Recent Progress in Intensifying Synthesis of Acrylic Microspheres for Catalysis

Over the past decades, there has been an escalating rise in the need for chemicals and catalytic materials to keep up with global demands. Addressing those issues by conventional methods often becomes inefficient, with myriad operational risks. Process intensification methods through procedural and equipment‐based modifications have been considered greener, have higher heat and mass transfer rates, and operate with lower costs. In this review, research using ultrasonic reactors and microreactors, along with developments through an integrated external energy source, for synthesizing acrylic microspheres is covered extensively. Acrylic microspheres have garnered much interest for their biocompatibility, affinity toward functionalization, and wide range of applications. Core–shell, composite, functional‐group modified, and porous acrylic microspheres are used for enzyme immobilization and as catalyst carriers. The use of acrylic support has provided huge improvements in catalytic activity, reusability, recyclability, and overall stability. Finally, various other process intensification methods and alternate support materials are covered to help enhance future developments in the field of catalysis.

is any advancement in chemical engineering that results in a significantly smaller, cleaner, safer, and more energy-efficient technology. Compared to their conventional equivalents, these advances include new machinery, processing technologies, and process development approaches that follow a smart, secure, and environmentally friendly procedure. In the longer run, the reaction run through a Process Intensification process would incur fewer costs of land, investments, and raw materials as well as generate less waste. Process intensification can be broadly classified based on intensifying the equipment and the methodologies used to intensify chemical processes.
Alongside the growing demand for chemicals, there is a need for accelerated growth of pharmaceutical and therapeutic industries in aspects of reaction efficiency and production quality. In addition to changes required in the reactor configurations through intensification, improvements in catalysis are also expected. Enzymes comprised of proteins have greatly contributed to the research on biocatalysis. Despite the awareness of enzymes as naturally available, sustainable materials which can redefine the way biocatalytic processes occur, there is hardly any attention in the industry. Some of the main challenges of using biocatalysts include developing stable, reliable, and active materials with efficient regeneration and the ability to prevent degradation under harsh thermal and pH conditions. [5] Microspheres have been a primary choice to solve the issue regarding the supporting material for enzymes.
Polymeric microscopic particles which lie in the size range of tens to thousandths of nanometers are termed microspheres. The polymeric microspheres typically derived from acrylic acid, methacrylic acid, and various acrylate or methacrylate-based monomers are called acrylic microspheres. The various ways of synthesizing acrylic microspheres include solvent evaporation, suspension polymerization, [6] emulsion polymerization, [7] precipitation polymerization, [8] dispersion polymerization, [9] seed swelling polymerization, [10] photopolymerization, [11] membrane emulsification [12] and step-growth click polymerization. [13] The types of polymerization procedures can also be characterized based on the source of energy used for initiation (thermal, light, microwaves, and γ-ray) and surfactant (e.g., surfactantfree emulsion polymerization).
The primary goal of the current review is to investigate process intensification aspects of methods that generate environmentally friendly and sustainable materials (acrylic microspheres) using safer and cleaner chemical procedures (through process intensification). Figure 1 represents the schematic illustration of process intensification methods, conventional methods, and catalyst applications of microspheres. It is not simple to create polymeric materials with applications in various fields, including chemistry, biotechnology, medicine, and food. However, recent developments in nanofabrication methods and expanding polymeric material research have reduced this enormous task to a routine task with well-crafted sets of regulations.

Process Intensification Techniques
Primarily the role of process intensification is to physically down-sizing both the process equipment and the number of operating units without compromising the chemical reaction efficiency as well as the system performance. [14] However, there is a distinction between process intensification methodology and overall process improvements. No matter how large the improvement; observed by an alternative catalyst or changes in the reaction routes, they are not characterized under process intensification. Hence, some of the key features of process intensification adopted by leading scientists in academia and industry are mentioned in (Figure 2).
The synthesis of various polymeric materials has accelerated rapidly due to the advent of flow chemistry and advancements in reactors employing continuous flow methodologies. In addition, techniques employing process intensification have been www.advmatinterfaces.de preferred over conventional methods to utilize the resources available in an efficient manner.
The use of intensified strategies can increase the overall heat, mass, and momentum transfer rates. In addition to enhanced transfer rates, a reduction in energy consumption and overall process costs is seen through the utilization of synergy between various multifunctional phenomena. [15] Adopting emerging approaches such as structural intensification, energy intensification through rotation, vibration, sonication and pulsation, and temporal intensification via microwaves is vital to enhance mass transfer taking place in conventional reactor systems. [16] Due to the increasing demand for chemicals, conventional batch reactors using conventional technology are destined to be ineffective. It could be challenging to switch from a reactor that has been in operation for centuries to a completely new design with different specs, flow patterns, and other variables. Hence, systematic process intensification (SPI) is vital for making the transition more convenient. SPI involves using computational methods to predict the most promising intensified alternatives based on factors such as feasibility, operability, control, and safety. [17] Below mentioned are a few process intensification technologies that have been employed. The discussion is limited to the scope of acrylic microspheres synthesis.

Ultrasound-Assisted Process Intensification
Process intensification techniques that involve external energy transfer by ultrasonic waves are described below. Ultrasonication is most popular for cleaning and removal of rust from surfaces. Sound waves within the frequency range of 20-100 kHz are used in chemical reaction systems.
Within the chemical reaction environment, ultrasonic effects generate alternating movements of molecules. [18] Chemical reactors or systems employing ultrasonication typically go through a process of cavitation. Cavitation bubbles are formed when the repulsive forces exceed the compressive forces during the wave cycle, caused when the amplitude of alternating movements is greater than a critical value. [18] As a whole, cavitation constitutes the formation, growth, and implosive collapse of the cavities (in the micron range) generated when the solution is irradiated with ultrasonic waves. The collapse in the microcavities results in the formation of high temperature and high pressure "hotspots," which facilitate the necessary chemical transformation. Various process parameters (frequency, intensity of the ultrasonic wave, exposure time) as well as product variables (solvent characteristics, environment-gas properties, solid loading, external pressure, and temperature) affect the cavitation, which alter the product quality.
In terms of physical effects, acoustic cavitation provided by ultrasonic devices provide efficient mixing and strong dispersion effects. [19] For the processes involving polymerization, the use of ultrasonication can reduce the amount of external initiator being used. Additional benefits include higher polymerization rate, narrow particle size distribution, higher monomer conversion, increased homogenous chain growth, higher yields, and require milder reaction conditions. [20] In terms of the functionalization of existing polymeric materials, it allows the fine dispersion of inorganic nanoparticles. Especially for the preparation of core-shell microspheres, ultrasonication has been found to be simple, clean, and efficient and proves its universality in terms of the polymerization procedure. [21] Considering chemical reaction systems, ultrasonic devices can be classified based on how the ultrasonic energy is transmitted to the reaction medium. The most common implementation includes ultrasonic baths (indirect soft energy transmission of energy) and ultrasonic probes (direct high energy transmission of energy).

