key: cord-0949811-uowkfgbf authors: Geiselhart, Christina M.; Mutlu, Hatice; Barner‐Kowollik, Christopher title: Prevent or Cure—The Unprecedented Need for Self‐Reporting Materials date: 2021-02-26 journal: Angew Chem Int Ed Engl DOI: 10.1002/anie.202012592 sha: f5f48a736f2f23e7930d9b817e529de3d45663a5 doc_id: 949811 cord_uid: uowkfgbf Self‐reporting smart materials are highly relevant in modern soft matter materials science, as they allow for the autonomous detection of changes in synthetic polymers, materials, and composites. Despite critical advantages of such materials, for example, prolonged lifetime or prevention of disastrous material failures, they have gained much less attention than self‐healing materials. However, as diagnosis is critical for any therapy, it is of the utmost importance to report the existence of system changes and their exact location to prevent them from spreading. Thus, we herein critically review the chemistry of self‐reporting soft matter materials systems and highlight how current challenges and limitations may be overcome by successfully transferring self‐reporting research concepts from the laboratory to the real world. Especially in the space of diagnostic self‐reporting systems, the recent SARS‐CoV‐2 (COVID‐19) pandemic indicates an urgent need for such concepts that may be able to detect the presence of viruses or bacteria on and within materials in a self‐reporting fashion. Theg rowing demand on technologies in our daily lives requires evermore complex, innovative,a nd long-lasting materials.T herefore,s cientists are taking inspiration from biological systems,w hich often possess the unique ability to sense,report and, if required, self-heal damages immediately, often relying on visual indication systems.P rominent examples are the bioluminescence of marine phytoplankton, falling leaves next to acolor change from green to brown of plants in the absence of water, the red color of bleeding wounds,orthe color change during the healing process of bruises.Indeed, the successful transfer of such properties to human-made materials has been reported and ap lethora of bioinspired, stimuliresponsive smart materials has emerged. [1] [2] [3] [4] [5] [6] [7] [8] These materials possess the ability to change their properties triggered by one or multiple stimuli, [9] for example,mechanical forces,temperature,p H, light, ultrasound, magnetic fields,o rc hemicals. Judiciously combining stimuli-responsive elements with suitable polymeric structures,f ascinating smart materials have been developed, one important representative class being the self-healing materials. [10] [11] [12] [13] [14] [15] [16] Similar to biological organisms, such materials are able to repair damaged areas.T he mechanisms of self-healing processes are thereby highly dependent on the initial design strategy.O nt he one hand, the mechanism can be autonomic,meaning the damage itself triggers the healing process by releasing healing agents embedded in for example,m icrocapsules,h ollow (glass) fibers,o rv ascular systems at the damaged area. On the other hand, non-autonomic systems require an external trigger such as thermal, light, or chemical activation to induce for example (reversible) crosslinking or polymerization reactions to heal the damage. [17] [18] [19] [20] [21] [22] Unfortunately,most of the self-healing processes are irreversible.Once the healing agent is released or the polymerization is carried out, it cannot be used again to heal further damage.T herefore,itis of critical importance to first report the existence and the exact location of the damage before the actual healing process can take place.T hus,afast detection of the damage is enabled and the healing process can be carefully monitored. Taking renewed inspiration from biological systems,t he scope of stimuliresponsive materials has been expanded with the development of diverse self-reporting smart materials.Due to the advantages of such self-reporting properties for load-bearing materials,n anotechnology,b iomedicine,ortheranostics,wesubmit there is acritical need to review the self-reporting systems that have been developed based on the stimuli triggering the operating mechanisms (such as mechanical forces,temperature,pH, solvation, light, and chemicals). Self-reporting smart materials are highly relevant in modern soft matter materials science,asthey allowfor the autonomous detection of changes in synthetic polymers,materials,a nd composites.Despite critical advantages of such materials,for example,p rolonged lifetime or prevention of disastrous material failures,t hey have gained much less attention than self-healing materials.H owever,a sdiagnosis is critical for any therapy, it is of the utmost importance to report the existence of system changes and their exact location to prevent them from spreading. Thus,weherein critically review the chemistry of selfreporting soft matter materials systems and highlight how current challenges and limitations may be overcome by successfully transferring self-reporting researchconcepts from the laboratory to the real world. Especially in the space of diagnostic self-reporting systems,the recent SARS-CoV-2 (COVID-19) pandemic indicates an urgent need for suchconcepts that may be able to detect the presence of viruses or bacteria on and within materials in aself-reporting fashion. More specifically,t he current Review focuses mainly on polymer-based smart materials that are able to indicate changes or damages immediately in av isible manner by changing color,fluorescence,orchemiluminescence.Furthermore,current challenges and limitations are highlighted along possibilities how they may be overcome by successfully transferring self-reporting research concepts from the laboratory to the real world. Finally,t he (undervalued) potential of self-reporting materials as biomedical diagnostic tools will be discussed with regard to the latest SARS-CoV-2 pandemic. Noting that the plethora of stimuli-responsive triggers is very broad, we herein critically focus on specifically selected representatives,w hich are summarized in Scheme 1. To aid the reader,w ei nitially start with the most common selfreporting materials,t hat is,t hose featuring mechano-responsive properties.Subsequently,thermo-, pH-, solvation-, light-, chemically,a nd multi-stimuli-responsive systems will be discussed. Throughout, current issues as well as (future) possibilities are explored. As indicated above,m echano-responsive self-reporting materials (also known as self-sensing or self-monitoring) [23] are considered the most prevailing ones based on the multitude of studies and possible applications (e.g.l oad bearing,h igh performance,a erospace,a utomobiles,b iotechnology). [23] [24] [25] [26] [27] [28] Mechanical forces apply to all different types of such materials,t hus it is of critical importance to detect damages as early as possible to prevent catastrophic failures. In addition, preventive maintenance can be conducted more precisely (on demand) to increase the reliability and the lifetime of the materials at lower costs.I ndeed, various techniques have been developed to report mechano-induced damage in aself-reporting manner.Generally,asillustrated in Scheme 1, the techniques are based on the incorporation of dye-filled capsules, [24, [29] [30] [31] [32] [33] [34] mechanophores, [35, 36] fibers, [23, 37, 38] or sensor molecules [39] [40] [41] into composites,p olymer matrices, or networks/hydrogels in order to mimic the nerve systems and tissues of biological organisms.U pon mechanical damage,t he self-reporting output is triggered and made visible by changes in fluorescence,l uminescence,orc olor. Fore xample,s piropyrans (SPs) have been incorporated into polymeric materials as the most investigated mechanophore to report microscale damages via distinct changes in color and fluorescence. [23, 35, 37, [42] [43] [44] [45] Mechanical forces lead to bond cleavage of the colorless SP,r esulting in the isomerization into the fluorescent red colored merocyanine( MC, Scheme 1). Fore xample,S ilberstein and co-workers synthesized ah igh-performance SP polycarbonate,w hich responds to mechanical forces already at ambient temperature. [42] In another example,aSP-containing graft copolymer of rubbery poly(butyl acrylate) (PBA) as the backbone and glassy poly(methyl methacrylate) (PMMA) as comb side chains was synthesized, as illustrated in Figure 1A . [43] Theo btained polymer with SP (orange dots) as covalently incorporated connection between the PBA( blue lines) and the PMMA (red lines) exhibits green fluorescence (l em = 530 nm) due to the fluorophore nitrobenzoxydiazole (NBD,g reen triangles) located in the PMMA side chains.Upon mechanical stimulus, the SP is converted into the MC derivative (red dots). Due to Fçrster resonance energy transfer (FRET), the green fluorescence of the NBD is quenched and the red fluorescence (l em = 656 nm) of the MC is observed. With increasing strain, the intensity of the green fluorescence decreases,w hile the intensity of the red fluorescence increases,u ntil the material breaks down ( Figure 1B,C) . Thebenefits of such acombina-tion in one polymer are the high contrast between green and red fluorescence,t he ability to monitor the change via laser scanning confocal