key: cord-0995555-8bql74ul
authors: Niculescu, Adelina-Gabriela; Chircov, Cristina; Bîrcă, Alexandra Cătălina; Grumezescu, Alexandru Mihai
title: Nanomaterials Synthesis through Microfluidic Methods: An Updated Overview
date: 2021-03-28
journal: Nanomaterials (Basel)
DOI: 10.3390/nano11040864
sha: 4b8e6997e9c2ddb6308323ce81081ddf6fb97af8
doc_id: 995555
cord_uid: 8bql74ul

Microfluidic devices emerged due to an interdisciplinary “collision” between chemistry, physics, biology, fluid dynamics, microelectronics, and material science. Such devices can act as reaction vessels for many chemical and biological processes, reducing the occupied space, equipment costs, and reaction times while enhancing the quality of the synthesized products. Due to this series of advantages compared to classical synthesis methods, microfluidic technology managed to gather considerable scientific interest towards nanomaterials production. Thus, a new era of possibilities regarding the design and development of numerous applications within the pharmaceutical and medical fields has emerged. In this context, the present review provides a thorough comparison between conventional methods and microfluidic approaches for nanomaterials synthesis, presenting the most recent research advancements within the field.

Nanotechnology gained significant importance when scientists realized that the size of the material is a major factor that influences the properties of a substance. Since then, several conventional methods have been employed for nanomaterials production, including condensation, chemical precipitation, and hydrothermal synthesis as the most common approaches [1] [2] [3] . Choosing an appropriate synthesis method with accurate control over the reaction conditions is essential for delivering high-quality products destined for specific applications. In this respect, a promising new technology emerged: microfluidics [4] .

As one of the most prominent figures in the field of microfluidics, George Whitesides, stated, microfluidics is "the science and technology of systems that process or manipulate small (10 −9 to 10 −18 L) amounts of fluids, using channels with dimensions of tens to hundreds of micrometers" [5] [6] [7] .

Microfluidic devices' dimensions and unique geometries allow for smaller reagent volume use, precise control of fluid mixing, efficient mass transport, improved heat transfer, ease of automation, and reduced reaction time [7] [8] [9] [10] [11] [12] [13] . The advantages of using microfluidic methods over traditionally known approaches led to the design, fabrication, and usage of portable, low-cost, and disposable devices [6, 9, 14] .

All the characteristics mentioned above make microfluidics highly advantageous for diverse applications, ranging from chemical, biological, and material industries to the pharmacy, clinical diagnosis, translational medicine, and drug discovery [11, 14, 15] . Being able to overcome some of the most challenging downsides of scale-up reactors, microfluidic technology is increasingly used in preparing nanoparticles and in carrying out various able to overcome some of the most challenging downsides of scale-up reactors, microfluidic technology is increasingly used in preparing nanoparticles and in carrying out various chemical syntheses [7, 16] . It should be noted that microfluidic devices are also found in the literature under the term "microreactors" when used as synthesis vessels [7, 10, 14] .

This work presents nanomaterials synthesis from the perspective of conventional and microfluidic methods, the advantages and challenges of each category, and the possible products they may yield. Thus, it provides a thorough comparison between traditional methods and microfluidic approaches, describing the most recent advancements and applications within the field.

Nanomaterials are structures that have at least one dimension between 1 and 100 nm [17, 18] . Such materials have revolutionized many domains, out of which the most intensively researched are related to modern medicine, especially regarding biosensors, diagnostics, targeted drug delivery, and therapeutics [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] . Having such a broad spectrum of applications, nanomaterials should be synthesized as efficiently as possible in order to gain extensive market reach.

Nanostructure formation can be achieved using two main approaches: top-down and bottom-up [16, 38, 39] (Figure 1 ). As the name implies, the top-down approach is based on the size-reduction of larger structures by means of mechanical force. Such methods are preferred for industrial scale-up, but they require expensive equipment and intensive energy without providing control over particle growth. By contrast, the bottom-up approach involves the growth and self-assembly of nanostructures from atomic or molecular precursors. Generally, this method results in the production of amorphous particles with increased solubility and bioavailability, which, however, tend to agglomerate. Nonetheless, such methods are simple, rapid, and energy-and cost-efficient, ideal for laboratory-scale production and synthesis of smaller particle sizes with narrow particle size distribution [7, 16] . [40] .

A variety of techniques are available for the synthesis of nanostructures (Table 1) . Despite their diversity, these conventional approaches lack tight control over experimental variables, generating nanoparticles with wide size distribution and large interbatch variability [41] . The poor selectivity of batch reactors results in their mediocre performance in terms of synthesizing products with controllable structures and properties [42] . Table 1 . Conventional methods for the synthesis of nanoparticles and nanocomposites.

Refs.

Co-precipitation Simultaneous occurrence of nucleation, growth, coarsening, and/or agglomeration processes [17, 43] Hydrothermal synthesis

Chemical reactions between substances found in a sealed, heated solution above the ambient temperature and pressure [17, 43] Inert gas condensation Metals undergo evaporation in an ultrahigh vacuum chamber filled with He or Ar at high [17, 44] Adapted from an open-access source [40] .