Ultrasound Bath and Ultrasound Probe
Chemical processes that require a low amount of ultrasonic irradiation, in the range of 1-5 W cm -2 can be carried out using the ultrasonic bath. A detailed comparison of various types of ultrasonic baths commonly used in laboratories is shown in (Table 1). Figure 3 represents the ultrasound probe and bath sonicator.
Due to the larger surface area of ultrasonic-wave irradiation, the ultrasonic intensity distribution inside a bath is found to be non-homogenous. To achieve the maximum sonochemical effect, an aluminum foil erosion test would help locate the most efficient locations where the reaction vessel must be placed.
Most chemical synthesis reactions inside an ultrasonic bath are performed for a time long enough to cause the bulk reaction medium to heat up. This causes disturbances in the reaction kinetics and often reduces reproducibility. To tackle this, temperature control is employed in various ultrasonic baths.
In terms of the effects observed through ultrasonication over polymerization methods, experiments conducted by Bhanvase et al. [23] revealed fast dissociation of the initiator provided. In www.advmatinterfaces.de addition to that, acoustic cavitation causes violent shearing which causes the generation of small uniform size monomer droplets and the inability to generate radicals on its own without the use of an external initiator.
An ultrasonic probe is also referred to as a "horn," or a "sonotrode." In certain synthesis reactions, a higher ultrasonication intensity generally a 100-fold rise is required, which is when ultrasonic probes are considered. Compared to an ultrasonic bath in which the reaction container is immersed-in, an ultrasonic probe is immersed into the container containing the reaction mixture. The ultrasonic probe is generally preferred to attain effects that cannot be replicated using an ultrasonic bath. For instance, compared to an ultrasonic bath, probe sonication can operate with a lower input energy source and create a higher ultrasonic power density (measured in W m −3 ). It's generally a tough task to maintain a uniform distribution of ultrasonic energy inside an ultrasonic bath, whereas the probe allows localized energy transfer. [24] Also, studies reported by Monnier et al. [25] concluded that the bath-type sonicator needed more energy cost compared to the probe-type.
A typical ultrasonic probe comprises a generator, an ultrasonic transducer, optional booster horns (used to increase the sonication amplitude), and the probe itself. Some of the common probe-tip shapes (shown in Figure 4) include uniform cylinder, exponential taper, linear taper, and stepped. Depending on the shape of the probe, the ultrasonic amplitude magnification (amplitude gain) varies. In practice, the stepped probe gives the highest amplitude magnification. Generally, the tips of commercially available probe sonicators are made of stainless steel or carbon steel. However, the tip of an ultrasonic probe can get eroded because of repetitive cavitation bubble collapse. To prevent that from happening, replaceable tips are available.
Similar to an ultrasonic bath, the ultrasonic probe might also be attached to a temperature control device. Due to the increase in the ultrasonic amplitude as compared to bath type, the temperature control might be even more aggressive. In addition to that, strategies such as using an ice bath ensure rapid dissipation of heat for shorter sonication times. Also, using dedicated vessels specially crafted to dissipate heat might be helpful. Finally, in the most modern ultrasonic probes "pulse" mode is used to automatically switch the probe's power to avoid the buildup of reaction temperature.
When it comes to the synthesis procedures, ultrasoundassisted polymerization was found to be rapid compared to magnetic stirring. [23] In most cases, due to the rapid rate of  polymerization provided, it takes about 10 min to polymerize the monomer after its addition to the reaction mixture.

Sonoreactors
Sonoreactors are currently replacing the traditional ultrasonic bath in various applications. They perform as a compact, powerful ultrasonic bath while being reliable in rapidly reducing chemical reaction times. [26] Nevertheless, large-scale sonoreactors have also been built ( Figure 5) and performed better than a comparable ultrasonic bath. [27] They concluded that in comparison with bath-type sonicators; the sonoreactor with a similar fixed frequency of 170 kHz had improvements in full-scale flow-through (a 33% rise) and time-corrected flowthrough (a 683% rise).

Integrating Ultrasound with Other PI Methods
Microwaves-Based Process Intensification Integrated with Ultrasound: Generally, ultrasound cavitation is found to be good enough to carry out the necessary chemical synthesis. However, recent research on combining ultrasound with another energy sources, such as microwaves, is helpful. The combined effects of ultrasound and microwaves as a hybrid technology improved the drying and preserving of the quality of foods, higher yields in shorter duration in terms of extraction, and efficient bioactive peptide production through enzymatic hydrolysis. [28] Calinescu et al. [18] have designed an ultrasound-microwave-assisted hybrid reactor (shown in Figure 6) controllable over both energy sources. This hybrid installation ensures operation at various frequency levels. In addition, the Reproduced with permission. [26] Copyright 2008, Wiley-VCH.
Adv. Mater. Interfaces 2023, 10,2202125 www.advmatinterfaces.de mono-mode microwave cavity allows a more uniform treatment of the reaction mixtures.

Microreactor Introduction
Microreactors are systems used for chemical transformation involving flow patterns with characteristic length scales in the orders of microns. Over the last few decades, microreactor has been in the spotlight for their efficiency and wide range of applications. For instance, microreactors allow better control over kinetics and product properties for synthesis reactions involving multiple immiscible phases. [29] In the case of continuous nanoparticle production, microreactors are preferred over conventional flow reactors due to their versatile heat and mass transfer effects and efficient mixing characteristics. [30] When it comes to heat transfer effects, microreactors are advantageous over conventional macro-scale reactors for various reasons, especially in heat dissipation. The rate and amount of heat generation on the large reactor volume is large during the radical polymerization process. On the contrary, heat removal rates decrease due to the decrease in the wall-surface area/reactorvolume ratio. [31] Regardless of the reactor type, synthesizing particles via a solvothermal way requires control over parameters describing the system's reaction, growth, and crystallization. [32]