microscopy,aswell as the self-calibration of the ratiometric fluorescent signal. Thus,s uch SP-containing materials are promising candidates for sensor applications to self-report damages on the microscale.H owever,d uring the synthesis of mechanophores-containing polymers it has to be ensured that the initial high-performance or load-bearing properties of the desired materials are not depleted. Addi-Scheme 1. Overview of stimuli (e.g. mechanical, thermal, pH, solvation, photochemical, and chemical) employed to switch on/off self-reporting properties of human-made materials, which are visualized by achange in color,f luorescence, or chemiluminescence. Foreach stimulus, selected representative examples are displayed, which will be further discussedt hroughout the current Review in the order shown above. tionally,mechanophores such as the spiropyrans,are responsive not only to mechanical stimuli, but also to for example, temperature or light (for more details see Section 2.7). [43, 46, 47] One possible method developed to overcome such multiresponsiveness of mechanophores is the formation of supramolecular complexes.W eder and co-workers successfully applied rotaxanes as molecular shuttles in polyurethane elastomers,e nabling the non-covalent encapsulation of mechanophores. [48] Thew orking principle of such ar otaxane-based molecular shuttle and the respective molecular structure are displayed in Figure 2A ,B.Acycle containing the fluorophore (gray/green) is located around as uitable quencher (brown) with two stoppers (blue) and anchor groups (red) for incorporation into polymer chains (e.g. polyurethanes,P Us). Mechanical force separates the cycle with the fluorophore from the quencher and the fluorescence is turned on. Upon relaxation, the molecular shuttle returns to its former position around the quencher due to chargetransfer interactions,and the fluorescence is turned off again as displayed in Figure 2C .These authors also showed that the turn-on/off process can be repeated several times (20 cycles tested) and is specific to mechanical stimuli, since no fluorescence was turned on at elevated temperatures.H owever,harsh conditions (temperatures > 150 8 8Corsonification) lead to ad ecomposition of the polymer films or irreversible cleavage of the mechanophores from the polymer.N evertheless,t he introduced concept of supramolecular shuttles is ideally suited to visualize mechanical forces in ar eversible and specific manner.F urther, the concept can possibly be fine-tuned by application of other supramolecular systems (e.g. catenanes,k nots) and/or different chromophores to adjust the color and fluorescence emission, thus allowing the design of various kinds of mechano-responsive self-reporting systems. Indeed, the concept of supramolecular complexes has been similarly exploited in the field of composites.S uch materials provide light weight in combination with high mechanical strength and thus,t hey find application as structural components in for example,aircraft or automotive industry. [23, 49] Therefore,i tw ould be highly beneficial for composites to self-report damages and fatigue to prevent catastrophic failure.Analogous to the rotaxane-based molecular shuttle, [48] Das et al. [38] introduced asupramolecular host molecule,namely cucurbit [8] uril (CB [8] ), into acarbon fiber epoxy (CFR) composite matrix. Ah ighly fluorescent perylene monoimide (PER) as fluorophore and either an azobenzene (AZO) or dibenzofuran (DBF) derivative as quencher were simultaneously encapsulated by the CB [8] ,as shown in Figure 3 . Viat erminal amino groups,t he fluorophore and the quencher were covalently cross-linked into the The rotaxane is equipped with anchor groups for incorporation into polymer chains (red), two stoppers (blue), and afluorophore-containingcycle (gray/green) located around asuitable quencher (brown). Upon exposure to mechanicalf orce, the fluorophore and the quencher are separated, switching on the fluorescence emission of the fluorophore. B) Molecular structure of the mechanoresponsive rotaxane. C) Images of aPUfilm, whose fluorescence is turned on via stretching and turned off again by relaxation of the film. The films were irradiated at 365 nm and ambient illumination, respectively.Reprinted from ref. [48] with permission from ACS. (https:// pubs.acs.org/doi/10.1021/jacs.7b12405. Further permissionsr elated to the material excerpted have to be directed to ACS.) composite matrix. While no fluorescence is observed if both the fluorophore and the quencher are encapsulated in the CB [8] ,t he fluorescence of the PER derivative is turned on upon mechanical force,w hich leads to as eparation of the fluorophore and the quencher ( Figure 3 ). Over 1000 cycles, no changes in fluorescence or stiffness were observed, starting slightly above 10 000 cycles and above 100 000 cycles astiffness drop of 40 %and fluorescence along the fibers were detected. Nonetheless,the supramolecular approach in the field of CFR composites allows the facile incorporation of self-reporting units into polymeric materials and can surely be transferred to other materials and suitable fluorophore-quencher pairs. An alternative method to obtain mechano-responsive smart materials is the embedding of hollow microcapsules [24, [29] [30] [31] [32] [33] or fibers [23, 38] into the respective initial material. Themicrocapsules or fibers can be filled with dye molecules, which are released upon damage of their shell, thus indicating damaged areas.N ot only does this method offer ab road versatility of applicable dye molecules,but it also enables the simultaneous incorporation of self-healing agents.I ft he stimuli-responsive container is broken by mechanical forces, the self-reporting as well as the self-healing agent are released. Clearly,s uch combined properties would be highly beneficial to prolong the lifetime and safety and to reduce warranty costs of human-made materials.I ndeed, various materials with such combined self-healing and self-reporting properties have been reported, especially in the field of coatings. [34, 40, [50] [51] [52] [53] [54] Yang and co-workers for example synthesized microcapsules with both hexamethylene diisocyanate (HDI) as self-healing agent and atetraphenylethylene (TPE) derivative as self-reporting agent ( Figure 4A ). [31] Embedded into polymer coatings,t hese microcapsules break upon exposure to mechanical forces and release their content. TheH DI solution initiates the self-healing process with no need for any additional catalyst, and the damaged areas can be monitored under UV light by the blue fluorescence of the TPE, as illustrated in Figure 4B .T oprove the applicability of the dual-function microcapsules as self-reporting and selfhealing coating material, steel panels were coated with pure epoxy resin (Epolam 5015, E-epoxy), E-epoxy embedded with microcapsules containing only the self-healing HDI solution, and E-Epoxy embedded with the dual function microcapsules.S ubsequently,t he coated steel panels were damaged with as harp blade and soaked in 10 wt %N aCl aqueous solution. Figure 4C -E clearly shows as trong corrosion of the steel panel coated only with the pure E-epoxy ( Figure 4C ), while the steel panels coated with HDI-(and TPE-)containing microcapsules show almost no corrosion ( Figure 4D ,E). Under illumination with UV light, as trong fluorescence in the repaired area is exclusively obtained for the steel panel coated with the dual-function microcapsules ( Figure 4F-H) . Similarly,Song et al. reported the synthesis of microcapsules with as ingle aggregation-induced emission (AIE) fluorophore,that provides different fluorescent colors in the liquid (intact) or in the solid state (damaged). [32] There exist many more related dual-function smart mechano-responsive materials,c learly indicating the importance,a ctuality and demand to further investigate such materials.Y et, more research needs to be conducted to improve the contrast between the intact and damaged parts and to make such materials suitable and affordable for industrial applications.P articularly,t he reversibility and the Figure 3 . Operating mechanism of the cucurbit [8] uril (CB [8] )-based damage-reporting CFR composites and the moleculars tructures of the applied host molecule (CB [8] ,g ray/red),t he fluorophore (PER, yellow), and the two quencher derivatives (azo and DBF, blue). Reprinted from ref. [38] with permission from ACS. (https://pubs.acs.org/doi/10.1021/ acsapm.9b00694. Further permissions related to the material excerpted have to be directed to ACS.) Figure 4 . A) Dual-functionm icrocapsule containing the tetraphenylethylene (TPE) as AIEgena nd hexamethylene diisocyanate (HDI)) as self-healinga gent. B) Self-reportinga nd self-healingofthe coating containing dual-function microcapsules. Pictures (C-E) of steel panels coated with C) pure E-epoxy coating, D) E-epoxy coating embedded with HDI microcapsules, and E) E-epoxy coating embedded with TPE/ HDI microcapsules under white light. Pictures( F-H) of steel panels coated with F) pure E-epoxy coating, G) E-epoxy coating with HDI microcapsules, and H) E-epoxy coating embeddedw ith TPE/HDI microcapsules under UV light. Reprinted from ref. [31] .C opyright 2020 ACS. selectivity of the self-reporting output needs to