A variety of techniques are available for the synthesis of nanostructures (Table 1) . Despite their diversity, these conventional approaches lack tight control over experimental variables, generating nanoparticles with wide size distribution and large inter-batch variability [41] . The poor selectivity of batch reactors results in their mediocre performance in terms of synthesizing products with controllable structures and properties [42] .

Physical and chemical processes may provide uniform-sized nanoparticles yet at the expense of negatively impacting the environment. In other words, such techniques release toxic/hazardous materials into the environment [71, 72] , acting as pollutant sources and high-energy consumers [73] . Moreover, the need for large spaces, expensive equipment, and high-power consumption translates into high costs [7, 71, 72, 74] . Other industrial scaleup issues include alternation of synthesis conditions and insufficient control of the mixing process during the preparation of nanoparticles [75] , complex stepwise operations, waste of resources, poor reproducibility, safety concerns [42] , highly specialized and difficult to manufacture equipment, and long synthesis times [76] . In addition to the disadvantages associated with the synthesis process, the obtained products may also suffer from uncontrolled particle growth (narrow size distribution shifted to large particle dimensions [77] ), potential contamination [7], non-proper surface structures [72] , and poor size distribution (high polydispersity index values) [42] , which further affect the functionalities of the materials. Such limitations contribute to the hampering of synthetic chemistry from evolving towards green synthesis, big data, chemo/bioinformatics, and precision biomedicine [42] . Moreover, the limitations of conventional synthesis techniques result in a slow translation from research to practical applications, especially in the medical field [78] [79] [80] . Therefore, it is an urgent matter to develop an easy to manipulate technique for the efficient synthesis of high-quality nanomaterials [4] . Table 1 . Conventional methods for the synthesis of nanoparticles and nanocomposites.

Synthesis Method Description Refs.

Co-precipitation Simultaneous occurrence of nucleation, growth, coarsening, and/or agglomeration processes [17, 43] Hydrothermal synthesis

Chemical reactions between substances found in a sealed, heated solution above the ambient temperature and pressure [17, 43] Inert gas condensation Metals undergo evaporation in an ultrahigh vacuum chamber filled with He or Ar at high pressure, collide with the gas, and condense into small particles, forming nanocrystals in the end [17, 44] Sputtering Ejection of atoms from the surface of a material by bombardment with energetic particles [17, 45] Microemulsion An isotropic, macroscopically homogeneous, and thermodynamically stable solution containing a polar phase, a nonpolar phase, and a surfactant; reactant exchange occurs during the collision of droplets within the microemulsion [17, [46] [47] [48] Microwave-assisted Synchronized perpendicular oscillations of electric and magnetic fields produce dielectric heating throughout the material at the molecular/atomic level [48, 49] Laser ablation Removing material from a (usually) solid surface by irradiating it with a laser beam [17, 48, 50] Sol-gel 5-step method: hydrolysis of precursors, polycondensation (gel formation), aging (continuous changes in the structure and properties of the gel), drying, and thermal decomposition [51] Ultrasound Ultrasonic cavitation induced by irradiating liquids with ultrasonic radiation [17, 52] Spark discharge An abrupt electric discharge occurs when a sufficiently high electric field creates an ionized, electrically conductive channel through a normally insulating medium, thus producing a highly reactive soot [17, 53] Template synthesis Uniform void spaces of porous materials are used as hosts to confine the synthesized nanoparticles as guests [17, 54] Biological synthesis Synthesis using natural sources, avoiding any toxic chemicals and hazardous byproducts, usually with lower energy consumption [55] Nanocomposites Spray pyrolysis A thin film is deposited by spraying a solution on a heated surface, upon which the constituents react to form a chemical compound [17, 56] Infiltration A preformed dispersed phase is soaked in a molten matrix metal, which fills the space between the dispersed phase inclusions [17, 57] 

Rapid extraction of thermal energy to include both super heat and latent heat during the transition from a liquid state at high temperature to a solid material at room temperature [17, 58] High energy ball milling High mechanical forces provide energy for the activation and occurrence of a chemical reaction [59] Vapor deposition (VD)

Chemical VD

The substrate is exposed to volatile precursors that react and/or decompose on its surface to produce the desired deposit [17, 48, 60, 61] Physical VD

The material goes from a condensed phase to a vapor phase and then back to a thin film condensed phase [17, 62] Colloidal method

Under controlled temperature and pressure, different ions are mixed in a solution to form insoluble precipitates [47, 63] Powder process Compression, rolling, and extrusion are used to obtain a compact mass that is further sent to a sintering furnace [17, 64] Polymer precursor A polymeric precursor is mixed with the matrix material, undergoes pyrolysis in a microwave oven, thus generating the reinforcing particles [17, 65] Melt blending

Melting of polymer pellets to form a viscous liquid followed by the use of high shear force to disperse the nanofillers [60, 66] Solution mixing

Dispersion of nanofiller in a polymer solution by energetic agitation, controlled evaporation of the solvent, and composite film casting [17, 67] In situ intercalative polymerization Polymer formation occurs between the intercalated sheets of clay [17, 68, 69] In situ formation and sol-gel A multi-step process including the embedding of organic molecules and monomers on sol-gel matrices followed by the introduction of organic groups by the formation of chemical bonds, resulting in situ formation of a sol-gel matrix within the polymer and/or simultaneous generation of inorganic/organic networks [17, 70] 

Microfluidic technology provides the means to overcome some of the most pressing drawbacks of conventional synthesis methods due to the small capillary dimension and the resulting large surface-to-volume ratio. Through these features, rapid and uniform mass transfer and superior control over the produced nanomaterial characteristics are enabled in microfluidic syntheses [75] . In comparison to bulk methods, highly stable, uniform, monodispersed particles with higher encapsulation efficiency can be obtained by efficiently controlling the geometries of the microfluidic platform and the flow rates of the involved fluids [81] .

