIC TOOTH MOVEMENT IN MUTIILATED DENTITIONS Kelton T. Stewart ABSTRACT Adults seeking orthodontic treatment often present with a number of problems that create unique challenges for orthodontists. One problem commonly associ- ated with adult orthodontic patients is multiple missing teeth. The loss of teeth creates not only an esthetic and functional obstacle, but also an anchorage prob- lem that must be addressed to ensure successful orthodontic treatment. Without sufficient anchorage, common occlusal discrepancies like midline deviations become extremely difficult and sometimes impossible to correct. Skeletal an- chorage in the form of dental implants and miniscrew implants has emerged as an effective method of addressing a lack of suitable anchorage in adult patients. This case report describes the management of a partially edentulous adult with proclined incisors, moderate mandibular midline discrepancy, minor maxillary spacing and extensive dental history. Treatment for this patient involved the placement of two vertical miniscrew implants with composite crown buildups and one horizontal miniscrew implant to supplement the lost posterior anchor- age. Interproximal reduction from canine to canine in both dental arches was performed and powerchain was used to reduce incisor proclination. A Sentalloy NiTi coil spring was utilized to correct the mandibular midline discrepancy. After eleven months of active adjunctive orthodontic treatment, good dental esthetics and function was achieved; the patient’s facial harmony was main- tained. By using miniscrew implants to provide anchorage in this mutilated den- tition, an acceptable and cost efficient treatment result was obtained. The patient was referred for the fabrication of maxillary and mandibular removable partial dentures at the conclusion of orthodontic treatment. KEY WORDS: adult orthodontics, anchorage, mutilated dentition, midline dis- crepancy, miniscrew implants Over the last decade the number of adults seeking orthodontic treatment has continued to increase (Gottlieb et al., 2009). Orthodontic treatment for adult patients often is more complex and technically chal- 3.11 Miniscrew Implants lenging than treatment in younger patients. Furthermore, adult patients often are seeking adjunctive as opposed to comprehensive orthodontic treatment. Adjunctive orthodontic treatment is defined as tooth move- ment carried out to facilitate other dental procedures necessary to control disease, restore function and/or enhance appearance (Proffit et al., 2007). Because the primary goal of such orthodontic treatment is to replace missing or damaged teeth more easily or effectively, the management of adult patients presents a unique challenge for orthodontists. Occlusal discrepancies, such as midline deviations, are problems that orthodontists confront when treating adult patients. Midline discrep- ancies are among the most complex and commonly seen problems in clinical orthodontics (Nanda, 1996). The treatment mechanics to correct midline discrepancies must be established biomechanically in order to attain the desired treatment results without experiencing unwanted side effects. Correction of midline discrepancies is achieved most often with the use of midline elastics. In this approach, elastics are placed from an- terior teeth in one arch to more posterior in the opposite arch. This treat- ment method can be effective but is rendered useless in adult patients with multiple missing teeth, often lacking the required posterior anchor- age needed to correct this discrepancy without detrimental side effects, such as canting of the occlusal plane. Missing teeth is another common problem that orthodontists must overcome when treating adult patients. As one might expect, the probability of observing missing teeth in a patient increases with the pa- tient’s age (Battistuzzi, 2007). Patients with several lost teeth and/or an occlusion exhibiting great instability, secondary to the loss of multiple teeth, are characterized as having a mutilated dentition (Adler, 1965). The lack of teeth is troubling particularly for orthodontists because suc- cessful orthodontic treatment is characterized by optimal anchorage, which is created by utilizing individual or groups of united teeth. Anchorage control methods are less efficient or even non- existent in partially edentulous patients who are missing multiple poste- rior teeth (Willems et al., 1999). When patients are missing teeth, nor- mally mundane orthodontic mechanics increasingly become complicated, with some treatment goals becoming nearly impossible without drastic treatment interventions. Today, implants commonly are used to replace missing teeth in partially edentulous adult orthodontic patients (Kokich, 1996). Dental implants come in a variety of forms and have become one solution to treating adult patients with missing teeth, thus overcoming the anchorage dilemma that missing teeth pose for the orthodontist. The in- 312 Stewart corporation of temporary dental implants allows the orthodontist to com- plete complex tooth movements successfully and to achieve optimal treatment results efficiently for their adult patients. This case report describes the management of an adult with a Class I malocclusion, midline discrepancy, edentulous sites distal to the left maxillary and mandibular second premolars and proclined maxillary and mandibular incisors. Miniscrew implants (MSIs) placed in the alveolar ridge were used to replace the lost posterior anchorage. With the MSIs as anchorage, interproximal reduction and powerchain was used to reduce the incisor proclination. A nickel titanium (NiTi) coil spring against the MSI was used to correct the non-coincident mandibular midline. DIAGNOSIS AND ETIOLOGY A 67-year-old African-American woman with several missing teeth presented for orthodontic treatment and had a chief concern of a lost retainer and flared incisors. Her medical history revealed an allergy to sulfa drugs but otherwise was unremarkable; her dental history, how- ever, was extensive. She had several composite restorations and was characterized as having a mutilated dentition, missing several posterior teeth. The patient explained that she felt that the mercury in her fillings was poisoning her. She was unable financially to cover the cost required to have her amalgam fillings replaced with composite restorations and, therefore, had all of these teeth extracted to eliminate her discomfort. The patient reported that she had undergone adjunctive orthodontic treatment for two years to close a diastema and eliminate maxillary and mandibular crowding. Her initial orthodontic treatment had been com- pleted four months prior and she was seeking orthodontic treatment again because she had lost her retainer and was experiencing relapse. Specifi- cally, she was displeased with the returned diastema and felt that her teeth were flared too far forward. The patient had a convex facial profile, predominantly due to a slightly protruded lower facial third. She had a normal nasolabial angle, shallow mentolabial fold, well-proportioned nose and soft tissue chin, and her lips were well positioned to Ricketts’ E-line. From the frontal View, the patient was characterized by a mesoprosopic facial outline. She had a well-balanced face with no gross facial asymmetries. She had an acceptable incisor display upon smiling but showed no gingiva (Fig. 1). 3.13 Miniscrew Implants Figure 1. Extraoral pre-treatment photographs. The intraoral examination (Fig. 2) showed the absence of the left maxillary and mandibular molars as well as the right mandibular second molar. Only a mild amount of alveolar ridge resorption was observed in the edentulous areas. She had occlusal composite restorations on the maxillary right first and second molar and the mandibular right first mo- lar, as well as a distal-occlusal composite filling on tooth maxillary right first premolar. All restorations were functioning well and free of voids or defective margins. Asymptomatic abfractions also were noted on the right posterior teeth, from canine to molars in both the maxillary and mandibular arches. The molar relationship on the right was Class I while it was un- determinable on the left side. Both the right and left canines were posi- tioned in Class I relationships. With the loss of the patient’s retainer, a mm diastema between the patient’s maxillary central incisors had re- turned. The patient’s incisors were triangular in nature and black trian- gles were present between the upper incisors. An average overbite Was noted during the intraoral examination, but an increased overjet (2.5 mm) on the patient’s left anterior region was noted, even with the proclined incisors. The maxillary arch had an ovoid archform and a +3 tooth size arch length discrepancy (TSALD), while the mandible also demonstrated an ovoid form and no TSALD. The mandibular arch also had a slight asymmetry with the incisors and left canine positioned to the left. Both the curve of Spee and curve of Wilson were level. The patient had good oral hygiene and a healthy periodontium. The panoramic radiograph showed symmetrical condyles and a lack of confounding pathology. Moderate pneumatization was seen in the 3.14 Stewart Figure 2. Intraoral pre-treatment photographs. maxillary sinuses, which now extended to the apical third of the maxil- lary molars, premolars and canines. Mild bone loss was observed around the anterior teeth and the bone support ranged from 50% to 80%. The 100t morphology of the dentition appeared normal and showed no signs of past or current root resorption (Fig. 3). Cephalometric evaluation revealed an orthognathic hard-tissue profile with an ANB angle of 3.4°, a low mandibular plane angle (SN- MP, 24.5°), and proclined maxillary (U1-SN, 115.2°) and mandibular (L1-MP, 102.5°) incisors (U1-L1, 117.8°: Fig. 4). The patient had a Class I denture base relationship (Wits appraisal, -1.7 mm), but both the maxilla (SNA, 91.5°; A-N Perpendicular 7 mm) and mandible (SNB, 88.2°, 315 Miniscrew Implants Figure 4. Pre-treatment cephalometric tracing. Pog-N Perpendicular 6 mm) were protruded with relation to the cranial base. The Soft tissue analysis corresponded to the hard-tissue findings, with the lower lip being slightly protrusive (1.0 mm) with respect to the E-plane (Table 1). 316 Stewart Table 1. Cephalometric summary. Pre-treatment Post-treatment SNA (°) 91.5 91.9 A-N Perpendicular (mm) 6.9 7.3 SNB (9) 88.2 88.4 Pog-N Perpendicular (mm) 6.4 7.0 ANB (9) 3.4 3.5 Wits Appraisal (mm) – 1.7 –2.5 MP-SN (9) 24.5 24.7 U1-SN (9) p 115.2 111.6 L1-MP (9) 102.0 97.3 U1-Ll 1 18.3 126.3 UL to E-Plane (mm) –2.2 -1.6 LL ro E-Plane (mm) 0.6 –0.3 The etiology of the patient’s malocclusion could be attributed to both genetic and environmental factors. The genetic factors most likely contributed to the patient’s protruded and hypodivergent facial pattern. The environmental factors led to the multiple missing teeth and the sub- sequent spacing observed in the maxillary arch. The mandibular midline discrepancy probably was the result of the teeth migrating to the patient’s left side because of the loss of the mandibular left premolars and molars. TREATMENT OBJECTIVES The maxillary and mandibular incisors needed to be uprighted to reduce the amount of flaring the patient perceived. The mandibular mid- line needed to be repositioned about 2 mm to the patient’s right. Other dental objectives included eliminating the midline diastema and reducing or eliminating the black triangles between the maxillary incisors. The anteroposterior relationship present on the patient’s right buccal occlu- Sion was to be maintained. The facial and skeletal objectives were to maintain their current relationships during orthodontic treatment. After adjunctive orthodontic treatment the patient would be referred for the fabrication of a removable partial denture (RPD). TREATMENT ALTERNATIVES 1. Extraction of premolars to reduce the incisor procli- nation. This approach would allow for the desired in- 317 Miniscrew Implants cisor uprighting and provide the space needed to cor- rect the midline discrepancy. During incisor retraction the maxillary incisors could be reshaped to eliminate the black triangles. Miniscrew implants could be used on the left side to help retract the anterior dentition or dental implants could be placed to achieve the same goal and then be used for the prosthetic restoration of the edentulous space after orthodontic treatment. 2. Interproximal reduction (IPR) of the maxillary and mandibular incisors with space closure completed with Invisalign aligners. The desired dental upright- ing and reduction of the black triangles could be achieved with the use of clear aligners and IPR. After adequate uprighting of the incisors, elastics could be employed along with the aligners to try and correct the midline discrepancy. 3. Absolute anchorage with MSIs placed vertically into the alveolar ridge, in the position of the maxillary and mandibular left first premolars. These MSIs would be built up with composite resin to allow a bracket to be bonded onto its surface. This treatment approach would help replace the lost anchorage and allow for a more traditional treatment approach. Interproximal reduction of the incisors and the use of powerchain would allow for the desired incisor uprighting and black triangle reduction. After incisor repositioning, a NiTi coil spring could be used against the mandibular MSI to push the mandibular incisors to the right, thereby correcting the mandibular midline discrep- ancy (Fig. 5). The first treatment option was discounted for two major reasons. First, the patient presented with a harmonious facial profile and the goal of treatment was to maintain its current relationship. Extracting teeth and retracting incisors could result in a potentially detrimental change of the soft tissue profile. Secondly, the patient already had lost several teeth and was unwilling to pursue a treatment approach that required loss of more teeth. The second option was considered because aligners have been shown to be effective at retroclining incisors when used along with IPR. 3.18 Stewart - º º _\ – - (`ſ Ni-Ti Coil Spring Figure 5. Biomechanics for the correc- tion of the mandibular midline discrep- ancy. Having just completed two years of orthodontic treatment, however, the patient was looking for a faster method of obtaining the goals of treat- ment. The union of the patient’s desires and the established goals of treatment justified the use of the third treatment option. This option Would utilize MSIs to help achieve the orthodontic tooth movements (OTMs) that would have been difficult to achieve without the presence of sufficient posterior anchorage. TREATMENT PROGRESS Due to the bone loss present on the maxillary and mandibular in- cisors, the patient was referred to the Indiana University School of Den- tistry Graduate Periodontic Department for a periodontal evaluation prior to the placement of any appliances. The referral was made to ensure that no active periodontal disease was present and that the patient was clear to undergo orthodontic treatment. The periodontist confirmed our clinical findings that the patient had a healthy periodontium, free of active perio- dontal disease and cleared her to initiate a second phase of orthodontic treatment. 3.19 Miniscrew Implants The patient’s treatment plan was divided into three major phases: 1. Placement of the orthodontic appliances; 2. Incisor uprighting and black triangle reduction/elimi- nation; and 3. Mandibular midline correction. The first phase of treatment involved the bonding of the maxil- lary and mandibular dentition with Speed 0.022.” brackets (Strite Indus- tries, Ontario, Canada) and the placement of two vertically oriented MSIs (Rocky Mountain Dual Top Anchor System, 1.6 mm x 8.0 mm, Denver, CO; Fig. 6A). The two MSIs were placed in the maxillary and mandibu- lar left first premolar positions. To eliminate potential patient discomfort during the MSI placement procedure and because there was little risk of hitting the root of the adjacent teeth, both MSIs were placed under 18 mg of 2% Lidocaine with 1/100,00 epinephrine. Following MSI insertion, the heads of both MSIs were built up with composite resin (Transbond" XT, 3M Unitek, Monrovia, CA). The composite buildups were shaped to allow them to be treated as ankylosed teeth during treatment but they were left out of occlusion to reduce the probability of failure. After the composite crowns were completed, the premolar brackets were bonded to the facial surface (Fig. 6B). During the incisor uprighting phase of treatment, approximately 4.5 mm of IPR was completed in both arches from canine to canine. A 0.016” stainless steel wire was placed and powerchain was used to close the resulting space and upright the incisors. After a few months of active treatment, the majority of the space was consolidated and a 0.019.” x 0.025” beta titanium (3M Unitek, Monrovia, CA) archwire was placed to facilitate the correction of the minor tooth rotations present at the begin- ning of treatment. After incisor uprighting and rotation correction, a Sentalloy Ni- Ti open coil spring (Dentsply GAC Intl., Bohemia, NY) was placed be- tween the mandibular left MSI and the mandibular left canine to initia- tion the correction of the midline discrepancy. During space closure, the mandibular midline had moved even further to the patient’s left, but the planned method of midline correction remained the same. During mid- line correction, the mandibular left MSI became noticeably mobile and ultimately had to be removed. After a two-week healing period, the same MSI was re- implanted into the ridge and a second MSI was placed horizontally in the 320 Stewart -- | - | - | - | - | Figure 6. Miniscrew implants utilized as anchorage during treatment. A Rocky Mountain Dual Top MSI. B. MSI with composite resin crown and bonded bracket. alveolar ridge between the mandibular left canine and the MSI; approxi- mately 7 mm from the crest of the soft tissue alveolar ridge (Fig. 7). A 0.010” ligature wire was used to tie the vertical and horizontal MSIs to- gether for increased anchorage support. After two weeks, a 1 mm shim Was placed between the Sentalloy open coil spring and the vertical MSI to facilitate continued midline correction. During this visit, approxi- mately 1 mm of IPR was conducted between the mandibular right canine and incisors and powerchain was placed from the mandibular right cen- tral incisor back to the mandibular right first molar. Five weeks after the 321 Miniscrew Implants Figure 7. Modified biomechanical de- sign for midline correction. A. Frontal intraoral photograph. B. Occlusal in- traoral photograph. C. Buccal intraoral photograph. D. Radiograph of mandibu- lar MSIs. The horizontal MSI was just beyond the left mandibular canine PDL and produced no pain or discomfort for the patient during treatment. re-implantation of the left mandibular vertical MSI, correction of the mandibular midline was achieved, with no signs of MSI mobility. Minor case detailing and finishing was completed over the last two months of orthodontic treatment and all appliances were removed after eight months of active orthodontic treatment. Bonded retainers Were placed in the maxillary (0.016” stainless steel, lateral to lateral) and man- dibular (0.028° stainless steel, bonded to canines only) arches. All three MSIs were removed atraumatically at the end of treatment with no diffi: culties and without the use of local anesthetic. TREATMENT RESULTS The specified goals for this patient were achieved during adjunct tive orthodontic treatment. The patient’s skeletal and soft tissue harmony was maintained (Figs. 8-11). The maxillary and mandibular incisor proclin- 322 Stewart Figure 9. Intraoral post-treatment photographs. 323 Miniscrew Implants Initial 5/28/2009 Final 4/2/2010 j Figure 11. A. Cranial base superimposition. B: Maxillary superimposition. C. Mandibular superimposition. - ation was reduced by several degrees and the patient found their new position satisfactory. The planned IPR not only allowed for the upright- ing of the incisors, but also facilitated morphological changes that re- sulted in the elimination of the black triangles present before treatment. The treatment mechanics used allowed for the acquisition of coincident midlines, amongst not only the two dental arches but also between the dentition and the patients facial midline. The minor rotations and midline diastema present at the beginning of treatment also were addressed Suc- 324 Stewart cessfully. The Class I occlusal relationship on the patient’s right side also was maintained. The main impact of this treatment was observed at the level of the dental arches. The reduction of the incisor inclination and correction of the mandibular midline discrepancy allowed for the establishment of a more stable occlusal scheme. The obtained mutually protected occlusion will allow for the best long-term prognosis for both the remaining ante- rior and posterior dentition. As was stated previously, the goal of adjunc- tive orthodontics was to correct dental irregularities and prepare a patient for the successful completion of other dental procedures. This case achieved this directive as well, with the patient being prepared suitably for the fabrication a RPD to replace the multiple missing posterior teeth. The post-treatment panoramic radiograph showed the mainte- nance of adequate bone levels around the remaining dentition, especially the teeth that will serve as abutments for the RPD (Fig. 10). Acceptable root parallelism at the end of treatment also was seen in the radiograph. There were no signs of root resorption or other pathology on this final radiograph. DISCUSSION Obtaining successful orthodontic treatment outcomes can be a difficult task; this challenge becomes even more complicated when working with adult patients. Lack of growth (Proffit, 2007), increased esthetic demands (Douglass, 2000) and more complex medical and den- tal histories can account for some of the challenges faced by orthodontics when treating adult patients. Adult patients also are more prone to pre- sent for orthodontic care with multiple missing teeth (Battistuzzi, 2007), mutilated dentitions, caused by a number of factors including pervasive dental caries, periodontal disease and trauma. The lack of multiple teeth poses a serious biomechanical problem for orthodontists, who may find that their traditional treatment approaches are ineffective in this particu- lar patient population. During the last several decades, dental implants have emerged as a viable option of replacing teeth for esthetic and functional reasons (Odman et al., 1988; Moberg et al., 1999). Orthodontics also has found that dental implants, and more recently miniscrew implants, can be used to supplement or in some instances totally replace dental anchorage (Heymann, 2006; Janssen et al., 2008; Leung et al., 2008). 325 Miniscrew Implants Miniscrew implants provide a stable form of anchorage and have allowed orthodontists to redefine the way we view basic laws of physics. The use of MSIs modifies the treating environment and previously estab- lished treatment principles like Newton’s third law: “for every action there is an opposite and equal reaction” (Lenzen, 1938). By incorporating MSIs, teeth can be moved into desired positions, while the usually un- wanted reactive forces on anchorage units are reduced or totally elimi- nated. Furthermore, the addition of MSIs and other forms of skeletally supported anchorage has enabled orthodontist to obtain satisfactory treatment results in adult patients, even when these patients present with incomplete or mutilated dentitions. Despite the absence of multiple posterior teeth, the patient pre- sented with good facial harmony and a relatively healthy dentition. While cephalometric evaluation illustrated that the patient had signifi- cantly proclined incisors, even for her ethnic group, the patient was un- willing to have more teeth removed to correct their position. Having just completed 24 months of orthodontic treatment, she also was unwilling to initiate any treatment approach that would require more than twelve to fourteen months of active treatment time. Considering these treatment limitations, both extraction and Invisalign therapy were refused as treat- ment options. Interproximal reduction of the incisors and space closure using powerchain was the only remaining viable option once the other treat- ment alternatives were declined. Without the posterior teeth on the left side, however, properly and completely consolidating the space without shifting the dental midlines to the patient’s right would be difficult. By placing the MSIs vertically with a composite crown, space closure could be completed as though the posterior teeth were present. Had the MSIs been placed horizontally, near the mucogingival junction, depending on the type of MSI used, either a ligature wire, an auxiliary arch wire or the main archwire would have needed to be contoured to run from the MSI to the neighboring canine in both the maxillary and mandibular arches. This extension could have resulted in significant soft tissue trauma be- cause both the MSI and the connecting wire would have been positioned near the corner of the patient’s mouth. Vertically positioned MSIs elimi- nated this discomfort concern completely while still providing the me- chanical advantage needed by the orthodontist to obtain the desired tooth movement. 