be considered. As indicated above,t he mechano-responsive behavior based on the cleavage of covalent bonds (e.g.t he isomerization of SPs) can be triggered by multiple stimuli. Microcapsules or fibers,o nt he other hand, are able to report damages only once,since they break upon mechanical deformation and the self-reporting component is released. Therefore,t he most promising strategy is perhaps the supramolecular approach based on non-covalent interactions,s ince they provide selective and recyclable self-reporting response towards mechanical forces.E xtensive research into such materials may help to prevent accidents due to material failure or catastrophes such as the collapse of the motorway bridge in Genoa, Italy in August 2018 in the future. [55] [56] [57] While intensive research has been conducted to design smart self-reporting (and self-healing) mechano-responsive materials,p olymeric materials and their characteristics can also be influenced by temperature.C hanges in temperature can lead to ac hange in for example,t he aggregation state, color,o rb rittleness,t hus it is of the utmost importance to consider the impact of the temperature and how the material adapts to alterations. [58] [59] [60] [61] Indeed, various thermo-responsive materials have been developed by synthesizing composites/ polymers/hydrogels (e.g. poly(N-substituted (meth)acrylamide)s,polyoxazolines,polyethers,polycaprolactones,polyphosphazenes,o rp olypeptides), [62] which possess al ower or upper critical solution temperature (LCST or UCST,r espectively), thermochromic moieties,atemperature-dependent self-assembly-behavior,o ri ncorporate thermo-responsive additives such as (leuco-)dyes,q uantum dots,o ri norganic thermochromic complexes. [61] Especially in the context of energy saving and solar modulation, thermo-responsive materials are of key interest. [63] [64] [65] [66] [67] [68] [69] [70] Heating and cooling systems in any vehicle,s torage place,orindoor space require high amounts of energy,cause environmental problems (toxic cooling substances,p ollution) [71, 72] or may result in health issues (dry skin, headaches, colds). [73, 74] Therefore,s mart thermo-responsive glazing systems along window coatings have been developed. Fore xample,L in and co-workers mixed dodecanedioic acid (DDA) with glycerol to obtain ac ross-linked polyester network (PGD) as illustrated in Figure 5A ,B. [64] Thematerial contains both amorphous domains (the cross-linked PGD network) and semi-crystalline domains (non-cross-linked DDAs ide chains,F igure 5B). Below the transition temperature (39.1 8 8C), the two domains possess different refractive indices (RI) and thus the material is translucent (left side in Figure 5C ). Above the transition temperature however, the non-cross-linked DDAu nits melt and the RI of the semicrystalline domain becomes similar to the one of the amorphous domains.A sar esult, the material becomes transparent (right side in Figure 5C ). Additionally,t he mechanical strength of PGD-coated glass was up to 10 times higher than for bare glass,depending on the thickness of the coating. On the other hand, ap olyurethane (PU)-based ionogel was synthesized changing from transparent to translucent properties upon heating. [65] Thei onogel consists of ionic liquids (IL) cross-linked with poly(propylene oxide) (PPO) via urethane chemistry.Atambient temperature,the ionogel is homogeneous and transparent, while elevated temperatures lead to aphase separation between the IL and the PU network, which results in light scattering and ar eduction of the optical transmittance.Bychanging the composition of the IL, the transition temperature range could be tuned from below zero to > 100 8 8Cw ith ag radual change in the transparencyb elow and above the transition temperature.I na n experimental setup of am odel house with either as mart ionogel window or ac onventional float glass window,t he house with the ionogel window showed ar educed temperature of 20 8 8Cc ompared to the conventional one.A dditionally,t he optical properties were further adjusted by incorporating organic dye molecules or plasmonic nanoparticles into the ionogel. Similar phase transitions from transparent to translucent (or vice versa) were obtained in liquid-crystal siloxane polymers, [66] polyacrylamide hydrogels, [67, 68] nanoparticlepolymer composites, [69] or dynamic porous silicon films. [70] Clearly,t hese materials are promising for future developments of smart, thermo-responsive systems for solar control coatings and windows,d isplays,o rs ensors with tunable thermal and optical properties. Another application field for thermo-responsive materials is biomedicine and drug delivery. [75] [76] [77] [78] [79] Fore xample,i nverse optical particles obtained from poly(N-isopropylacrylamide) (pNIPAM) hydrogels show thermo-responsive characteristics. [80] Depending on the temperature,the particles shrink or swell accompanied by ac olor change form red to blue,a s depicted in Figure 6A ,making them an ideal system for drug delivery applications.T he particles provide macropores for active drug loading, which can be precisely released by adjusting the temperature.I ntriguingly,t he drug release was fine-tuned, hence allowing for the regulation of the drug delivery and the recovery of the initial particles ( Figure 6B ). Since the reflection spectra of the drug-loaded particles shown in Figure 6C also reveal ablue shift from approx. 650 to 475 nm during the release process,the system becomes selfreporting and enables the in situ monitoring of the drugs. Yet, further research is required to improve the drug loading, since the loading mainly functions for macromolecular drugs.F urther, the temperature applied for the drug release lays between 45 and 55 8 8C, which needs to be decreased in order to facilitate in vivo applications.N evertheless,c ombined with the non-toxicity and biocompatibility of pNIPAM, such inverse opal particles are promising for biomedical applications,especially for drug delivery systems. Furthermore,t hermo-responsiveness has proven to be apowerful tool in the field of bonding/debonding on demand polymeric materials. [81] [82] [83] Therequired bonding or debonding process can be readily induced by heating or cooling of the material. Certainly,asignificant temperature difference is required to avoid undesired bonding/debonding by coincidence rather than on demand. One of the most attractive reactions fulfilling such criteria is the hetero Diels-Alder (HDA) reaction, since various dienes and dienophiles are available to precisely tune the range of the thermo-responsiveness. [84] [85] [86] Forexample,cyclopentadienes and dithioesters are able to undergo aH DA reaction at ambient temperature,w hile the reaction can be reversed by increasing the temperature,f or example,i nt he range of 30-140 8 8C. Therefore,aHDA-based monomer has been synthesized from am ethacrylic cyanodithioester and ac yclopentadiene,w hich allowed subsequent incorporation of pyrene as fluorophore. [87] By copolymerizing this HDA monomer with 2,2,6,6-tetramethylpiperidine-4-yl methacrylate in afree radical polymerization, the statistical copolymer P1 with strong fluorescent properties is obtained, as illustrated in Figure 7 . Upon oxidation with meta-chloroperbenzoic acid (mCPBA), the fluorescence is quenched due to conversion of the piperidine moiety to an itroxide radical, yielding the profluorescent copolymer P2 in Figure 7 . Finally, the debonding process is initiated by heating of the polymer to 90 8 8C, when the HDAunit is released and the fluorescence of the pyrene is recovered in such an intensity that it can be readily observed with the naked eye ( Figure 7) . Hence,aselfreporting thermo-responsive polymer system is obtained based on HDAc hemistry combined with spin fluorescence silencing,which ideally lends itself to molecular sensing. In ad ifferent, yet related example based on the HDA chemistry,p olymeric methacrylic (HDA-PMA) [88] or dimethylcarbonate (HDA-PC) [89] networks have been formed, consisting of ad i-or tricyclopentadiene (Di-/TriCp) and ap hosphoryl dithioester (PDT), displayed in Figure 8A ,B. While the bonding process for the network formation is carried out at ambient temperatures to avoid early cleavage of the HDAm oieties,t he debonding process is conducted at elevated temperatures between 30 and 140 8 8C. Theprocesses were reversible in several cooling/heating cycles,a se vident from UV/Vis ( Figure 8C )and 1 HNMR ( Figure 8D )analysis. During three heating/cooling cycles from 20 to 100 8 8C, similar absorbance spectra are recorded ( Figure 8C ), clearly evidencing the reversibility of the (de-)bonding process.S pecifically,t he resonance changes associated with the cyclopentadienyl moiety (6.5-6.5 ppm) and the HDAu nit (5.85-5.6 ppm) in the 1 HNMR spectra ( Figure 8D )s upport the successful (de-)bonding on demand properties.I na ddition, the (de-)bonding process can be readily followed by the naked eye.W hile the bonded HDA-PC network is solid and slightly yellow,t he cleavage of the PDT moiety during the retro-HDAresults in aliquid, highly red colored material due to debonding of the polymer chains and the absorption of the . Statistical copolymer P1, whose strong fluorescence is silenced after oxidation