As previously mentioned, microfluidic devices' working principle is based on the movement of fluids within micro-scaled channels and chambers of special geometry, integrating sample preparation, reaction, separation, and detection [38, 82] .

Concerning synthesis strategies, there are two main types of microreactors depending on flow pattern manipulation, namely single-phase (continuous-flow microfluidics) and multi-phase flow (droplet-based microfluidics) ( Figure 2 ) [16, 83] . Each of these categories is further described in more detail.

mass transfer and superior control over the produced nanomaterial characteristics are enabled in microfluidic syntheses [75] . In comparison to bulk methods, highly stable, uniform, monodispersed particles with higher encapsulation efficiency can be obtained by efficiently controlling the geometries of the microfluidic platform and the flow rates of the involved fluids [81] .

As previously mentioned, microfluidic devices' working principle is based on the movement of fluids within micro-scaled channels and chambers of special geometry, integrating sample preparation, reaction, separation, and detection [38, 82] .

Concerning synthesis strategies, there are two main types of microreactors depending on flow pattern manipulation, namely single-phase (continuous-flow microfluidics) and multi-phase flow (droplet-based microfluidics) ( Figure 2 ) [16, 83] . Each of these categories is further described in more detail. 

When it comes to nanoparticle production within microfluidic devices, single-phase systems are the most commonly used. This pattern flow is the variant of choice in many studies due to its simplicity, homogeneity, and versatility in controlling process parameters, such as flow, reagent amount, reaction time, and temperature [7, 11] .

Generally, single-phase synthesis is performed under laminar flow (with a Reynolds number lower than 10). Due to the absence of turbulence, the main mixing mechanism is molecular interdiffusion [7, 11, 16] . Therefore, continuous flow microfluidics is an excellent solution for nanoprecipitation processes, improving controllability, reproducibility, and homogeneity of product characteristics [7, 84] . Therefore, the homogeneous environment present in single-phase flow systems is ideal for the synthesis of small nanoparticles with a narrow particle size distribution, which is especially needed in pharmaceutics formulations [7, 83] .

Nonetheless, molecular interdiffusion is a slow process, limiting reaction speed [85] . Moreover, single-phase flow reactors have a parabolic velocity profile that causes a nonuniform residence time distribution [86] . This velocity profile becomes problematic in the case of nanomaterials for which crystallization kinetics is sensitive to the residence time distribution in the early stages of growth, causing the nanoparticles flowing near the walls to have larger dimensions than those flowing near the center [16] . However, these drawbacks can be overcome by creating turbulence through bending/folding and stretching the microchannels, thus enhancing mixing [7,11].

Unlike single-phase microfluidics, multi-phase flow (also known as segmented flow) systems involve two or more immiscible fluids [11] . Such heterogeneous systems facilitate passive mixing by enhancing mass transfer, narrowing the deviation of residence time and minimizing the deposition of reagents/products on channel walls [11, 16, 84] . 

When it comes to nanoparticle production within microfluidic devices, single-phase systems are the most commonly used. This pattern flow is the variant of choice in many studies due to its simplicity, homogeneity, and versatility in controlling process parameters, such as flow, reagent amount, reaction time, and temperature [7, 11] .

Generally, single-phase synthesis is performed under laminar flow (with a Reynolds number lower than 10). Due to the absence of turbulence, the main mixing mechanism is molecular interdiffusion [7, 11, 16] . Therefore, continuous flow microfluidics is an excellent solution for nanoprecipitation processes, improving controllability, reproducibility, and homogeneity of product characteristics [7, 84] . Therefore, the homogeneous environment present in single-phase flow systems is ideal for the synthesis of small nanoparticles with a narrow particle size distribution, which is especially needed in pharmaceutics formulations [7, 83] .

Nonetheless, molecular interdiffusion is a slow process, limiting reaction speed [85] . Moreover, single-phase flow reactors have a parabolic velocity profile that causes a nonuniform residence time distribution [86] . This velocity profile becomes problematic in the case of nanomaterials for which crystallization kinetics is sensitive to the residence time distribution in the early stages of growth, causing the nanoparticles flowing near the walls to have larger dimensions than those flowing near the center [16] . However, these drawbacks can be overcome by creating turbulence through bending/folding and stretching the microchannels, thus enhancing mixing [7,11].

Unlike single-phase microfluidics, multi-phase flow (also known as segmented flow) systems involve two or more immiscible fluids [11] . Such heterogeneous systems facilitate passive mixing by enhancing mass transfer, narrowing the deviation of residence time and minimizing the deposition of reagents/products on channel walls [11, 16, 84] .

As the name implies, droplet-based microfluidics concerns the formation and manipulation of discrete droplets inside microchannels [87] . Droplet production is regulated through device geometry, channel dimensions, and flow rates of each fluid, allowing precise monitoring and control over material fabrication processes [88, 89] .