326 Stewart The most difficult challenge in this case was the correction of the mandibular midline discrepancy. Presence of the left posterior teeth would have allowed this mild discrepancy to be corrected more easily. Correction of the discrepancy could have been achieved with the use of strategically placed elastics. By using a combination of Class III elastics on the patient’s right side and Class II elastics on the left or by placing a midline elastic from the maxillary right canine down to the mandibular left lateral incisor or canine, the necessary forces required to correct the midline could have been incorporated. The major drawback to this method of midline correction is the canting of the occlusal plane, with the occlusal plane tipping down on the patient’s right side and up on the left side, which could result in decreased facial esthetics. Without poste- rior teeth in the left side, the first approach would have been impossible and the second approach would have had an increased likelihood of caus- ing an occlusal cant. Using the mandibular MSI with open Sentalloy coil spring on one side with minor IPR and powerchain on the other allowed for the rapid correction of the midline discrepancy without the tendency of cant- ing the occlusal plane. Approximately 196 ch (Proffit, 2007) were needed to translate the mandibular left incisors and canine. The mechani- cal system placed on the MSI to correct the midline potentially would enact a force and moment that would distalize and rotate the MSI in a counterclockwise manner, respectively. This possible side effect initially was deemed unlikely because of the relatively low force levels. As treatment of the midline discrepancy progressed, minor cor- rection was noted and it was decided that the coil spring should be re- activated. Therefore, after a few months of correction, a 1 mm metal shim was added to the archwire to further activate the coil spring and complete the midline correction. The addition of the spring resulted in a slightly higher force level, 215 ch, as compared to the initial value. This increase was verified with a dontrix force gauge (DONG-16, OrthoPli, Philadelphia, PA) and deemed acceptable. The day following shim activation, the patient was seen for an emergency visit and it was found that the MSI had significant mobility. It was decided that it was in the best interest of the patient to remove the MSI temporarily and allow the area to heal for two weeks, after which time the MSI would be reinserted. After the healing period, the MSI was replaced and a second horizontal MSI (Fig. 7C,D) was added mesial to the 327 Miniscrew Implants vertical MSI to reduce the chances of a second failure. The addition of the horizontal MSI functioned to reduce/eliminate the counterclockwise moment and distalizing force placed on the vertical MSI by the Sentalloy coil spring. The modified biomechanical scheme worked effectively and the midline was corrected in less than two months. Are the force levels required to translate three teeth too high to be supported by a vertically oriented MSI'? While various studies have shown that MSIs are capable of withstanding large levels of forces (Kim et al., 2005), with some studies indicating that MSIs are stable up to 450 cN (Kyung et al., 2003), information evaluating MSIs experiencing rota- tional forces is less robust in the literature. Some animal studies have shown that the application of immediate counterclockwise rotational moments on machined-surface mini-implants detrimentally impact their stability (Cho, 2007). The literature also lacks sufficient human studies on the topic to allow for any significant treatment recommendations. In this case, the possibility exists that the failure observed resulted from applying too great a force while trying to correct the midline. The anchorage design shown in this case report closely emulates that of a regular tooth. The composite build functions as a “tooth crown,” while the area below the transmucosal collar, including the screw threads, serves as a “tooth root.” Because little if any osseointegration occurs with MSIs lacking surface treatment, extreme force levels can result in failure of the device just as extreme forces can affect a natural tooth adversely. When evaluating what level of force a tooth can withstand, a number of factors must be considered including its crown-to-root (C/R) ratio. A tooth’s C/R ratio corresponds to the ratio between the non-bony supported and bony supported portions of the tooth (Penny, 1979). The idea and importance of C/R ratio has been well established in the litera- ture; a ratio of 1:2 is considered ideal, 1:1.5 is viewed as acceptable and a ratio of 1:1 is seen as minimal or questionable (Dykema, 1962; Rey- nolds, 1968; Johnston, 1971). The basic principles of C/R ratios have been translated to dental implants. With implant-supported crowns, the relationship is referred to as a crown-to-implant (C/I) ratio (Rosenstiel et al., 2001). While the C/I ratio is still an important parameter in determining the success of dental implants (Romeo, 2010), the ratio delineating clinical success with im- plants is different than with normal teeth. A C/I ratio range of 0.5:1 to 3:1 has been shown to be successful clinically (Schulte, 2007). In a study 328 Stewart of 889 single tooth implants, Schulte and coworkers (2007) reported that the mean C/I ratio of successful implants was 1.3:1 and the mean ratio of unsuccessful implants was 1.4:1. The overall dental implant success rate in this study was 98.2%; while these ratios indicate that implant- Supported crowns can be successful with ratios that would result in clini- cal failure for normal teeth, one must keep in mind that these are im- plants that osseointegrate. Acceptable C/I ratios for MSIs, which lack significant osseointe- gration, have not been established in the literature. The more conserva- tive ratio standards established for teeth seem more suitable for MSIs used in the manner described in this case report. Therefore, when incor- porating this type of anchorage into orthodontic treatment, the orthodon- tist should strive to attain a C/I ratio of 1:2 but no less than 1:1. The C/I ratio for the maxillary MSI was 1:1, while it was 1.4:1 for the mandibu- lar MSI (Fig. 12). It appears that a 1:1 ratio was acceptable for the maxil- lary MSI, which demonstrated no signs of mobility or other complica- tions throughout treatment. With the mandibular MSI, however, a C/I ratio closer to 1:1 and probably even closer to 1:2 seems to have been Warranted. This ratio could have been achieved by using a 10 mm length MSI and/or by reducing the height of the composite crown. While the less than optimal C/I ratio partially explains the observed failure of the mandibular MSI, it still does not answer totally the question of adequate force levels for this type of anchorage system. Figure 12. Periapical radiographs showing Ci ratios of Msis. A Maxillary MSI With a 1:1 C/I ratio. B: Mandibular MSI with a 1.4:1.0 C/I ratio. 329 Miniscrew Implants Close examination of the patient records, however, reveals an- other possible explanation for the MSI failure. During the re-activation of the NiTi coil spring, the 1 mm shims used to continue midline correc- tion were placed anterior to the coil spring rather than posterior to it (Fig. 13). This oversight, unnoticed by the treating resident and faculty attend- ing until after the case was completed, created a force system that inhib- ited midline correction and substantially increased the probability of MSI failure. The clinical error resulted in a slightly increased treatment time and provides a logical explanation as to why the MSI failed during treatment. Figure 13. Sentalloy open coil spring compressed against MSI. Note the ante- rior placement of the 1 mm shims, which inhibited midline correction and facilitated MSI failure. - While the C/I ratio and unnoticed clinical error provide a better understanding of why the MSI failed in this case, they fail to answer the previously posed question: Are the force levels required to translate three teeth beyond the supportive limits of a vertically oriented MSI? Perhaps animal and human research in the near future more clearly will identify the force and moment limitations vertically oriented MSIs can withstand. With these answers, orthodontists will be provided with the knowledge necessary to design effective and stable mechanical anchorage systems. This case report demonstrates a novel method of utilizing MSIs to achieve OTM, Two MSIs were used to correct the excessive incisor proclination and ultimately two MSIs were used in conjunction with mi- nor IPR and powerchain to correct the mandibular midline discrepancy. The use of MSIs in mutilated dentitions is a viable and effective way to overcome the anchorage restrictions and achieve clinically acceptable Orthodontic results in our adult patients. 330 Stewart ACKNOWLEDGEMENTS The author would like to thank Dr. Brad Dawson for his work in treating and documenting this case. The staff at Indiana University School of Dentistry, Department of Orthodontics also is acknowledged for their continual and invaluable support. REFERENCES Adler P. The incidence of dental caries in adolescents with different oc- clusion. J Dent Res 1965; 135:344–349. Battistuzzi PG. Dissertations 25 years after 16: The mutilated dentition. [In Dutch]. Ned Tijdschr Tandheelkd 2007; 114:255-259. Cho YM. Influence of the rotational moment on the stability of orthodon- tic miniscrew. Seoul: Unpublished thesis, Department of Orthodon- tics, Yonsei University, 2007. Douglass CW, Sheets CG. Patients’ expectations for oral health care in the 21" century. 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In: Proffit WR, ed. Contemporary Orthodontics. St. Louis. Mosby Elsevier 2007:635-685. Reynolds, JM. Abutment selection for fixed prosthodontics. J Prosthet Dent 1968; 19:483. Romeo E. Bivio A, Mosca D, Scanferia M. Ghisolfi M, Storelli S. The use of short dental implants in clinical practice: Literature review. Minerva Stomatol 2010:59:23–31. Rosenstiel SF, Land MF, Fujimoto J. Contemporary Fixed Prosthodon- tics. 3rd ed. St. Louis: Mosby Inc., 2001. Schulte J, Flores AM, Weed M. Crown-to-implant ratios of single tooth implant-supported restorations. J Prosthet Dent 2007;98:1-5. Willems G, Carels CE, Naert IE, van Steenberghe D. Interdisciplinary treatment planning for orthodontic-prosthetic implant anchorage in a partially edentulous patient. Clin Oral Implants Res 1999; 10:331-337. 332 ALVEOLAR CORTICAL PLATE MOVEMENT ASSOCIATED WITH INCISOR RETRACTION USING SKELETAL ANCHORAGE John S. Lippincott, Chester S. Handelman, Myung-Rip Kim ABSTRACT Introduction: The extent to which the remodeling behavior of the anterior den- toalveolus limits tooth movement remains unclear. In this study, we compared the pre- and post-treatment position of the labial and lingual cortical plates of the anterior alveolus after incisors were retracted in subjects with protrusive dentitions using skeletal anchorage in the form of miniscrews. Methods: Pre- and post-treatment lateral cephalometric radiographs of sixteen bimaxillary pro- trusive patients of South Korean descent were examined. Each patient’s treat- ment consisted of two premolar extractions in one or both arches with retraction of the incisors using miniscrews. Labial and lingual measurements of both tooth position and cortical plate position were made at various increments along the length of the root and then compared using paired t-tests. Results: Despite the use of miniscrew anchorage, the incisors were retracted in a controlled tipping fashion rather than bodily movement. Paired t-tests found significant differences in position for both the maxillary and mandibular labial cortical plates. The posi- tion of the maxillary lingual cortical plate was not found to be different signifi- cantly from pre- to post-treatment. In the mandible, the lingual cortical plate position was found to be different significantly only at the level closest to the cementoenamel junction (CEJ). Conclusions: During incisor retraction, the la- bial cortical plates of both the maxilla and mandible remodeled to follow tooth movement. With one exception, the lingual cortical plates did not remodel to follow tooth movement. These findings suggest that lingual cortical plates of the maxilla and the mandible may act as limitations to planned orthodontic tooth movement (OTM). KEY WORDS: alveolus, limitations, miniscrews, retraction, orthodontics INTRODUCTION A primary goal of any orthodontic treatment involves reposition- ing the maxillary and mandibular incisors to achieve a proper occlusion 333 Alveolar Cortical Plate Movement and improve the patient’s dental and facial esthetics. Ideally, orthodontic treatment should move these teeth in a manner that maintains their posi- tion within the alveolar housing and preserves the health of the surround- ing bony and soft tissues. When treatment moves the incisors beyond their alveolar housing, iatrogenic sequelae can occur, most notably in the form of bone loss (Wainwright, 1973; Wingard and Bowers, 1976; Bim- stein et al., 1990), gingival recession (Batenhorst et al., 1974; Steiner, 1981; Artun and Krogstad, 1987) and apical root resorption (Kaley and Phillips, 1991; Horiuchi et al., 1998; Parker and Harris, 1998; Sa- meshima and Sinclair, 2001). While the incidences of such sequelae are relatively low (Lupi et al., 1996), every effort should be made to prevent their occurrence as they can compromise the health of the dentition and the stability of the achieved treatment result significantly. The occurrences of such sequelae suggest that there are limita- tions or biologic boundaries to the amount of incisor movement possible (Handelman, 1996). Traditionally, these limitations have been ascribed to the remodeling capacity (or lack thereof) of the alveolus that houses the teeth (Fig. 1). Several classical studies have shown that tooth move- ment is related directly to the remodeling capacity of alveolus (Reitan, 1960, 1967; Epker and Frost, 1965; Rygh, 1973, 1986). However, several aspects of alveolar remodeling remain unclear: 1. The way in which the mechanical, chemical and pro- tein signaling factors interact to carry out the meta- bolic activities in bone remodeling is still under de- bate (Krishnan and Davidovitch, 2006; Masella and Meister, 2006); 2. The extent to which alveolar bone will remodel under orthodontic loading is not known; and 3. It is important to note that most of the studies to date concerning alveolar remodeling typically have been confined to the trabecular bone adjacent to teeth, while relatively few studies have addressed the be- havior of the outer alveolar cortical plates during tooth movement (Epker and Frost, 1965; Baumrind, 1969; DeAngelis, 1970; Melsen, 1999). As reported in the orthodontic literature, several limitations to orthodontic tooth movement (OTM) have been recognized (Hixon and Klein, 1972; Barrer, 1974; Meikle, 1980; Handelman, 1996). Early studies 334 Lippincott et al. Alveolar Process Labial Cortical Plate _-T Trabecular Bone Figure 1. Schematic representation of the anterior dentoalveolus. of limitations to incisor movement in clinical subjects (Edwards, 1976; Mulie and Ten Hoeve, 1976; Ten Hove and Mulie, 1976) showed that the palatal cortex in the maxilla and the lingual cortex in the mandible act as barriers to incisor movement. Edwards’ study (1976) of upper incisor retraction in 188 Class II division I patients was the first to suggest that in some subjects, only 1.5 to 2.5 mm of maxillary incisor retraction is possible at the apical level. The studies Mulie and Ten Hoeve (1976) and Ten Hove and Mulie (1976) not only agreed with Edwards’ findings but also importantly elaborated on the iatrogenic phenomena that occur when incisors are retracted into the alveolar cortex. More recent studies have confirmed these findings (Vardimon et al., 1998; Sarikaya et al., 2002). The investigation by Sarikaya and col- leagues (2002) particularly is notable due to their use of computed tomo- graphy scans to examine incisor retraction. They found not only that the lingual cortical plates did not remodel as the teeth retracted but also that alveolar bone dehiscences and fenestrations occurred in several of the patients. Conceptually, Proffit and Ackerman (1982) provided an overall framework for limitations to OTM. Their work elaborated on the limita- tions to OTM by constructing three “envelopes of discrepancy” that would help clinicians identify those cases that could be treated by ortho- 335 Alveolar Cortical Plate Movement dontic means alone, which would require growth modification in combi- nation with orthodontic treatment and which would require a combined orthodontic/orthognathic surgical approach. While these envelopes con- tinue to be useful as a foundational framework, their basis appears to be derived from clinical experience rather than scientific study. Addition- ally, Proffit and Ackerman did not elaborate on what might represent the borders of envelopes, either biological or biomechanical. With the advent of skeletal anchorage, particularly in the form of miniscrews, biologic boundaries to tooth movement have come under renewed scrutiny, especially because previous studies regarding limita- tions to OTM utilized retraction mechanics susceptible to anchorage loss (Proffit et al., 2000; Geron et al., 2003). The small size of the miniscrews, their relative ease of placement and removal, and low risk of complications has made them a more common method of anchorage (Ka- nomi, 1997; Costa, 1998; Deguchi et al., 2003; Cope, 2005; Kravitz, 2007). To date, several clinical studies and case reports have demon- strated their utility in a wide variety of situations, particularly those when tooth retraction under maximum anchorage is desired (Park et al., 2001; Bae et al., 2002; Liou et al., 2004). While this anchorage is helpful indeed, only one clinical study on the treatment effects of miniscrew anchorage in tooth retraction has been published (Upadhyay et al., 2008) with no studies yet on whether using maximum anchorage during incisor retraction allows clinicians to retract incisor teeth farther. Furthermore, it is not known yet whether re- traction using miniscrew anchorage can overcome the recognized anat- omic limitations while avoiding any associated adverse outcomes. The purpose of our study was two-fold: first, to observe the changes that occurred in the position of the teeth and cortical plates when the incisors were retracted using skeletal anchorage in the form of miniscrews. Second, to re-examine what, if any, limitations may exist to tooth movement when miniscrew anchorage is employed during incisor retraction. METHODS AND MATERIALS Our study examined pre- and post-treatment lateral cephalomet- ric radiographs of sixteen bimaxillary protrusive patients of South Ko- rean descent (thirteen females, three males). From these sixteen patients, sixteen maxillary and eight mandibular arches were analyzed. The pa- tient’s ages ranged from thirteen to twenty-five years of age. Only non- 336 Lippincott et al. growing patients with non-significant medical and dental histories were included in the sample. All patients received two premolar extractions in either one or both arches and had incisors retracted using skeletal anchorage in the form of miniscrews. The miniscrews were placed between the first molar and second premolar in the maxilla and between the first and second mo- lars in the mandible. Retraction of the incisors was carried out in a 0.018” pre-angulated bracket system on 0.016.” x 0.022” stainless steel archwire using either elastic chain or nickel-titanium (NiTi) coil springs attached from the miniscrew to power arms soldered to the archwire at the canine-lateral contact area (Fig. 2). Figure 2. Clinical photo representing the typical mechanical Scheme for retraction. While the location of the miniscrew placement was identical for each patient, the modality of the retraction force varied by clinician, with one clinician using elastic chain to retract and the other clinician using NiTi coils. All cephalometric radiographs were taken using a Soredex Cra- nex 3 radiograph machine. The pre- and post-treatment radiographs were Captured digitally using a UMAX flatbed scanner (Techville Inc., Dallas, TX) and Adobe Photoshop image editing software (Adobe Systems Inc., San Jose, CA). The radiograph scans then were captured using the Dol- phin Imaging Software System (Dolphin Imaging and Management Solu- tions, Chatsworth, CA) and traced using a custom cephalometric analysis after Yue (2005) and Mockaitis (2006). Along with standard cephalometric measures to document inci- SOr position and mandibular divergence, this analysis also uses custom tooth and cortical plate landmarks located at various levels along the 337 Alveolar Cortical Plate Movement length of the tooth root (Fig. 3). These root length levels were con- structed by placing lines parallel to the palatal plane in the maxilla and the mandibular plane in the mandible at points 25%, 50% and 75% of the root length, as defined by the distance from the cementoenamel junction (CEJ) to the root apex. Subsequently, the CEJ represented the 0% point and the root apex represented the 100% point. To determine the retrac- tion of both the tooth and cortical plate that may have occurred during tooth retraction, the analysis also used two reference lines from which millimeter measurements to the tooth and cortical plate landmarks were made. These lines were constructed by drawing a line through Sella point perpendicular to the palatal plane in the maxilla and the mandibular plane in the mandible (Fig. 4). The pre- and post-treatment measure- ments between these lines and the tooth and cortical plate landmarks were compared using paired t-tests. Apex/100% level Apex/100%level 75% level 75% level 50% level 50% level 25% level 25% level 25% level 25% level 50% level 50% level 75% level 75% level Apex/100% level Apex/100% level Figure 3. Constructed landmarks used to measure retraction achieved at various levels along the surface of the root. The custom landmarks used for the teeth are shown on the left. The custom landmarks for the cortical plate are shown on the right. 338 Lippincott et al. º *= Figure 4. Constructed planes and measurements used to quantify corti- cal plate and tooth retraction. Tooth retraction measurements are repre- Sented on the left. Cortical plate retraction measurements are shown on the right. Note that although labial and lingual measurements were made for both tooth and cortical plate, only labial measurements for the maxilla and lingual measurements for the mandible are illustrated in this figure. RESULTS Error Testing Intra-examiner calibration was carried out using ten cephalomet- ric radiographs. The radiographs were traced and then retraced by the principal investigator one week after the initial tracing. Pearson correla- tions then were performed to determine if a statistically significant amount of tracing error existed. The analysis found all skeletal, dental and alveolar measurements had significant Pearson correlations higher than 0.9. Tooth Movement T-testing showed that both maxillary and mandibular incisal edges retracted significantly when compared to pre-treatment measure- ºnents. In contrast, neither incisor apex moved significantly, although significant Variability existed (Table 1). The retraction values of the max- illary and mandibular incisors decreased incrementally when moving from the incisal edge to the apex (Tables 2-3). 339 Alveolar Cortical Plate Movement Table 1. Change in skeletal and dental cephalometric measurements (n = 16). T1 T2 T1-T2 Measurement º + Mean + S.D. | Mean + S.D. sº Skeletal SNA (*) 83.5 + 5. | 82.0 + 4,6 - |.5 + 2.6 (),036* SNB (9) 78.4 + 4.2 77.7 -- 4.1 —0.7 -- 1.9 NS ANB (°) 5.1 + 2.5 4.4 + 1.8 –0.8 + 2.2 NS FMA (*) 28.6 + 5.3 29.8 + 5.2 1.2 + 2.2 NS Wits (mm) 1.1 =E 4.9 —0.7 -- 3.2 -1.8 + 2.6 0.0.15% UFH: LFH Ratio (%) || 77.0 + 7.2 77.1 + 7.3 -0.1 + 2.6 NS Dental Interincisal Angle (*) || 107.6 + 6.4 || 137.6 + 1 1.8 || 29.9 +10.8 0.000+ U1-SN (*) 112.7 + 4.2 || 96.1 + 7, 1 – 16.7 -- 7.9 0.000% U1-Apog (mm) 13.0 + 2.5 5.8 + 2.0 –7.2 + 2.7 0.000+ IMPA (9) 12.6 + 6.7 || – 1.0 + 10.7 - 13.6 + 7.2 0.000+ L1-Apog (mm) 8.4 + 2.7 2.7 -- 1.9 –5.7 -- 3.4 0,000+ * P × 0.05 Cortical Plate Movement In the maxilla, paired t-testing found statistically significant dif- ferences for all labial cortical plate measurements. No significant differ- ences were detected for the maxillary lingual cortical plate at any of the root levels (Table 2). In the mandible, the labial cortical plate at the 25%, 50% and 75% root levels had statistically significant differences, while the 100% root level showed no difference from pre- to post-treatment. There were no significant differences for the mandibular lingual cortical plate at the 50%, 75% and 100% root levels (Table 3). DISCUSSION Tooth Movement Our study found that incisor retraction using skeletal anchorage was achieved mainly through a controlled tipping movement rather than the anticipated bodily translation. Post-treatment dental angulation meas- urements (U1-SN, IMPA) confirmed this observation with the angula- tions of the maxillary and mandibular incisors decreasing 16.7° + 7.9° and 13.6°-E 7.2° respectively during the course of treatment. These findings are comparable to those reported by Bills and associates (2005). Bills and colleagues examined the treatment outcomes of 48 bimaxillary protrusive 340 Lippincott et al. Table 2. Change in maxillary tooth and cortical plate position (n = 14). T1 T2 T1-T2 Maxillary Tooth Mean + Mean + Mean + Significance Measurements (mm) S.D. S.D. S.D. (P) Labial Root Points 72.3 + 5.8 68.6 + 5.8 –3.7 ± 2.6 0.000+ 25% root level 70.2 + 5.6 67.4 + 5.7 –2.9 + 2.6 0.001 * 50% root level 67.9 + 5.6 65.9 + 5.7 -2.0 + 2.7 ().016% 75% root level 65.3 + 5.9 62.2 + 6.0 -3.0 + 2.7 0.001% Lingual Root Points ñ. 25% root level 64.0 + 5.6 61.8 + 6.0 –2.3 + 2.6 0.007+ 50% root level 63.2 + 5.4 61.5 + 6.0 -1.7 -- 2.7 ().04.1 * 75% root level 63.8 + 5.3 62.8 + 6.0 - 1.0 + 2.9 NS Ul Incisal Tip 76.1 + 6.6 69.1 + 6.4 –7.0 + 3.3 0.000+ U1 Apex 63.8 + 5.3 62.8 + 6.0 -1.0 + 2.9 NS Maxillary Cortical Plate Measurements (mm) Labial Cortical Plate Points 25% root level 73.0 + 5.9 69.4 + 5.8 –3.7 -- 2.6 0.000% 50% root level 71.6 + 5.7 68.6 + 5.5 –2.9 + 2.4 0.001 * 75% root level 69.8 + 5.5 67.8 + 5.5 –2.0 + 2.3 ().006* 100% root level 68.4 + 5.1 67.0 + 5.2 -1.4 + 2.2 0.034% Lingual Cortical Plate Points 25% root level 62.3 + 5.9 60.9 + 6.1 - 1.3 + 2.5 NS 50% root level 59.9 + 5.6 59.2 + 5.6 -0.7 -E 2.2 NS 75% root level 57.4 + 5.4 56.9 + 5.6 –0.5 + 2.2 NS 100% root level 54.7-E 5.4 53.8 + 5.5 –0.9 + 2.3 NS P 3 0.05 patients treated without miniscrew anchorage and found that orthodontic Space closure was accomplished primarily through controlled tipping. Their study found that treatment resulted in a mean maxillary incisor up- righting of 12.7° = 7.5° and a mean mandibular incisor uprighting of 5.6° + 5.8°. A recent study conducted by Upadhyay and colleagues also con- firmed our findings (2008). Their randomized controlled clinical trial of incisor retraction using miniscrew anchorage also found the maxillary incisors uprighted 15.1° + 7.2° and the mandibular incisors uprighted 14.2° -- 3.8°. 341 Alveolar Cortical Plate Movement Table 3. Change in mandibular tooth and cortical plate position (n = 8). T1 T2 T1-T2 Mandibular Tooth Mean + Mean + Mean + Significance Measurements (mm) S.D. S.D. S.D. (P) Labial Root Points 25% root level 96.9 + 5.8 93.6 + 5.9 –3.4 + 1.3 0.000+ 50% root level 95.9 + 6.0 93.3 + 6.3 -2.6 + 1.4 ().001% 75% root level 94.8 + 6.2 93.2 + 6.7 - 1.6 + 1.5 0.017% Lingual Root Points 25% root level 91.7 -- 5.9 88.4 + 5.8 -3.3 + 1.3 0.000+ 50% root level 91.3 + 6.1 88.7 -- 6.2 -2.6 + 1.4 0.001 * 75% root level 9 || 2 + 6.3 89.4 + 6.7 -1.7 == 1.6 0.016% Li Incisal Tip 97.1 + 5.4 || 90.7 -- 4.4 || -6.3 + 2.0 0.000+ Ll Apex 92.4 + 6.6 91.6 + 7.2 –0.8 + 2.0 NS Labial Cortical Plate Points 25% root level 97.5 + 5.8 94.1 + 5.9 –3.4 + 1.2 (),000% 50% root level 96.8 + 6.0 94.3 + 6.2 –2.5 + 1.3 ().001% 75% root level 95.9 + 6. I 94.6 + 6.4 - 1.3 + 1.2 0.0.19% 100% root level 95.7 -- 6.4 95.5 + 6.8 ().2 + 1.2 NS Lingual Cortical Plate Points 25% root level 90.7 -- 6.3 88.4 + 6.4 –2.4 + 1.4 0.002* 50% root level 89.5 + 6.8 || 88.4 + 7.0 | -1.0 + 1.4 NS 75% root level 88.6 + 6.9 88.5 + 7.5 -0.1 + 1.4 NS 100% root level 87.7 + 6.9 88.0 + 7.4 0.3 + 1.2 NS P & 0.05 Some incisor retroclination during retraction observed in our and other’s studies can be explained because the wire does not fill the bracket slot completely. For example, retracting on a 0.016” x 0.022” stainless steel wire in 0.018” pre-angulated brackets, such as the ones in this sam- ple, around 10° completely of torque loss can be expected (Kusy and Whitley, 1999; Siatkowski, 1999). However, our findings are surprising because they exceed the expected value of 10° for torque loss. Also im- portant, our findings regarding tooth movement were comparable to find- 342 Lippincott et al. ings from studies where miniscrew anchorage was not employed. This may suggest that the need for or advantage of using miniscrew anchorage to retract incisors may not be as great as thought initially. Maxillary Cortical Plate Movement Generally, the labial cortical plates moved during incisor retrac- tion, while the lingual cortical plates did not (Figs. 5-6). In the maxilla, all labial cortical plate measurements were different significantly from pre- to post-treatment, with remodeling occurring close to 100% of the distance the tooth was retracted, findings that agree with the studies of Edwards (1976), Vardimon and coworkers (1998) and Sarikaya and col- leagues (2002). In contrast, none of the maxillary lingual cortical plate measurements were found to be statistically significantly different from their pre-treatment counterparts, demonstrating that while the tooth re- tracted the plate did not. The findings of Edwards (1976) and Ten Hoeve and Mulie (1976) also further confirmed these findings. This lack of cor- tical plate remodeling may lead to an increased tendency for develop- ment of marginal bone loss and fenestrations, as postulated by Handel- man (1996) and Yue (2005), if the amount of tooth retraction required is large. Mandibular Cortical Plate Movement In the mandible, the labial cortical plate behaved similarly to its maxillary counterpart, remodeling at the 25%, 50% and 75% root levels (Figs. 7-8). With the exception of the apex level, the data showed that the labial cortical plate remodeled close to 100% of the distance the tooth was retracted, findings that further support the studies of Mulie and Ten Hoeve (1976) and Sarikaya and associates (2002). With respect to the lingual cortical plate, only measurements at the 25% root level were found to be significant. Here, the plate movement was coordinated mod- erately with tooth movement, findings that correlate to those of Sarikaya and colleagues (2002). At all other levels, the lingual cortical plate did not remodel significantly, which may predispose patients to marginal bone loss and fenestrations if the amount of tooth retraction required is greater that the pre-treatment position of the cortical plate. 