with mCPBA, yielding the profluorescent copolymer P2. Upon heating of P2, the debondingo fthe HDA unit is initiated and the fluorescence of the pyrene units is recovered. Reproducedf rom ref. [87] with permission from the Royal Society of Chemistry. Reviews formed C=Sdouble bond, as depicted in Figure 8E .Since the properties and thermo-responsiveness can be fine-tuned depending on the polymerization process,addition of suitable comonomers,ordifferent HDApairs,such materials disclose promising application possibilities in various fields,f or example,adhesives or medical technologies. Thed iscussion regarding the above pNIPAM particles already suggests the importance of particle sizes and their swelling/shrinking behavior. However, the change of the particle size and state does not have to be solely induced by temperature,b ut can also be caused by pH changes. [90] [91] [92] [93] Especially in the fields of drug delivery,bio-or nanotechnology,pH-responsive materials are of high interest since certain pH values are characteristic for either healthy (pH % 7.4) or diseased tissue (pH < 7). [94] [95] [96] Therefore,particles with different fluorescent characteristics in their swollen or shrunken state facilitate the reporting of environmental changes depending on the pH values. Wang and co-workers took advantage of such particles to monitor the microenvironmental pH in the endocytosis process for the transportation of nanomedicines. [97] Ab is-(pyrene) (BP) moiety was conjugated with poly(amino ester)s (P) terminated by cyclic peptides to build ap H-sensitive nanocarrier (P-BP) as displayed in Figure 9A .T he BP enables the formation of J-type nanoaggregates through hydrophobic and p-p interactions in water, while the tertiary amine groups of P( blue arrow in Figure 9A )e nsure the reversible protonation and thus the shrinking and swelling of the particle depending on the pH value.T he cyclic peptide units at the chain ends enable the targeted cell uptake.A t neutral pH, the P-BPs were self-assembled into nanoparticles with ah ydrophilic shell (P) and ah ydrophobic core (BP), which enabled the encapsulation of Nile Red (NR) to visualize the self-assembly via red fluorescence emission ( Figure 9B ). In the presence of NR, the fluorescence of BP is quenched due to Fçrster resonance energy transfer (FRET) between NR and BP.Ifthe pH value decreases from 7.4 to 5.0, the protonation of the tertiary amine groups in the polymer chains induces swelling of the particles (from 41.7 to 183.2 nm). TheN Ri sr eleased and its fluorescence is quenched due to aggregation in water, while simultaneously the fluorescence of the BP moieties is turned on due to ab reaking of the fluorescence-quenching J-type nanoaggregates in the shrunken state and thus,t he elimination of the FRET effect. Thus,t he changes in the fluorescence emission allow the in situ monitoring of microenvironmental pH values,w hich is especially useful in the field of biology and medicine for the precise development of nanomedicine,f or example,f or the treatment of (benign/malignant) cancer diseases.B yl oading pharmaceutical active molecules into pH-responsive nanoparticles,t hese entities are exclusively released upon uptake of diseased cells within the range of suitable pH values.T hus,i nc ontrast to conventional nanomedicines without pH-responsive properties,t he selectivity, sensitivity,a nd efficiencyo ft he active compounds were improved, while simultaneously unwanted cellular cytoxicity and side effects may be reduced. [98] [99] [100] [101] [102] Similarly,aminobromomaleimide (ABM) has been incorporated into particle cores as fluorophore to probe the core hydrophobicity. [103] Thep articles were synthesized via emulsion copolymerization of ah ydrophilic shell-forming monomer (oligoethylene glycol methacrylate,O EGMA), ah ydrophobic core-forming segment (N,N-diethylaminoethyl methacrylate,D EAEMA), and the respective fluorescent ABM monomer,represented in Figure 10 A. In the presence of CO 2 , the pH decreases due to the dissociation of CO 2 into HCO 3 À , CO 3 2À ,a nd H + ,w hich leads to the protonation of the amine moieties and thus,toaswelling of the particles.The increased hydrophilicity of the swollen particles results in the quenching of the former fluorescence,a llowing af acile observation of the swelling process via fluorescence measurements (Figure 10 B) and DLS analysis (Figure 10 C) . Importantly,t he swelling can be reversed by simply purging the solution with N 2 and thus the fluorescence is turned on again. However,the reversibility is highly dependent on the density and stability of the shell. Although the fluorescence emission intensity adjusts to ar ather constant change after several purging cycles with CO 2 /N 2 as evident from Figure 10 D, the hydrodynamic diameter shows drastic fluctuation (e.g. up to 150 nm difference between two N 2 purging cycles,F igure 10 E). Therefore,i ntensive research needs to be conducted to improve the stability of the particles,f or example by alternating the monomers for the emulsion copolymerization or increasing the amount of crosslinker.N evertheless,s uch self-reporting pH-responsive materials promise great potential for applications in sensor technology and biomedicine. Figure 9 . A) Nanocarrier P-BP with poly(amino ester)s as the pHresponsive backbone (blue) terminated by cyclic peptides (green) to enable cell uptake and aconjugated bis(pyrene) (BP, orange) as fluorophore. B) Self-assembly of P-BP into nanoparticles with ahydrophilic shell (P) and ah ydrophobic core (BP). Encapsulation of Nile Red (NR) leads to ared fluorescence, which is blue shifted at lower pH values due to the elimination of the FRET effect. Reprinted from ref. [97] with permission from the Royal Society of Chemistry. In addition to temperature and pH as stimuli for selfreporting properties,polymer nanoparticles and micelles have been developed that respond to solvation stimuli. Upon dilution, the self-assembly of copolymers,decorated with both hydrophilic and hydrophobic segments,i nto micelles is induced. Similar to the previously introduced pH-responsive materials,such self-assembling polymers are of key interest in the biomedical field, especially for imaging and sensing. [104] [105] [106] Thus,a mphiphilic block copolymers have been developed with integrated fluorophores and dye molecules,toallow the self-reporting monitoring of assembly and encapsulation behavior. Most importantly,t he synthetic routes have been optimized so far to not only enable the covalent attachment of the fluorophore to the materials,b ut also to position the fluorophore variably,e ither in the micelle core or shell. This variability was achieved by synthesizing copolymers poly(triethylene glycol acrylate)-b-poly(tert-butyl acrylate) (P-(TEGA)-b-P(tBA)) with ad ithiomaleimide (DTM) fluorophore (green) either in the core forming (P(tBA)) block (red, CLP) or the shell forming (P(TEGA)) block (blue,S LP) by reversible addition-fragmentation chain-transfer (RAFT) polymerization. [106] Thes tructures of the obtained CLP and SLP are displayed in Figure 11 A. Direct dissolution in water afforded the desired micelles,e ither core-labeled (CLM) or shell-labeled (SLM), as illustrated in Figure 11 B. Indeed, the position of the fluorophore plays acritical role regarding the fluorescent properties.While the DTM fluorophore in SLMs suffers from solvent quenching effects,good protection of the chromophore is provided in the predominantly solvent-free core of CLMs.Therefore,CLMs show abrighter emission and al onger fluorescence lifetime in the micellar state than the SLMs.F urthermore,t he CLMs could be used to self-report the presence of fluorescent hydrophobic guest molecules such as Nile Red (NR) due to the FRET effect (Figure 11 C. On uptake of the guest molecule into the core of the CLMs,t he DTM emission at 515 nm was quenched, while the emission of NR at 610 nm was enhanced (the emission being higher than for non-labeled micelles with only NR present), as can be clearly seen in the emission spectra in Figure 11 E. Thelatter is only possible when the two fluorophores are in close proximity (generally < 4nm), which proves that the FRET occurs in the core of the CLMs.However, in the presence of ah ydrophilic guest molecule,f or example,R hodamine B (RhB), no FRET is observed (Figure 11 F) , indicating that the RhB is not encapsulated into the micelle core,asillustrated in Figure 11 D. Thus,t he CLMs not only self-report on the formation of the micelles upon dilution of the polymer,b ut also on the presence (or absence) of small guest molecules by simply measuring the changes in the fluorescence emission, which is of particular interest for drug delivery applications. Moreover,the fluorescent properties can be readily tuned by carefully choosing the substituents of the maleimide-based Figure 11 . A) Structureso fthe core-labeled( CLP) and shell-labeled (SLP) block copolymers.B)Synthesis strategy for core-labeledm icelles (CLMs) and shell-labeled micelles (SLMs). C) Interactions between CLMs and Nile Red (NR). D) Interactions between CLMs and Rhodamine B (RhB). Emission spectra (E-F) of CLMs at t = 0, 1, and 60 min after addition of E) NR (NR in water/0.1 %1,4-dioxane) and F) RhB (RhB in water). All spectra