Classification of Microreactors
Due to advancements in nanofabrication technologies, there are innumerable types of microreactor systems that can be modified depending on the application. There is also an option of having a custom-made microfluidic device which in some cases is more cost-efficient, that supports the chemical reactivity of the reaction mixture. There are various materials currently being used for fabricating microreactors. Attributes such as mechanical stability and chemical inertness are crucial for choosing materials used for microreactor fabrication. [33] Earlier, glass and silicon were widely considered due to their wide usage in semiconductors and microelectromechanical systems. But they require further functionalization and processing which is not very cost-effective. Hence, the use of polymers as primary construction material in microreactors is recommended due to their ease of fabrication and adaptability Figure 6. Schematic representation of the hybrid ultrasound-microwave reactor. Reproduced with permission. [18] Copyright 2021, Elsevier.

www.advmatinterfaces.de
in bio-applications. Due to its biocompatible nature, low cost, transparent appearance, and flexibility, PDMS is often preferred in bio-applications. On the contrary, issues such as swelling in certain organic solvents, changes in solution concentrations due to water evaporation, and non-specific adsorption of biomolecules owing to hydrophobicity might cause refrainment from its use. [33] Additional polymeric materials have also been explored, such as poly methyl methacrylate (PMMA), [34] polystyrene (PS), [35] polycarbonate (PC), [36] polytetrafluoroethylene (PTFE), [37] polyethylene terephthalate (PET) [36] which have made a promising impact. Cerqueira et al. developed a PMMA-based microreactor that was simple to construct and demonstrated stable enzyme immobilization (extensive tests were conducted with ≈1000 runs). [34a] Kim et al. used porous polystyrene microspheres with interconnected open pores for constructing catalytic microreactors. [38] For chemical reactions demanding extreme temperature and pressure operations, stainless-steel and ceramic-based microreactors are used, [29,39] but are instead associated with high manufacturing costs.
Coming to design and functionality, microreactors are classified based on the flow and mixing patterns of the phased being processed as continuous-flow, segmented-flow microreactors.
Continuous Flow Microreactors: Continuous flow microreactors employ the mixing pattern which is primarily governed by molecular diffusion due to its turbulence-free condition. [40] Following a diffusion-led mixing leads to greater homogeneity in the product stream. [41] The continuous-flow microreactors are known to overcome the transport property limitations of conventional batch reactors and are generally more productive in producing a homogenous product. Woitalka et al. [42] reported that the flow pattern in a continuous-flow microreactor affects the mixing, which controls the mass transfer in a reactor, the particle size, and its distribution. They are also known for their excellent polymerization performance. [43] Continuous laminar flow microreactors are the most basic microreactors extensively used in developing biocatalysts. However, one of the biggest challenges of using a laminar flow reactor is to overcome the boundary layer effects which cause uneven axial mixing and uneven residence time distribution due to the parabolic distribution of the fluid velocity. [44] This results in a product that is not monodisperse having a wide size distribution. To quantitively prove this, Khan et al. contrasted single-phase (liquidliquid) laminar flow reactors (LFRs) and two-phase (gas-liquid) segmented flow reactors (SFRs) in terms of product size and distribution. The LFR produced monodisperse particles only when there was minimal axial dispersion (under provided feasible conditions). Whereas axial dispersion is non-existent in the case of SFR. [45] There are various design-based variations of microreactors based on the microchannel structure assembly: capillary tube microreactor, coaxial flow microreactor, and 2-D micromixingbased microreactors. [44] Capillary tube microreactors are tubular reactors with a micron-scale flow cross-sectional area (Figure 7a). They are known for their flexibility, ease of usage, and manufacturing. However, some of the limitations associated with the use of capillary microreactors are: [46] • They are susceptible to blockage with certain particulate reaction mixtures. • They can cause huge pressure buildup when a highly viscous fluid (including polymeric solutions) is passed through. • A product formed has a wide size distribution.
Hence using a coaxial flow microreactor, as shown in Figure 7b, can mitigate the clogging and product distribution issues of using a capillary tube. [47] A coaxial flow microreactor allows the mixing multiple fluid streams through diffusion co-axially. However, mixing is often incomplete when highly viscous fluids are used. A broad residence time distribution leads to production of particles of varying sizes. To generate efficient mixing inside the microchannel, 2-D micromixingbased microreactors are used. Structurally, they are classified as Y-shaped (Figure 7c), T-shaped (Figure 7d), and flow-focusing microreactors (Figure 7e).
Segmented Flow Microreactors: Regardless of how appealing the design is from the standpoint of fluid dynamics, the mixing provided by diffusion alone cannot be relied upon to process the reaction emulsions. Segmented flow microreactors facilitate active mixing strategies to mix reagents through chaotic advection between multiple immiscible phases. [49] A schematic of typical segmented flow microreactors is shown in Figure 7d. Unlike the continuous flow reactors, the segmented flow approach excludes the no-slip boundary condition. [40] Representation of the comparison in mixing strategies of the reactants is shown in Figure 8. Adding to the benefits of good mixing, the use of segmented flow can also contribute to the reduction in axial dispersion. In the case of gas-liquid segmented flow, the gas bubbles' separation of liquid particles is possible. [44] Hence, the combination of enhanced mixing with non-existent axial dispersion may assure narrow RTD and size distributions.
Droplet-Based Microreactor: Traditional emulsification methods involving homogenization or straight-microchannel emulsification have been found to form particles with a coefficient of variation (CV) of nearly 40%. [51] Hence, droplet-based microreactors are considered for their ability to produce particles with multi-functional properties and complex structures. [52] In a droplet-based microreactor, each droplet is expected to act as a separate segmented flow reactor dividing the reagent phase into equal-volume parts by an immiscible reagent phase. [53] Representation of a typical droplet-based microreactor is shown in Figure 7g, with the droplet formation schematic in a flowfocusing microchannel in Figure 7h. The droplet formation in the microchannels depends on the balance between the inertial force, buoyancy, interfacial tension, and viscous shear force. [54] Additionally, Bai et al. observed that parameters of fluid, such as flow rate, and viscosity also affect the droplet formation rate. [55] Droplet-based microfluidics is also considered to be energy efficient compared to traditional emulsification methods which are prone to heat dissipation. [56]