There are two subcategories of multi-phase flow: gas-liquid (bubbles) and liquidliquid segmented flows [16] . Gas-liquid segmented flow microfluidics is of interest due to the simple separation of gas from liquid, which can be useful for nanoparticle synthesis [11, 84] . Another feature specific to gas-liquid flow systems is carrying reactions in segmented liquid slugs, where segmenting gas is introduced to create recirculation and to enhance mixing efficacy [11, 84] . Bubbles can be created either by using active methods (e.g., short high-voltage pulses [85] , acoustic micro streaming [90, 91] , and liquid metal actuators [92] ) or in a passive manner (by simply bubbling a gas [93, 94] ). Through these methods, a microfluidic channel's roughness is exploited towards rapid mixing and homogenization of the fluids [91] . Depending on the gas and liquid superficial velocities, annular flow patterns can also be employed. Such patterns appear when there is a continuous gas core flow in the channel center and a liquid film on the channel's inner surface [16] . In liquid-liquid segmented flow systems, segmentation is achieved through surface tension differences between the immiscible fluid streams [16] . The flow patterns are often presented as water-in-oil or oil-in-water dispersions, requiring the addition of surfactants to minimize coalescence of the dispersed droplets [11] .

Due to rapid production and analysis, droplets can be employed when developing reproducible and scalable particles with specific sizes, shapes, and morphologies, which are difficult to achieve otherwise [88, 89] . In addition, droplet microreactors show enhanced mass and heat transport, accurate manipulation, reliable automation, and greater production capacity [7, 10] . Hence, there is no surprise that multi-phase flow systems have become indispensable tools in various science applications [89] . These devices find use in producing emulsions, microdroplets, microparticles, and nanoparticles with distinct morphologies [7, 88] . Moreover, droplets can act as single reaction vessels for cell growth [95] .

However, several downsides to multi-phase flow systems must be considered when designing these applications. One of the disadvantages is the poor stability of droplets. This can be overcome through the addition of surfactants, but this solution is not suitable for all situations. Another issue comes from the fact that droplets are never completely isolated, as almost always, an extent of material exchange between droplets takes place [89] . However, whether these problems affect the desired outcome or not depends on what the device is used for.

For a better understanding of microfluidic methods, the most common microreactor flow types are gathered in Figure 3 .

liquid segmented flows [16] . Gas-liquid segmented flow microfluidics is of interest due to the simple separation of gas from liquid, which can be useful for nanoparticle synthesis [11, 84] . Another feature specific to gas-liquid flow systems is carrying reactions in segmented liquid slugs, where segmenting gas is introduced to create recirculation and to enhance mixing efficacy [11, 84] . Bubbles can be created either by using active methods (e.g., short high-voltage pulses [85] , acoustic micro streaming [90, 91] , and liquid metal actuators [92] ) or in a passive manner (by simply bubbling a gas [93, 94] ). Through these methods, a microfluidic channel's roughness is exploited towards rapid mixing and homogenization of the fluids [91] . Depending on the gas and liquid superficial velocities, annular flow patterns can also be employed. Such patterns appear when there is a continuous gas core flow in the channel center and a liquid film on the channel's inner surface [16] . In liquid-liquid segmented flow systems, segmentation is achieved through surface tension differences between the immiscible fluid streams [16] . The flow patterns are often presented as water-in-oil or oil-in-water dispersions, requiring the addition of surfactants to minimize coalescence of the dispersed droplets [11] .

Due to rapid production and analysis, droplets can be employed when developing reproducible and scalable particles with specific sizes, shapes, and morphologies, which are difficult to achieve otherwise [88, 89] . In addition, droplet microreactors show enhanced mass and heat transport, accurate manipulation, reliable automation, and greater production capacity [7, 10] . Hence, there is no surprise that multi-phase flow systems have become indispensable tools in various science applications [89] . These devices find use in producing emulsions, microdroplets, microparticles, and nanoparticles with distinct morphologies [7, 88] . Moreover, droplets can act as single reaction vessels for cell growth [95] .

However, several downsides to multi-phase flow systems must be considered when designing these applications. One of the disadvantages is the poor stability of droplets. This can be overcome through the addition of surfactants, but this solution is not suitable for all situations. Another issue comes from the fact that droplets are never completely isolated, as almost always, an extent of material exchange between droplets takes place [89] . However, whether these problems affect the desired outcome or not depends on what the device is used for.

For a better understanding of microfluidic methods, the most common microreactor flow types are gathered in Figure 3 . [96] , (c) flow-focusing [96] , (d) continuous flow [97] , (e) slug flow [98] , and (f) annular flow [98] . Reprinted from openaccess sources. [97] , (e) slug flow [98] , and (f) annular flow [98] . Reprinted from openaccess sources.

As more and more synthesis reactions are moving towards microfluidic production, it is clear that there are several advantages in comparison to classic methods. In this context, Table 2 comprises these benefits in an organized manner. 

There is no doubt that microfluidic technology has many advantages compared to preexisting synthesis and testing methods. However, certain aspects become more pronounced when miniaturizing equipment down to the microscale, e.g., surface roughness, capillary forces, and chemical interactions between materials [101] . Hence, some specific challenges and limitations are to be considered.