were recorded at l ex = 422 nm, the peaks at 495 nm correspond to the Raman scattering of water.R eprinted from ref. [106] with permission from ACS. (https://pubs.acs.org/doi/10.1021/acs.macromol.5b02152. Further permissions related to the material excerpted have to be directed to ACS.) fluorophore and the solvent, [107] making such micelles aversatile tool in the fields of biology,medicine,orchemical sensor applications. However,solvation-responsiveness can also be applied to better understand chemical reaction mechanisms and thus,to develop soft matter smart materials in am ore precise and straightforward manner.U ntil recently,i tw as challenging to gain further insight into the mechanism of precipitation polymerization, although this reaction is of key interest in industry due to its surfactant-free nature,s ize control and functionality tolerance.W hile it was only suggested that the process includes two steps,n amely nucleation and the growth, [108, 109] Tang and co-workers were able to monitor the different stages of the reaction directly in as elf-reporting manner by using fluorophores with aggregation-induced emission (AIE) properties. [108] A4 -vinylbenzyl-modified tetraphenylethylene (TPE-VBC) was synthesized with typical AIE-characteristics,m ore precisely showing only weak emission in solution, yet strong fluorescence upon aggregation in the precipitated polymers.D uring the precipitation polymerization with styrene,m aleic anhydride and azobisisobutyronitrile (AIBN), the previously transparent solution becomes turbid, the fluorescence intensity strongly increases and can be monitored under daylight or UV light, as demonstrated in Figure 12 . Evaluation of the various analytical results (microscopy (TEM, SEM, CLSM), dynamic light scattering (DLS) and UV/Vis/Fluorescence spectroscopy) allows for the detailed characterization of the underlying mechanism and the precise allocation of the different reaction steps.Besides the in situ monitoring of the reaction progress, the obtained polymeric fluorescent particles (PFPs) with uniform (PDI DLS < 0.15) and tunable sizes possess bio-labeling and photosensitizing properties for imaging and therapy applications.T he authors successfully coated the PFPs onto Natural Killer (NK) cells,w hich play ac rucial role in the immune system as defense against infection and cancer cells. Indeed, the coated PFP-NK cells revealed advanced immu-notherapy efficiency towards cancer cells in comparison to non-coated NK cells,w hich can be easily followed by fluorescence analysis.T his enhanced efficiencyi sa ttributed to the photosensitizing behavior of the TPE-VBC.Irradiation with light induces the generation of reactive oxygen species (ROS), which in turn triggers the immunotherapy activity of the NK cells.While native NK cells and PFP-coated NK cells show similar immunotherapy activity towards cancer cells in the absence of light, ah igher immunotherapy activity was obtained for the PFP-coated NK cells under light irradiation (xenon lamp,1KW m À2 ). Thus,s imilar to the previously introduced pH-responsive materials,s uch solvation-responsive polymeric self-reporting materials are auspicious for future developments in biomedical and analytical technologies. Thea bility to trigger and control chemical reactions by light is ac ritical method in various fields in chemistry, materials science,a nd biomedicine.T his is attributed to the rather rapid associated process at ambient temperature, spatiotemporal controllability,a nd enhanced penetration depths at low energies in the visible light range (400-800 nm), which is especially critical for biomolecules to prevent undesired damage. [110] [111] [112] [113] [114] By combining photo-sensitive moieties with self-reporting properties,ap owerful tool for sensing and in situ monitoring applications is created. For example,T ang and co-workers took advantage of photosensitive aggregation-induced emission fluorogens (AIEgens), namely tetraphenylethenethiophene (TPETP) and tetraphenylsilole (TPS), with different-colored AIE (red for TPETP and green for TPS). [115] Both AIEgens were incorporated into ap eptide substrate with ac aspase-3/-7 responsive amino acid sequence Asp-Glu-Val-Asp (DEVD) between the two AIEgens and acyclic amino acid sequence Arg-Gly-Asp (cRGD) at the TPS-containing chain end to enable the cell uptake,asdepicted in Figure 13 A. Upon cell up-take (step 1i nF igure 13 B), TPETP is cleaved from the peptide substrate by intracellular glutathione,a nd the red emission (l em = 650 nm) is turned on (step 2i nFigure 13 B). Subsequent irradiation with light triggers the cleaved TPETP to generate reactive oxygen species (ROS), which in turn induce cell apoptosis and activate the caspase-3/-7 enzyme (step 3i nF igure 13 B). Theactivated caspase enzyme cleaves the DEVD sequence from the apoptosis sensor and the green fluorescence (l em = 480 nm) of the TPS is turned on (step 4inF igure 13 B). In this way,aself-reporting system for application as photosensitizer (PS) in photodynamic therapy (PT) is created, allowing the real-time monitoring of PS activation and therapeutic response simultaneously by simple color change of the AIE. Similarly,t he in situ monitoring of cell apoptosis was recently reported by applying an ew,y et related AIEgen tetraphenylethene-tetraethylpyridinium iodine (TPE-4EP +). [116] This AIEgen proved to have remarkable selectivity for cancer cells accompanied by an efficient ROS( specifically 1 O 2 )g eneration. Thes electivity towards cancer cells is attributed to electrostatic interactions between the negative transmembrane potential of the dysfunctional mitochondria within cancer cells and the positively charged pyridinium moieties in the TPE-4EP + .U pon cell uptake of the AIEgens into the cancer cell, an increased fluorescence emission is measured in contrast to normal cells,which did not take up the AIEgen. Irradiation with white light (4.2 mW cm À2 ,4 00-700 nm) induces the formation of 1 O 2 and thus,c ell apoptosis.S ince the apoptosis process leads to ad epolarization of the mitochondrial membrane potential and an increased cell permeability,t he AIEgen is cleaved form the mitochondria and relocated to the nucleus via electrostatic interactions with the nuclear DNA. Although the introduced studies are merely ap roof-of-concept, they surely promise to improve therapeutic treatments and evaluation of therapeutic responses.W ith future developments on AIEgens that display prolonged absorption and emission wavelengths,t he way is paved for multifunctional, self-reporting in vivo applications. Complementary to the self-reporting output of the precipitation polymerization introduced in Section 2.4 ( Figure 12 ), methods have been developed to monitor the progress and monomer conversion during light-triggered polymerization processes.F or example,aporphine zinc derivative applied in ap hoto-induced electron/energy transfer (PET) RAFT polymerization as photocatalyst enabled the real-time monitoring of the monomer conversion via changes in the fluorescence emission. [117] Another possibility is the application of the nitrile imine-mediated tetrazole-ene cycloaddition (NITEC) reaction, displayed in Scheme 1. Under light irradiation, nitrogen is released from the tetrazole moiety and an itrile-imine dipole is generated, which subsequently undergoes a1 ,3-dipolar cycloaddition with an alkene to yield ahighly fluorescent five-membered pyrazoline cycloadduct. By taking abifunctional tetrazole chain transfer agent (CTA) and ab ismaleimide,f luorescent polymers are formed in as tep-growth fashion upon irradiation at 320 nm. [118] While the initial reaction mixture shows no fluorescence emission, the poly(pyrazoline)s exhibit ab road fluorescence emission between 470 and 670 nm and thus,the progress of the reaction can be easily followed by fluorescence spectroscopy.S imilarly,t he NITEC reaction has been applied to monitor the formation of polymeric networks and their characterization. [119] Polymers having tetrazole chain termini can be crosslinked into polymeric networks in the presence of trimaleimides under UV irradiation. Fore ach crosslinking point, one fluorescent pyrazoline ring is formed and the kinetics of the network formation can be monitored in aq uantitative way.T herefore,a ne ffective self-reporting method is presented for the facile and detailed characterization of polymer networks,w hich so far has been often challenging due to the complexity of the network systems. Furthermore,l ight has been used as trigger for the intramolecular collapse of well-defined polymers to yield single-chain nanoparticles (SCNPs). In recent years,t he research into SCNPs has gained intensive attention since they find applications in catalysis,d rug delivery,p rotein mimics,orsensing.Among the various synthesis strategies for tailor-made SCNPs,the photo-induced chain collapse displays amild and versatile pathway,especially when combined with self-reporting properties.T hus,d ifferent strategies for the crosslinking have been developed, ranging from the earlier introduced NITEC reaction to single-chain collapse based on radical species.B yi ncorporating nitroxides [120] or pyrenesubstituted oxime esters [121] into polymers,l ight irradiation results in the formation of