Integrating Microreactors with Other PI Methods
Using a reactor for chemical synthesis often demands overcoming a significant energy barrier, which was conventionally carried out through the use of thermal energy or, creating an alternative pathway through catalysis. Iwasaki and Yoshida [31] have demonstrated the use of process intensification through microreactors using thermal initiation to control highly exothermic radical polymerization. To promote greener and more efficient chemical synthesis, external stimuli such as light, electric, or mechanical forces have been shown to be crucial. [57] Hence, below mentioned are some approaches where microreactors have been combined with an external stimulus for further performance enhancements.
Microreactor in Combination with Ultrasound: Considering multiphase chemical reactions, combining micro-scale reactor systems with ultrasound increases the interfacial areas across . Description/representation of various types of microreactors. a) Schematic of a capillary tube microreactor, b) coaxial flow microreactor constituting a same axle dual pipe. Reproduced with permission. [47] Copyright 2004, Elsevier. c) Y-shaped microchannel, d) T-shaped microchannel, e) flow-focusing microchannel, f) schematic of a segmented flow microreactor, g) a typical droplet-based microreactor based on a flow-focused microchannel, h) schematic representation of the droplet formation in a droplet-based flow focusing microchannel system. Reproduced with permission. [48] Copyright 2021, MDPI.
www.advmatinterfaces.de various immiscible phases. [58] The combination of using ultrasound with micro-scale flow reactors has proven to provide improvements in clogging and mixing-related issues. [59] Aljbour et al. [60] developed an ultrasound-assisted capillary microreactor (shown in Figure 9), which enhanced mass transfer through its mechanical effects. The capillary-flow rate, a deciding factor in mass transfer improvements, was found to have intensified due to the ultrasonic effect.
Using a low-frequency ultrasound through a probe-sonicator may promote deagglomeration through enhanced cavitation activity. On the other hand, combining low frequency with high intensity through ultrasonic probe results in decreased temperature control. Degradation of the microchannel is a huge concern when there is no control over the temperature rise. Hence, the choice of the ultrasonic device (coupled with the microreactor) must be made keeping the particular application/ use case in mind.
Light-Assisted or Photochemical Microreactor Technology: The benefits of using a photochemical approach in terms of chemical reactions include using ambient temperature conditions and faster reaction rates. Furthermore, control over space and time coordinates and energy efficiency by special lamps is also obtained. [61] The use of ultraviolet (UV) radiation (by UV fluorescent lamps or UV-light emitting diodes (UV-LEDs)) as a way of initiating the polymerization procedure is found to be a much safer, compact, energy-efficient, and environmentalfriendly process compared to a thermally initiated one. In terms of reaction performance, UV radiation induction has improved the overall polymerization rate. [62] Moreover, the reaction could proceed via a solvent-free process.
Despite the above advantages, at an industry-scale use of light-assisted reaction systems has found limited applications as they are inherently built in combination with conventional reactors. [62] Corning developed G1 Photo Reactor [63] shown in Figure 10. one of the commercially available microreactors integrated with a LED lighting module. The reactor supports the LED module to operate through multiple wavelengths; combined with a patented design, the reactor is claimed to have greater mixing and heat transfer characteristics.
Microwave Assisted: Additionally, microwaves are one of the most traditional alternative external energy sources which can be used. The use of microwave-assisted systems offers clear advantages [64] such as: • The transmission of microwave energy through electromagnetic radiation is at the speed of light which is nearly instantaneous. • Improvements in process control and mitigate limitations in heat transfer. • Selective dissipation of electromagnetic energy.
• Rapid rise in the reaction mixture temperature of about 10 K s −1 without any high temperature at the vessel walls. [65] Nevertheless, conclusive remarks on the interaction between chemical reactions and microwaves cannot be drawn as the research is still developing. [64] Microwaves can be used for various processes such as precipitation/crystallization, catalytic reduction, particle size reduction, and drying. The usage of microwaves creates a temperature gradient between the solvent and the nanomaterial, which increases the mass transfer  . Schematic representation of ultrasound-assisted capillary-based microreactor. Reproduced with permission. [60] Copyright 2009, Elsevier. www.advmatinterfaces.de rate and nucleation. [66] Compared to a conventional evaporative crystallization process, the use of microwaves reduced the crystallization time by 60-fold. [67] Comer and Organ used a microwave-assisted capillary-based microreactor to carry out various organic reactions. [68] It was found that the amount of product formed was directly correlated with the reaction time.
Horikoshi et al. [69] designed a hybrid microwave-assisted microreactor system for the synthesis of silver nanoparticles. The microwave effect supplied the necessary thermal energy for the uniform growth of the nanoparticles. Compared to batch reactors, the use of this hybrid setup carries synthesis: without the need for stirring the reactant mixture with the necessary support to scale up at a large scale.

Monomers
Some of the most used monomers for the acrylic microspheres are shown in Table 2. Figure 11 is the classification of various polymerization procedures commonly employed to synthesize polymeric products. The abovementioned polymerizations have recently been implemented using microreactor technology, allowing us to produce continuously and reproducibly without batchto-batch variation. Considering the scope of this review of synthesizing acrylic microspheres, uncontrollable and living/controllable heterogenous radical polymerization, chitosan-based acrylic microspheres, and the application of photopolymerization using microreactor are discussed on the Section 3.6.

Given in
In recent years, emulsion polymerization has been studied extensively for being an environmental-friendly way to produce microspheres with higher molecular weights. [70] The process involves an emulsion comprising the monomer, initiator, and the surfactant/emulsifier going through either micellar nucleation [71] or homogenous nucleation, [72] depending on the concentration of the surfactant. However, excessive surfactant usage was found to deteriorate the particle size distribution. Hence, surfactant-free emulsion polymerization is used to achieve monodispersity of particles wherein the initiator involved is water-soluble. Microemulsion polymerization constitutes the preparation of an oil-in-water or water-in-oil based thermodynamically stable dispersion system used for preparing smallsize microspheres.
Suspension polymerization proceeds through the rigorous stirring (either mechanical or magnetic) of a reaction mixture consisting of a water-insoluble monomer, initiator, and steric stabilizer in an aqueous medium. The intense mixing is expected to divide the monomer mixture into droplets, eventually forming polymeric spheres which stay suspended in the liquid phase. [73] Product properties will likely get affected if the reaction medium consists of partially miscible components or through less-intense mixing.
To produce highly crosslinked, monodisperse microspheres, precipitation polymerization can be used. The reaction medium consists of a monomer, initiator, crosslinking agent, and poreforming agent. Usage of this method is generally limited, raising concerns over pollution caused by using multiple solvents, slower reaction rates, and relatively lower yields compared to other polymerization methods.
Seed swelling polymerization is preferred for the production of monodisperse porous microspheres. Generally, it's characterized based on the number of steps involved. Two-step seed swelling initially consists of the swelling of pre-existing monodisperse microspheres, which absorb and polymerize the monomer. [74] [63] Copyright 2016, Corning Incorporated.