343 Alveolar Cortical Plate Movement Comparison of Tooth and Cortical Plate Movement in the Anterior Maxilla 5 100% E ~ - : 7so º: ovo : $ 50% º - - 3 25% º __ - -4 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0. Movementin Millimeters - Tooth Retraction - Cortical Plate Retraction Figure 5. Graph comparing the maxillary anterior cortical plate move- ment with the amount of tooth retraction achieved. The 100% root level is at the apex of the tooth, 0% is at the cementoenamel junction (CEJ). Comparison of Tooth and Cortical Plate Movement in the Posterior Maxilla 100% 75% 50% 25% -3 -2.5 –2 -1.5 -1 -0.5 0. Movementin Millimeters | Tooth Retraction ºn Cortical Plate Retraction Figure 6. Graph comparing the maxillary posterior cortical plate movement with the amount of tooth retraction achieved. The 100% root level is at the apex of the tooth, 0% is at the CEJ. 344 Lippincott et al. Comparison of Tooth and Cortical Plate Movement in the Anterior Mandible 25% . 50% 75% 100% -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0. Movementin Millimeters - Tooth Retraction º Cortical Plate Retraction Figure 7. Graph comparing the mandibular anterior cortical plate movement with the amount of tooth retraction achieved. The 100% root level is at the apex of the tooth, 0% is at the CEJ. Comparison of Tooth and Cortical Plate Movement in the Posterior Mandible 25% 50% 75% -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0. 0.5 Movementin Millimeters - Tooth Retraction º Cortical Plate Retraction Figure 8. Graph comparing the mandibular posterior cortical plate movement with the amount of tooth retraction achieved. The 100% root level is at the apex of the tooth, 0% is at the CEJ. 345 Alveolar Cortical Plate Movement Limitations to Orthodontic Treatment Our study found that neither the maxillary nor the mandibular apices moved a statistically significant amount and that incisor retraction occurred in a controlled tipping fashion. These findings may suggest ei- ther that the alveolus did not remodel at the apical level and, therefore, restrained the tooth, or that the orthodontic force system was not able to generate a significant force at the apex. Regarding apical alveolar remodeling, several studies have dem- onstrated that incisor apex movement is possible during retraction (Ed- wards, 1976; Vardimon, 1998; Mockaitis, 2006). In particular, Mockaitis (2006) used similar alveolar measurements as in the present paper to ex- amine incisor retraction using the Tweed technique and found that apex retraction as well as apex intrusion is possible. In light of these studies, our findings point to fact that the orthodontic force system used in this study was not able to generate a significant force at the apex, leading to the lack of movement. A recent study by Reimann and colleagues (2007) has suggested that it may be more difficult technically than previously thought to retract incisors at the apical level. In patients where the initial malocclusion has proclined maxillary and mandibular teeth, this con- trolled tipping retraction movement is beneficial to upright and retract incisors. However, in cases where the initial malocclusion has well- angulated incisors and increased overjet, retracting the incisors in a con- trolled tipping fashion may compromise esthetics by producing unfavor- able incisor angulation and a large interincisal angle, as noted by Meikle (1980). As Edwards (1976), Handelman (1996) and Yue (2005) have noted and our findings suggest, a small root to cortical plate width pre- treatment may limit the amount of retraction possible before marginal bone loss or root resorption may occur, primarily due to lack of lingual cortical plate movement during incisor retraction. More specifically, our study showed that the maxillary cortical plate did not remodel signifi- cantly, suggesting that the pre-treatment position of the lingual cortical plate represents the boundary of possible retraction for maxillary inci- sors. In the mandible, the cortical plate at the 25% level retracted, but the 50% and 75% root levels did not retract significantly. Here as well, the lack of cortical plate remodeling at these levels also may act as a barrier that, if violated, may produce undesirable iatrogenic side effects. These data closely match the findings of Sarikaya and coworkers (2002), indi- cating that planned tooth movement should not move the mandibular 346 Lippincott et al. incisors beyond the pre-treatment position of the cortical plate to avoid iatrogenic occurrences. CONCLUSIONS 1. In spite of the use of skeletal anchorage in the form of miniscrews, biologic limitations to incisor retraction continue to exist. 2. In this sample population, retraction of the incisors utilizing skeletal anchorage was by controlled tip- ping. 3. During retraction of maxillary incisors, the maxillary labial cortical plate remodeled at all root levels to fol- low tooth movement in a 1:1 ratio. The lingual corti- cal plate was not found to remodel significantly at the 25%, 50%, 75% or 100% root levels during retrac- tlOn. 4. During retraction of mandibular incisors, the man- dibular labial cortical plate at the 25%, 50% and 75% root levels remodeled in close to a 1:1 ratio to tooth movement. 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Retrieved January 1, 2008, from ProQuest Digital Dissertations database (Publication No. AAT 1425059). 351 A NEW MEASURE OF GINGIVAL RECESSION AND THE SIGNIFICANCE OF ATTRITION, GENDER AND RACE Anthony P. Eltink, Chester S. Handelman, Ellen A. BeGole ABSTRACT The aim of this study was to establish a new approach to the diagnosis of gingi- Val recession by evaluating three different measures of recession: clinical reces- sion, clinical crown height and the gingival margin-papillae measurement; the latter being a new measure of gingival recession. Using these measures, the in- fluence of attrition, gender and race were evaluated. Measurements were per- formed on the pre-treatment study models of 120 adult Caucasian and African American orthodontic patients. The mean values and standard deviations for clinical crown height and gingival margin-papillae are reported by race and by gender and can be used for comparison to other samples. Both the clinical crown height and gingival margin-papillae measurements gave a “true positive” result for the detection of changes in gingival architecture. Tooth wear shortens the clinical crown and therefore the measure of clinical crown height can give a “false negative” result when gingival recession is present. However, the gingival margin-papillae measurement is not affected by tooth wear and gives a “true positive” result for gingival recession. This measure also is useful in detecting prodromal recession, recession prior to cemental exposure. The gingival margin- papillae measurement demonstrated no association between attrition and reces- sion. This measure also showed more recession in males than in females and more recession in Caucasians than African Americans. In addition, Caucasians had greater levels of tooth wear than African Americans. Conclusions: The gin- gival margin-papillae measurement offers a simple and reliable method for the assessment of gingival recession. KEY WORDS: gingival recession, clinical crown height, attrition, gender, race The architecture of the gingival tissues and their supporting periodontal structures has been studied extensively (Schroeder and List- garten, 1997). While researchers in periodontics have looked to understand 353 Attrition, Gender and Race the biology of the periodontium (Listgarten, 1972), the fields of esthetic dentistry and orthodontics have led to a greater appreciation for the role that gingival architecture plays in dental esthetics (Kokich, 1996; LaVacca, 2005). Further research into the role of the soft tissues in clini- cal orthodontics continues to stimulate evolution of the profession’s ap- proach to gingival esthetics. In health, the shape of the papilla in a given interdental space depends on the contact point between the two adjoining teeth (Tarnow et al., 1992). In the absence of interproximal bone loss, the gingival papilla fills the gingival embrasure completely (Schroeder and Listgarten, 1997). As stated by Löe (1968), the physiological position of the gingival mar- gin is 0.5 mm to 2.0 mm coronal to the cemento-enamel junction. As the cemento-enamel junction of the tooth curves apically from its more cor- onal interdental position, the gingival margin follows this curvature cre- ating the characteristic scalloping contour of healthy gingiva. Pathologic gingival recession results in characteristic changes in the gingival architecture that can be distinguished from changes resulting from periodontal disease (Hara and Hosada, 1976). In cases of gingival recession in the absence of gingivitis or periodontitis, the papilla main- tains its normal position while the curvature of the gingival margin on the facial aspect of the tooth deepens (Watson, 1984). Using Miller's (1985) classification of gingival recession, true gingival recession in the absence of periodontal disease and bone loss is limited to Miller Class I and Class II recessions. Many authors (Gorman, 1967; Watson, 1984; Löe, 1992) have stated that a variety of etiological factors can cause recession of the gin- giva, among them oral hygiene habits (especially over-zealous tooth brushing), tooth malposition, frenal pull, bone dehiscences and iatrogenic factors related to various restorative, periodontal and orthodontic proce- dures. Muller and coworkers (2002) found that while smoking puts one at risk for periodontal disease, there was no significant difference in the prevalence of gingival recession between smokers and non-smokers. The literature also supports the contention that gingival recession seems not to be limited to those patients with poor oral hygiene and periodontal disease. In a twelve-year longitudinal study, Serino (1994) found that recession of the gingiva is a common feature in population groups who have practiced daily mechanical home care and who have received state-of-the-art dental care throughout their lives. 354 Eltink et al. Gingival recession is measured clinically as the millimetric dis- tance from the cemento-enamel junction to the free gingival margin us- ing a periodontal probe (Fig. 1). While this clinical recession measure- ment is useful in following the progression of gingival recession, it is not an accurate assessment of the true apical migration of the gingival mar- gin due to its reliance on the cemento-enamel junction as a reference point. Given that the gingival margin’s physiological position is 0.5 mm to 2.0 mm coronal to the cemento-enamel junction (Lóe, 1968), the ref- erence point for clinical recession is obscured by the gingiva itself. Thus the early stages of gingival recession (known as prodromal recession) can go undiagnosed using this method of measurement. Clinical crown height is an objective measure of the position of the gingival border that could be used in determining the “normal” posi- tion of the gingival margin (Volchansky and Cleaton-Jones, 2001). Pow- ell and McEniery (1981) showed that the norms for clinical crown heights are useful in the diagnosis of gingival recession. The use of clinical crown height as a measure of gingival reces- Sion is complicated by wear of the enamel of the incisal edge or the cusp tip of the tooth being measured. Attrition over time leads to a decrease in the clinical crown heights of a patient’s teeth; similarly, continued wear of a cusp tip over time can mask the presence of continued gingival re- cession over time if clinical crown height is used as an objective meas- ure. Occlusal tooth wear is recognized as a universal phenomenon and as such, its mild form is considered as a physiologic process (Pindborg, 1970). Given the complexity of assessing gingival recession, it is pro- posed that a new measure of gingival recession should be established that Would combine the strengths of these two measures (clinical recession as measured by cemental exposure and clinical crown height) and yet eliminate their shortcomings. Gorman (1967), Albander and Kingman (1999) and Löe and colleagues (1992) all found that interproximal reces- sion in the absence of periodontal disease is rare and that gingival reces- Sion occurs almost exclusively on the buccal surfaces of teeth. Recession, then, appears as an increase in the convexity of the marginal gingiva between the two adjacent papillae (Watson, 1984; Fig. 2). Thus the apico-coronal distance measured from the depth of the gin- gival margin to a line tangent to the two adjacent papillae would serve as a more accurate assessment of gingival recession. So-called prodromal re- 355 Attrition, Gender and Race | Clinical recession measure • Gingival papillae - - - Leval of attrition A -------. Prodromal recession |cºls: crown height, no attrition |cºlſ: crown height, with attrition • Gingival papillae - Gingival papillae line C | Gingival papillae measure Figure 1. A: Clinical recession. B: Clinical crown height. C. Gingival margin-papillae clinical crowns of the upper left quadrant where the horizontal dashed line indicates the possible level of tooth wear (attrition). The dotted line indicates the level at which the gingival margin would be prior to prodromal re- cession. 356 Elſink et al. Figure 2. Advanced gingival recession: retraction of the gingival mar- gin with no apical migration of the gingival papillae. Cession would be detected and enamel attrition would not confound the IſleaSurementS. If norms could be established in the same manner, the gingival margin-papillae measurement could be useful for diagnosis of gingival recession and for study of the influence of tooth movement on gingival architecture. This chapter will establish norms for the different measures of recession for each tooth back to the first molars in adult orthodontic patients subdivided by gender and race, and the prevalence of recession Will be established for each group. In addition, the relationship of attri- tion and gingival recession will be discussed. MATERIALS AND METHODS Selection Criteria The initial sample search began by examining pre-treatment re- cords for all adult African American and Caucasian patients from a pri- Vate orthodontic practice in Chicago, IL. The following inclusion criteria then were applied: 1. The subjects were between the ages of 20 to 59 years; 2. No more than three areas of bone loss (3 mm or more from the cemento-enamel junction to the crest of the alveolus) evident on full-mouth radiographs and no 357 Attrition, Gender and Race more than three teeth that have a pocket depth reading of more than 4 mm: 3. No evidence of gingivitis as noted in the patient’s re- cord and in the intraoral photographs; 4. Individual teeth with radiographic evidence of local- ized bone loss were excluded: 5. Individual teeth blocked out of the arch and teeth ad- jacent to edentulous spaces were excluded: 6. No history of prior orthodontic treatment; and 7. Fixed prosthodontic crown and fixed bridge abut- ments were excluded. Study Sample The study sample consisted of 30 patients in each of the four demographic groups, Caucasian and African American males and fe- males, for a total sample size of 120 patients. Clinical recession, clinical crown height and gingival margin-papillae measurements were per- formed on a total of 1,522 teeth in these 120 subjects. Tooth wear was measured on a total of 1,467 teeth. Data Gathering Age in years, race and gender were the recorded data for each subject. In order to evaluate subjects’ gingival health and cemental expo- sure, 35 mm film slides of each subject’s buccal and anterior teeth were mounted in the Professional Table Viewer (Olden Camera, New York, NY) with 5x magnification. Using the intraoral photographs as an aid in identification of landmarks, the following measurements were made on each tooth on the standard orthodontic study models: clinical recession, clinical crown height, gingival margin-papillae and attrition. The data for clinical crown height and gingival margin-papillae were measured and recorded using a Mitutoyo Absolute Digimatic digi- tal caliper with sharpened points (#99MAD014M, Series No. 500, Mitu- toyo American Corp., Aurora, IL). An input tool with connecting cable (#99MAM014B1, Series No. 264 and #959149, Mitutoyo American Corp., Aurora, IL) was used for the automatic transfer of the data into a Microsoft Excel spreadsheet. All data were stored and organized in Mi- crosoft Excel and transferred to SPSS (Statistical Package for the Social Sciences, Version 11.5, SPSS Inc., Chicago, IL) for statistical testing. 358 Eltink et al. Clinical Recession Clinical recession was recorded on all teeth as the shortest dis- tance from the cemento-enamel junction to deepest curvature of the gin- gival margin (Fig. 1A). For this measurement, intraoral photographs were used to aid in the identification of the cemento-enamel junction on the study models. A similar study by Allais and Melsen (2003) evaluated the position of the cemento-enamel junction in the same way. The measure- ments were made to the nearest whole millimeter using a standard perio- dontal probe, always rounding up so that even minimal cemental expo- Sure was scored at 1 mm. . Clinical Crown Height The height of the clinical crown was measured with the digital calipers to the nearest one-hundredth of a millimeter on the facial surface of each crown on the orthodontic study models from cusp tip or incisal edge to the deepest curvature of the gingival margin along the long axis of the tooth for premolar, canine and incisor teeth (Fig. 1B). The meas- urements on the molar teeth were made at the mesiobuccal cusp. Gingival Margin-Papillae The gingival margin-papillae measurements were recorded using the digital calipers to the nearest one-hundredth of a millimeter as the distance between the inter-papillae line (drawn with a 0.3 mm mechani- cal pencil) and the deepest curvature of the gingival margin along the long axis of the tooth (Fig. 1 C). The measurements on the molar teeth were made at the mesiobuccal cusp. Tooth Wear Tooth wear, or attrition, was scored on all teeth using Hooper and colleagues’ (2004) tooth wear index. Each tooth was assigned a score from zero to five according to the criteria outlined by this index. In the illustrations in Figure 1, the long horizontal dashed lines indicate the possible level of tooth wear. RESULTS Study Sample The age data for the study sample were analyzed to determine if the four demographic groups (Caucasian male, Caucasian female, Afri- can American male and African American female) differed with respect 359 Attrition, Gender and Race to age. The results of the ANOVA comparison revealed that there was no difference in age among the groups using P º 0.05. Reproducibility Reproducibility and accuracy of the four measurements were evaluated by analyzing statistically ten randomly selected cases. The study models for each case were measured and then re-measured ten days later, with the two data sets compared using Pearson correlations. All re-measured values showed a significant correlation at the 0.01 level. Descriptive Statistics for Typical Clinical Crown Height Mean values and standard deviations for the measurement of clinical crown heights are listed in Table 1. Descriptive Statistics for Typical Gingival Margin-Papillae Mean values and standard deviations for the measurement of gingival margin-papillae are listed in Table 2. Independent t-tests for Clinical Recession Groups The overall data set that included African Americans, Cauca- sians, males and females (N = 1,522 teeth), was separated into two sub- sets on the basis of the clinical recession measurement (cemental expo- sure) for each tooth. The first subset, called non-recession teeth (N = 1,222 teeth), was comprised of all teeth whose measurements were scored 0 mm for the clinical recession measurement. The second subset, called recession teeth (N = 300 teeth), was comprised of measurements on all teeth that were scored 1 mm or greater of root exposure – includ- ing teeth with minimal recession – for the clinical recession measure- ment. Independent t-tests were performed for clinical crown height and gingival margin-papillae to determine whether differences exist between these two subsets of teeth for these three measurements. For clinical crown height, the independent t-tests found signifi- cant differences between the recession and non-recession teeth for all tooth classes. The clinical crown height measurement for the recession teeth was found to be larger than the clinical crown height measurement for the non-recession teeth for all tooth classes. For gingival margin-papillae, a significant difference was found between the teeth in the recession subset and the non-recession subset for 360 Eltink et al. Table 1. Clinical crown height means. CAUCASIAN AFRICAN AMERICAN Male (N = 30) º Male (N = 30) º o". 0) Tooth Mean Mean Mean Mean Mean Class (mm) SD (mm) SD (mm) SD (mm) SD (mm) SD U6 7.2() | ()4 6.68 0.93 7.08 1.05 6.07 1.04 6.74 1. 10 U5 7.6() 0.93 7.2 | 1.07 7.18 ().87 6.64 0.82 7. 16 0.98 U4 8.46 1.03 8.20 0.90 8.27 0.86 7.72 0.83 8. 16 0.94 U3 10.49 | . 15 9.80, 1.00 10.22 1.05 9.50 1.02 10.00 1.11 U2 8.97 1.05 8.96 1.06 8.79 ().98 8.50 1.06 8.81 1.04 Ul 10.49 1.22 9.96 0.81 10.60 0.98 10.02 1.23 10.27 1.10 L6 7.08 0.64 7.03 1.22 6.49 0.63 6.30 ().79 6.73 0.89 L5 7.54 1.01 7.54 0.89 7.41 0.90 7.09 ().78 7.40 0.91 L4 8.81 0.95 8.34 ().59 8.48 0.74 7.68 0.64 8.33 0.85 L3 10.40 1.15 9.7 | 1.14 10.00 1.20 9.03 1.25 9.78 1.27 L2 8.29 0.99 8.57 0.99 8.27 0.87 8. 14 1.23 8.32 1.03 Ll 8.15 1.17 8.33 0.99 8.24 ().91 8.13 1.33 8.21 1.10 Table 2. Gingival margin-papillae means. CAUCASIAN AFRICAN AMERICAN º º º, Male (N = 30) § º o" ºso Tooth | Mean Mean Mean Mean Mean Class (mm) SD (mm) SD (mm) SD (mm) SD (mm) SD U6 3.07 || 0.95 2.56 0.79 2.59 0.72 1.99 0.54 2.54 0.84 U5 3.03 || 0.83 2.77 0.91 2.47 0.56 2. 12 0.51 2.60 0.79 U4 3.51 1.00 3.25 0.83 3.24 0.66 2.83 0.60 3.21 0.81 U3 4.86 1.24 4.47 0.75 4.38 1.08 3.77 0.83 4.37 1.06 U2 3.85 1.40 3.64 0.79 3.11 0.69 2.94 0.77 3.39 1.01 U1 4,37 1.71 3.84 0.67 3.80 0.61 3.54 0.69 3.90 1.07 L6 2.93 || 0.75 3.14 1.22 2.35 0.59 2.25 0.34 2.67 0.85 L5 3.00 || 0.73 3.22 0.85 2.75 0.62 2.49 0.53 2.87 0.74 L4 3.69 || 0.72 3.68 0.64 3,40 0.64 3.04 0.64 3.45 0.70 L3 4.58 || 0.97 4.33 0.83 4. 12 1.02 3.54 0.84 4.15 0.99 L2 2.80 || 0.99 3.47 0.76 2.79 O.75 2.81 0.73 2.97 0.85 Ll 2.99 || 0.88 3, 16 0.64 2.76 0.64 2.93 0.77 2.96 0.74 361 Attrition, Gender and Race all tooth classes except for the lower lateral incisor. The gingival margin- papillae measurement was larger for the recession teeth than it was for the non-recession teeth. A summary of these findings is displayed in Ta- ble 3. Independent t-tests for Tooth Wear Groups The overall data set (N = 1,467 teeth) then was separated into two subsets on the basis of the tooth wear index for each tooth. The first subset, which was called the normal wear teeth (N = 1,230 teeth), was comprised of all teeth measured on all subjects that were scored with a value of two or less on Hooper’s tooth wear index. The second subset, called the severe wear teeth (N = 237 teeth), was comprised of all teeth measured on all subjects that were scored with a value of three or greater on the tooth wear index. With the teeth sorted according to these criteria, independent t-tests were performed for clinical recession, clinical crown height and gingival margin-papillae to determine whether differences exist between these two subsets for these three measurements. The results of the independent t-tests for clinical recession be- tween the normal wear and severe wear subsets revealed no significant differences for any tooth class. - For clinical crown height, significant differences were found be- tween the normal wear and the severe wear teeth for all tooth classes ex- cept the maxillary first molar. For all other tooth classes, the clinical crown height measurements for teeth in the normal wear subset were larger than the measurements for teeth in the severe wear subset. In contrast to the clinical crown height measurement, the gingi- val margin-papillae measurement showed no significant differences be- tween the normal wear teeth and the severe wear teeth. A summary of these findings is shown in Table 4. Descriptive Statistics by Gender and Race In order to test the usefulness of the measure for gingival reces- sion, incidence of recession and attrition was examined for the four sub- groups based on gender and race. Means were calculated for each of the four measurements using all teeth measured for each patient. For exam- ple, if the clinical recession was measured for 22 of the 24 teeth on a par- ticular patient (i.e., two of the 24 teeth were excluded because they did not meet the selection criteria), the 22 values were averaged to give one number for each patient called “clinical recession average.” This “clinical 362 Eltink et al. Table 3. Summary of independent t-tests for sample sub-groups. R = recession group; NR = non-recession group; NW = normal wear group; SW = severe wear group. Clinical Clinical Crown Gingival Margin- Sub-Groups Recession Height Papillae Recession R - NR R → NR Tooth Wear NW = SW NW - SW NW = SW Table 4. Independent t-tests for tooth wear subsets and clinical recession meas- ure for overall data set including African American, Caucasian, male and female subjects. * = P × 0.05. Tooth Class Group Il Mean SD t P U6 Normal wear 107 0.29 0.59 0.12.... 