The enhancement of material properties can cause unexpected experimental complications as the reactor behaves differently from traditional laboratory equipment [101] . The small dimensions impose a limitation on the nanoparticle production rate as the possible flow-rates do not compare with those from conventional bulk mixing methods [16, 38] . In addition, the formation of undesired products due to side reactions is not completely solved by microreactors. However, secondary chemical reactions are minimized through the accurate control of reaction conditions, leading to much smaller amounts of by-products than in macroscale processes [108, 109] .

Moreover, the small diameters of the channels make them susceptible to clogging [11] . The solute concentration can be increased to solve the production rate issue, but this may lead to precipitation on channel walls, followed by particle growth inside the chip [38] . A similar effect is caused by the production of insoluble materials during polymerization reactions when very high molecular weights are obtained [8] . Nanoparticle agglomeration or formation of aggregates may also be behind channel blockage [14, 38] . The effect is stronger at the wall surface due to the longer residence time induced by the laminar velocity profile [8] . Microchannel clogging remains a major concern in synthesis processes as it alters mixing and may result in experimental failure [11, 14] .

Another challenge consists of choosing the right device substrate, especially because many materials have poor solvent compatibility and low resistance to high temperature. In this respect, novel materials should be developed to manufacture reliable and costeffective chips [11] . Furthermore, the manufacturing techniques, supply, and demand are not in favor of microfluidic industrialization, as there is a lack of large-scale production development [10, 16, 95] . To increase interest in mass production, purification and extraction processes should be improved and integrated with nanoparticle synthesis to create fully automated production [11] .

As nanotechnology is still in its infancy, nanoparticles' production and application are expected to continuously improve [16] . In recent years, microfluidic methods were exploited to synthesize nanoparticles with different sizes, shapes, and surface compositions, Nanomaterials 2021, 11, 864 9 of 28 with small size distribution, high drug encapsulation efficiency, prolonged circulation time, and heightened tumor accumulation [13, 41] . Depending on the reaction conditions and finite products' requirements, chips of various materials and geometries can be employed. Typical substrates include glass, silicon, metals, polymers, and ceramics, but the diversity and quality of materials are continuously increasing [10, 14, 104, 110, 111] . In terms of channel geometry, two main classes of devices can be distinguished: flow-focusing and T-junction [112] .

To correlate these aspects with the synthesis methods and the obtained products, several research studies concerning nanomaterials synthesis through microfluidic methods were summarized in Tables 3-6.

Inorganic nanoparticles find use in various fields, ranging from electronics, energy, and textiles to biotechnology, bio-imaging, and bio-sensing. Most of these applications are based on materials such as gold, silver, silica, alumina, titanium oxide, and zinc oxide, but not exclusively [16, 41, 113] .

Noble metal nanoparticles, such as gold, silver, and platinum, are of special interest in medical applications due to their size and shape properties [84, 88] . Various metal nanoparticles of controlled size and structure can be synthesized in droplet-based microfluidic reactors via the reduction of metal ion precursors in the presence of stabilizing ligands [113] .

Gold nanoparticles (Au NPs) were produced via microfluidic methods by several researchers, inspired by the outstanding properties and potential applications of this material. Generally, the reduction of a gold precursor takes place in the presence of different types of ligands and stabilizers. The use of strong reducing agents, such as sodium borohydride, ensures fast nucleation and small sizes of finite products. The reduction of gold ions fits in a timeframe of seconds, following fast kinetic crystallization at the nanoscale [16] . Spheres, spheroids, rods, and other various shapes can be obtained from spherical Au NP seeds (of less than 4 nm in size) by adjusting the concentrations of reagents, feed rates of individual aqueous streams, reduction potentials of the metal complex, and adsorbate binding strength [11, 88] .

Silver nanoparticles (Ag NPs) are another category of noble metal nanoparticles with properties much different from the bulk material [101] . Over the past decade, Ag NPs have been widely used, especially due to their antimicrobial, optical, and electrochemical properties [114] . The intrinsic features of AgNPs are in strong correlation with particle size, shape, composition, crystallinity, and structure, among which size and shape are the most important [103] . For this reason, the possibility for precise control within microfluidic devices increased the research interest in microreactor synthesis.

Zinc oxide nanoparticles (ZnO NPs) have drawn much attention recently in the field of nanomedicine, especially for tissue engineering, targeted drug delivery, contrast agents, and therapeutics against cancer [115] . To obtain high-quality ZnO NPs, their synthesis can be performed in microfluidic devices as well. The controlled production of ZnO NPs with well-defined physicochemical properties has already been demonstrated to be effective for various shapes, such as wires, spheres, rods, spindles, ellipsoids, and sheets [116] .

Titanium oxide nanoparticles (TiO 2 NPs) of uniform size can also be rapidly and economically produced in microreactors [117, 118] . The synthesized particles have excellent photodegradation efficiency, rendering them suitable for environmental remediation applications [117] .

Silica nanoparticles (SiO 2 NPs) are also considered valuable in various fields, attracting interest in their microfluidic production [119] . One of the most important configurations for biomedicine purposes is mesoporous silica, a material of intensive research in recent years [120, 121] .