Conventional Methods and Need for Process Intensification
Although inefficient in their reaction conditions and procedures, conventional reactors involving batch processes helped us set benchmarks in the synthesis of various polymeric materials. Polymers are currently used in drug delivery, therapeutics, biocatalysis, food industries, and manufacturing of various commercial every day-use products. Synthesis of acrylic microspheres in the traditional way primarily involved the use of a mechanical or magnetic stirring device. [7c,75] Molecular weight distribution, viscosity, surface area, and functionalization are major quality indices of polymerization. These are significant challenges to control, which could be possible using the population balance, optimization models,  and molecular weight distribution models of process intensification tools. In the case of the microspheres, the mixing, surfactant concentration, initiator concentration, and concentration of the comonomer will impact the monomer's average droplet size and hence, the size distribution of polymer particles and porosity of the microspheres. On the industrial scale, the polymer microspheres will have impact by the process variables. The process intensification and optimization will play a major role in the drastic improvement in the quality of the polymer microspheres desired for delivery and support preparation applications.
Due to the advent of automation in various industries, research on an end-to-end system for chemical synthesis has become a topic of discussion. Coley et al. [76] discussed the contributions and benefits of using automation in various chemical processes. More specifically, how the assistance from hardware (robots) and machine learning has accelerated the synthesis in various fields such as synthetic chemistry, drug discovery, and material science. Rubens et al. [77] developed an ultra-precise automated polymer synthesis system (schematized in Figure 12). It is capable to generate polymers with molecular weight deviation amounting to less than 1% of the predefined value. The system is controlled computationally via a flow reactor combined with a size exclusion chromatography (SEC) system. SEC was used for the online monitoring of the Reversible-addition fragmentation chain transfer (RAFT) polymerization of nBA. An algorithm in the feedback loop was used to optimize the values of number average (M n ) , weight average (M w ), and peak (M p ) molecular weights from the SEC based on the user-defined values before the optimization process.
To achieve added benefits such as high rigidity, flexibility, thermal stability, processability, and ductility, the functionalization of microspheres can be carried out. Various approaches to functionalizing acrylic microsphere include: • Functional group (amine, aldehyde, hydroxyl, or carboxyl) modification • Composite microspheres • Core-shell microspheres • Porous microspheres • Hollow microspheres and • Fluorescent microspheres A typical synthesis procedure of microspheres is demonstrated: [78] The reaction mixture consisted of the GMA monomer, poly(N-vinylpyrrolidone) (PVP) as the stabilizer, α, α'-azoisobisbutyronitrile (AIBN) as the initiator, methanol as aqueous medium and N, N-dimethylformamide.
• The reaction mixture was deoxygenated with nitrogen and placed in an oil bath to maintain a temperature of 65 °C. The beaker was stirred for 8 h at the rate of 160 rpm.

www.advmatinterfaces.de
• Once the polymerization culminated, the mixture was centrifuged and washed with excess methanol twice. Once centrifuged at the desired level, the particles were allowed to dry at 40 °C.
After the synthesis, various characterizing features of the synthesized microspheres are determined by various sophisticated sets of hardware and tools. The most used devices for determining the structural and morphological properties such as polydispersity, size, and the shape of microspheres are scanning electron microscope (SEM), transmission electron microscope (TEM), and atomic force microscope (AFM). Functional variations of SEM and TEM often include the operation at higher resolutions (HR-TEM) or the use of field effect guns (FE-SEM) for electron generation. Nuclear magnetic resonance (NMR) spectroscopy gives information on the atomic composition and the electronic core structure. X-ray diffraction (XRD) helps determine the crystalline structure and lattice parameters. The particles' absorption, emission, and photoconductivity spectra are obtained using Fourier transform infrared spectroscopy (FTIR). Depiction of the PGMA microspheres characterizations through the use of SEM, FTIR, and XRD is shown in Figure 13. Table 3 mentions the synthesis of various acrylic microspheres through conventional reactors grouped based on their monomer. Table 4 illustrates the widely used co-polymer microspheres composite through conventional methods.

Synthesis of Acrylic Microspheres through Ultrasound
Bhanvase et al. reported some major advantages over conventional reactors: improvements in polymerization rate, controlled particle size distribution, and higher conversion. [92]