SCNPs with the ability to selfreport the status of the folding.O nt he one hand, nitroxidecontaining polymers exhibit no fluorescence in the unfolded state,w hereas folding in the presence of ac rosslinker into SCNPs leads to abroad emission between 380 and 550 nm, as can be seen in Figure 14 A. Oxidation with mCPBAr everses the process and the non-fluorescent, unfolded polymer is regained (Figure 14 A) . On the other hand, pyrene-substituted oxime ester polymers show the inverse behavior. While the unfolded polymer chain exhibits broad fluorescence emission between 400 and 800 nm due to the incorporated pyrene unit, light irradiation splits the oxime ester and the pyrene unit is cleaved from the polymer.S ince also CO 2 can be released during the reaction, the polymer chains have several possibilities to crosslink, as illustrated in Figure 14 B. Thus,b yc arefully choosing the incorporated species into polymer backbones,SCNPs with self-reporting characteristics depending on the folding-state are accessible.I nt his way, powerful tools for prospective biomedical, imaging,orsensor applications can be constructed, however, limitations such as folding in highly diluted media (c = 20 mg L À1 )o rc omplex monomer and polymer synthesis need to be overcome for industrial purposes. Thediscussion in the previous section on light-responsive materials revealed the importance of light as trigger for selfreporting properties.However,light is not only able to induce the self-reporting,b ut may also be the self-reporting characteristic itself.L ight as direct output of ac hemical reaction, that is,c hemiluminescence (CL), [122] [123] [124] [125] offers beneficial advantages such as high sensitivity and real-time monitoring over awide dynamic range without the need for sophisticated equipment. [124, [126] [127] [128] [129] [130] Therefore,CLreactions find widespread applications in biomedical or analytical fields with ongoing research for persistent improvement. However,the challenge to gain higher CL quantum yields,tune the emission range,or simplify the CL system is to modify the reaction environment or the luminophore itself in such away that the CL properties are not diminished accidentally.Nevertheless,recent research into common luminophores,s uch as dioxetanes, [131, 132] peroxyoxalates (POs), [122, [133] [134] [135] [136] [137] acridinium esters, [138] [139] [140] [141] luminol, [129, 142] and their respective derivatives,led to the development of aplethora of advanced, promising self-reporting CL systems.T he CL of acridinium esters,f or example,c an be triggered by antioxidants,e nzymes or peroxides and thus finds application in (biomedical) analytics as self-reporting sensor for these substances. [138] [139] [140] [141] In the presence of atrigger, the acridinium esters are oxidized to dioxetanones,w hich decompose with the release of CO 2 to form the highly emissive 10-methyl-9-acridone, [139, 143] as displayed in Scheme 2A.S of ar, alkaline conditions were required for the CL emission of acridinium esters.H owever,r ecently,a cridinium ester derivatives were synthesized which allow the CL reaction to proceed under neutral conditions.T his was achieved by introducing electron withdrawing groups (e.g. cyano,nitro,bromide,ortrifluoromethyl) in the 4-position of the phenol moiety. [139] Addition of cetyltrimethylammonium bromide also resulted in an increased CL of such acridinium ester derivatives. [140] Similarly,p eroxyoxalate (PO) luminophores are ideally suitable for analytical methods in food and environmental analysis,s ensor technology,p harmacology,b iology,o rm edicine. [122, 135, 136] As for the acridinium esters,the CL reaction of POs can be induced by various active species such as peroxides,m icroorganisms,g lucose,t oxins,o ra ntioxidants. [122, 144] Oxidation of POs,s uch as the bis(2,4,6-trichlorophenyl)oxalate (TCPO), results in the decomposition of the PO and the formation of an unstable energy-rich dioxetanone.I nc ontrast to the acridinium esters however,t he Reviews decomposition of the dioxetanone into CO 2 does not result in the emission of light unless af luorophore is present. In the presence of the latter,f or example,9 ,10-diphenylanthracene (DPA), the decomposition of the dioxetanone evokes excitation of the fluorophore and light is emitted during the relaxation into the ground state, [133] as can be seen in Scheme 2B.Although the need for an additional fluorophore for the CL reaction could be seen as disadvantage,t he possibility to readily adjust the emission wavelength from the UV/Vis to the NIR spectral range on demand by carefully choosing the fluorophore,rather than modifying the luminophore in a(complicated) synthesis strategy,clearly outweighs the need for two components. [134] Indeed, recently,t he successful combination of the PO moiety and the fluorophore in one material was reported to enable solid-phase CL readout. [133] This was achieved by synthesizing microspheres with apoly(divinylbenzene) core and apoly(2-hydroxyethyl methacrylate) shell, allowing the subsequent functionalization with at etrazole carboxylic acid. Finally,amaleimide-PO (MDCPO) was photochemically linked to the tetrazolecontaining microspheres via the aforementioned NITEC reaction, as presented in Figure 15 A. Theo btained "all-inone" microspheres provide high fluorescence and CL emission at low concentration of oxidative species,t hus acting as aself-reporting sensor for these oxidative species.Inaddition, the emission wavelength of the light output can be readily tuned by varying the incorporated tetrazole moieties.W ith the use of red-shifted tetrazoles,s uch microspheres are also applicable for biological systems and the solid-phase CL holds key potential to exceed current PO-CL multicomponent systems for sensing and detecting low concentrations of active species in aself-reporting manner. Correspondingly,t he improvement and simplification of complex CL systems has emerged into the field of the luminol chemistry.The well-known and most adopted luminophore in forensic science [145, 146] offers advantages such as low cost, broad analytical compatibility and expansive application spectrum. [147, 148] Similar to the CL of PO,t he CL of luminol is triggered by an oxidation reaction. As depicted in Scheme 2C,l uminol is present in its deprotonated species, namely the luminol mono-anion, in (basic) solution, and addition of an oxidant (e.g.ROS), the mono-anion is oxidized to the excited 3-aminophthalic acid, whose decay to the ground state is accompanied by as triking blue-green light. Unfortunately,the CL quantum yield of luminol is rather low in polar aprotic solvents,s uch as DMSO,o ra queous media, [123] thus diverse catalytic systems containing nanomaterials, [130, [149] [150] [151] [152] metal ions, [147, 148] or other enhancers [153] [154] [155] have been developed to improve the CL emission. Since all these systems suffer from individual disadvantages (cost, toxicity,a ir/moisture sensitivity,o rs tability issues,a mongst others), the development of new,a dvanced luminol-CL systems is of high importance.The critical point for achieving such improved luminol-CL systems is to identify aw ay to reduce the number of components to am inimum, while simultaneously boosting CL emission. Indeed, significant improvements were achieved by implementing an organic superbase,n amely 1,5,7-triaza-bicyclo-[4.4.0]dec-5-ene (TBD), into the oxidation reaction of luminol. [142] Superbases such as TBD find widespread application in organic synthesis and provide high pK a values (26.0 in acetonitrile for TBD), Scheme 2. CL reaction pathways of A) acridinium esters, B) POs in the presence of af luorophore, and C) luminol. Reviews combining two essential characteristics-basicitya nd catalysis-for the CL reaction of luminol in one molecule.U pon addition of H 2 O 2 to as olution containing only TBD and luminol, astriking blue light visible even with the naked eye is observed. Comparison of the CL emission of the luminol-TBD system with the organic superbases 1,1,3,3-tetramethylguanidine (TMG) and 1,8-diazabicyclo [5.4 .0]undec-7-ene (DBU) as well as with the already known inorganic base KOHand catalyst CuSO 4 ,respectively,revealed the superior CL emission of the luminol-TBD system, which can be clearly seen in Figure 15 B. Importantly,i nc ontrast to conventional inorganic bases applied in the luminol-CL reaction, organic superbases offer the possibility to be incorporated into polymeric materials.W ithout the need for a( complicated) TBD-monomer synthesis,t he TBD itself could be readily incorporated into the same polymeric backbone as luminol via ap ost-polymerization modification (PPM) approach, as demonstrated in Figure 15 C. [129] Thep ost-modified polymer further enables supramolecular (dis)assembly with randomly methylated b-cyclodextrin, analogous to the binding behavior between biomolecules and substrates,w hich results in as trong CL output that can be detected without the need for sophisticated instrumentation, such as nuclear magnetic resonance (NMR) and dynamic light scattering (DLS). Therefore,t he implementation of organic superbases to the CL reaction of luminol on the small molecule as well as on the macromolecular level not only expands the scope of luminol