Magnetic nanoparticles (MNPs) are an important class of nanomaterials due to their unique properties, such as chemical stability, magnetic response, biocompatibility, and low cost [16] . These advantageous features created interest in the microfluidic production of MNPs to be further used for a wide range of applications in biomedicine-related fields, such as biomedical imaging (e.g., contrast-enhancing agents in magnetic resonance imaging), site-specific drug delivery, bio-sensing, diagnosis, biological sample labeling, and sorting [11, 84, 119, 122, 123] . Cobalt nanoparticles (Co NPs) are an example of MNPs with different properties depending on the crystal structure [119] . Other MNPs that have gained research attention are iron oxide nanoparticles (IONPs) [119] . These materials have promising properties required in nanomedical applications, making their microfluidic production a natural step towards enhancing IONPs quality [76] .

Quantum dots (QDs) can be produced in microfluidic systems by miniaturizing the traditional synthesis methods, leading to high-quality, monodisperse particles [124] . Semiconductor QDs, in general, and Cadmium Selenite (CdSe) QDs, in particular, have attracted much interest in scientific research due to their tunable bandgap, narrow emission spectrum, high conductivity and mobility, and outstanding chemical and light stability [114] . Moreover, their tunable photoluminescence in the visible spectrum allows CdSe QDs to be used for biomedical purposes and optical-electronic applications [113] .

Besides metallic-based nanoparticles, microfluidics has attracted recent interest for the synthesis of non-metallic materials, as well. One such example is represented by sulfur, the ability of which to inhibit bacteria and fungi makes these nanoparticles suitable for sterilization of food and utensils. The controllable particle size and uniform morphology attained through microfluidic technology improve sulfur nanoparticles' bactericidal performance [125] . 

Microfluidic methods have also been employed for the synthesis of organic nanoparticles due to their potential use in pharmaceutical formulations [113] . This emerging technology is promising for improving treatment outcomes by enhancing the bioavailability and specificity of the therapeutic agent while reducing its toxicity [7, 81] .

Liposomes are of special interest, being efficient transport vehicles for in vivo applications, as hydrophilic drugs can be entrapped in their interior aqueous core while lipophilic and amphiphilic substances can be incorporated into the lipid bilayers [83, 124] . Liposomes are highly efficient drug delivery systems due to their biocompatibility, enhanced drug encapsulation, and ease of surface modification [41] . Such systems achieve selective and sufficiently precise localization of the diseased site while also ensuring a slow and sustained release [124, 133] . Such features are critically required for the treatment of chronic and acute disorders, including cancer, inflammatory disorders, or infectious diseases [134, 135] . The challenge to produce liposome formulations with a defined or limitedly variable size [124] was overcome by microfluidic production, demonstrated since 2004 [41] . The most common approach is to synthesize liposomes in droplet-based microfluidic systems [81] , but reproducible control of particle size and size distribution can be achieved in continuous-flow microfluidic devices as well [83] .

Polymer-based nanoparticles (PNPs) synthesis within microfluidic devices is considered promising as well, as it offers improved control over size, size distribution, morphology, and composition of such particles [16, 78] . Poly-(lactic-co-glycolic acid) nanoparticles (PLGA NPs), a polymer approved by the Food and Drug Administration (FDA), can be fabricated via a flow-focusing method in microchannels. Nanoparticles of this polymer can also be obtained using the droplet-based method by combining microfluidic droplet generation with solvent extraction techniques [41] . The synthesis of PLGA-poly-(ethylene glycol) nanoparticles (PLGA-PEG NPs) has been performed by nanoprecipitation in a hydrodynamic flow-focusing microchannel. The desired size, polydispersity, and drug loading can be achieved through the variation in flow rates, polymer composition, and polymer concentration [84] . A similar nanoprecipitation process was conducted to obtain polycaprolactone (PCL) nanoparticles, biodegradable entities with extensive potential for controlled drug delivery [136] . Some other polymers, such as heparin, chitosan, and hyaluronic acid, can be assembled in microfluidic devices for PNPs useful in the delivery and controlled release of drugs [41] . 

The pharmaceutical industry benefits from microfluidic approaches as they allow for cheaper, more effective, and more accessible production of drug formulations [143, 144] . Enhanced control over reaction conditions and the excellent quality of the products are the main reasons behind several pharmaceutical companies' decision to implement this technology as an alternative to hazardous exothermic power-intensive processes [145, 146] .

Up to date, various active pharmaceutical ingredients have been reportedly produced within microfluidic systems. Their list includes but is not limited to nitroglycerin [147] , ibuprofen [146] , lactose [148] , aspirin [148] , telmisartan [149] , hydrocortisone [150] , indomethacin [151] , danazol [152] , cefuroxime axetil [153] , piroxicam [154] , piracetam [154] , and carbamazepine [154] . Table 5 . Summary of active pharmaceutical ingredients synthesized via microfluidic approach.

Ref.

Acrylic chip Glycerol, nitric acid, sulfuric acid (catalyst)

The reaction rate is controlled by the diffusion process and the medium viscosity; the higher the concentration of the reactants, the higher the probability of particle collisions

The use of the microchannel produces more nitroglycerin reaction products compared to using the batch reactor system [147] 

Multifunctional entities can be formed by loading inorganic nanomaterials in polymer particles [16, 155] , benefiting from their components' synergic properties. Microfluidic devices also offer the possibility to produce complex hybrid nanostructures in simple processes, shorter times, and controlled reaction conditions, which would otherwise be unattainable [16] . Thus, composites comprising two inorganic materials can be efficiently synthesized in microfluidic reactors [155] to match the requirements of applications in the biomedical field, especially as fluorescent biological labels [156] .