Synthesis Using an Ultrasonic Bath
Lei et al. demonstrated various studies involving the use of an ultrasonic bath (sonochemical irradiation time of 30 min) to prepare PGMA on the Fe 3 O 4 /SiO x surface. [93] The magnetic particles were synthesized through ATRP. The synthesized materials were found to have a small diameter (100 nm) confirmed by transmission electron microscope (TEM) and showed greater magnetic responsibility at room temperature confirmed by the use of a vibrating sample magnetometer (VSM). Also, the saturation magnetization was observed to be high at 8.3 kA m −1 .
Synthesis through a sonochemical approach is found to proceed rapidly compared to a conventional reactor. Phutthawong and Pattarawarapan synthesized P(MAA-co-EGDMA) using an ultrasound bath (operating at 37 kHz). [20b] It was found that the variation of acrylic polymers synthesized via ultrasoundassisted polymerization had a relatively small pore size, with all within the same range. Combining ultrasound techniques with precipitation polymerization was found to be an efficient and facile means of synthesis.
Chowdhury et al. [94] synthesized poly (N-isopropyl acrylamide) grafted with functionalized mesoporous silica nanoparticles. The particles were prepared sonochemically using an ultrasonic bath (40 kHz for 5 h at 50 °C) and observed exhibition of superior pH sensitivity, better biocompatibility, and antibacterial activity compared to using conventional reactors and following synthesis methods such as RAFT, RGP, and solutioncasting. All this was made possible without the requirements of additives such as cross-linkers, hydrophobic agents, and organic solvents.
Using the Hall method [95] Woznica et al. [96] carried out the synthesis of P(nBA-PVA) and P(nBA-MA) microspheres using an ultrasonic bath (5 min, cycle 0.5, power 70%) for the development of a novel Zinc based fluorometric sensor.
Graft polymers are branched polymeric materials with components of each side-chain being different compared to the main chain structurally. In terms of grafting reactions, Chu et al. observed a significant increase in graft ratio (GR), graft efficiency (GE), and monomer conversion (MC) compared to conventional graft polymerization which did not involve sonication. [97] Graft polymerization of starch and nBA was carried out with ultrasound-assisted mechanical stirring. Moreover, the GR and GE increased when the contents of the reaction mixture were pre-treated with ultrasound before the addition of monomer. This was made possible because, the use of ultrasonication facilitated effective collisions caused among the initiator, starch, and the monomer. The increase in the GR, GE, and MC with an increase in temperature was found to be more rapid with ultrasound application, as shown in Figure 14. The temperature rise was enhanced in the presence of the ultrasound. This allows us to achieve increased process flexibility and product quality, resulting in process intensification.     without ultrasound. Reproduced with permission. [97] Copyright 2015, Elsevier.
www.advmatinterfaces.de over a thermally initiated stirred tank reactor. Improvements were observed in parameters such as higher reaction rates and larger particle sizes of PMA microspheres. However, the reaction yield through the low-frequency ultrasonic initiation was lower compared to the usage of a thermally initiated stirred tank. Moreover, the lower frequency (24 kHz) ultrasonic probe achieved excellent emulsification but was found inefficient in terms of radical generation. The radical formation depends on the frequency and the amplitude of the bubble formation and collapse during the cavitation. The lower frequency sonication will form the smaller bubble that collapses with least kinetic energy. The higher frequency leads to least shear forces that do not form the transient bubble formation and collapse. [99] A graphical representation of the shear force generated and radical formation with respect to frequency of sonication was presented in (Figure 15). This result concluded that using ultrasonic frequency in the range of 300-500 kHz is optimal for the radical generation, proper mixing, and the overall polymerization reaction. Teo et al. observed the variation in the particle size with the ultrasonication time for various monomers. [19] Monomers considered in the study were MMA, nBMA, and 2-ethyl hexyl methacrylate (2EHMA). The reaction was found to proceed through pseudo-first-order kinetics, following a zero-one model for polymerization. This enables pseudo-instantaneous termination when a radical enters a particle during the radicalgrowth phase. In the case of PMMA and poly(nBMA), the particle size was initially found to increase and plateau. Whereas in the case of poly(2EHMA), the particle size was found to be approximately the same irrespective of the sonication duration as depicted in Figure 16. This is because, for Poly(2EHMA), the droplets don't show shrinkage at lower percentages of conversion as it is insoluble in water. This concludes that monomer conversion rates correlate with the monomers' surface properties such as hydrophobicity.
Through ultrasonically initiated emulsion polymerization, PnBA/SiO 2 core-shell microspheres were synthesized using an ultrasonic probe. [21] The synthesized microspheres were observed to have a well-defined spherical size and were mono-disperse (narrow size distribution). TEM analysis confirmed the resultant microspheres had no adhesion in between and were core-shell structures with diameter and shell thickness of 150 nm and 15 nm, respectively. Depiction of the resultant TEM of PnBA/SiO 2 core-shell microspheres is shown in Figure 17. There was a correlation observed between the concentration of CTAB (used as a cationic surfactant) and the particle size distribution. Additionally, a rise in the amount of CTAB increased ζ (Zeta) potential (which describes the electrokinetic properties). This was attributed to the microspheres' continuous adsorption of positively charged CTAB cations.
The development of particles comprising multiple (two or more) chemically compatible materials is categorized as hybrid nanoparticles (HNPs). HNPs are found to have improved chemical, structural and mechanical properties than their individual counterparts. Potdar et al. [20a] used ultrasound-assisted free radical polymerization for synthesizing ZnO-PMMA HNPs. The Figure 16. Effects of ultrasonication time on the particle diameters of various monomers: a) PMMA, b) PBMA, and c) poly(2EHMA). Reproduced with permission. [19] Copyright 2008, Elsevier. www.advmatinterfaces.de polymerization process didn't involve the use of an external initiator; instead, the radicals generated via acoustic cavitation initiated the reaction. Adding ZnO to the reaction mixture eventually reduced the size of the HNPs, which can be imputed to the turbulence and micro-jet-like free radical motion provided by ultrasound.
Guo et al. [80] demonstrated the synthesis of PMMA microspheres through microemulsion polymerization by comparing various dispersion modes. With the emulsion of water as an aqueous medium, KPS as initiator, and SDS as the emulsifier, the reaction was carried on for 1 h. Sonication involved the combination of probe-sonicator and bath sonication.

Semibatch Polymerization
Bhanvase et al. [23] demonstrated the synthesis of PMMA nanoparticles through semi-batch emulsion polymerization using an ultrasound probe at a relatively lower ultrasonic frequency (22 kHz) and a higher ultrasonic intensity of 44.7 W at 50% amplitude (measured by calorimetric method). The effects of the initiation produced by the sonicator along with an external initiator (KPS) during the short polymerization time (<10 min) were studied. At 1.5% w/w KPS of MMA monomer, the lowest PDI (0.255) and lowest particle size (47 nm) were observed. However, as expected, the blue point time decreased with the rise in initiator concentration. The blue point describes the time and temperature at which the reaction medium turns blue, indicating the quick oligomer formation and rapid free radical initiation rates. Likewise, through the route of semibatch emulsion copolymerization P(MMA-co-St) copolymer nanoparticles were also produced. [92] Assistance through the ultrasound effect facilitates polymerization at relatively mild temperature conditions. Through ultrasound-assisted semi-batch in situ polymerization in a jacketed glass vessel; operating at 65 °C, composite PMMA/CaCO 3 nanoparticles were produced. [101]

Light-Assisted Synthesis of Microspheres
Synthesis through the combination of energy sources: ultrasound, and light is described. Noor et al. synthesized PnBA microspheres with a narrow particle size distribution (0.6 to 1.8 µm) via the facile microemulsion UV lithography technique. [102] The reaction mixture was ultrasonicated in a bath initially for 10 min and was subsequently subjected to UV photo curation in an N 2 atmosphere, followed by centrifugation and washing. The microspheres were found to have a high surface-to-mass ratio, useful for physical adsorption of reagent molecules, and enhancements in chemical loading capacity due to enhanced mass transfer kinetics.
Using the modified Hall method, Kisiel et al. synthesized PnBA microspheres with the use of 1,6 hexanediol diacrylate (HDDA) and DMPP as an initiator using an ultrasonic probe. [103] Following the ultrasonication, the reaction mixture was photopolymerized after the dispersion in an aqueous PVA solution. Encapsulation with KCl followed by partial conversion with AgCl resulted in finely dispersed uniformly distributed www.advmatinterfaces.de particles which had higher stabilized potential readings compared to the PnBA-based reference electrode.