0.906 Severe wear 12 0.27 0.47 US Normal wear || 1 || 0 || 0.22 0.41 1.88.... |006. Severe wear 16 0.03 0.12 U4 Normal wear || 109 ().27 0.48 || 0.86.... |0.3% Severe wear 9 (). 13 0.35 H-Hi-HT-Hi-H-H= |0.58 Severe wear 18 0.25 0.43 U2 Normal wear 106 0.16 0.36 0.65.... |osis Severe wear | 1 0.09 0.30 Ul Normal wear || 97 0.18 0.43 1.92.... |0.038 Severe wear 22 0.00 0.00 - L6 Normal wear 78 0.11 0.42 –0.82.... | 0.415 Severe wear 44 0.18 0.48 L5 Normal wear 104 0.18 0.40 0.59.... | Oss. Severe wear 17 (). 12 0.33 L4 Normal wear || 107 || 0.21 0.44 | -0.63.... | 0.532 Severe wear 10 0.31 0.70 L3 Normal wear || 103 0.26 0.51 1.48.... |0.14 Severe wear 29 0.12 0.28 L2 Normal wear || 102 || 0.09 0.30 || 0.78.... | 0439 Severe wear 23 0.04 0.20 L1 Normal wear || 97 0.19 0.41 1.14.... |0.256 Severe wear 26 0.09 0.28 363 Attrition, Gender and Race recession average” number for each patient then was combined with the averages for other patients in the same demographic group to determine the descriptive statistics for this measurement. The same process was repeated for each of the other three measurements (clinical crown height, gingival margin-papillae and tooth wear). The descriptive statistics for these four measurements are reported for the four demographic groups in Table 5. Clinical Recession and Tooth Wear Frequencies The data for clinical recession and tooth wear were compiled to evaluate these measurements by demographic group. A tooth was con- sidered to have recession if it scored at least a value of one for clinical recession, meaning that there was exposed cementum on the tooth. A tooth was considered to have severe tooth wear if it scored at least three on Hooper and colleagues’ (2004) tooth wear index. For clinical recession, the African American female demo- graphic group had less than 33% as many teeth affected as the other three demographic groups (Tables 6). For tooth wear, African American subjects showed approximately 50% as many teeth with severe tooth wear as Caucasian subjects (Tables 6). Clinical Recession by Gender and by Race The groups were tested for normality using Shapiro-Wilk; none of the four were found to be distributed normally at the P × 0.05 level. Therefore, the non-parametric Kruskal-Wallis test was used followed by the Mann-Whitney U tests to isolate pair-wise differences if the overall Kruskal-Wallis test was significant. For clinical recession, the Kruskal-Wallis test found a difference among the groups (P<0.05). The Mann-Whitney U test found three pair- wise differences, all significant at the P × 0.05 level. African American females showed less clinical recession than the other three groups (Cau- casian males and females and African American males). A summary of the pair-wise differences can be found in Table 7. Clinical Crown Height by Gender and by Race The groups were tested for normality using Shapiro-Wilk; only one of the four groups was found to be non-normally distributed at the P < 0.05 level. Hence, the decision was made to use the parametric analysis of variance, followed by the Scheffé post-hoc test for pair-wise compari- SO11S. 364 Eltink et al. Table 5. Overall descriptive statistics. CR = clinical recession; CCH = clinical crown height; GMP = gingival margin-papillae; TW = tooth wear. African African Ameri- Caucasian Caucasian American Male Male (N = 30) | Female (N = 30) (N = 30) ºº Measure Mean SD Mean SD Mean SD Mean SD CR (mm) 0.23 0.27 0.26 0.30 0.25 0.30 0.07 0.11 CCH (mm) 8.69 0.82 8.47 0.78 8.45 0.68 7.97 0.87 GMP (mm) 3.58 0.67 3.50 0.55 3.16 0.49 2.90 0.49 TW 1.71 0.60 1.70 0.47 1.47 0.31 1.48 0.26 Table 6. Clinical recession and tooth wear frequencies by demographic group. Demographic Total Number of Teeth with Number of Teeth with Group Teeth Clinical Recession (%) | Severe Tooth Wear (%) Caucasian Male 684 134 (20%) 126 (18%) Caucasian O O Female 665 133 (20%) 117 (18%) African O 0. American Male 668 130 (19%) 65 (10%) African American O O Female 662 41 (6%) 56 (8%) Table 7. Clinical recession comparisons. * P × 0.05. Pair-wise Differences Mean Chi- Group Rank square P Groups P Caucasian 65.67 11.199 || 0.01.1% Coſ" X- 0.007* cyl 0 ~. † g AA* e Caucasian C} > AA% 2k female # 0 69.37 0.002 African AAd" > American 64.07 0.021* cy 0 AA* African American * | 0 42.90 Total 20 365 Attrition, Gender and Race For clinical crown height, the analysis of variance found a dif- ference among the groups (P º 0.05). The Scheffé post-hoc test found only one pair-wise difference. Caucasian males showed greater clinical crown height than African American females. A summary of the pair- wise differences is shown in Table 8. Gingival Margin-Papillae by Gender and by Race The groups were tested for normality using Shapiro-Wilk and all four groups were found to be distributed normally at the P × 0.05 level. Hence, the decision was made to use the parametric analysis of variance, followed by the Scheffé post-hoc test for pair-wise comparisons. For gingival margin-papillae, the analysis of variance found a difference among the groups (P<0.05). The Scheffé post-hoc test found three pair-wise differences. Caucasian males showed greater gingival margin-papillae than African American males. Caucasian males also showed greater gingival margin-papillae than African American females. Finally, Caucasian females showed greater gingival margin-papillae than African American females. A summary of the pair-wise differences can be found in Table 9. Tooth Wear The analysis of tooth wear was handled differently because some detectable attrition was present on almost all of the teeth measured in this study. The sensitivity of Hooper and coworkers’ (2004) tooth wear index revealed that scores of zero, one and two were common. The tooth wear frequency data, when analyzed as either normal wear or severe wear (Table 6), compelled us analyze the data further using the same criteria to classify the teeth. Again, a tooth was considered to have severe tooth wear if it scored at least three on the tooth wear index. The results of the chi square analysis revealed that male teeth showed a higher frequency of severe tooth wear than female teeth for this sample (Table 10), and that Caucasian teeth showed a higher frequency of severe tooth wear than African American teeth (Table 11). DISCUSSION Clinical Crown Height and Gingival Margin-Papillae Values The means and standard deviations for clinical crown height and gingival margin-papillae measurements (Tables 2 and 3) are reported to allow for comparison to other samples in the future. The clinical crown 366 Eltink et al. Table 8. Clinical crown height comparisons. * P × 0.05. Sum of Mean Pair-wise Source | Squares df Square F P Power | Differences Group 8.354 3 2.785 || 4.475 || 0.005% | 0.870 | Coº-AA% Error 72. 190 | | | 6 0.622 Total | 80.544 || || 9 Table 9. Gingival margin-papillae comparisons. * P × 0.05. source j| dr ..., | f | r | Power | . Group 9.008 3 || 3.003 º * | 000 || 0.997 | Can-AA& Error || 35.596 || 1 || 6 || 0.307 Coº-AA* Total || 44.603 || 1 19 Cº-AA% Table 10. Genderſtooth wear cross-tabulation. N*= 8.1; P × 0.05. Number of Teeth (%) Pair-wise Gender Normal Severe Total Differences Male 1111 (83%) 228 (17%) 1339 (100%) cº-? Female 1143 (87%) 172 (13%) | 1315 (100%) || || Total 2254 (85%) 400 (15%) 2654 (100%) Table 11. Race/tooth wear cross-tabulation. Nº =41 .7; P × 0.05. Number of Teeth (%) *m-- Pair-wise Race Normal Severe Total Differences Caucasian 1070 (80%) 260 (20%) 1330 (100%) * 1184 (89%) 140 (11%) 1324 (100%) TT. 2254 (85%) | 400 (15%) 2654 (100%) height has been studied extensively only in children and adolescents. The gingival margin-papillae measurement never has been evaluated; there- fore, the values for this measurement are new to the literature. With val- ues for adults reported by race and by gender, the effects of other vari- 367 Attrition, Gender and Race ables on the architecture of the gingiva can be studied. The effects of vari- able oral hygiene practices (especially over-zealous tooth brushing), malocclusion, orthodontic treatment and as well as other factors can be assessed. While orthodontists have been interested in the effect of tooth movement that challenges the alveolar and gingival architecture, such as that which may occur with incisor proclination (Artun and Krogstad, 1987) or excessive premolar expansion (Vanarsdall, 1999), this chapter focused on naturally occurring recession in untreated subjects. However, patients who have frank recession or even a tendency for recession (pro- dromal recession) before orthodontic treatment are likely to demonstrate further recession if their orthodontic treatment challenges the limits of their alveolar housing (Handelman, 1996). Statistical Evaluation of the Measurements A major focus of this study was to determine if either clinical crown height or gingival margin-papillae could serve as indirect meas- ures to detect gingival recession. To evaluate these relationships, the overall data set was divided into two: one set comprised of teeth with clinical recession (cemental exposure) and the other comprised of teeth with no measurable clinical recession. The clinical crown height meas- urement detected the differences in the position of the gingival margins between the recession and non-recession teeth for all tooth classes. Therefore a “true positive” result was achieved whereby a difference was detected where a difference did exist (Fig. 1B, tooth numbers 1 and 6, no recession versus tooth numbers 3 and 4, recession). The gingival margin- papillae measurement revealed similar results, detecting a difference be- tween the recession and non-recession teeth, another “true positive” find- ing (Fig. 1C, tooth numbers 1 and 6, no recession versus tooth numbers 3 and 4, recession). The ability of a measurement to detect a “true positive” is use- less if the same measurement cannot provide a “true negative,” finding no difference where no difference exists (Fig. 3). To test this principle, the overall data set was divided into two subsets: teeth with normal wear and teeth with severe wear (depicted as the difference between the actual cusp tips and the dashed line in Fig. 1B-C). No differences were found in the position of the gingival margin relative to the cemento-enamel junc- tion with respect to attrition. So while differences in the presence and severity of tooth wear were evident, the architecture of the gingiva was the same for these two groups. 368 Eltink et al. Recession present” No recession present True positive Recession (high sensitivity) detected Clinical crown height False positive Gingival margin-papillae Clinical crown height True negative Recession e (high specificity) not detected False negative Gingival margin-papillae Figure 3. Summary of sensitivity and specificity for clinical grown height and gingival margin-papillae measurements. * = cemental exposure. The clinical crown height measurement (Table 3), however, found differences between the subsets with the values for the normal wear teeth being larger than the values for the severe wear teeth. While this measure demonstrates the shortening of tooth length due to attrition, if the clinician or researcher were relying on these measurements as an objective assessment of the position of the gingival margin, S/he would be misled by the “false positive” result for gingival recession (Fig. 3). In contrast, the gingival margin-papillae measurement showed no difference where no difference in the position of the gingival margin existed, a “true negative” finding. This observation adds further support for the use of this measurement to assess gingival recession (Fig. 3). The use of the adjacent papillae as landmarks for the measurement of the position of the gingival margin eliminates the problems that result from tooth wear over time (Fig. 1 C; the level of tooth wear is indicated by the long horizontal dashed lines). The gingival margin-papillae measurement may prove most useful in diagnosing prodromal recession, when the gingiva recedes but the root cementum has not been exposed (Fig. 1C, tooth numbers 2 and 5). Many clinicians intuitively visualize this measure When they diagnose a tendency for gingival recession in their patients (Fig. 4). When comparing clinical crown height to the gingival margin- papillae measurement, the latter not only has the advantage of avoiding the problems attendant with attrition, but it also sidesteps the variability of tooth size of individuals due to race, sex and genetic expression. The gingival margin-papillae measurement will prove most useful in the realm of clinical research, as attrition is a process that occurs over time. 369 Attrition, Gender and Race Figure 4. Prodromal recession: teeth with arrows do not show cemental exposure, but do show an increase in their gingival margin-papillae measurement. Although the emphasis of this chapter has been to present and verify the usefulness of a new measure for gingival recession, the ging- val margin-papillae measure, we also were able to determine if tooth wear was associated with an increase in gingival recession. There was no association between tooth wear and clinical recession; therefore, any as- Sociation of bruxism and recession is questionable. Attrition and Gingival Architecture Some clinicians feel that excessive occlusal forces that are ass0- ciated with attrition through a process called abfraction (the loss of tooth structure by flexural forces) will increase the level of gingival recession (Lyons, 2001). It is hypothesized that enamel, especially at the cemento- enamel junction, undergoes this pattern of destruction by separating the enamel rods. The data in this chapter (Table 3), however, indicates that there is no association between attrition and gingival recession. Clinical Recession by Gender and Race As displayed in Tables 6 and 7, the frequency of clinical recº sion (cemental exposure) for the African American female sample in this study differed vastly from the other three demographic groups. As shown in Table 7, this study found that African American females had IeSS clinical recession than each of the three other demographic groups: While it has been shown that males have more recession than females (Joshipura et al., 1994; Albander and Kingman, 1999) and that females 370 Eltink et al. exhibit better periodontal health than males (Brown et al., 1996), the limitation of this gender difference to the African American race was Surprising. In fact, this same epidemiologic study concluded that Cauca- sians exhibit better periodontal health overall than African Americans. These findings initially may seem to be in direct opposition to the find- ings in our study, but this conflict is no doubt reflective of the complex and multi-factorial nature of gingival health. Looking at the clinical recession frequencies by tooth class (Ta- ble 7), it is not surprising to see that canine teeth had the highest fre- quency of recession for both the maxillary and the mandibular arches. These teeth have the largest and most prominent roots of any tooth in the mouth; it is logical to assume that this prominence makes cuspid teeth more prone to exposure to heavy forces of tooth brushing and bony de- hiscences which can cause gingival recession. A study of human skulls (Pindborg, 1970) showed that canines are associated most frequently with bony dehiscences and fenestrations. All of these findings seem to point to one unifying theme: that alveolar bone thickness, which seems to vary by tooth class, jaw and ge- netic makeup, renders teeth more or less resistant to bony dehiscence and therefore, more or less resistant to gingival recession (Wennström, 1987). Thicker alveolar bone in African Americans versus Caucasians that is observed clinically, thicker alveolar bone supporting the mandibular den- tition and thinner alveolar bone supporting canine teeth all predispose individuals or teeth with thin labial and buccal bone to a retraction of the gingival margin and eventual cemental exposure. This discussion of gin- gival esthetics in the periodontal literature revolves around variations in gingival “biotype” (Fu et al., 2010). Clinical Crown Height by Gender and Race Earlier we argued against the use of clinical crown height as an objective measure of the position of the gingival margin. It is not surpris- ing then that our analysis did not detect the same group differences for clinical crown height as it did for the clinical recession measurement (Table 8). Caucasian males were found to have greater clinical crown height than African American females, but all other groups showed no difference despite the fact that African American females were found to have less clinical recession than all three other demographic groups. These differences in gingival architecture may have been “washed out” by the variability in tooth morphology and tooth wear caused by these other confounding factors. 371 Attrition, Gender and Race Gingival Margin-papillae by Gender and Race Earlier, we also argued for the use of the gingival margin- papillae as an objective measure of the position of the gingival margin on the tooth. The results of this study seem to be consistent with the conten- tion that the gingival margin-papillae measurement is a more sensitive measure when used to assess the position of the gingival margin and that it is less susceptible to differences in tooth morphology caused by ge- netic variation and tooth wear. Indeed, the gingival margin-papillae seems to have more potential as a measurement when comparing groups with respect to gingival architecture (Table 9). Tooth Wear by Gender and Race Given that tooth wear appears to be a naturally occurring phe- nomenon as a person ages (Pindborg, 1970), it seems logical that an analysis of tooth wear should try to look for differences between tooth wear that might be deemed normal and that which might be considered severe or part of some pathological process. The fact that the African American subjects in this study had approximately 50% as many teeth with severe wear as the Caucasian subjects (Table 6) again justified the need for further investigation to determine that these differences were significant. For our sample, male teeth showed a higher frequency of se- vere tooth wear than female teeth (Table 10) and Caucasian teeth showed a higher frequency of severe tooth wear than African American teeth (Table 11). - Although no controlled studies have been conducted to compare frequencies of tooth wear between different racial groups, psychologist Hicks and coworkers (1999) looked at self-reported bruxism among four different racial groups. In this study in which subjects responded to the critical item, “Do you ever experience bruxism (teeth grinding)?” by an- swering yes or no, African Americans were almost 2.5 times less likely to report that they had experienced bruxism. Interestingly, a study of fac- tors associated with tooth wear (Johansson, 1993) found that self- perception of wear correlates significantly with actual occlusal wear. These findings are consistent with the decreased frequency of severe tooth wear in this study’s African American subjects. The literature also is ambivalent as to the relationship between gender and tooth wear. While some studies, including this study, have shown that tooth wear is greater in males than in females (Ekfeldt et al., 372 Eltink et al. 1990; Johansson et al., 1993; Pigno et al., 2001), other studies (Oguny- inka et al., 2001) seem not to support this finding. CONCLUSIONS The gingival margin-papillae measurement is sensitive ade- quately and specific to detect changes in the position of the gingival margin and can be used to document prodromal gingival recession. Caucasian males and females as well as African American males all showed greater clinical recession than did African American females. Caucasian males showed greater clinical crown height than did African American females. 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Semin Orthod 1999;5:171-180. Volchansky A, Cleaton-Jones P. Clinical crown height (length): A re- view of published measurements. J Clin Periodontol 2001:28: 1085- 1090. Watson PJ. Gingival recession. J Dent 1984;12:29-35. Wennström JL. Lack of association between width of attached gingiva and development of soft tissue recession: A 5-year longitudinal study. J Clin Periodontol 1987; 14:181-184. 375 REGISTRATION OF ORTHODONTIC DIGITAL MODELS Dan Grauer, Lucia H. Cevidanes, Donald Tyndall, Martin A. Styner, Patrick M. Flood, William R. Proffit ABSTRACT Current methods to assess outcomes and change in orthodontics are comparison of photographs, cephalometric measurements and superimpositions, and com- parisons/measurements on dental casts. Digital models are a relatively new re- cords modality in orthodontics. They offer numerous advantages in terms of Storage space, spatial registration and superimposition. The purpose of this chap- ter is to determine the reproducibility of: 1) establishing occlusion of independ- ently scanned digital models; and 2) registering digital models obtained after treatment on their homologous digital model setups produced before treatment. Reliability of both procedures was assessed with two random samples of five patient’s models. In both experiments, three replicate positionings of the models per patient were created and variability in position was evaluated by the maxi- mum surface difference between replicates, and the standard deviation of the surface distances between replicates respectively. Based on the data obtained, we concluded that it is reliable to register independently scanned models to a scanned surface of the models in occlusion. Surface-to-surface registration of final orthodontic digital models to planned setup models also is reproducible. KEY WORDS: digital models, registration, digital orthodontic casts, orthodontic treatment outcomes, orthodontic tooth movement Excellence in orthodontics depends on careful assessment of treatment outcomes. In order to evaluate and quantify changes, records and measurements are obtained at different time points and compared. Current methods to assess outcomes and change in orthodontics are comparison of photographs, cephalometric measurements and super- impositions, and comparisons/measurements on dental casts. Photo- graphs offer a qualitative assessment in orthodontics and are a valuable communication tool. However, due to the likelihood of different camera angulation during photograph acquisition, it is not practical to obtain 377 Digital Models quantitative information for precise assessment of change (McKeown et al., 2005). Cephalometric superimpositions are the current gold standard for assessment of change in orthodontics and it has been shown that they provide great precision and accuracy (Björk, 1966; Johnston, 1996). Cephalometric measurements also can be compared to normative data (Hunter et al., 1993). Their main disadvantage is that cephalometric ra- diographs are a two-dimensional (2D) representation of three- dimensional (3D) structures; due to the overlapping of the left and right sides of the dental arches, it is difficult to obtain a precise assessment of tooth movement. Dental casts are the most frequently used 3D record in orthodon- tics and are, after the clinical evaluation, the most valuable orthodontic record (Han et al., 1991). However, their physical nature prevents them from being superimposed in space and hence, only linear 2D measure- ments can be obtained. Moreover, they cannot be registered within the same coordinate system. Because we do not know the spatial relationship between models acquired at different time points, measurements of change are not directional. For example, we know that a change occurred between point 1 and point 2 but we do not know whether that change was due to movement of point 1, point 2 or both, and we cannot quantify the percentage of change at each point (Fig. 1). The American Board of Orthodontics developed an Objective Grading System (OGS) in order to assess treatment outcomes in ortho- dontics (Casko et al., 1998). This method has proven to be reliable and is now a standard method for orthodontic outcomes assessment. The OGS is based in linear measurements on dental casts and includes the disad- vantages previously mentioned. A digital version of the OGS is currently under development but has not been validated yet (Okunami et al., 2007; Hildebrand et al., 2008). Digital models are a relatively new records modality in ortho- dontics. They offer numerous advantages in terms of storage space, spa- tial registration and superimposition. Digital models are not different qualitatively from conventional dental casts in terms of diagnosis and treatment planning (Rheude et al., 2005; Whetten et al., 2006). Quantita- tively, some differences have been found when comparing measurements between digital and dental casts, but these differences were not signifi- cant clinically (Motohashi and Kuroda, 1999; Tomassetti et al., 2001; Bell et al., 2003; Zilberman et al., 2003; Quimby et al., 2004; Stevens et 378 Grauer et al. Figure 1. During treatment the width between the premolars and molars was increased. Dental casts allow for measurement of linear distances but not relative measurements. The orange bar represents the initial distance between second premolars (A). The green box represents the increase in interpremolar width (B). Measurements on dental casts do not allow for de- termination of whether interpremolar expansion occurred by the right premolar moving facially, the left premolar moving facially, or most likely both premolars moving facially. al., 2006; Gracco et al., 2007; Mullen et al., 2007; Leifert et al., 2009: Sjogren et al., 2009). Digital models of the same patient obtained at different times can be registered in the same coordinate system, which allows for assessing change among time points. The challenge is finding stable references across time to be used as registration structures (Choi et al., 2010). The rugae region of the palate has been suggested as stable region (van der Linden, 1978: Almeida et al., 1995; Bailey et al., 1996; Hoggan and Sadowsky, 2001; Ashmore et al., 2002; Cha et al., 2007; Christou and Kiliaridis, 2008; Jang et al., 2009). It seems that once these difficulties are overcome, digital models will offer a quantifiable, directional, accu- rate and reliable way of assessing change. The purpose of this chapter is to: 1) determine the reproducibility of establishing occlusion of independently scanned digital models; and 2) determine the reproducibility of registering digital models obtained after treatment on their homologous digital model setups produced before treatment. ESTABLISHING OCCLUSION WITH INDEPENDENTLY SCANNED DIGITAL MODELS One method of creating digital models from dental casts involves Scanning each dental cast upper and lower independently and then scan- ning the facial surfaces of both models in occlusion. This last scan is 379 Digital Models used as mutual information to reposition the independently scanned up- per and lower models in a spatial relationship that reproduces the pa- tient’s occlusion. Methods Sample: In order to register the dental arches in space to repre- sent the patients’ occlusion, a sample consisting of pretreatment models of five patients was selected randomly from a population of 94 consecu- tively treated patients. The