Another promising combination is the creation of lipid-polymer nanoparticles for drug delivery [11] . What makes these hybrid nanomaterials so appealing is the possibility of encapsulating drug molecules in both the polymeric core and the lipid shell through microfluidic methods [41, 78] . Additionally, drug-loaded particles can also be obtained through microfluidic techniques, resulting in products of reduced size and higher drugloading capacity [157] .

Other interesting delivery systems that can be synthesized in microfluidic devices are lipid nanoparticles loaded with nucleic acids. In the context of the COVID-19 pandemic, the fabrication of monodispersed lipid vesicles became essential for the encapsulation of messenger RNA (mRNA) required in vaccines' formulation [158] [159] [160] . Particularly, this is achieved through the mixing of an ethanol phase (containing the hydrophobic lipids) and an aqueous phase (containing mRNA in a buffer, e.g., acetic acid, at pH 4) in a droplet-based microreactor [159, 161] .

Moreover, artificial leukocytes and lipoproteins can be fabricated via assembling proteins with lipid molecules. Thus, by assembling phospholipids with apolipoproteins within a microfluidic device, high-density lipoproteins were mimicked [41] . Microfluidic elongational flow method; magnetite particles obtained by co-precipitation were further coated with oleic acid and dried to obtain a powder; polymer nano-emulsion is left overnight in an oven at 70 • C becoming a stable colloidal suspension, by thermal polymerization Excellent product quality, homogenous composite particle size distribution; encapsulation of a lower content of iron oxide nanoparticles but with a smaller size than those encapsulated by batch processes [164] Ag NP-loaded chitosan particles PMMA chip with a cross-junction channel Chitosan, silver nitrate, glucose, sodium hydroxide A one-step mechanism involving the reduction of Ag NPs and solidifying the chitosan particles in emulsions simultaneously

The size of products can be controlled to achieve a narrow size distribution; various uniform chitosan microparticles impregnated with Ag NPs were successfully obtained [165] 

Nanomaterials can have many different shapes and chemical compositions, which means that their properties (such as size, design, solubility, surface modifications, charge, deformability, etc.) can be tailored to meet specific application requirements. However, conventional synthesis methods do not offer precise control over reaction parameters, affecting the desired outcomes. By precise manipulation of nanoliter volumes, microfluidic devices enable the synthesis of high-quality nanoparticles, drug carrier systems, active pharmaceutical ingredients, composite nanomaterials, and even cells. As there is a long list of advantages of microfluidic production over conventional synthesis, it is expected that this technology would exponentially gain interest in developing new materials, processes, and functionalities. Moreover, translating microfluidics to large-scale production should be considered to make this technology more popular and industrially appealing. Hence, research should also be directed towards standardization, automation, and high-throughput. 

The authors declare no conflict of interest. 

Nanomaterials: Classification, properties, and environmental toxicities

Evaluation of the physical parameters of nano-sized tetrachlorosilane as an inorganic material a mixed solvent using Fuoss-Shedlovsky and Fuoss-Hsia-Fernandez-Prini techniques

Experimental investigation of rheological properties and formation damage of water-based drilling fluids in the presence of Al2O3, Fe3O4, and TiO2 nanoparticles

Microfluidic Generation of Nanomaterials for Biomedical Applications

The origins and the future of microfluidics

Materials for Microfluidic Chip Fabrication

A review on novel methodologies for drug nanoparticle preparation: Microfluidic approach

Micromixer-assisted polymerization processes

Capillary microfluidics in microchannels: From microfluidic networks to capillaric circuits

Controllable synthesis of nanocrystals in droplet reactors

Controllable synthesis of functional nanoparticles by microfluidic platforms for biomedical applications -a review

Microchannel Fabrication on Glass Materials for Microfluidic Devices

Microfluidic technologies for accelerating the clinical translation of nanoparticles

Microfluidic synthesis of nanomaterials

Sticker Microfluidics: A Method for Fabrication of Customized Monolithic Microfluidics

High and efficient production of nanomaterials by microfluidic reactor approaches

Chapter 5-Methods for Synthesis of Nanoparticles and Fabrication of Nanocomposites

An overview on the green synthesis of nanoparticles and other nano-materials using enzymes and their potential applications

Harnessing nanoparticles for immune modulation

Nanomaterials for direct and indirect immunomodulation: A review of applications

Editorial (Thematic Issue: Interaction Between the Immune System and Nanomaterials: Safety and Medical Exploitation)

Antimicrobial effect, electronic and structural correlation of nano-filled Tin Bismuth metal alloys for biomedical applications

Nano metal oxides for sensing the VOC based gaseous pollutants

Effect of nano metal oxides on the electronic properties of cellulose, chitosan and sodium alginate

Synthesis, characterization of Ag@PANI core-shell nanostructures using solid state polymerization method

Simulation & modelling of dilute solutions in drop-on-demand inkjet printing: A review

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Nano-capacitors as batteries including graphene electrodes and Ga-N mixed with biopolymers as insulator

Biodegradable Poly(Lactic Acid) Nanocomposites for Fused Deposition Modeling 3D Printing