Synthesis of Acrylic Microspheres Using Microreactors
In terms of the synthesis of acrylic microspheres, over the conventional techniques (such as magnetic stirring, batch reactor, continuous stirred tank reactor, and plug flow reactors), microreactors tend to have greater control over handling polymers with high molecular weight and provide high conversion with reproducible results. [30,43,104] In addition to that, the product obtained is found to be monodisperse with a narrow particle size distribution. [34c] Microreactors have also been found to have higher control over process parameters, and product characteristics such as size and size distribution. [30] Concluded from experiments, microreactors are effective in terms of molecular weight control for free radical polymerization reactions. [31] Microreactors also have quantitatively higher polymerization rates over conventional reactors. [105] Making additional changes to the existing microreactor configurations such as a higher volumetric flow ratio of the aqueous phase to the organic phase as well as a longer pre-polymerization time turned out to be helpful to boost the overall rate of polymerization. [106] Inherently, in the case of microreactors, there was always the fear of fouling and clogging while synthesizing polymer lattices. However, using differential microemulsion polymerization in microreactors combined with a biphasic slug flow achieves rapid and stable production of polymers. [106] Through a segmented flow reactor, through slug polymerization, PMMA particles were synthesized through a continuous production capability. [107] Through this procedural setup, control over molecular weight and precipitation was found to have been gained independently. With the internal circulation flow of the slugs in the microreactor, lower PDI was observed (1.56 at 75 °C and 1.55 at 85 °C) compared to a similar process run through a batch reactor (1.82 at 75 °C).
Using a coaxial capillary microreactor PnBA particles were synthesized with a much higher average molecular weight and lower polydispersity index compared to using a conventional stirred vessel. [104c] Employing a microreactor helped optimize the free radical polymerization reaction. Through CFD simulations, polymerization inside a microreactor was found to be near-isothermal. The polymer's molecular weight was found to correlate with reaction temperature and the concentration of the initiator (AIBN) used.
Through a controlled radical polymerization following the RAFT mechanism using a continuous flow process in a stainless steel tubing microreactor, a diverse set of acrylamides and acrylates were polymerized. [46] Hornung et al. achieved high conversions (80-100%), low PDI (1.15-1.20), and average molecular distribution similar to the process through a conventional reactor. Continuing with the RAFT solution polymerization, Derboven et al. [108] investigated the synthesis of poly (nBA) in the microreactor through both experimentation and simulation.
Yang et al. [109] synthesized pH-sensitive poly(sodium acrylateco-acrylamide) (P(AAcNa-co-AMm)) beads with a core-shell structure. A coaxial channel structure was developed for the microsphere's fabrication, and the reaction mixture was subjected to an inverse suspension polymerization process. Also, the product was found to have a narrow molecular weight distribution, with the core and shell's diameters easily controlled because of the use of microreactors and the manipulation of the liquid-liquid phase separation process.
Using a coaxial microfluidic device, monodispersed polyacrylamide (PAM) hydrogel microspheres were produced. [110] The schematic of the coaxial microfluidic device used in the synthesis is shown in Figure 18. They observed controllable preparation of PAM microspheres even when the temperature exceeded 95 °C, much higher than the limit of 20-60 °C recommended while using conventional reaction procedures. In addition to that, the microspheres also showed an entirely homogenous porous structure. Also, the preparation time was 2 min or less (10 min to h in the case of conventional methods), with the CV (coefficient of variation) of particle diameter being less than 4%.
Similarly, Sen et al. [111] synthesized polyacrylamide microspheres using the microfluidic T-junction through the process of continuous inverse suspension polymerization. With the increase in the O/A ratio (ratio of volumetric flow rates of organic carrier phase and aqueous phase), the size of the microspheres and the PDI were reduced. This was because Figure 18. Schematic depiction of setup containing a microfluidic channel and coiled teflon pipe. Reproduced with permission. [110] Copyright 2012, ACS.