originating sample is composed of consecu- tive cases treated with Incognito"M lingual technique and debonded be- tween January 2008 and January 2009. In order to create the scanned surfaces, poly-vinyl siloxane impressions were made with Bisico"Mim- pression material (Bielefelder Dentalsilicone GmbH & Co. KG, Biele- feld, Germany) and poured with Type IV extra hard white stone. Models were scanned with an ATOS optical scanner (GOM mbH, Braunschweig, Germany) at a spatial resolution of 20 microns. For each patient, three scans were created: one surface of the upper arch, one surface of the lower arch and one surface of the models in occlusion. The latter scan included only the facial aspect of the models in occlusion (Fig. 2A). Software The upper arch surface was registered to the corresponding buc- cal upper arch surface on the occlusion models using Occlusomatch" software (TopService, 3M, Bad Essen, Germany). Parameters for the registration were set to select 2500 points on each surface and with a search radius of 1 mm (reduced to 0.25 mm, factor of 0.5 mm). Iterations were performed automatically until a 0.06 mm average surface distance was obtained. The success threshold was set at 0.06 mm (Fig. 2B). This two-step process was repeated three times per patient for each dental arch, rendering three positions for the upper dental arch and three posi- tions for the lower dental arch. Dental arches were compared pair-wise and average surface distances were computed between homologous den- tal arches in Geomagic StudioTM 10.0 software (Geomagic US, Research Triangle Park, North Carolina). The variable of interest was the maxi- mum surface distance between homologous dental arches as a proxy for the maximum discrepancy due to the registration process (Fig. 3). Statistical Analysis In order to assess whether the discrepancy in positioning varies by dental arch, the largest discrepancy in replicate positioning was analyzed 380 Grauer et al. Figure 2. Independently scanned models (A) are registered using a scanned sur- face of the facial aspect of the models in occlusion (B). C and D. The scan of the models in occlusion is used only for the registration of the upper and lower models in occlusion. º º U2 | Figure 3. Three-dimensional comparison of the models is per- formed by Geomagic Studio" 10.0 (Geomagic US, North Carolina). Replicate positions are compared based on the ab- solute value of the maximum distance between surfaces and graphically displayed as color maps. Color segments corre- spond to distance (mm) between surfaces. using a repeated measures analysis, allowing for different compound Symmetry covariance structures for each dental arch. 381 Digital Models Results The estimated maximum difference in replicate positioning is shown in Table I. Three positions per dental arch were compared pair- wise across patients. The summary of the statistical model analysis is displayed in Table 2. Table 1. Estimated maximum difference in replicate positioning by dental arch. Dental Arch Estimate (mm) Standard Error (mm) Upper 0.007 0.003 Lower 0.009 0.004 Table 2. Type 3 tests of fixed effects. Effect DF F-statistic P-Value Dental Arch 1,24 0.21 0.65 These data suggest that there is no statistically significant differ- ence between the upper and lower arches in the average discrepancy in replicate positioning and that there are no statistically significant differ- ences between replicate positioning across the entire sample. Positioning the digital models in occlusion by using the scanned surface of the buccal surface of the models in occlusion is reproducible. DISCUSSION Even though it is likely that validation studies like this one have been conducted, we could not find any publication of a similar approach. A second method to position the digital models in occlusion in- volves using a 3D surface scan of a wax bite – an interocclusal record – to obtain a reference to which the digital models could be registered in space. This method is based in registering the upper model to the upper surface of the wax bite and the lower model to the lower surface of the wax bite. The structures involved in this surface-to-surface registration are the upper and lower cusps and incisal edges in the digital models and their homologous indentations produced in the wax material while the patient bit on it. This second method requires surface-to-surface registra- tion of complimentary surfaces (e.g., dental cusps and indentations on the wax bite) rather than homologous surfaces (e.g., facial surfaces of dental model in occlusion and not in occlusion); it is likely to involve a 382 Grauer et al. greater error of the method due to approximation operations during the complementary surfaces registration. A third method of establishing occlusion of the digital models would involve scanning the models mounted in an articulator. By using fiducial structures attached to the articulator, the relative position of the upper model to the lower model could be calculated. This is a potentially accurate method, but requires constant recalibration of the scanner to register the spatial position of the articulator to the scanner coordinate system. Currently the scanned surface of the models in occlusion to reg- ister digital models (but with different registration parameters) is used widely by clinicians thanks to the introduction of in-office model scan- ners. The 3Shape model scanner (3Shape, Copenhagen, Denmark) is a relatively economical device that allows the user to scan models inde- pendently and in occlusion. Through the proprietary OrthoAnalyzer"M software, the user can establish the occlusion of the models and perform measurements, digital setup and export the models as non-proprietary files (stereolithography or STL extension). It is important that when the models are locked in occlusion, this position remains the same through- out the entire scanning process. There are different devices to maintain the models in a fixed position while the scanner platform is moving to allow scanning of all surfaces of the models. Extreme care should be taken because a minimal movement of the models in occlusion during Scanning will render a non-valid occlusion registration. We have chosen the absolute value of the maximum discrepancy between surfaces (homologous dental arches were compared pair-wise in three replicate positioning) as our variable of interest. This variable is representative of the maximum error between registration instances and it may overestimate the error. However, given the small variability ob- tained, we considered it safer to overestimate rather than to underesti- mate. This small magnitude estimates for the upper and lower dental arch are not considered significant clinically. Aegyſ/a/rom of Seſa/, //ode/, ſo Aºmaſ Mode/, ſo Assess 7Peaſmem. Arecision Digital models offer a clear advantage over dental casts in as- Sessing longitudinal changes given that they can be registered and super- imposed in space (Jang et al., 2009; Choi et al., 2010). Among other methods of treatment results assessment in orthodontics, outcomes in Orthodontics also can be assessed by comparing the obtained outcome 383 Digital Models with the planned setup. Spatial registration of the setup model on the fi- nal digital models is achieved by an iterative closest point (ICP) algo- rithm or “best fit” of surfaces. In order to evaluate the reliability of the ICP registration of setup models to their homologous final outcome model, the following study was accomplished. Methods Sample: In order to assess the reliability of registration of final digital models to digital models of initial setups, a second sample con- sisting of models of five patients was selected randomly from the popula- tion of 94 consecutive treated patients. For each patient two sets of mod- els were available: final models post-orthodontic treatment obtained the day of bracket de-bonding and setup model made on a duplicate of the malocclusion models before orthodontic treatment. Models were scanned with an ATOSTM optical scanner (GOM mbH, Braunschweig, Germany) at a spatial resolution of 20 microns. Software Models were repositioned in space to reproduce their occlusion relationship using method described in the first part of this chapter. The surfaces were simplified to 50,000 points using the Qslim 2.0 tool (Gar- land and Heckbert, 1997) and then cleaned to delete the gingival tissues. Once simplified, the upper setup model was registered to the upper final model using eModelTM 9.0 software (Geodigm Corporation, Chanhassen, MN) to combine both models in the same coordinate system. The same process was followed for the lower setup model. The registration process was repeated three times per dental arch, per patient, rendering three relative positions of the upper and lower setup arches to the final models (Fig. 4). Setup and final dental arch posi- tions were compared pair-wise and average surface distance was com- puted between homologous record arches. The variable of interest was the absolute value of the standard deviation surface distance between final and setup models as a proxy of the average discrepancy due to the registration process. Statistical Analysis In order to assess whether the error in replicate positioning varies by dental arch, the standard deviation was used to summarize the deviation 384 Grauer et al. º º - - | º Aº - E. . Figure 4. A Final and setup orthodontic digital models are registered. B: The surfaces corresponding to the gingival tissues are removed. C. Registered digital models can be superimposed in space. between replicates. A repeated measures analysis was performed, allow- ing for different compound symmetry covariance structures for each den- tal arch. Results The estimated maximum difference in replicate positioning is shown in Table 3. The average difference in absolute value of the standard devia- tion was not different significantly from zero for the upper jaw (P=0.08) or for the lower jaw (P = 0.22). The summary of the statistical model analysis is displayed in Table 4. Table 3. Estimated standard deviation by dental arch. Dental Arch Estimate (mm) Standard Error (mm) Upper 0.07 0.04 Lower 0.05 0.03 Table 4. Type 3 tests of fixed effects. Effect DF F-Statistic P-Value Dental Arch 1,24 0.15 0.71 385 Digital Models These data suggest that there is no statistically significant differ- ence between the upper and lower arches in the average discrepancy in replicate positioning and no statistically significant differences between replicate positioning across the entire sample. DISCUSSION Longitudinal change assessment using sequential digital models is based in the following process: 1. A coordinate system has to be defined; 2. Models from different time points must be registered to that coordinate system; and 3. Models are superimposed and the differences among them are evaluated. In order to combine different records in the same coordinate system, sta- ble structures – which did not change with time or treatment – are de- fined and used as registration regions. Once registered, structures that did change can be described qualitatively and quantitatively. While the orthodontic community is waiting for a reliable longi- tudinal registration of sequential dental models to assess tooth move- ment, other methods to assess treatment outcomes are being used. The ABO OGS is a validated tool to assess orthodontic outcomes. Even though it is one of the best methods available at this point, it depends on fixed anatomical relationships rather than on actual tooth movement. Due to that limitation, its results often are influenced by the tooth anatomy. Researchers have been looking for stable structures within the dental models to be used as registration landmarks or surfaces (Baumrind et al., 2003; Beers et al., 2003; Miller et al., 2003; Kravitz et al., 2009). The main problem using rugae as stable registration surfaces is that, as in any registration process, the further away from the registration surface a point is, the greater the registration error becomes (Cha et al., 2007; Choi et al., 2010). While the rugae may be reliable to assess tooth movement in the premolar region (mainly in cases treated with no extractions), it may not be precise enough to assess changes in the molar region. In addi- tion, small changes in rugae morphology will have great effects on the relative vertical position of molars between time points. Recently Jang and colleagues (2009) compared the rugae registration method with reg- istration on miniscrews placed in the maxilla and concluded that the me- dial points of the third palatal rugae and the palatal vault could be used as reference landmarks. 386 Grauer et al. An efficient way to assess treatment outcomes, not tooth move- ment, would be to register and superimpose the models obtained after orthodontic treatment on the setup or planned correction. While this method does not allow for calculation of tooth movement due to treat- ment and growth, it does allow for calculation in the discrepancy be- tween planned position and obtained position relative to intra-arch tooth alignment. The first step for such method is the establishment of repro- ducible registration method. ICP registration does not depend on stable structures, but rather utilizes the whole surface during the computation of the registration parameters. Given that the differences between surfaces (final treatment and planned setup) are relatively small, the registration error is divided among all teeth based on their size. The reliability of this method depends on the relative initial posi- tion of the surfaces before registration process, because ICP registration uses optimization methods to identify a minimum surface distance value between surfaces. Given that the surfaces we register are similar but not equal, we have chosen the standard deviation as a proxy variable for the registration variability. If we use the average surface distance between Surfaces, we would underestimate the error in registration because posi- tive errors would cancel negative ones. The absolute value of the maxi- mum distance between surfaces also is not representative of the discrep- ancy between registration instances given that the surfaces are not equal. CONCLUSION Based on the data presented above, it is reliable to register inde- pendently scanned models to a scanned surface of the models in occlu- Sion. Surface-to-surface registration of final orthodontic digital models to planned setup models also is reproducible. Further research is needed to establish the most stable land- marks/surfaces for longitudinal registration of sequential digital models. Once surfaces are registered, the difference between positions of individ- ual teeth can be measured and expressed in terms of six degrees of free- dom (Fig. 5). ACKNOWLEDGEMENTS We would like to thank Dr. Ceib Phillips, Lindsay Kornrumpf and Mike Marshall for their help and support. Partially funded by R01 DE005215. 387 Digital Models Figure 5. Once registered in the same coordinate system the six degrees of freedom describing tooth movement can be computed (Euler sys- tem). Computation of translation is based on the relative position of the tooth centroid. From eModel"M software (Geodigm Corporation, Chanhassen, MN). Computation of rotation is based on the relation of the local coordinate system of each tooth and the general coordinate System. REFERENCES Almeida MA, Phillips C, Kula K, Tulloch C. Stability of the palatal ru- gae as landmarks for analysis of dental casts. Angle Orthod 1995;65. 43–48. Ashmore JL, Kurland BF, King GJ, Wheeler TT, Ghafari J, Ramsay DS. A 3-dimensional analysis of molar movement during headgear treat- ment. Am J Orthod Dentofacial Orthop 2002; 121:18-29. Bailey LT, Esmailnejad A, Almeida MA. Stability of the palatal rugae as landmarks for analysis of dental casts in extraction and nonextraction cases. Angle Orthod 1996;66:73–78. Baumrind S, Carlson S, Beers A, Curry S. Norris K, Boyd R.L. Using three-dimensional imaging to assess treatment outcomes in orthodon- tics: A progress report from the University of the Pacific Orthod Craniofac Res 2003;6 S1:132-142. 388 Grauer et al. Beers AC, Choi W, Pavlovskaia E. 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Whetten JL, Williamson PC, Heo G, Varnhagen C, Major PW. Varia- tions in orthodontic treatment planning decisions of Class II patients between virtual 3-dimensional models and traditional plaster study models. Am J Orthod Dentofacial Orthop 2006; 130:485-491. Zilberman O, Huggare JA, Parikakis KA. Evaluation of the validity of tooth size and arch width measurements using conventional and three- dimensional virtual orthodontic models. Angle Orthod 2003;73:30.1- 306. : 391 ASSESSING THE OUTCOME OF ALVEOLAR BONE GRAFTING USING CONE-BEAM COMPUTED TOMOGRAPHY (CBCT) Snehlata Oberoi and Karin Vargervik The aim of this chapter is to describe the radiographic outcomes of alveolar bone grafting in non-syndromic unilateral and bilateral cleft lip and palate (UCLP and BCLP) individuals using cone-beam computed tomography (CBCT) and to evaluate the eruption path of the permanent maxillary canine during one year after bone grafting. This prospective study was conducted on 21 consecu- tive non-syndromic complete cleft lip and palate individuals between eight and twelve years of age who required alveolar bone grafting. Pre- and post-operative CBCT scans were analyzed using Amira 3.1.1 and Dolphin 3D imaging 10.5 Software. The average volume of the pre-operative alveolar cleft defect in UCLP was 0.61 cm and the combined average volume of the right and left alveolar cleft defects in BCLP was 0.82 cm'. The average percentage bone fill in both UCLP and BCLP was 84% at the one-year follow-up. The radiographic outcome was not affected significantly by cleft type, size of the pre-operative defect, presence or absence of a lateral incisor, root development stage of the maxillary canine on the cleft side, timing or surgeon. Most canines on both the cleft and non-cleft side moved incisally, facially and mesially. Twelve percent of the ca- nines on the cleft side appeared to require surgical exposure. Secondary alveolar bone grafting of the cleft defect in our center was successful based on radio- graphic outcome using CBCT scans. KEY WORDS: alveolar bone grafting, cone-beam computed tomography (CBCT), cleft lip and palate, volumetric assessment INTRODUCTION Secondary alveolar bone grafting presently is the standard of care in most cleft centers for individuals with complete cleft lip and pal- ate. A successful alveolar bone graft procedure results in continuity of the maxillary arch, facilitates eruption of permanent teeth, provides ade- quate bone support and preserves periodontal health of teeth adjacent to the cleft, permits orthodontic tooth alignment, allows placement of os- 393 Alveolar Bone Grafting Seointegrated implants and improves alar base symmetry (Bergland et al., 1986b; Trindade et al., 2005). Imaging before and after alveolar bone grafting is necessary to evaluate the size of the alveolar cleft defect, position and level of bone on adjacent teeth and presence of supernumerary teeth and to determine the outcome of the procedure by evaluating the bone fill of the defect, eruption status of the lateral incisor or canine adjacent to the cleft and adequacy of bone for placement of endosseous implant. Presently, two dimensional (2D) radiographs including panoramic, occlusal and periapi- cal films are used to assess pre-surgical conditions and after surgery to determine the success of alveolar bone grafting by measuring inter- alveolar bone height or using the Bergland grading system (Bergland et al., 1986b; Kindelan et al., 1997: Aurouze et al., 2000: Newlands, 2000; Dempf et al., 2002; Witherow et al., 2002; Hynes and Earley, 2003; Fig. 1). Using these 2D imaging methods, the success rates for secondary al- veolar bone grafting has been reported to vary from 67% to 95% on the Bergland scale. Da Silva Filho and colleagues (2000) achieved a success rate of 72% in 50 patients with bone grafts done before the eruption of the canine. Lilja and coworkers (2000) achieved a success rate of 91% in 70 patients. Jia and Mars (2000) had a success rate of 95% when bone grafting was carried out before eruption of the canine and a success rate of 67% when done after canine eruption. In general, the reported out- come of bone grafting was better when done before eruption of the ca- nine adjacent to the cleft. There are drawbacks, however, to the 2D images including lack of volumetric information, enlargement and distortion, structure overlap and a limited number of identifiable landmarks, all of which affect image quality and reliability (Waitzman et al., 1992). Conventional CT scans have been used to assess outcome of al- veolar bone grafting (Lee et al., 1995; Rosenstein et al., 1997; Honma et al., 1999; Tai et al., 2000; van der Meijet al., 2001). Lee and associates (1995) found that the number of clinically successful bone grafts was overestimated by 17% on dental radiographs as compared to conven- tional CT. This inaccuracy was attributed to the fact that standard radio- graphs cannot show depth and volume of bone in the grafted site. Rosenstein and colleagues (1997) compared 3D calculations from CT with 2D calculations from standard dental radiographs when evaluating bone support of teeth adjacent to the cleft after primary bone grafting. They found that root coverage might be overestimated by as much 394 Oberoi and Vargervik Figure 1. Occlusal films of alveolar cleft defect before and after secondary al- Veolar bone grafting. as 25% on 2D dental radiographs when compared with CT scans and, therefore, cautioned use of 2D radiographs for evaluating the success of bone grafts. They concluded that 3D CT was a superior method for de- termining total 3D bone support for the teeth adjacent to the cleft. Using 3D CT pre-operatively on a unilateral alveolar cleft defect, the alveolar defect volume was found to be 1.3 cm and the palatal defect to be 0.3 cm (Bradrick et al., 1990). In another study, the average bone graft volume of 2.1 cm with a range of 0.9 to 3.6 cm was needed to fill the defect (Boyne et al., 1993). Botel and coworkers (1993) reported Similar results with bone wax impressions of 13 cleft individuals and found a range of 1.0 to 3.5 cm with a mean of 1.5 cm'. Despite the benefits of CT imaging, the radiation dose for stan- dard CT of the maxillofacial region is high and repeated scanning is a concern. Medium field of view cone-beam computed tomography (CBCT) radiation ranged from 69 to 560 microSv, whereas a similar- FOV medical CT produced 860 microSv. Ludlow and Ivanovi (2008) Calculated doses of radiation in microSV for three different CBCT sys- tems: NewTom3G (45, 59 microSv), i-CAT (135, 193 microSv) and CB Mercuray (477, 558 microSv). These dosages are four to 42 times greater than comparable panoramic examination doses (6.3, 13.3 microSv; Lud- low et al., 2006). In addition, the resolution of spiral CT images usually is insufficient for observation of alveolar bony architecture and periodon- tal condition (Arai et al., 1999). In a study by Hamada and colleagues (2005), the use of limited CBCT (Dental 3D-CT) was compared with dental occlusal and pano- ramic radiographs in evaluating bone grafts of the alveolar cleft. They found Dental 3D-CT to provide more precise information about 3D mor- 395 Alveolar Bone Grafting phology of the bone bridge at the cleft site and 3D relationships between the bone bridge and the roots of the teeth adjacent to the cleft. This type of imaging also offered more information about the alveolar bony archi- tecture, bone support of teeth adjacent to the cleft and better assessment of the alveolar bone graft for placement of dental implants. However, this study did not perform a quantitative assessment of the alveolar cleft. Studies on 3D localization of impacted maxillary canines with CBCT have been done in non-cleft individuals. These findings show that 40% to 92% of the impactions were palatal, 8% to 45% were buccal and lateral incisor resorption occurred in 27% to 66% of cases (Walker et al., 2005; Liu et al., 2008). These studies used linear and angular measure- ments of the inclination and location of the impacted canines at one time point only. Few studies have evaluated the eruption status of the canine in cleft lip and palate individuals at a given time point. To our knowl- edge, no 3D study has been reported on the eruption path of the canine over time. Although studies have found that most canines erupt through the bone-grafted site (Turvey et al., 1984; Collins et al., 1998; Da Silva Filho et al., 2000), the eruption path previously has not been reported. METHODS Subjects The sample for this study consisted of all consecutively scanned and bone grafted non-syndromic cleft lip and palate subjects from the University of California San Francisco (UCSF) Center for Craniofacial Anomalies over a period of two years; these subjects underwent secon- dary alveolar bone grafting as part of their treatment protocol (CHR ap- proval #H44601-27916-02). This prospective study included 21 indi- viduals, fifteen males and six females, seventeen with unilateral and four with bilateral complete clefts. The average age at time of alveolar bone grating was ten years seven months = two years eight months. The exclu- sion criteria were diagnosed syndromes associated with the clefting con- dition, previous bone grafting and erupted canine. All individuals had primary lip and palate repair, typically at three and ten months of age, respectively. The maxilla was expanded prior to alveolar bone grafting. In all cases, the grafting procedure was done before the canine on the cleft side had erupted into the alveolar de- fect. The autogenous cortico-cancellous bone grafts were harvested from the anterior iliac crest using the standard lateral approach and alveolar cleft repair performed using a lateral sliding flap, as described by Boyne 396 Oberoi and Vargervik and Sands (1972). All bone-grafting procedures were performed by one of two team surgeons: the first operated on 11 individuals and the second on 10 individuals. Method for Volumetric Assessment of Pre- and Post-operative Scans CBCT scans with 0.4 mm slices were obtained at two time points on the Hitachi Mercuray CBCT machine (Hitachi Medical Corp., Ja- pan). The first scans were taken after orthodontic expansion and before alveolar bone grafting, and the second at least one year after alveolar bone grafting (Fig. 2). The first step was reorienting the DICOM files by using CB Works 2.01 (Seoul, Korea). The lines were dragged to reorient the axis and the file renamed and saved. After reorienting, the data were re-sliced and the file saved in a separate folder from the source file. Data then were imported into volume rendering software, Amira 3.1.1 (Visage Imaging, Carlsbad, CA). Based on anatomic landmarks to delineate broadly the alveolar cleft, five planes were chosen in order to define the area of interest (Fig. 3). Using image segmentation, the different regions of interest were identified on selected sequential slices in the axial, coronal and sagittal planes and the Volume interpolated. Volume in cubic cm was assessed using the “tissue statistic” tool in Amira. Volume of the cleft defect (depicted as A) was measured as on the pre-operative scans and the volume of any residual defect (depicted as B) was measured on the post-operative scans. The radiographic suc- cess of alveolar bone graft was calculated as a percentage bone fill using the formula (A-B)/A x 100 (Oberoi et al., 2009). Method for Assessment of Canine Eruption Volumetric data were loaded and oriented such that the X, Y and Z planes were set at internal landmarks and cranial base structures. The Sagittal cross section was used to set the X plane at the Sella-Nasion (S- N) as a line from the geometric center of sella (S) to the fronto-nasal su- ture (N). The A-P view was used to set the Y plane at mid-sagittal as a line bisecting the clivus in the base of the skull. The axial cross section Was used to set the Z plane as a line bisecting the optic foramina (Fig. 4). After reorienting, the canine cusp tip and a point along the long axis of the developing root were selected on both the cleft and non-cleft sides in the volumetric view using the digitizing landmarks tool. These 397 Alveolar Bone Grafting Figure 2. Volumetric rendering using CBCT of one individual before and one year after secondary alveolar bone grafting. 