chemistry,b ut also paves the way for the design of new, artificial luminol materials in sensor technology or biomedical applications.Chemically responsive materials are of substantial interest in the fields of sensor,d iagnostic,o rb iomedical technology due to their fast and sensitive detection of specific active species via ac hemiluminescent output, visible even to the naked eye.H ence,s uch CL materials will certainly play acrucial role not only in future analytical processes,but also in the fast detection of (new) diseases and (benign/malignant) biomolecules. So far, self-reporting systems have been discussed which are responsive to one exclusive stimulus shown in Scheme 1. However,t here exist substrates that are able to respond to various stimuli, depending on the substituents of the selfreporting unit and the stimulus. [156] [157] [158] [159] [160] [161] One important class providing such multi-responsiveness are light emitting 1,2dioxetanes.I nc ontrast to the aforementioned CL systems in Section 2.6, the CL of 1,2-dioxetanes can not only be triggered by chemical reactions,b ut also by mechanical forces and temperature.T he thermal decomposition of 1,2-dioxetanes accompanied by the emission of light has already been reported in the 1970s. [162] [163] [164] Though elevated temperatures of up to 250 8 8C [165, 166] were required to induce decomposition, the Reprinted form ref. [142] .C opyright2 019, Springer Nature. C) Synthesis of the luminol-TBD-containingpolymer via free radical polymerization and subsequent post-polymerization modification.R eproducedfrom ref. [129] ,p ublished by the Royal Society of Chemistry. research into thermo-responsive 1,2-dioxetane derivatives was disregarded except for afew examples reported by Roda and co-workers. [165] [166] [167] [168] [169] [170] By synthesizing acridine-based 1,2dioxetane derivatives as depicted in Scheme 3A,t emperatures between 80 and 110 8 8Clead to the decomposition into 2-adamantone and an excited acridone species,w hich emits light upon returning to the ground state (similar to the 10methyl-9-acridone of the acridinium ester CL, Scheme 2A). On the other hand, significantly more research has been conducted to broaden the responsiveness of 1,2-dioxetanes towards chemical/biological stimuli. Based upon Schaaps findings in 1987, [131, 132] ap lethora of chemiluminescent 1,2dioxetane derivatives have been developed. Generally,a1,2dioxetane with an enzyme-or analyte-responsive protecting group was synthesized, whose removal triggers the chemically initiated electron-exchange (CIEEL) process.D uring this process,t he deprotected dioxetane decomposes and an excited benzoate ester species is obtained, which returns to the ground state accompanied by the emission of light (Scheme 3B). [123, 125, 132] By carefully choosing the phenol substituents (and their position) of Schaapsd ioxetane discovered in 1987, aplethora of CL 1,2-dioxetane derivatives for (bio-)labeling and imaging have been developed, which are also suitable for in vivo applications under physiological conditions. [126, [171] [172] [173] [174] [175] [176] [177] Besides the thermal and chemical activation, the CL of 1,2-dioxetanes can also be triggered by mechanical forces. Theincorporation of bis(adamantyl)1,2-dioxetanes into polymeric materials (e.g.p olyurethane, [178] [179] [180] [181] poly(methyl methacrylate), [182] poly(methyl acrylate), [183, 184] )p oly(dimethylsiloxane) [185] )e nabled the facile,r eal-time monitoring of bond breaking events in such materials,s ince mechanical force leads to ab ond scission of the dioxetane moiety into two adamantone-terminated polymer chain visualized by the emission of light, as can be seen in Scheme 3C.C learly,1 ,2dioxetanes represent an important class for the development of versatile,s mart, self-reporting materials since the CL can be easily tailored to the desired stimulus by thorough choice of the respective 1,2-dioxetane derivative. Another important class of self-reporting materials are liquid crystals (LCs). LCs find widespread applications in biology and medicine as well as in photovoltaic systems, displays,o pto-electronics,o rs ensors. [186] [187] [188] [189] [190] [191] Such diverse applications are attributed to the beneficial properties of LCs combining the order of crystals with the mobility of liquids.Upon exposure to stimuli (e.g.chemical or biological substrates,e lectrical fields,t emperature,o rm echanical forces), the initial order and mobility of the LC is disrupted and the optical appearance is adjusted. Abbott and coworkers took advantage of such self-reporting LCs and expanded the concept by introducing self-regulating properties. [192] This was achieved by synthesizing LC films of 4'pentyl-4-biphenylcarbonitrile( 5CB) dispersed with microdroplets containing ar ed dye for visualization (Figure 16 A,B) . Placed in amini-well with an overlying aqueous phase,the microdroplets are enclosed by strained LCs.Inthe presence of at hermal stimulus,t he LC undergoes ap hase transition and the original state of the LC is disturbed, which is visually indicated by the release of the red microdroplet. Since the phase transition of 5CB already takes place at 35 8 8C, the heat provided by ah uman finger is able to trigger the phase transition (Figure 16 C-E). Precisely at the moment when the phase transition takes place,aspecific amount of microdroplets is released, and subsequently the release stops. This behavior can be observed for several heating/cooling cycles,making the system self-regulating.Incontrast, conventional materials released their loadings unless the trigger was removed or the loading was completely released. In addition, the disturbance of the LC can be induced by mechanical forces,asdisplayed in Figure 16 F, G. While the LC does not release microdroplets into the overlying aqueous phase in the passive state (Figure 16 F) , the aqueous phase turns red upon mechanical shear stress induced by magnetic stirring (Figure 16 G) . Interestingly,m otile bacteria are also able to induce mechanical stress and thus trigger the release of microdroplets (Figure 16 H) . If the microdroplets are filled with an additional antibacterial agent (cationic DTAB and silver salts), the release of the droplets not only reports the presence of bacteria in av isible way,b ut also induces the killing of the bacteria. Thed ead bacteria are not moving anymore,t hus there no longer exists am echanical force and the release stops.C learly,t he combination of self-reporting and self-regulating properties in LCs responding to several stimuli holds great potential for future developments of programmable materials.V arious systems with the desired stimuli-responsive properties can be designed by carefully choosing the LC material and the composition of the microdroplets. Correspondingly,t he isomerization of the previously introduced spiropyrans (SP,see Section 2.1) into merocyanine (MC) can not only be induced by mechanical forces,but also by,f or example,t emperature,p H, solvation, or light. [193] [194] [195] [196] [197] [198] [199] [200] Intriguingly,S P-based self-reporting systems have been developed that respond to several stimuli simultaneously. [46] [47] [201] [202] [203] [204] Forexample,Qui et al. reported the synthesis of poly(hydroxyethyl acrylate) with incorporated SPs,w hich changed color upon light irradiation or swelling in water. [205] Furthermore,amphiphilic copolymers have been synthesized bearing SP moieties that self-assembled into micellar nanoparticles triggered by either light, pH, or temperature. [206] In another example,M ondal et al. synthesized an organic cage functionalized with SP units,w hich change their color from yellow to orange in the presence of thermal or photochemical stimuli. [207] This behavior was observed in solution and in the solid state.T ests of up to 20 UV/Vis-and heating/cooling cycles in both states proved the reversibility of the SP-MC isomerization upon thermal or photochemical treatment. Similarly,l uminogens such as hexakis(pyridine-4-ylthio)benzene show different-colored phosphorescence in the liquid and solid state depending on the applied stimulus (e.g. solvent, pH, metal ions). [208] Additionally,networks with acoordinated triphenylamine fluorophore have been synthesized which gradually change their emission color depending on either temperature (from cyan to green) or pressure (green to red) in areversible manner. [209] Such self-reporting multi-stimuli-responsive properties hold key potential for the development of innovative smart materials which are exposed to several stimuli at the same time,for example,outdoor materials or materials operational in extreme environments.M aterials often need to defy different stimuli simultaneously,f or example,t emperature and light (winter/summer,h eating/air conditioning,n atural/ artificial light, day/night,), chemicals (pollution, cleaning agents,a erosols), mechanical forces (wind, earth quakes, thunder), and weather conditions (rainy,d ry,h umid, foggy). Therefore,t he ability to report any damages or changes evoked by an interaction of several stimuli in avisible manner would help to increase the lifetime and safety of the materials. Additionally,c osts could be reduced due to ap rolonged lifetime