Understanding Nanoparticle Toxicity to Direct a Safe-by-Design Approach in Cancer Nanomedicine

Current Nanoparticle-Based Technologies for Osteoarthritis Therapy

Photons to Formate: A Review on Photocatalytic Reduction of CO2 to Formic Acid

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A review on the classification, characterisation, synthesis of nanoparticles and their application

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Sputtering based synthesis of CuO nanoparticles and their structural, thermal and optical studies

Microemulsion method: A novel route to synthesize organic and inorganic nanomaterials: 1st Nano Update

Chapter 14 -Nanomaterials With Different Dimensions for Electrocatalysis

Preparation of Nanoparticles

Progress in microwave-assisted synthesis of quantum dots (graphene/carbon/semiconducting) for bioapplications: A review

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Metal oxides nanoparticles via sol-gel method: A review on synthesis, characterization and applications

Comparison and Characterization of Fe3O4 Nanoparticles Synthesized by Conventional Magnetic Stirring and Sonochemical Method

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Template synthesis of graphitic hollow carbon nanoballs as supports for SnOx nanoparticles towards enhanced lithium storage performance

Biological Synthesis of Nanoparticles from Plants and Microorganisms

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Synthesis of CdSe and CdTe nanocrystals without precursor injection

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Nanoparticle synthesis in microreactors

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Microfluidic synthesis of functional inorganic micro-/nanoparticles and applications in biomedical engineering

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Preparation of nanoparticles by continuous-flow microfluidics

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Continuous flow nano-technology: Manipulating the size, shape, agglomeration, defects and phases of silver nano-particles

Governing factors for preparation of silver nanoparticles using droplet-based microfluidic device

Hydrothermal synthesis of ZnO nanocrystals using microreactor

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Ultrasound-enhanced Microfluidic Synthesis of Liposomes

Microfluidic-assisted preparation of PLGA nanoparticles for drug delivery purposes: Experimental study and computational fluid dynamic simulation

Three-dimensional flash flow microreactor for scale-up production of monodisperse PEG-PLGA nanoparticles

Production of hyaluronic acid (HA) nanoparticles by a continuous process inside microchannels: Effects of non-solvents, organic phase flow rate, and HA concentration

Microfluidic process intensification for synthesis and formulation in the pharmaceutical industry

The Use of a Microfluidic Device to Encapsulate a Poorly Water-Soluble Drug CoQ10 in Lipid Nanoparticles and an Attempt to Regulate Intracellular Trafficking to Reach Mitochondria

Process intensification in green synthesis

Recent advances for serial processes of hazardous chemicals in fully integrated microfluidic systems

The Effect of Concentration Reactan to Mixing Nitroglycerin Using Microchannel Hydrodynamics Focusing

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Microfluidics nanoprecipitation of telmisartan nanoparticles: Effect of process and formulation parameters

Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors

A high-throughput system combining microfluidic hydrogel droplets with deep learning for screening the antisolvent-crystallization conditions of active pharmaceutical ingredients

Controlled Liquid Antisolvent Precipitation of Hydrophobic Pharmaceutical Nanoparticles in a Microchannel Reactor

Microfluidic synthesis of amorphous cefuroxime axetil nanoparticles with size-dependent and enhanced dissolution rate

Crystallization Optimization of Pharmaceutical Solid Forms with X-ray Compatible Microfluidic Platforms

Core-shell nanoparticles used in drug delivery-microfluidics: A review

Highly Luminescent CdSe/ZnS Nanocrystals Synthesized Using a Single-Molecular ZnS Source in a Microfluidic Reactor

Using microfluidic platforms to develop CNS-targeted polymeric nanoparticles for HIV therapy

Lipid Nanoparticles as Delivery Systems for RNA-Based Vaccines

Nanomaterial Delivery Systems for mRNA Vaccines

Next-Generation Vaccines: Nanoparticle-Mediated DNA and mRNA Delivery

Self-assembled mRNA vaccines

Continuous synthesis of CdSe-ZnS composite nanoparticles in a microfluidic reactor

Microfluidics revealing formation mechanism of intermetallic nanocrystals

Fabrication of polystyrene-encapsulated magnetic iron oxide nanoparticles via batch and microfluidic-assisted production

Microfluidic assisted synthesis of silver nanoparticle-chitosan composite microparticles for antibacterial applications

Microfluidic Directed Self-Assembly of Liposome−Hydrogel Hybrid Nanoparticles

A Microfluidic Platform to design Multimodal PEGcrosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications

Microfluidic-assisted nanoprecipitation of (PEGylated) poly (d,l-lactic acid-co-caprolactone): Effect of macromolecular and microfluidic parameters on particle size and paclitaxel encapsulation

Microfluidics as tool to prepare size-tunable PLGA nanoparticles with high curcumin encapsulation for efficient mucus penetration

Facile synthesis and functionalization of color-tunable Ln3+-doped KGdF4 nanoparticles on a microfluidic platform

Microfluidic approach for highly efficient synthesis of heparin-based bioconjugates for drug delivery

Microfluidic assisted self-assembly of chitosan based nanoparticles as drug delivery agents

Microfluidic-assisted nanoprecipitation of antiviral-loaded polymeric nanoparticles

Production of dry-state ketoprofen-encapsulated PMMA NPs by coupling micromixer-assisted nanoprecipitation and spray drying