2) Y-anterior Plane Postęrior Plºe pittal Plane 4) Z-inferior Plane Figure 3. Landmarks in the X, Y and Z planes used to define the alveolar cleft. 1) X-midsagittal plane. 2) Y-anterior (a plane three slices posterior to the ANS). 3) Y-posterior (a plane located at the mesial of the tooth adjacent to the cleft on the distal cleft segment). 4) Z-inferior (the plane at the level of the CEJ of the adjacent teeth). 5) Z-superior (the plane at three slices below the anterior nasal spine [ANSI). 398 Oberoi and Vargervik points were verified in the sagittal, coronal and axial views (Fig. 1). The X, Y and Z coordinates of each digitized point were determined by the software and pasted onto an Excel spreadsheet. The direction and amount of movement of the canine was calculated by subtracting the individual X, Y and Z coordinates in the post-scans from the values determined in the pre-scans (Oberoi et al., 2010). Statistical Methods SAS Proc MIXED, SAS Ver 9.1 (SAS Institute, Cary NC) was used to perform the statistical analyses and to accommodate the correla- tions in measurements due to the contribution of two measurements from each of the bilateral patients. The outcome was defined as log (1-9% bone fill) and each of the factors above was fit separately due to the small size of the sample. The estimates were back transformed to the original scale. To assess inter- and intra-rater reliability, two investigators each measured and re-measured five sets of pre- and post-scans and calculated the percentage bone fill for each set. The reliability of the measurements within and between raters was analyzed statistically using the Lin’s con- cordance and Pearson correlation coefficient. SAS Proc MIXED and SAS Proc NLMIXED, SAS Ver 9.1 (SAS Institute, Cary NC) were used to perform the statistical analyses. Mixed model analyses were used to accommodate the correlations in measure- ments due to the contribution of two measurements from each of the bi- lateral patients. Two operators repeated the method ten times each on the same scans. The average pairwise difference in measurements between raters was found to be 0.51 (SD = 0.26), 0.30 (SD = 0.29) and 1.03 (SD = 0.31) for the X, Y and Z coordinates, respectively. RESULTS There was good agreement between the two raters and within a single rater with Lin’s concordance and Pearson correlation coefficient of above 0.9 for both. In the UCLP group, the average volume of the pre- operative alveolar cleft defect was 0.61 cm (range = 0.22 to 1.4 cm’ ) and the average size of the residual cleft defect was 0.08 cm (range = 0.02 to 0.17 cm’). In the BCLP groups the average combined size of the right and left pre-operative alveolar cleft defects was 0.82 cm and the average size of the combined residual cleft defect was 0.21 cm ranging from 0.01 to 0.24 cm’. 399 Alveolar Bone Grafting Optic Foramen (axial) - Figure 4. Reorientation. One year after the alveolar cleft was grafted, the average per- centage bone fill in the UCLP group was 84.1%, ranging between 61.9% and 96.5%. The average percentage bone fill in the BCLP group Was 84.8%, ranging from 48.9% to 97.4%. The average percent filled was 84 in the unilateral group and 85 in the bilateral group with bootstrapped confidence intervals ranging from 0.7 to 0.9 (Table 1); no significant diſ- ference was reported between the unilateral and bilateral groups. The size of the pre-operative defect did not appear to affect the outcome in terms of bone fill (Table 2). The average pre-defect size was 0.7 cm.” ---1 S.D (0.3 to 1.1 cm'). For these defect sizes, the percentage bone fill ranged from 86% to 91%. However, the sample size was small. Lateral incisors were missing in 88% of the unilateral and 75% of the bilateral clefts. In addition, the unilateral cases were missing 24% of the contralateral lateral incisors. The percent bone fill in the presence of a lateral incisor was 80.02% vs. 89.45% in the clefts where the lateral incisor was missing (P=0.25); no significant difference was seen. 400 Oberoi and Vargervik Table 1. Average percent bone fill in the combined UCLP and BCLP groups. º Bootstrapped Observation Average percent bone fill 95% CI Total n = 2 l 84% 0.78 to 0.89 – O UCLP n = 1 7 84% 0.78 to 0.89 BCLP n = 4 85% 0.71 to 0.93 Table 2. Table showing the average pre-operative defect size and the average percent bone fill with the 95% confidence intervals. Obs Pre-operative Average 95% 95% defect size percent fill Lower CI Upper CI 1 0.3 86% () 0.98 2 ().7 89% 0.16 0.98 3 1.1 91% 0.23 ().99 The stage of root development of the canine did not appear to af- fect the percent bone fill (P = 0.89). In previous studies, root develop- ment of the canine and outcome of bone grafting has been assessed at one-third, two-thirds and complete root development. In our study, we had only one in the one-third root development category and therefore had only two groups: less than half and greater than half root developed. There was no statistical difference (P = 0.74) when comparing the percentage bone filled before nine years of age and after nine years of age. There was no difference in percentage bone fill between males and females (P = 0.88). There was no statistically significant difference be- tween surgeons in percentage bone fill (P = 0.87). Adequacy of bone for implant placement requires that the mesio- distal width, anterior-posterior width and the height are at least 7 mm, 6 mm and 10 mm, respectively. One year after alveolar bone grafting (av- 401 Alveolar Bone Grafting erage age at bone grafting = 10.6 years), 80% of the unilateral cleft and 100% of the bilateral cleft individuals had adequate bone for implant placement. However, at this stage the patients were too young for im- plant placement. In general, the canines on both the cleft and non-cleft sides moved incisally, facially and mesially as shown on the histograms (Figs. 2-4). Only one canine on the cleft side appeared to move apically 0.9 mm. This is a relative movement due to change to a more mesial inclination. The canines moved incisally in 24 of the 25 cleft sites. Facial movement was seen in 20 of the cleft-side canines and 10 of the non- cleft-side canines. Palatal movement occurred in five of the cleft-side canines and seven of the non-cleft-side canines. Mesial movement oc- curred in 22 of the cleft side canines and ten of the non-cleft-side ca- nines. Most of the distal movement was on the non-cleft side. The mean, median, minimum and maximum movements in the different directions are shown in Tables 4 and 5. The estimated percentage of the canines that needed surgical ex- posure due to impaction was 12% with a bootstrapped 95% confidence interval of 4%, 33%. The presence or absence of lateral incisors did not affect vertical eruption. The younger group (< 9 years) consisted of five individuals (23.8%) and the older group (> 9 years) had 16 individuals (76.2%). We analyzed canine movements in the mesial or distal directions and canine movements in the facial or palatal directions separately. There was no statistical difference between the older and younger groups in the amount of movement of the canine in the mesial-distal group (P = 0.39) or in the facial-palatal group (P = 0.20). Eighty percent of canines had root development less than 50% and 20% had root development greater than 50%. Individuals with root development less than 50% had incisal movement amounts 5.13 mm less than individuals with root development greater than 50% (bootstrapped 95% C.I. -8.32, -1.9; P = 0.002). DISCUSSION The outcome of alveolar bone grafting traditionally has been studied using 2D imaging such as periapical, occlusal and panoramic radiographs. However, 2D images of a 3D defect permit analysis only of bone height and do not allow measurement of defect volume or of percen- 402 Oberoi and Vargervik Table 4. Movement on the cleft side. Number Direction of of Median Mean SD Min – max movement canines (mm) (mm) (mm) (mm) Incisal 24 5.75 6.8 4.92 0.4 to 16 Apical | 0.9 0.9 0 | --------- Mesial 22 2.8 3.25 2.5 0.6 to 9.8 Distal 3 0.7 2.03, 2.84 0.1 to 5.3 Facial 20 1.8 2.5 2.14 0.1 to 7.5 Palatal 5 3.1 2.42 1.5 0.4 to 3.9 Table 5. Movement on the non-cleft side. Number : Direction of of Median Mean SD Min – max movement canines (mm) (mm) (mm) (mm) Incisal 17 5 5.95 4.73 0.1 to 18.2 Mesial 10 1.55 1.6 1.19 0.1 to 3.7 Distal 7 2.6 3 1.62 1.5 to 6.3 Facial 10 1.75 2.51 1.74 0.4 to 4.9 Palatal 7 ().5 1.24 1.66 0.2 to 4.9 tage of bone fill of the defect. A pre-surgical volume measure of the de- fect is useful for the surgeon to determine the amount of graft material needed. Post-surgically 3D scans are useful for the orthodontist and prosthodontist to determine and plan for orthodontic tooth movement and implant placement. The alveolar cleft defect has the shape of a pyramid: the side Walls are the bony cleft margins; the superior wall is the nasal floor; the inferior surface is the posterior alveolus and palate; and the base of the pyramid is the anterior surface of the alveolus (Craven et al., 2007). We measured the volume of the bony defect at the time of bone grafting and stipulated that the entire defect would be packed with bone graft material. Measuring the residual defect one year later was determined to be more reliable than to attempt to measure volume of new bone. This is due to the fact that the new bone showed complete incorporation and maturation and could not be distinguished from the adjacent alveolar bone as described by others (Tai et al., 2000). The one-year post-graft residual defect thus would indicate the amount left after resorption dur- ing the one-year interval. 403 Alveolar Bone Grafting In our study, the average volume of the pre-operative alveolar cleft defect was 0.61 cm in UCLP and 0.82 cm in the combined clefts in the BCLP group. Previous studies have shown the pre-operative defect size to range from 1.3 to 2.1 cm' (Bradrick et al., 1990, Botel et al., 1993; Boyne et al., 1993). Compared to other studies, our defect size was smaller even though the maxilla had been expanded before bone grafting. Regarding the size of the pre-operative defects, the cleft segments were rotated medially and in contact before expansion in all our subjects. The expansion resulted in correction of the lateral crossbite but did not result in excessive increase in cleft width. We believe that our method of Volumetric assessment is more accurate and, therefore, does not overes- timate the bony defect as compared to previous studies. The percentage bone fill was 84.1% in the UCLP group and 84.8% in the BCLP group, indicating an average bone loss or resorption of 16% after one year in both groups. Our study showed percentage bone fill at an average one year post-surgery to be lower than reported from 2D studies and higher than the results assessed by 3D conventional CT studies (Honma et al., 1999; Feichtinger et al., 2006). We used CBCT scans with a slice thickness of 0.4 mm, which is more accurate than pre- vious studies where 1.5 mm slices were used (Feichtinger et al., 2006). Conventional CT studies have shown high bone resorption par- ticularly in the bucco-palatal dimension. Feichtinger and coworkers (2006, 2008) used axial CT scans in their study and found extensive bone resorption in the bucco-palatal dimension with a mean bone loss of 51% in the first year and 52% in the second year after alveolar bone grafting. Tai and associates (2000) found the total volume loss was 43.7% coron- ally and 42.5% axially, which indicates the bone loss was almost equal in the bucco-palatal and vertical dimensions. Honma and colleagues (1999) found the mean cleft volume was lower significantly after one year when compared with the volume at three months post-operatively. Hamada and coworkers (2005) used cone-beam tomography to show the 3D morphol- ogy of the bone bridges. The common conclusion from all these studies was that the amount of bone loss was higher significantly than that shown by 2D imaging. Tai and coworkers (2000) found the highest decrease in bone volume at one year post-surgery when compared with the initial volume of the pre-operative defects. The mean bone loss was 95.2% after one year in cases where orthodontic space closure was not possible. In cases of orthodontic space closure, the resorption rate was lower significantly; 404 Oberoi and Vargervik this previously has been shown in the literature (Schultze-Mosgau et al., 2003). In our study, most of the canines were substituted for the missing lateral incisors, thereby increasing the bone Volume as the erupting tooth is osteogenic. We compared the outcome relative to the following variables: Type of cleft (unilateral/bilateral); Small or large clefts; Lateral incisor (presence/absence); Root development of the canine (greater than/less than 50%); 5. Timing (less/greater than nine years); 6. Sex (male/female); and 7. Surgeon (surgeon 1/surgeon 2). : No statistically significant differences were found in one-year post-surgery bone volumes between any of these subgroups. Also, no statistically significant differences in percentage bone fill between the unilateral and bilateral clefts were found. A similar finding was reported in a 2D evaluation of alveolar bone support of the permanent canine, where no difference was found between unilateral and bilateral clefts (Boyarskiy et al., 2006). In a conventional CT study, no differences were found between UCLP and BCLP in immediate post-operative coronal and axial bone volumes (Tai et al., 2000). van der Meij (2001), however, found a mean bone loss of 31% in a unilateral group and 55% in a bilat- eral group. We found no significant difference in outcome when comparing Small with large defect volumes. Long and associates (1995), however, have shown an inverse relationship between pre-surgical cleft width and ultimate graft success using an objective 2D radiographic method of as- sessment. van der Meij and colleagues (2003) showed a correlation of -0.29 for cleft width in relation to the percentage of residual bone. Honma and coworkers (1999) stated that the wider the gap between the teeth, the more bone loss occurs. When comparing the outcomes between the presence or absence of lateral incisor, no statistically significance in the bone fill was noted. Ozawa and colleagues (2007) showed that migration and eruption of the germs of teeth at the bone-grafting site was not caused by resorption of the bone graft, but involved induction and addition of bone. These were similar to 2D studies findings that showed tooth eruption increases verti- 405 Alveolar Bone Grafting cal height of the bone bridge (Boyne and Sands, 1972: El Deeb et al., 1982; Enemark et al., 1987). Several studies have concluded that the optimal time for secon- dary alveolar bone grafting is between nine and eleven years, before the eruption of the canine, when the canine root is between half to two-thirds developed (Boyne and Sands, 1972; Bergland et al., 1986b). In our study, we compared the outcome with the canine root development greater or less than 50% and found no significant difference. Similar re- sults were found by Long and coworkers (1996) who reported no signifi- cant relationship between degree of canine eruption and ultimate bone graft success. It is with caution that we interpret these results and cannot conclude that the position of the canine and root development has no in- fluence on graft outcome. However, we believe it is important that in none of our cases had the canine crown broken through the defect margin at the time of bone grafting. We found no difference in outcome between the bone graft groups before and after nine years of age. Similar findings have been shown in 2D studies where neither chronologic age nor root development of the canine significantly affected bone support of the canine (Boyarskiy et al., 2006). However, in a study on secondary alveolar bone grafting in bilateral cleft lip and palate, a greater number of failures occurred in the older age group (older than ten years of age; Bergland et al., 1986a). In a study on early results bone grafting in 106 alveolar clefts, the 100% suc- cess rate and the lower morbidity in the pre-teen group of patients fa- Vored operating on patients at the younger age. Late secondary grafting, usually done after the completion of maxillary growth and tertiary graft- ing following the failure of other grafts, have less successful outcomes due to an increased risk of impaired healing, resorption of the grafted bone and narrowing of the cleft width (Isono et al., 2002). There seems to be a consensus in the literature that early secondary alveolar bone grafting most reliably meets the standard requirement of success (Dempf et al., 2002; Kawakami et al., 2004; Duskova et al., 2007). We found no difference in outcomes between males and females. A previous study showed that females had a 3.79 times more likely chance of success than males (Aurouze et al., 2000). A statistically sig- nificant association (P = 0.0253) was found between the sex and success of the bone grafting surgery (Aurouze et al., 2000). None of the other studies found that sex was a variable in the rate of success of secondary alveolar bone grafting (Turvey et al., 1984; Bergland et al., 1986b). 406 Oberoi and Vargervik Several factors have been reported to influence directly the out- come of secondary alveolar bone grafting. These include dental hygiene and periodontal status (Keese and Schmelzle, 1995), width of the original cleft defect (Long et al., 1995) and origin of the bone graft (Long et al., 1995). Oral hygiene and periodontal status were well maintained pre- dominantly in our study sample. All bone graft material was obtained from the iliac crest. In our study, the size of the original defect did not influence the outcome. Our protocol included pre-surgical orthodontic expansion, thereby allowing approximation of wide cleft defects with a well-vascularized, tension-free gingival flap. Both surgeons also had many years of experience in performing the bone graft procedures. Among the several factors that influence the outcome of alveolar bone grafting, the absence of physiologic stress is an important one. A significantly lower resorption rate has been shown when the edentulous space is narrow (Schultze-Mosgau et al., 2003). In Feichtinger and col- leagues’ study (2008), the mean bone loss was 57% after one year, but two years later the residual bony bridges had increased in volume as a response to the erupting canine. Kearns and associates (1997) indicated that the longer the interval between bone grafting and implant placement, the greater the likelihood of alveolar bone resorption. Honma and co- workers (1999) showed that the volume of bone at one year was smaller significantly than at three months, indicating that bone formed in the cleft site decreases with time. This suggests that the grafted site should be restored with a functioning tooth soon after adequate formation of bone to prevent further bone resorption. We believe that the high success rate in our study was due to mesial eruption of the canines into the grafted alveolus in 80% of the cases. The most common eruption path of the canine was incisal, facial and mesial. A detailed study of the eruption path of the canine is underway. Our study may be the first to assess the eruption path of the ca- nine three dimensionally during a one-year period after secondary alveo- lar bone grafting using CBCT. Most prior studies on canine eruption have been based on 2D assessments using periapical and panoramic ra- diographs. A few studies have looked at canine position using conven- tional CT, but have not quantified the movement of the canine over time. The optimal timing of bone grafting has been debated for many years, but there now appears to be a consensus that the most successful outcome is seen when secondary alveolar bone grafting is undertaken between the ages of nine and eleven and the canine root development is 407 Alveolar Bone Grafting between one-half to one-third developed (Boyne and Sands, 1972; Tur- vey et al., 1984; Bergland et al., 1986a). Long and coworkers (1996) noted several studies suggesting decreasing bone graft success if the pro- cedure is performed after eruption of the permanent canine into the cleft site. Similarly, Tai and associates (2000) cite many previous studies which conclude that overall surgical success is improved if bone grafting is performed before canine eruption or when only two-thirds to three- fourths of the canine root is formed. We found no difference in canine eruption path between the younger (<9 years) and older (> 9 years) groups and between those who had canine root development above or below 50% in our sample. It is important to note that none of our patients had the crown of the canine broken through the cortical bone of the alveolar defect. Thus, the canine crown was not exposed during the procedure. Spontaneous canine eruption through the bone-grafted site has been reported to vary from 27% to 97% (Turvey et al., 1984; Enemarket al., 1985; Bergland et al., 1986a; Paulin et al., 1988; da Silva Filho et al., 2000; Hogan et al., 2003). Arch expansion before bone grafting allows for arch development and more room for spontaneous eruption of the canine. In our study, the risk for canine impaction was found in three clefts, or 12% as compared to the general population prevalence of 1% to 2%. This is lower than recent studies by Enemark and coworkers (2001) and Matsui and colleagues (2005) who reported rates for canine impac- tion in clefts at 35% and 18.9%, respectively. A recent study by Russell and McLeod (2008) showed a 20-fold anticipated increase in impaction over normal risk for canine impaction. They also found that the canine became more vertical with eruption through the bone graft in contrast to Gereltzul and associates (2005) who reported no change in angulation with eruption. In addition they reported a higher impaction rate on the non-cleft side as compared with the general population. Presence or absence and size and shape of the adjacent lateral incisor have been known to influence canine eruption (Bishara, 1992; Peck et al., 1994). Individuals with clefts have an increased number of lateral inci- sor anomalies that potentially may place them at a higher risk for canine impactions. In some studies, the risk for canine impaction was 1.5 to 2.0 times higher when the lateral incisor was missing, malformed or a super- numerary tooth was present. Gerultzul and associates’ study (2005) showed that the status of the lateral incisor had no effect. In our study, most canines on the cleft side erupted mesially and most of the lateral 408 Oberoi and Vargervik incisors were missing. Canine substitution was the preferred treatment plan whenever possible. In non-cleft individuals, the eruption path of the canine has been found to displace toward the occlusal plane, straighten gradually and de- viate toward a more vertical position (Tai et al., 2000; Gereltzul et al., 2005). In our study, we found that most of the non-cleft canines also moved incisally, facially and mesially. Most of the distal movement was seen on the non-cleft side in unilateral clefts. This could be attributed to presence of a lateral incisor on the non-cleft side, thereby allowing for a more vertical eruption path. CONCLUSION The one-year average bone loss of 16% was not influenced sig- nificantly by the size of the alveolar defect, type of cleft, root develop- ment stage of the canine, presence or absence of a lateral incisor and sur- geon. This is the first 3D study using CBCT to assess the eruption of the canine over a one-year period after secondary alveolar bone grafting. Most canines on both the cleft and non-cleft side moved incisally, fa- cially and mesially. Twelve percent of the canines on the cleft side needed surgical exposure, while the rest erupted spontaneously. The presence or absence of the lateral incisor did not affect the vertical erup- tion of the canine. The amount of root development did not affect the outcome in terms of canine eruption. Three-dimensional imaging using Dolphin 10.5 provides precise information on the eruption path of the canine through the grafted alveolar cleft. Alveolar bone grafting after orthodontic expansion and before eruption of the permanent canine crown into the defect allows a normal path of eruption of the canine, pre- dominantly without impaction, thereby enhancing alveolar bone devel- opment and facilitating orthodontic management. REFERENCES Arai Y, Tammisalo E, Iwai K, Hashimoto K, Shinoda K. Development of a compact computed tomographic apparatus for dental use. Den- tomaxillofac Radiol 1999:28:245–248. Aurouze C, Moller KT, Bevis RR, Rehm K, Rudney J. The presurgical status of the alveolar cleft and success of secondary bone grafting. Cleft Palate Craniofac J 2000:37: 179-184. 409 Alveolar Bone Grafting Bergland O, Semb G, Abyholm FE. Elimination of the residual alveolar cleft by secondary bone grafting and subsequent orthodontic treat- ment. Cleft Palate J 1986b;23: 175–205. 