and more effective maintenance. Throughout the current Review,wealready indicated the significance of self-reporting materials in the field of biology, medicine,a nd analytics.S ince the importance of novel, innovative materials in these fields has become particularly evident in consideration of the current SARS-CoV-2 (COVID-19) pandemic, [210] [211] [212] [213] the current chapter focuses on self-reporting materials as (biomedical) diagnostic tools. Forinstance,the detection of important biological substrates (e.g. biothiols) that influence physiological processes often requires sophisticated and complex analytical methods such Figure 16 . A) Structure of the LC 4'-pentyl-4-biphenylcarbonitrile (5CB). B) Dispersion of microdroplets in 5CB hosted in amini-well, which is immersed in an overlying aqueous phase. C-E) The heat of ahuman finger applied to release the microdroplets from the LC. F, G) Release of microdroplets from the LC F) before and G) after inducing mechanical stress by stirring of the overlying aqueous phase. H) Bacteriainduced release of the microdroplets. Reprinted by permission from Springer nature, ref. [192] ,C opyright2 018. as HPLC,capillary electrophoresis separations,and immunoassays,a nd time-consuming sample preparations are required. [214] [215] [216] Therefore,s elf-reporting systems based on fluorescence changes have been developed for the simple and fast detection of biothiols.T hese biothiols include cysteine (cys),h omocysteine (hcy), glutathione (GSH), or hydrogen sulfide (H 2 S), which are responsible for cell mobility and degradation, maintaining redox homeostasis and xenobiotic metabolism, apoptosis,o ra nti-inflammation. In addition, deviations from regular levels serve as indicators for disorders (Alzheimer,c ardiovascular diseases,s lowed growth, liver damage,o rl ethargy,a mongst others). [217] [218] [219] While several systems have been developed for the selective detection of single cys, [220] [221] [222] [223] cys/hcy, [214] or GSH, [214, 215] the production and metabolism of the biothiols are interconnected and often two or more of the biothiols are present at the same time. Therefore,i tw ould be highly beneficial to have sensor molecules for the simultaneous detection of such biothiols. [224] [225] [226] Despite the similar chemical structure and reactivity,s elf-reporting materials have been developed that are not only able to detect multiple biothiols,b ut also to distinguish between them. Fore xample,acoumarin-based fluorescent probe was successfully applied to distinguish between GSH and cys/hcyb ased on different fluorescent emission behavior. [227] Thef luorescence emission can also be altered by taking advantage of the unique binding behavior of the biothiols.F luorophores with several functional groups, each specifically reacting with asingle biothiol, reveal different fluorescence emissions depending on the biothiol and the reacted functionality. [228, 229] In another example,alysosometargetable probe with both 7-dimethylaminocoumarin and resorufin as fluorophores was synthesized as depicted in Figure 17 . [230] Thef ree resorufin exhibits red emission, while the bonded resorufin shows no emission and quenches the fluorescence of the coumarin fluorophore.Inthe presence of H 2 S, cys/hcy, or GSH, the resorufin is cleaved and the red emission is turned on. Depending on the present biothiol, the coumarin fluorophore exhibits different fluorescence emission:n of luorescent product is obtained in the presence of H 2 S, whereas agreen-emitting product is obtained when GSH is present and ab lue-emitting species in the presence of cys/ hcy ( Figure 17 ). Thus,t he distinctive fluorescence pattern (red, red-green, or red-blue) self-reports the presence of aspecific biothiol. Besides biothiols,p athogens such as bacteria, fungi, parasites,o rv iruses play ac ritical role in biology and medicine.P athogens are responsible for various health issues and diseases (inflammations,( food/water) poisoning, influenza, Middle-East Respiratory Syndrome (MERS) CoV, SARS-CoV-1/-2, cancer). [211, 217, 218, [231] [232] [233] [234] Therefore,i tw ould be highly beneficial to detect pathogens in as elf-reporting, fast, and efficient manner to stop them from spreading. Indeed, various methods for the self-reporting detection of pathogens have been developed. [235] [236] [237] [238] [239] Fore xample,c ertain pathogens are responsible for elevated levels of enzymes, which can be easily detected in the presence of suitable fluorophores. [231, 234, [240] [241] [242] Another strategy applies optical sensors with porous Si photonic crystals.T he pore size can be adjusted to capture targeted bacteria, for example, Escherichia coli (E. coli), which results in areflectivity change.T his method allows the facile and sensitive detection of various pathogens due to the tunable size of the pores. [243] Similarly,i ndium tin oxide screen-printed electrodes were coated with polyaniline (PANI) and antibodies able to capture targeted pathogens ( Figure 18 ). [244] In the absence of pathogens,aconstant potential leads to ac hange in the oxidation state and thus, the color changes from yellow to blue.I nt he presence of pathogens however,the resistance on the electrode surface is affected and different-colored PA NI oxidation states are obtained, depending on the concentration of the pathogen ( Figure 18 ). By carefully choosing the polymeric material and antibody for the electrode coating,various pathogens may be detected in asimple,fast and visible manner. Clearly,t he introduced self-reporting systems for the detection of biological substrates and pathogens hold great potential for innovative,s mart materials.D evelopments towards innovative systems that self-report the presence of any biomolecules or pathogens in as elective and fast way might help to prevent future pandemic outbreaks of diseases. First of all, the presence of anew potential pathogen (such as the current pandemic virus) needs to be detected before it can spread worldwide.Onthe other hand, rapid analytical results Figure 17 . Various fluorescence emission patterns of the lysosometargetable probe in the presence of H 2 S, cys/hcy,and GSH. Reprinted from ref. [230] ,C opyright2 018 American Chemical Society. will disburden clinical laboratories and infected patients could be isolated immediately to reduce the risk of infection. Inspiring ideas such as virucidal-active personal protective equipment, [212] antiviral surface coatings, [212] or even selfsanitizing surfaces [210] have been suggested. Since pathogens are not only transmitted via surfaces but, more importantly, via the air,f uture aerosols with self-reporting properties and possible antiviral activities would surely prove as ap owerful tool to combat and contain pathogens. Thes ignificant growth of studies on stimuli-responsive materials within the past decade indicates the importance and demand for further research and developments of such materials.W hile stimuli-responsive materials with self-healing properties remain mainly laboratory proof-of-concept constructs,s timuli-responsive materials equipped with selfreporting properties already find application in the industry. Examples are thermo-responsive inks,f orensic chemiluminescent mixtures,o rl iquid crystal displays.H owever,t here are still key challenges that need to be overcome to broaden the possibilities for commercial application:( i) the design of self-reporting materials is hampered by multi-step synthesis, low yield, high-cost, and non-practical up-scaling;(ii)the selfreporting function is often limited in terms of reactive functions,cycles or mobility;(iii)high energy input is required for self-reporting,p articularly in the presence of heat or UV light as stimuli, which tend to be replaced by softer stimuli, such as visible light;a nd (iv) self-reporting is generally limited to detecting nano-or microscopic damages.Therefore, the development of self-reporting materials addressing these issues is of high relevance to the field. Indeed, future progress will likely be driven by the combination of the different concepts described in the present Review.I mportantly,t he combination of chemical or physical feedback mechanisms within asingle material appears to be an attractive option to ensure that amaterial change is indeed reported. Finally,the development of combinatorial spectroscopic techniques in conjunction with detailed knowledge regarding the selfreporting mechanisms still remains in its early stages,y et is akey factor for designing efficient systems. 0428; Angew.C hem Angew.C hem. Int Mater.I nterfaces Polymer Composites with Functionalized Nanoparticles Genoa bridge collapse-what went wrong and are other bridges at risk? Italy Bridge Collapse Leaves 37 Dead As it happened: Genoa motorway bridge disaster Whittington Advances in Air Conditioning Technologies:Improving Energy Efficiency,S pringer Singapore Stimuli Responsive PolymericN anocarriers for Drug Delivery Applications T ang, Angew.C hem. Int 050; Angew.C hem Chemiluminescence and Bioluminescence:P ast, Present and Future,R oyal Society of Chemistry Macromolecules Mater.I nterfaces Revised manuscript received: November8 ,2 020 Acceptedm anuscript online Theauthors declare no conflict of interest.