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Craniofacial skele- tal measurements based on computed tomography: Part II. Normal values and growth trends. Cleft Palate Craniofac J 1992:29:118-128. Walker L, Enciso R, Mah J. Three-dimensional localization of maxillary canines with cone-beam computed tomography. Am J Orthod Dento- facial Orthop 2005; 128:418-423. Witherow H, Cox S, Jones E, Carr R, Waterhouse N. A new scale to as- sess radiographic success of secondary alveolar bone grafts. Cleft Palate Craniofac J 2002:39:255-250. - 414 CONTROL MECHANISMS OF TONGUE POSTURE Takashi Ono ABSTRACT The tongue is a multifunctional organ with a variety of functions including in- gestive (e.g., sucking, mastication, Swallowing) and rejective (e.g., coughing, Vomiting) behaviors. Moreover, the tongue is involved in non-digestive func- tions including speech and respiration. Several studies have examined the neural mechanisms that control tongue posture. These include peripheral somatosen- sory inputs to hypoglossal motoneurons from the trigeminal, glossopharyngeal, superior laryngeal and hypoglossal nerves; central inputs from the cerebral cor- tex; and central pattern generators for mastication, swallowing and respiration. The control mechanisms of tongue posture in association with respiration, reflex and mastication are discussed herein. KEY WORDS: tongue, posture, respiration, reflex, mastication The tongue in primates is a large intraoral organ with highly complex morphology (Lowe, 1981). It consists of extrinsic and intrinsic muscles. The extrinsic muscles determine the robust posture of the tongue, including the geniohyoideus and hyoglossus muscles as well as the major retractor, the styloglossus (SG) muscle and the major pro- truder, the genioglossus (GG) muscle. The intrinsic muscles modify the local shape of the tongue. The motor function of the tongue is innervated by the hypoglossal (XII) nerve, while the sensory function is innervated by the lingual and glossopharyngeal nerves. A number of studies have addressed the neural mechanisms con- trolling tongue posture. These include: 1. Peripheral somatosensory inputs to XII motoneurons (Mns) from the trigeminal (V) nerve (Morimoto et al., 1972; Sumino and Nakamura, 1974; Takata and Tomomune, 1986); 415 Tongue Posture 2. The glossopharyngeal nerve (Duggan et al., 1973; Hunter and Porter, 1974); . The superior laryngeal nerve (Sumi, 1969); The XII nerve (Morimoto and Kawamura, 1972); 5. Central inputs from the cerebral cortex (Sumi 1970a; Lund and Dellow, 1973); and 6. Central pattern generators for respiration (Sica et al., 1984), mastication (Dellow and Lund, 1971) and de- glutition (Sumi 1970a,b; Travers and Jackson, 1992). : In this chapter, the control mechanisms of tongue posture in association with respiration, reflex and mastication are discussed. RESPIRATION Respiration is a fundamental tongue function. Although respira- tory-related rhythmical activity has been reported in some XII motoneu- rons (Withington-Wray et al., 1988), the location of excitatory premotor neurons directly projecting to XII motoneurons that show respiratory- related rhythmical activity currently is unknown. It was demonstrated recently that medullary inspiratory neurons that projected to the spinal cord had axon collaterals projecting to Vagal (X) motoneurons innervating accessory respiratory muscles (Ezure and Manabe, 1989). In addition, some axon collaterals of these neurons were found in the vicinity of the XII nucleus (Sasaki et al., 1989). With regard to central mechanisms controlling the respiratory-related XII motoneuron activity, these reports strongly suggest the existence of respiratory neu- rons that possess bifurcating axons projecting to XII motoneurons as well as to spinal respiratory motoneurons, including phrenic (PH) motoneurons. Takada and colleagues (1984) found horseradish peroxidase (HRP)-labeled neurons bilaterally in the parvocellular reticular formation and reticular regions around the XII nucleus after HRP injection into the XII nucleus of the cat. On the other hand, when HRP was injected into the PH nucleus, retrograde labeled cells were seen bilaterally with a con- tralateral dominance in the region ventrolateral to the tractus solitarius (vl-NTS), the region dorsomedial to the nucleus ambiguus (dm-AMB) and the parvocellular reticular formation (Rikard-Bell et al., 1984). These results indicate that, in the medullary reticular formation, includ- ing the regions around the XII nucleus and the nucleus ambiguus, there may be respiratory neurons that project to the XII nucleus directly. A portion of these also might project to the PH nucleus with bifurcating 416 Ono axons. Such neurons with bifurcating axons, however, have not been found in previous studies. Thus, we performed histological and electro- physiological studies in cats (Ono et al., 1994). The first experiments were carried out in cats. In the first part of the study, the retrograde double-labeling technique revealed the exis- tence of neurons projecting to both the XII and the PH nuclei. Injection of a fluorescent dye (fast blue, FB) into the XII nucleus and another (nu- clear yellow, NY) into the PH nucleus led to retrograde labelling of me- dullary reticular neurons mainly in the regions Vl-NTS, ventrolateral to the hypoglossal nucleus (Vl-XII) and dm-AMB bilaterally (Fig. 1). In addition, some neurons in these regions were labeled with both FB and NY. In this animal, 129 FB-labeled neurons were found, 57 on the ipsi- lateral and 72 on the contralateral sides. A total of 62 NY-labeled neu- rons were found, 25 on the ipsilateral and 37 on the contralateral sides. Seven neurons were double labeled, one on the ipsilateral and six on the contralateral sides. Thus all three types of neuron were found to have a contralateral dominance. Despite the injection of a relatively small volume, the spread of fluorescent dye was seen outside the XII and PH nuclei. Although retro- gradely labeled neurons with one or both fluorescent dyes were found throughout the brainstem, they were clustered most densely in two dis- tinct regions (Fig. 1): the Vl-NTS and Vl-XII region, and the the dm- AMB region. In these two regions, neurons were found which were dou- ble-labeled with FB and NY. In the second part of the study, firing activity was recorded from medullary respiratory neurons. In the regions vl-NTS, vl-XII and dm- AMB, inspiratory neurons were found which responded to stimulation of the XII nucleus. Figure 2 illustrates one of 33 inspiratory neurons that responded to stimulation of the XII nucleus but not to stimulation of the PH nu- cleus. This neuron, in the right dm-AMB region, showed a rhythmical burst activity (Fig. 2A,BI) synchronous with rhythmical discharges in the XII and PH nerves (Fig. 2A, B2-3), indicating that it is an inspiratory neu- ron. It responded to stimulation of the left XII nucleus with spike poten- tials after a fixed latency of 0.6 milliseconds (ms; Fig. 2C1), which showed a collision with its spontaneous spikes (Fig. 2C2). Thus, the neu- ron was assumed to be a possible pre-motor neuron projecting to XII Mns, which show a respiratory-related rhythmical activity. Averaging the rectified and integrated discharges of both the XII and the PH nerves by 4.17 Tongue Posture 2mm Figure 1. Schematic illustration of transverse sections of the medulla, from an animal, indicating the location of neurons labeled with fluorescent dyes. Each section includes cell bodies from five consecutive histological slices. Circles: fast blue (FB)-labeled neurons; triangles: nuclear yellow (NY)-labeled neurons; stars, double-labeled neurons with FB and NY. Hatching: site of FB injection into the left hypoglossal nucleus; Stippling: site of NY injection into the left phrenic nucleus. Abbreviations: AMB = nucleus ambiguus; BC = brachium con- junctivum; DM = dorsal motor nucleus of the vagus; IO = inferior olivary nu- cleus; LLV = ventral nucleus of the lateral lemniscus; PR = nucleus prepositus hypoglossi; RFN = retrofacial nucleus; S = solitary tract; TB = trapezoid body; TRC = tegmental reticular nucleus, central division; VLD = lateral vestibular nucleus, dorsal division; VMN = medial vestibular nucleus; 5SP = spinal tri- geminal nucleus; 5ST = spinal trigeminal tract; 7 = facial nucleus; 12, = hypo- glossal nucleus. (Printed with permission, Ono et al., 1994.) spontaneous spikes of this inspiratory neuron revealed facilitation in the XII nerve discharge after 1.9 ms from the negative deflection of spikes of the inspiratory neuron (Fig. 2D2, upward arrow), but no facilitation in the PH nerve discharge (Fig. 2D3). The peak of the facilitation was 43% greater than the mean control level of rectified and integrated discharge for 1.0 ms immediately preceding the triggering spikes. 418 Ono 2 – - __ _ - |200|y C 1 | 3 –- * * * * * *— 2 |200|V 2ms 4 – A / / / / / / / / / / / / / 5s ſº D 1 --- |200|y 2 al 3 2 5cmH20 | - 2s 2ms Figure 2. Patterns of discharge and projection of a respiratory neuron. A. Simul- taneous record of extracellular spikes of a respiratory neuron (1), rectified and integrated hypoglossal (XII) nerve discharge (2), rectified and integrated phrenic (PH) nerve discharge (3) and tracheal pressure (4). B: A portion of A (under- lined) displayed on an expanded time base. C. (1) Fixed short-latency response of the respiratory neuron to stimulation of the contralateral XII nucleus (1.54 HZ, 0.1 ms, 40 mA); (2) collision of the spike with a spontaneous spike. D: Av- erage of integrated discharges of XII and PH nerves by spontaneous spikes of the neuron shown in A-C. Note facilitation in the XII nerve, but not in the PH nerve after a short latency (1) triggering spike; (2) XII nerve discharge; (3) PH nerve discharge. Traces 1-3 were obtained simultaneously by averaging 2000 traces. In this and following figures, negative deflection of single spikes is shown; downward and upward arrows indicate the onset of the increase in nerve activity. (Printed with permission, Ono et al., 1994.) - Figure 3 shows one of nine inspiratory neurons which antidromi- cally responded to stimulation of both the XII and the PH nuclei. This neuron was found in the right dm-AMB region and showed a burst activ- ity (Fig. 3A, B1) coincident with rhythmical bursts in the XII and PH nerves (Fig. 3A, B2-3). It responded with spike potentials after fixed short latencies of 0.4 ms to stimulation of the left XII nucleus (Fig. 3CI) and 1.4 ms to stimulation of the left PH nucleus (Fig. 3C2). The neuron re- Sponded with spikes to stimulation of the two nuclei when the interval of Stimulation was 2.0 ms or longer (Fig. 3D1, downward arrow). In con- trast, at intervals shorter than 2.0 ms, the spike potential evoked by Stimulation of the PH nucleus collided with the spike potential evoked by Stimulation of the XII nucleus (Fig. 3D2, downward arrow). Averaging the rectified and integrated discharges in the XII and PH nerves by 419 Tongue Posture fºL. R. L.L.I. wim º º º t - \- ~ | D 1 | | | 3 _____-_-_- 2 –– | 2 –H |200|W 5cmH20 - 2ms 4 A / / / / / / / / / / / / [. | B 1 − |200pw E 1 º |200|V 2s 2ms Figure 3. Patterns of discharge and projection of a respiratory neuron. The for- mat of A, B, E is the same as in A, B, D in Figure 2, respectively. C: Fixed short- latency responses of the respiratory neuron to stimulation of: (1) the contralat- eral XII nucleus (1.54 Hz, 0.1 ms, 17 mA); and (2) the contralateral PH nucleus (1.54 Hz, 0.1 ms, 40 mA). D. Collision of spikes evoked by stimulation of the PH nucleus (downward arrows) with preceding spikes evoked by stimulation of the XII nucleus. Intervals between stimulation of the XII and PH nuclei are 2.0 ms (1) and 1.0 ms (2). In E, note facilitation in the XII and PH nerve discharges after short latencies (upward arrows; printed with permission, Ono et al., 1994). spontaneous spike discharges of this neuron (Fig. 3 FI) revealed a 72% facilitation after a latency of 1.9 ms in the discharge of the XII nerve, while a 42% facilitation after a latency of 2.6 ms in the discharge of the PH nerve compared with the mean level of respective nerve discharges for 10 ms immediately preceding the triggering spike (Fig. 3 E2-3, up- ward arrows). The spike-triggered averaging technique revealed a prominent peak in the discharge of the XII nerve in 27 of 33 neurons which responded to stimulation of the XII nucleus and in the discharge of the XII and PH nerves in seven of nine neurons that responded to stimu- lation of both the XII and the PH nuclei. Of the 27 neurons, two and 25 neurons were activated antidromically by stimulation of the ipsilateral and contralateral XII nucleus, respectively. Likewise, of the Seven neut rons, one and six neurons were activated antidromically from the XII and PH nuclei on the ipsilateral and contralateral sides, respectively. The fa- cilitation in the XII nerve discharge started 1.5 to 2.0 ms (n = 27) after 420 Ono the triggering spikes in the former group of neurons, while the latencies of facilitation of the XII and PH nerve discharges were 1.7 to 2.3 ms and 2.2 to 2.7 ms (n = 7), respectively, after spikes of the latter group of neu- TOITS. From these findings, it was concluded that there are inspiratory neurons in the Vl-NTS and dm-AMB regions that are excitatory pre- motor neurons projecting to XII Mns showing the respiratory-related ac- tivity. Some of them have excitatory synaptic connections to XII and PH Mns via bifurcating axons. Despite the need for further study on behavior of two types of inspiratory, neurons, the presence of dual projection neu- rons and coupled activity between XII and PH Mns emphasizes a dual functional role of the tongue. In addition to its contribution to speech and mastication, it clearly plays an important part, in close harmony with diaphragmatic contraction, in the maintenance of a patent airway. Since the XII Mns show the respiratory-related activity, the tongue pressure at the mandibular incisors may change with respiration. Thus, we investigated whether the tongue pressure was dependent on the respiratory mode in ten healthy adults (Takahashi et al., 1999). Pressure from the tongue on the lingual surface of the lower anterior teeth was measured with a pressure sensor (PS-A type, Kyowa Co., Tokyo, Japan) incorporated in a lingual flange of a custom-made intraoral appliance (Fig. 4) made of silicon rubber impression paste (Exafine putty type, GC Co., Tokyo, Japan). The GG muscle showed a phasic activity during in- spiration (Fig. 5). The tongue pressure also showed a similar cyclic oscil- lation. The maximum tongue pressure in different breathing modes and body positions is illustrated in Figure 6. Significant differences were found between nasal breathing in the upright position and both oral breathing in the upright position (P<0.01) and oral breathing in the su- pine position (P<0.01). Significant differences also were found between oral breathing in the upright and supine positions (P<0.01) and between nasal and oral breathing in the supine position (P º 0.01). Thus, the maximum tongue pressure during oral breathing was greater significantly than that during nasal breathing in either body position. In addition, changes in body position had a significant effect on the maximum tongue pressure during oral breathing. We speculated, therefore, that during na- Sal respiration, the inspiratory drive slightly activates the GG muscle, whereas the GG muscle was activated during oral respiration considera- bly. 421 Tongue Posture Figure 4. Occlusal view of a custom pressure-recording appliance on a plaster model. Thickness of the appliance at pressure sensor is ap- proximately 1 mm. Arrow indicates surface of pressure sensor. (Printed with permission, Takahashi et al., 1999.) insp exp As vº f / \ } C – \\ ºf #4 time lag Figure 5. A. Typical simultaneous recording of chest wall movement. B. GG EMG activity. C. Integrated GG EMG activity. D: Tongue pressure on lingual surface of mandibular incisors in supine subject during oral breathing. Vertical bar represents 50 mV for raw GG EMG activity and 5 g/cmº for tongue pressure (insp = inspira: tion; exp = expiration; printed with permission, Takahashi et al., 1999). 422 Ono g/cm’ 12. 8. 4. olm- -----> --> ºf . - :::::::::::::::::::::::::::::::: - UPNB UPOB SUPNB SUPOB * | L ºr *: rººk | º: Figure 6. Comparisons of maximum tongue pressure among different breathing modes and body positions. UPNB = nasal breathing in the upright position; UPOB = oral breathing in the upright position; SUPNB = nasal breathing in the Supine position; SUPOB = oral breathing in the supine position. ** P × 0.01. (Printed with permission, Takahashi et al., 1999.) Numerous studies have focused on aberrant function of the ex- trinsic tongue muscles, especially the GG muscle, since abnormal activ- ity of this muscle contributes to snoring and obstructive sleep apnea (OSA). Both in experimental animals and humans the GG shows rhyth- mic activity in pace with respiration as well as tonic activity during tongue protrusion (Isono and Remmers, 1994). Some GG fibers run per- pendicular to the pharynx, therefore, activation of these fibers may result in both advancement of the base of the tongue and enlargement of the upper airway (UA) space. Previous physiological studies have shown that the muscle fibers of UA dilator muscles have faster contractile prop- erties and less resistance to fatigue than the diaphragm (Lowe, 1981; Van Lunteren et al., 1990). In addition, the GG contains type I, type IIa and type IIb fibers (Van Lunteren and Manubay, 1992; Bracher et al., 1997). It is not clear yet, however, which type of motor unit is responsible for the respiratory-related activity of the GG. 423 Tongue Posture It recently has been shown that there are at least two types of motor unit with respiratory-related activity in the human GG (Tsuiki et al., 1998): inspiratory motor units (IMUs), which show phasic firing dur- ing inspiration; and inspiratory/expiratory motor units (IEMUs), which fire during both inspiration and expiration, with a greater instantaneous firing frequency during inspiration. The different patterns of firing activ- ity indicate that these two types of motor unit play different physiologi- cal roles with regard to the respiratory/related control of tongue move- ment, but it is unclear whether the IMUs and IEMUs are heterogeneous. It is possible that the IMUs and IEMUs are homogeneous and their firing patterns are controlled differentially under unknown conditions. Thus, we investigated whether the IMUs and IEMUs were heterogeneous to determine whether there was functional divergence between these two types of motor units with respiratory-related activity (Tsuiki et al., 2000). A total of 24 GG motor units (12 IMUs and 12 IEMUs) record- ings were made. Figure 7 shows a representative record of the firing ac- tivities of IMUs and IEMUs in the natural head position. Figure 7A shows the typical firing activity of one of the 12 IMUs, which started firing 24.3 + 149.8 ms (mean + SD) before the onset of inspiratory air- flow. This IMU showed firing activity primarily during inspiration with a mean instantaneous firing frequency (IFF) of 14.4 + 4.1 Hz. Figure 7B shows the typical firing activity of one of the 12 IEMUs, whose IFF dur- ing inspiration (15.3 + 2.3 Hz) was greater significantly than that during expiration (10.8 + 2.5 Hz). Figure 8 shows representative changes in the IFF of an IMU and an IEMU in response to gradual changes in head po- sition. This IMU/IEMU pair was recorded simultaneously. The IMU showed a marked increase in IFF during inspiration when the head was tilted dorsally 15° and 30°. In the head-up position, the firing duration of the IMU extended to the expiratory phase immediately before and after the inspiratory phase when the head was dorsally tilted 15°, which resulted in an increase in the IFF during expiration. The IFF during expiration further increased in the 30° head-up position. Conversely, the IFF of the IMU markedly decreased during both inspiration and expiration when the head was tilted ventrally. The firing activity of the IMU almost ceased in the 30° head-down position. The change in the IFF of the IMU in response to gradual changes in head position followed a sigmoid curve. Seven of the 12 IMUs exam- ined showed this pattern of change in the IFF in response to gradual changes in head position. In contrast, the IFF of the IEMU gradually in- 424 Ono = . . />Jº-Jº Jºv > 4 O |l V †††† I ºw ". lº W *. A 2S C 5 mS *Tºlº * B 2 S D Figure 7. A and B: Typical firing activities of an inspiratory motor unit (IMU). C and D. An inspiratory/expiratory motor unit (IEMU). B: Superimposed spikes of the IMU shown in A. D. Superimposed spikes of the IEMU shown in C (twenty Sweeps are superimposed in B and D. V' = nasal airflow; insp = inspiration; exp = expiration; IFF = instantaneous firing frequency (bin width 200 ms; printed With permission, Tsuiki et al., 2000). - En XS pp IJ # : creased during both inspiration and expiration when the head was tilted dorsally. Conversely, the IFF of the IEMU gradually decreased during both inspiration and expiration when the head was tilted ventrally. In the 30° head-down position, the IEMU still showed firing activity. The change in the IFF of the IEMU was linear in response to gradual changes in head position. All 12 of the IEMUs examined showed this pattern of change in the IFF in response to gradual changes in head position. The firing activity of the IMU and the IEMU in the 30° head-down position may provide insight into their divergent functional roles. In the 30° head- down position, the firing activity of IMUs almost ceased, whereas IEMUs remained active (Fig. 8). 425 Tongue Posture Interestingly, IMUs became silent in the 30° head-down position even during inspiration, whereas IEMUs maintained the same rate of fir- ing activity during inspiration and expiration, regardless of head position. This suggests that IMUs and IEMUs are driven by different inputs. Gravitational pull in the head-down position would induce anterior dis- placement of the tongue, which would result in enlargement of the UA. Thus, it is assumed that IMUs are controlled mainly by commands from the central rhythm generator for respiration, whereas IEMUs are con- trolled mainly by peripheral feedback. This is consistent with previous studies in paralyzed animals (Withington-Wray et al., 1988; Ono et al., 1994, 1998b), which showed that neither XII Mns nor their pre-motor neurons exhibited respiratory-related activity, which is analogous to the firing activity of IEMUs in the present study. Although further studies are required on the input/output rela- tionship in inspiratory and inspiratory/expiratory motor units, it appears that the respiratory-related activity of inspiratory motor units phasically may counteract the intraluminal negative pressure during inspiration. Conversely, the respiratory-related activity of inspiratory/expiratory mo- tor units tonically may maintain tongue posture; otherwise the tongue would tend to collapse into the upper airway and jeopardize normal respira- tory function, as occurs in patients with OSA (Isono and Remmers, 1994). REFLEX The tongue position is known to be controlled reflexively by the jaw position. Moreover, it is known that the activity of extrinsic tongue muscles including the GG (primary protruding muscle) and SG (primary retracting muscle) muscles has an impact on the tongue position (jaw- tongue reflex; JTR). Subsequently, Blom (1960) found electromyog- raphic (EMG) activity of the GG and SG muscles in association with tongue retraction. On the other hand, tongue protrusion was observed by jaw opening in the cat and monkey (Lowe 1978a,b). As the receptors responsible for eliciting this reflex, afferents from the temporomandibular joint (TMJ) and the jaw-closing muscle have been postulated. Lowe and Sessle (1973) proposed that the TMJ afferents might exert a profound influence on the JTR, since they ob- served that the GG EMG activity elicited by jaw opening was abolished reversibly by bilateral infiltration of local anesthetic into the TMJ region. In contrast, Morimoto and coworkers (1978) reported that neither sec- tioning of the masseter nerve nor anesthesia of the TMJ capsule affected 426 Ono 30– : —— I T -30 -15 0 15 30 Head position 9 tilt Figure 8. Representative changes in the instantaneous firing frequencies (IFFs) of an inspiratory motor unit (IMU) and an inspiratory/expiratory motor unit (IEMU) in response to gradual changes in head position. The firing activities of the IMU and IEMU were recorded simultaneously. Head position was changed gradually between the 308 head-up and 308 head-down positions. The IFF was calculated for both the IMU and IEMU in each head position. Filled circles = IMU during inspiration; open circles = IMU during expiration; filled triangles = IEMU during inspiration; open triangles = IEMU during expiration. (Printed with permission, Tsuiki et al., 2000.) the tongue EMG activities. They assumed that the JTR was elicited mainly by the proprioceptors in the temporalis (TEMP) muscle, which appeared to be the Golgi tendon organs and the secondary endings of the muscle spindle rather than the primary endings. Effects of stimulation of the lingual (Morimoto et al., 1968; Sumino and Nakamura, 1974), mas- seter (Morimoto et al., 1972), XII (Morimoto and Kawamura, 1972) and glossopharyngeal (Duggan et al., 1973) nerves were reported to induce both an inhibitory post-synaptic potential (IPSP; Morimoto et al., 1968, 1972; Morimoto and Kawamura, 1972; Duggan et al., 1973) and an exci- tatory post-synaptic potential (EPSP)-IPSP sequence (Morimoto et al., 1968; Duggan et al., 1973) in XII Mns. Since the TEMP muscle plays an important role in determination of the mandibular position as the Syner- gist of the masseter muscle, the TEMP muscle afferents may exert simi- lar effects on XII Mns. However, no intracellular studies of effects of 427 Tongue Posture TEMP muscle afferents on XII Mns have been reported so far. Thus, we analyzed the JTR in terms of afferents, central pathway and patterns of intracellular responses of XII Mns to the TEMP muscle afferents evoked by mechanical stimulation of the muscle as well as by electrical stimula- tion of the TEMP muscle nerve (NTEMP) in the cat (Ishiwata et al., 2000). Figure 9A illustrates the nature of the depolarizing potential evoked in an antidromically identified protruding Mn (Fig. 9A1) by stimulation of the NTEMP. The amplitude of the depolarizing potential was increased by injection of hyperpolarizing currents and decreased by depolarizing currents (Fig. 9A1). The amplitude of the depolarizing po- tential correlated linearly with the intensity of the injected current (Fig. 9A2), showing that the main part of the depolarizing potential consisted of EPSPs. The mean latencies of the EPSPs evoked by single shocks at the intensity of five times the threshold (5.0 x T.) were 5.4 ms in protrud- ing Mns (range, 3.6 to 7.3 ms) and 5.1 ms in retracting Mns (range, 3.9 to 6.1 ms), respectively. There was no significant difference in the mean latency between protruding and retracting Mns. Figure 9B shows the na- ture of the hyperpolarizing potential evoked in an antidromically identi- fied retracting Mn (Fig. 9B3) by stimulation of the NTEMP. The ampli- tude of the hyperpolarizing potential was increased and decreased by injection of depolarizing and hyperpolarizing currents, respectively (Fig. 9B1), and correlated linearly with the intensity of the injected current (Fig. 9B2). Thus, the main part of this hyperpolarizing potential con- sisted of IPSPs. The mean latencies of the IPSPs evoked by single shocks at 5.0 x T in intensity were 7.6 ms in protruding Mns (range, 5.4 to 11.6 ms) and 8.2 ms in retracting Mns (range, 5.8 to 10.8 ms), respectively. There was no significant difference in the mean latency between protrud- ing and retracting Mns. EPSPs were evoked in 17 protruding Mns and four retracting Mns, while IPSPs were evoked in 21 protruding Mns and seven retracting Mns. There was no significant difference in the inci- dence of EPSPs and IPSPs between the two groups of XII Mns. How- ever, the latencies of the IPSPs were significantly longer than those of the EPSPS. Intracellular responses to pressure stimulation of the TEMP muscle were tested on seven protruding and four retracting Mns on the ipsilateral side. Punctate light pressure applied by a probe to the middle of the belly of the TEMP muscle evoked spike potentials superimposed on a tonic depolarization in a retracting Mn (Fig. 9C1). Depolarizing synaptic activation noise increased when superimposed on the tonic de- polarizing potential (Fig. 9C3) compared with the period before pressure 428 Ono 20mV º HTT ºl- WºlfºNºwWºw. ~~~ .."w M |20mv b Tsº 3 . *~!- 50ms Wºr Figure 9. Synaptic potentials in a (A) protruding and a (B) retracting motoneuron evoked by stimulation of the ipsilateral temporalis muscle nerve and those evoked by mechanical stimulation of the (C) ipsilateral temporalis muscle. A 1: Effects of intracellular current injection on the depolarizing potentials evoked by single shocks at the intensity of five times the threshold (0.1 ms, 7.5 V). A2: Relation between the intensity of intracellularly applied currents (abscissa) and amplitude of depolarizing potentials (ordinate). A3: Antidromic spike potentials evoked by stimulation (0.1 ms, 2.0 V) of the medial branch of the ipsilateral hypoglossal nerve; three sweeps are Superimposed. B1: Effects of intracellular current injection on the hyperpolarizing potentials evoked by single shocks at the intensity of five times the threshold (0.1 ms, 6.5 V). B2: Relation between the intensity of intracellularly applied currents (abscissa) and amplitude of hyperpolarizing potentials (ordinate). B3: Antidromic Spike potentials evoked by stimulation (0.1 ms, 4.0 V) of the lateral branch of the ipsilateral hypoglossal nerve; three sweeps are superimposed. In A1 and B1, each trace represents an averaged record of ten sweeps. Numerals on the left indicate the intensities of applied currents in nA, with plus and minus signs showing depolarizing and hyperpolarizing currents, respectively. In A2 and B2, plus and minus signs show depolarizing and hyperpolarizing currents (abscissa) or potentials (ordinate), respec- tively. Straight lines are regression lines drawn by the least-squares method. C1: Tonic depolarizing potential Superimposed by Spike potentials and depolarizing Syn- aptic activation noise in a retracting motoneuron induced by light pressure applied on the belly of the ipsilateral temporalis muscle; left and right arrows indicate the onset and offset of application of pressure, respectively. The resting interincisal dis- tance was fixed at 20 mm. C2 and C3; Records of parts of C1 marked by lines des- ignated b and c, with a faster sweep speed and higher gain. (Printed with permis- Sion, Ishiwata et al., 2000). 429 Tongue Posture application (Fig. 9C2). Similar synaptic responses were found in three protruding Mns and one retracting Mn. Neither EPSP nor IPSP was evoked in XII Mns by single-shock stimulation of the NTEMP at 2.0 x T or lower intensities, except for one protruding Mn and one retracting Mn, in which a small EPSP and IPSP, respectively, were evoked at 2.0 x T. The threshold for evoking synaptic potentials in all the other XII Mns was 2.5 x T (Figs. 10A1, B1). Figures 10A2 and 10B2 illustrate the rela- tionship between stimulus intensity and the amplitudes of EPSPs and retracting Mns. The amplitude increased with an increase in intensity from 2.5 to 5.0 x T., at which the amplitude reached the maximum. These results suggested that the group II fibers of muscle spindle origin were involved mainly in the JTR. The TEMP muscle has the greatest number of muscle spindles among the jaw-closing muscles (Kubota et al., 1974; Lund et al., 1978). Since the secondary endings of the muscle spindle mainly encode the muscle length (Matthews, 1981), the JTR would be involved deeply in regulation of the tongue muscle activity by the posi- tion of the mandible. In addition, since the spindle group II afferents from the TEMP muscle evoke IPSPs as well as EPSPs in both protruding and retracting Mns, these afferents may exert inhibitory as well as excita- tory effects on the XII Mns innervating the GG, SG or other tongue mus- cles, including the intrinsic muscles. An absence of the JTR may be related to aberrant function of the GG muscle in patients with anterior openbite (Lowe and Johnston, 1979). Thus, the JTR would play an important role in the control of tongue posture through an intricate combination of these excitatory and inhibi- tory effects on different extrinsic and intrinsic tongue muscles in animals and humans (Ishiwata et al., 1997). If the peripheral afferent is disturbed, what happens to the reflex- ive controlling system of the tongue posture? This may happen in sub- jects who breathe through the mouth (i.e., oral respiration) since the neu- romuscular system for controlling the jaw-closing muscle is modulated. We hypothesized that the EMG activity of the jaw-closing muscles changes immediately in association with an altered respiratory mode from the nasal to the oral passage. We used the masseteric static stretch reflex to determine the levels of jaw closing muscle activity during oral and nasal respiration. We also discussed the putative mechanism under- lying this neuromuscular adaptation to the altered respiratory mode. The masseteric stretch reflex, which is analogous to the spinal reflex in the spinal cord, has been identified in the craniofacial region. The central axonal terminals of the neurons in the V mesencephalic nucleus (Mes\V) 430 Ono 15+------- |2mv 0 XT 10ms 1 2 3 4 5 A a B Figure 10. Intensity-response relationship of (A) EPSPs and (B) IPSPs in hypo- glossal motoneurons evoked by stimulation of the ipsilateral temporalis muscle nerve. A 1: EPSPs evoked in a protruding motoneuron by single shocks at inten- sities shown by multiples of the nerve threshold (xT) on the left. A2: Diagram of intensity-response relationship of EPSPs. B1; IPSPs evoked in a retracting mo- toneuron by single shocks at intensities shown by multiples of the nerve thresh- old (XT) on the left. B2: Diagram of intensity-response relationship of IPSPs. In A2 and B1, each trace is an averaged record of ten sweeps. In A2 and B2, both Sets of data were obtained from two protruding motoneurons (circles) and two retracting motoneurons (stars). Abscissa = stimulus intensity in xT; ordinate = amplitude of (A2) EPSPs and (B2) IPSPs in percent of that evoked at the inten- sity of ten times the threshold. (Printed with permission, Ishiwata et al., 2000.) provide monosynaptic projection onto V Mns (Szenta'gothai, 1948). Thus, an afferent impulse from masseteric muscle spindles provides exci- tatory input to V Mns and this reflex arc plays an important role in con- trolling mandibular position. Because MesV neurons monosynaptically project to masseteric Mns, the changes in the amplitude of masseteric EMG activity elicited by electrical stimulation of the Mes W in response to external disturbance can be measured to evaluate the excitatory level of masseteric Mns. Thus, we investigated whether the EMG activity of the jaw-closing muscles changes immediately in association with an al- tered respiratory mode from the nasal to the oral passage (Ono et al., 1998a). Changes in the masseteric and diaphragm EMG activities during oral respiration are shown in Figure 11. As the respiratory mode changed from the nasal to the oral airway, a significant change was seen in masse- teric EMG activity. Masseteric EMG activity gradually decreased nearly to the tonic level before the masseteric stretch reflex was elicited; tonic masseteric EMG activity disappeared and phasic EMG activity remained in the expiratory phase. On the other hand, diaphragm EMG activity 431 Tongue Posture showed an abrupt burst. However, the succeeding diaphragm EMG activ- ity was nearly equal to that before the change in the respiratory mode. When the nasal airway was reopened, tonic masseteric EMG activity in- creased to the same level as before the nasal airway was obstructed, whereas diaphragm EMG activity was not affected by the change in the respiratory mode. When passive jaw opening was discontinued, masse- teric EMG activity decreased to the level before the masseteric stretch reflex was elicited, whereas no significant change was observed in dia- phragm EMG activity. Changes in the amplitude of the masseteric monosynaptic reflex elicited by electrical stimulation of MesV during oral respiration are shown in Figure 12. Obstruction of the nasal airway reduced masseteric EMG activity and reopening of the nasal airway elicited recovery of masseteric EMG activity, whereas no significant changes were observed in diaphragm EMG activity during this procedure (Fig. 12A). Further- more, no significant changes were observed in the amplitude of the mas- seteric monosynaptic reflex during oral respiration (Fig. 12B). Indeed, averaging of the masseteric monosynaptic reflex revealed no significant difference in the amplitude before, during and after oral respiration (Fig. 12C). Evidences suggested that the excitability of the masseteric alpha- Mns did not change significantly. Rather, inhibition of the masseteric gamma-Mns is more likely. The inhibition of the gamma-system may decrease the sensitivity of the muscle spindle in the jaw-closing muscles, resulting in the inhibition of the jaw-tongue reflex, which is important in controlling the tongue posture. MASTICATION The human tongue is an essential component of several precisely coordinated movements such as mastication. Penfield and Boldrey (1937) used electrical stimulation to examine the somatotopic representa- tion of the tongue in the cerebral cortex of epileptic patients and demon- strated that the tongue was represented bilaterally in the inferior region of the motor cortex. This area mediates the voluntary control of tongue movement via corticobulbar fibers, which finally impinge on the XII nu- cleus (Kuypers, 1958). Later, electrical stimulation of the cortical motor area in the rat was shown to evoke tongue movements associated with licking, chewing and swallowing (Kaku, 1984). Neurons in the primary motor cortex (M1) fired in relation to tongue movements in monkeys (Murray and Sessle, 1992). However, only limited information is available 432 Ono MASS “ |100py : l i. - DIA HºHº *}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}||500py if it mºnº in nº Tº Hill ºf Mº Hil'ºïlºſiſ; tı'Hºſ'. " | º " . it tº T Fi 'i | ** A " wº-wº ſMASS ſº- *WWWW B TDs Figure 11. Masseteric EMG activity before, during and after oral respiration. Down and up arrows indicate onset and offset of oral respiration, respectively. The masseteric stretch reflex was elicited by opening the jaw. A. Simultaneous record of masseteric and diaphragmatic EMG activities and nasal airflow. B: Same record as in A. The masseteric and diaphragmatic EMG activities are full- wave rectified and integrated. MASS = masseteric EMG activity; DIA = dia- phragmatic EMG activity; NA = nasal airflow; ſ/ASS = rectified and integrated masseteric EMG activity; ſpIA = rectified and integrated diaphragmatic EMG activity. (Printed with permission, Ono et al., 1998a.) on the cortical area that is activated during various kinds of Voluntary tongue movement in humans. Recently, brain activation during tongue protrusion was found to be bilateral in the sensorimotor cortex (S.1/M1), cerebellum, Supplementary motor area, operculum, insula, putamen and thalamus (Corfield et al., 1999). However, it is unclear whether lateral excursion of the tongue is associated with unilateral focal activation of the brain. Therefore, the current body of knowledge regarding the corti- cal control of tongue movement does not permit a definite description of the hemispheric lateralization during voluntary tongue movements. On the other hand, it has been reported that unilateral chewing occurs in 70% of consecutive masticatory cycles (Wictorin et al., 1971). A chew- ing-side preference, which is a preference for one side of the dentition Where mastication is performed consistently and predominantly, is hy- pothesized to be an expression of motivational and/or sensorimotor be- havior in humans (Helkimo et al., 1978; Christensen and Radue, 1985; Pond et al., 1986). Recently, Mioche and colleagues (2002) performed a Videofluorographic study of the intraoral management of food in humans. 433 Tongue Posture MASS DIA A | || ! !!! -- - | || |500w | ºf m n m ºn º m ºf I * ºn ºf | Tº º- ſMASS —ſM- ~~~~~~…~ A 10S | | |H|| ill|||||||||||||| ||||||||||||||||| || || || Mass H H |200px| • 1 2 3 2 DA H a tº dº | r HHH ºn wº | | | |500py 3 |100py - ni | || . 5ms * *-*. C 10s Figure 12. Effects of oral respiration on masseteric monosynaptic reflex. A. Si- multaneous record of masseteric and diaphragmatic EMG activities and nasal airflow. B. Simultaneous record of the masseteric monosynaptic reflex, dia- phragmatic EMG activity and nasal airflow. C. Changes in the amplitude of the masseteric monosynaptic reflex shown in: B1, before; B2, during; and B3, after oral respiration. Down and up arrows indicate onset and offset of oral respira- tion, respectively. MASS = masseteric EMG activity; DIA = diaphragmatic EMG activity; NA = nasal airflow; ſ/ASS = rectified and integrated masseteric EMG activity. (Printed with permission, Ono et al., 1998a.) They found that 66% of chewing occurred on one side only and the food Sample was replaced on either occlusal table by a combination of alter- nate tongue- and cheek-pushing movements during the unilateral chew- ing cycle (Mioche et al., 2002). However, little is known about whether the chewing-side preference is associated with tongue movement. Thus, We tried to: 1. Identify cortical areas responsible for producing vari- ous tongue movements, including lateral excursion of the tongue, by using functional magnetic resonance imaging (fMRI); and 434 Ono 2. Determine their relationship to the individual chew- ing-side preference in 15 normal volunteers (Shina- gawa et al., 2003). Tongue movements (TR = lateral movement to the right; TL = lateral movement to the left; TE = tongue protrusion) were designed to produce minimal or no displacement of the tongue or jaw to minimize artifacts due to movement of the orofacial area on acquired MRI. All of the subjects were trained to perform tongue movements with visual feed- back consisting of EMG activities of orofacial muscles before fMRI data acquisition. In this study, Statistical comparisons were made, first for the group and for each subject, which identified regions that significantly had increased activations during tongue movements relative to the “rest” condition. We used subtraction in the following comparisons: 1. TF1R L (i.e., the sum of Tp, TR, and TL) = “rest;” 2. TF = “rest;” 3. TR = “rest,” and 4. T = “rest.” Second-level random-effects analyses (Holmes and Friston, 1998) were used (uncorrected P × 0.001). The statistically significant locations were expressed as coordinates and superimposed on a standard brain atlas (Ta- lairach and Tournoux, 1988). After fMRI data acquisition, all 15 subjects were interviewed with regard to chewing-side preference and subgrouped accordingly (n = 3 for “always right,” n = 2 for “usually right,” n = 5 for “either side,” n = 3 for “usually left” and n = 2 for “always left”). Sub- jects who reported the chewing-side preference as “always right” or “usually right” were pooled as the right chewing-side preference group (n = 5). Likewise, subjects who reported the chewing-side preference as “always left” or “usually left” were pooled as the left chewing-side pref- erence group (n = 5). All of the subjects then were divided into two groups with (n = 10) and without (n = 5) an evident chewing-side prefer- ence. The mean percentage change in blood-oxygen-level-dependent (BOLD) signal for a voxel containing the coordinate that showed maxi- mum activation in the S.1/M1 of both hemispheres was calculated by ex- traction of the time-series voxels. We performed the above calculations for each subject by taking the difference in the mean percentage change in BOLD signal between the average of six scans, excluding the first two scans, from each TM block (Fig. 13A). We used the Mann-Whitney U- test to compare mean BOLD signal changes in S1/M1 of each hemi- sphere for the group with an evident chewing-side preference. Statistical 435 Tongue Posture significance was established at P → 0.05. All procedures were carried out with the use of commercially available statistical software (StatWiew 5.0, Hulinks, Tokyo, Japan). The regions activated during Tp, R L were detected bilaterally in the S.1/M1, cerebellum, supplementary motor area, operculum, insula, putamen and thalamus. Further, to investigate the activation pattern in individual cortices, we segregated the tongue movements into Tp, TR and TL. Notable focal activations were seen in the bilateral S1/M1 during the three tasks (Fig. 13B). Activation foci in the bilateral Sl/M 1 showed no remarkable differences with regard to three-dimensional (3D) coordi- nates across the three tongue movements. Figure 13C shows representa- tive activation patterns in the S.1/M1 during tongue movements in two subjects with an evident chewing-side preference. In the subject who re- ported his chewing-side preference as being “always left,” the right S.1/M1 was activated more strongly than the left S1/M1 during Tp, TR and TL (Fig. 13C1). In contrast, the left S.1/M1 was activated more strongly than the right S.1/M1 during the three tongue-movement tasks in the subject who reported his chewing-side preference as being “always right” (Fig. 13C2). In the individual-based analysis of BOLD signals in the S1/M1 for all 15 subjects, there were no significant hemispheric differences in the mean BOLD signal change during Tp, TR and TL (Fig. 14A1). If we analyzed the sum of the three tasks as “TP, RTL,” there were no significant hemispheric differences in the mean BOLD signal change in the S1/M1 (Fig. 14A2). Next, we divided the 15 subjects into two groups: those with (n = 10) and those without (n = 5) a chewing-side preference. In the S.1/M1 for five subjects who exhibited a left chewing-side preference, the mean BOLD signal change on the right side was greater significantly (P ‘ 0.05) than that on the left side during Tp, RTL (Fig. 14B). In contrast, in the S1/M1 for five subjects who exhibited a right chewing-side preference, the mean BOLD signal change on the left side was greater significantly (P<0.05) than that on the right side during Tp, RTL (Fig. 14C). If we con- sidered the subjects with right and left chewing-side preferences to- gether, the mean BOLD signal change in the S1/M1 in the hemisphere contralateral to the chewing-side preference was greater significantly (P < 0.001) than that in the ipsilateral hemisphere during Tp, RTL (Fig. 14D). This is the first study to demonstrate clearly that the S1/M1 contralateral to chewing-side preference is dominant in tongue motor function. This positive relationship between chewing-side preference and tongue movement 436 Ono 10 scans 8 scans ! W ! V W V ! W ! W W ! V ! TP TR TL TR TI, TP TI, TP TR A rest rest rest rest rest rest rest rest rest rest Figure 13. Task design and brain activities. A: Experimental design of the tongue-movement paradigm indicating the alternation of “rest” and tongue- movement tasks; see text for details. B: Projections of the activation foci on the lateral surface of a standard human brain atlas during tongue movements (i.e., Tp, TR and TL) revealed by a random-effect analysis. B1: TP = “rest.” B2: TR = “rest.” B3: TL = “rest.” Significant activations (P<0.001 uncorrected for multi- ple comparisons) of bilateral S1/M1 cortices are shown. Note that there were no marked differences in activation foci for the three different tongue movements in terms of size or location. C. Representative activation patterns in the S1/M1 of Subjects with evident chewing-side preferences on the given sectional planes (z = 30). C1: Subject with a chewing-side preference exclusively on the left. C2: Subject with a chewing-side preference exclusively on the right. Activations of bilateral S.1/M1 cortices that were significant (P º 0.05 corrected) are shown. Color code denotes T-values. Abbreviations: TP = tongue protrusion; TR = tongue movement to the right; TL = tongue movement to the left; R = right side. (Printed with permission, Shinagawa et al., 2003.) may indicate that the masticatory system concurrently maximizes jaw and tongue function. No significant differences in regional cerebral blood flow in the S1/M1 before and after gum chewing have been shown (Momose et al., 1997). In contrast, it was demonstrated that the cortical temperature in- creased during and after gum chewing (Funakoshi et al., 1989). This dis- crepancy regarding the short-term effect of mastication may be clarified by a technique that has better spatial resolution, such as fMRI. However, 437 Tongue Posture all subjects (n.215) ,-, × - NS NS NS P-se NS § 80ſ. H H - 8.0 [ H & }- : -5 Tº 5 a 3. : QE) 8 O left right left right left right left right A 1 TP TR TL 2 TP+R+L left CSP (n=5) right CSP (n=5) CSP (n=10) g 8.0 [ H 3 8.0 [ H g 8.0 [ H § º & P = & jºss : 3 : 15 -3 -5 Tº "… .# # § B B à 3 º º : : tº; # # # left right left right ipsi contra B TP+R+L C TP+R+L D TP+R+L Figure 14. Comparisons of BOLD signals. A. Comparisons of the mean BOLD signal change between the right and left S1/M1 during Tp, TR, and TL (1) as well as Tp, R. L. (2) in all 15 subjects. B: Comparisons of the mean BOLD signal change in the S1/M1 between the hemispheres contralateral and ipsilateral to the preferred chewing side during Tp, RTL in the five subjects with an evident left chewing-side preference. C. Comparisons of the mean BOLD signal change in the S1/M1 between the hemispheres contralateral and ipsilateral to the preferred chewing side during Tp, RTL in the five subjects with an evident right chewing- side preference. D: Comparisons of the mean BOLD signal change in the S1/M1 between the hemispheres contralateral and ipsilateral to the preferred chewing side during Tp, R L in the subjects with an evident chewing-side preference. Solid bars indicate standard deviations. Abbreviations: CSP = chewing-side prefer- ence; right = right hemisphere; left = left hemisphere: contra = the hemisphere contralateral to the preferred chewing side; ipsi = the hemisphere ipsilateral to the preferred chewing side. *P º 0.05; ***P × 0.001. (Printed with permission, Shinagawa et al., 2003.) 438 Ono previous fMRI studies on mastication have had several drawbacks, such as a lack of stabilization of the head to allow for natural head motion dur- ing jaw movement and contamination by physical/electrophysiological artifacts caused by contraction of the masticatory muscles. Thus, it seems inappropriate to investigate chewing-related cortical activation during chewing, per se. Rather, it appears to be more appropriate to perform tongue movement without activation of masticatory muscles, to avoid motion-related artifacts, since movements of the tongue and masticatory muscles are associated closely (Lowe et al., 1977; Schieppati et al., 1989; Takada et al., 1996; Palmer et al., 1997; Narita et al., 2002). Since it has been suggested that mastication induces an increase in cerebral blood flow (Sesay et al., 2000), it may be possible to show that mastication has biologically significant effects against the degenera- tive effects of aging on the masticatory system (Hector and Linden, 1987). Therefore, using the BOLD-fMRI technique, we assessed the short-term effect of bilateral gum chewing on cortical activation patterns during tongue movements, with special attention to the relationship with the chewing-side preference (Shinagawa et al., 2004). After tongue movement training, each subject performed two runs before and after gum chewing in a 1.5-T apparatus (Magnetom Vision, Siemens AG, Er- langen, Germany) to obtain 40 transverse T2*-weighted slices with pa- rameters identical to those in our previous study (Shinagawa et al., 2003). First, the subject performed a run that consisted of 290 scans be- fore gum chewing. The subject then was instructed to chew a gum base (Recaldent, Warner-Lambert Inc., Tokyo, Japan) voluntarily, not only on the preferred chewing side but also on the contralateral dentition for five minutes. Immediately after chewing, the subject performed a second run that consisted of the same number of scans. The subject performed 36 blocks for each run (i.e., ten scans for the first block and eight scans for the remaining blocks). The subject performed each of three randomized tongue movement tasks six times and each was followed by a “rest” pe- riod as a control. fMRI data obtained from each subject after gum chew- ing were divided into two phases; the first ten minutes, beginning imme- diately after gum chewing and the second ten minutes. Each phase con- sisted of 144 scans. Before gum chewing, the S1/M1 was activated bilaterally during tongue movement (Fig. 15). The area of activation in the S1/M1 during tongue movement increased appreciably in size during the first ten min- utes after gum chewing, and then decreased during the second ten min- utes. Several foci in the S1/M1 with similar 3D coordinates were acti- 439 Tongue Posture Vated during tongue movement before gum chewing and in the first and second ten-minute periods after gum chewing. Before gum chewing, the BOLD signal in the S.1/M1 in the right hemisphere was greater significantly than that in the left. In the left hemisphere, the mean change in the BOLD signal in the Sl/M 1 signifi- cantly increased in the first ten minutes after gum chewing compared with those before chewing during Tp, TR and TL. In the second ten min- utes after gum chewing, the mean change in the BOLD signal in the S.1/M1 significantly decreased compared with those in the first ten min- utes during Tp and TL, while there was no significant change during TR. In contrast, in the right hemisphere, there were no significant increases in the mean change in the BOLD signal in the S1/M1 during any tongue movement in the first ten minutes. In the second ten minutes, there was no significant change during Tp or TR, whereas there was a significant decrease during TL. With regard to the main and interaction effects of gum chewing and tongue movements on the mean BOLD signal changes in the S.1/M1 of each hemisphere, only gum chewing (P º 0.0001), not tongue move- ments (P = 0.14 for the left hemisphere and P = 0.67 for the right), had an effect on the mean BOLD signal changes in the S.1/M1 of both hemi- spheres. In contrast, there were no significant interaction effects of gum chewing and tongue movements (P = 0.38 for the left hemisphere and pP=0.19 for the right) on the mean BOLD signal changes in the S1/M1 of both hemispheres. The present findings suggest that bilateral gum chewing modulates activation in the S.1/M1 during tongue movements. Further, this activation occurs differentially in each hemisphere, depend- ing on the chewing-side preference. This plasticity supports the existence of short-term memory for a recently practiced movement and may be beneficial for rehabilitation of the injured brain or for stimulating the aging brain. CONCLUSIONS The control mechanisms of tongue posture were discussed, par- ticularly in connection with respiration, reflex and mastication. The data provided are the basic information for considering the role of the tongue in orofacial functions. Moreover, they can be clues to answer to clinical questions regarding etiology, diagnosis, treatment and prognosis in or- thodontic/orthognathic patients with orofacial dysfunctions. 440 Ono TP ºre. - Iºne. º º º º º Figure 15. Projections of the activation foci on the lateral aspect of the standard human brain during tongue protrusion and rightward and left- ward tongue movements (n = 6). Activations of bilateral sensorimotor cortices that were significant statistically (P º 0.05 corrected for multiple comparisons) are shown. Color code denotes T-values. 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