www.advmatinterfaces.de
an increase in the O/A ratio causes the increase in the shear force at the junction, leading to the formation of smaller drops/ slugs. With respect to the design considerations, the opposed T-junction was found to be better than the cross T-junction as it had formed less slug-shaped microspheres than the desirable spherical ones. Also, in situ as well as ex situ mixing produced microspheres of the same shape, but the latter is not good in the long term as it may lead to choking of the pump.
Following the nanoprecipitation process, Dobhal et al. synthesized PMMA nanoparticles through a continuous flow microreactor and compared the results with a batch reactor. [30] Effects of monomer concentration, rate of homogenization, homogenization time, reaction temperature, and surfactant concentration on particle size and PDI were studied. The monomer acquired was in commercially available form as Eudragit S100. In the microreactor, variations in particle homogeneity were observed by changing the microreactor process parameters such as flow rates, reaction time, and monomer concentrations. Through the tuning of process conditions such as external temperature, surfactant conditions, or homogenization speed in a batch reactor near-monodisperse particles were formed. On the contrary, the standard deviation of the particle size was higher than what's suitable for obtaining reproducible results.
Through a water-in-oil (W/O) slug flow in a microreactor, Watanabe et al. [105] produced PMMA particles via soap-free emulsion polymerization. The advantage of using W/O slug flow is that the production of PMMA takes place without clogging. This is because a thin oil film is generated around the dispersed aqueous phase, which prevents the adhesion of particles to the microreactor walls. Over the relatively less reaction time of 20 min, it was observed that increasing the linear flow rate of the slug flow resulted in PMMA with high molecular weight (≈1500 kg mol -1 ). The influence of particle diameter, which rose due to the change in linear flow rate is shown in Figure 19. A similar effect to an increase in flow rate was observed when ethanol was added to the aqueous phase. The presence of ethanol in the aqueous phase was found to decline the electrostatic repulsive forces between the PMMA particles, which eventually leads to coagulation.
For an even higher polymerization rate than in the case of soap-free emulsion polymerization, differential microemulsion polymerization combined with a biphasic slug flow (schematized in Figure 20) can be considered. Qiu et al. [106] observed factors such as a higher number of particle nuclei in the microemulsion along with the higher specific surface area which boosted the polymerization rate. The slug flow regime was achieved through the presence of immiscibility in solvents regardless of the reaction conditions. Yoshida et al. [112] synthesized microspheres with a binary blend of poly(4-butyltriphenylamine) (PBTPA) and PMMA in equal weight proportions through oil-in-water emulsion droplets in a Y-shaped microreactor and subsequent solvent evaporation. Depending on the flow rate of the continuous phase: core-shell, Janus, and dumbbell-type microsphere morphologies were obtained. Also, lowering the molecular weight of the PMMA in the dispersed phase changed the Janus microspheres to a partial core-shell structure. The reduction of the interfacial tension between oil and aqueous phases, and the difference in interfacial energies of both polymer solutions achieved change of the morphology to Janus type from porous type. Variation in interfacial energies was made possible through the addition of SDS to the continuous phase. Core-shell type, nonporous microspheres were formed by increasing the time of evaporation.
Through single-emulsion droplet-based microfluidics, Chen et al. [113] synthesized Janus microbeads using a T-junction microreactor. The reaction mixture contained poly(N-isopropyl acrylamide) (PNIPAm) branched polymer, Fe 3 O 4 magnetic nanoparticles, and PMMA microparticles. The PNIPAm branched polymer was synthesized through solution polymerization of PNIPAm, poly(ethylene glycol)diacrylate (PEGDA), and PMAA monomers with the molar composition of 1:0.038:0.5. In the T-junction of the microfluidic device, the three reaction contents were pumped using syringe pumps. Different flow rates for inner and outer phases, 0.1 mL min -1 and 0.05 mL min -1 respectively were used. The emulsion droplets formed were collected and dried overnight at 60 °C. While drying a magnetic field was generated externally for the movement of Fe 3 O 4 particles to the tops of the droplets. In addition, the resultant material was applied to water evaporation and subsequently washed with pentane to remove the excess oil present. The role of the PMMA and magnetic nanoparticles was to move in opposite directions and form particle agglomerations on either side of the droplets, which eventually resulted in the formation of anisotropic Janus microbeads.
Shevchenko et al. [114] used a custom-made cross-flow microfluidic droplet generation unit based on a glass chip to synthesize cross-linked poly(styrene-MAA-divinyl benzene) and poly(styrene-MAA-EDGMA) microspheres. Using microfluidics, microspheres with a well-defined pore structure can be obtained with a specific surface area of greater than 200 m 2 g -1 .
The variation influenced the pore structure in nature and the concentration of the cross-linker used. The cyclohexane concentration was a parameter affecting the hydrophobicity, which in turn helps in controlling the microsphere size and distribution.
Marcati et al. [115] developed an end-to-end microparticle synthesis system based on microchannels. The system as described in Figure 21 consists of a droplet generation unit, a polymerization unit, and a microparticle management unit. This system was used to produce microparticles with tripropylen-glycol diacrylate as the organic phase liquid and hydroxyl-cyclohexylphenyl ketone as the initiator. The reactivity was found to be high due to the presence of two acrylate groups in the monomer and the system was able to produce microparticles within a short exposition time.

Via Living/Controlled Radical Polymerization
Recent developments in the living/controlled radical polymerization methods have provided great results in synthesizing alkyl methacrylates. [116] Some of the recently developed approaches with the use of a capping agent include exchange chain transfer, nitroxide-mediated radical polymerization, ATRP, and RAFT. On the other hand, living anionic polymerization methods don't require a capping agent for synthesizing alkyl methacrylates. Parida et al. [117] demonstrated ATRP through the use of coil-flow inversion via a coiled-capillary microreactor for the synthesis of linear and branched polymers of 2-dimethyl amino ethyl methacrylate (DMAEMA).
Nagaki et al. [116] demonstrated comparative studies describing polymerization through a conventional reactor and a microflow system. Using a conventional reactor for anionic polymerization of MMA required extreme temperature conditions (-78 °C). Applying fast mixing and control over the residence time, the microflow system was able to synthesize particles with narrow molecular-weight distribution at -28 °C to 24 °C.
Through a stainless-steel, coiled tube microreactor and continuous flow process, Parida et al. synthesized poly (DMAEMAco-benzyl methacrylate (BzMA)) through varying BzMA compositions(20% and 40%) through ATRP. [104a] The copolymers are composed of higher overall conversion and higher molecular weight with lower PDI. However, it was observed that after an hour of residence time inside the reactor; for both Reproduced with permission. [105] Copyright 2019, Wiley-VCH.

www.advmatinterfaces.de
BzMA composition variations, the difference between theoretical and actual molecular weight starts to rise along with the rise in the PDI. This was because of the unavailability of the monomer and an increase in the viscosity which leads to poor growth of polymer chains and unpredictable terminations. A study of comparison based on micromixing properties concluded that polymerization in microreactors had higher control when a multi-lamination mixer was used in the initial mixing step.
Parida et al. [118] studied the continuous flow ATRP of poly(DMAEMA). It involved the use of tubular microreactors ranging over various sizes and geometries (from micro to milli scale), and varying lengths of coil flow inverter (CFI) reactors. Over a residence time of 2 hours, it was found that increasing the diameter of the microreactors caused an increase in throughput, and caused the PDI to rise, but had a negligible change in conversion. However, with the use of a flow-inversion mechanism, PDI can also be controlled with the rise in reactor diameter.
Using a PFA (perfluoro (alkoxy alkane)) tube reactor (ID: 1.65 mm) with recycle stream, the production of PnBA was studied through a RAFT polymerization mechanism. The use of BTR and CTR yielded unimodal polymers whereas the products from the LTR setup were multimodal. In simple terms, multimodality in terms of polymers describes the polymerization of polymers with multiple molecular weight distributions. The CTR gave higher conversion than the BTR With changes in the residence time and recycle Figure 21. Schematic of the end-to-end microparticle management system. Reproduced with permission. [115] Copyright 2010, Wiley-VCH. Figure 20. Schematic of the experimental setup of differential microemulsion polymerization carried out in a biphasic slug flow. Reproduced with permission. [106] Copyright 2021, Hindawi Publishing Corporation.
www.advmatinterfaces.de ratio, the molecular weight distribution and polymerization rates got changed.

Chitosan-Based Acrylic Microspheres
Chitosan (CS), which is produced by the alkaline deacetylation of chitin, is one of the most important polysaccharides on earth. [119] In recent years, CS has been getting a lot of interest for its use in biological and biomedical applications. In addition to being the second most available biopolymer in the world after cellulose, CS is biocompatible, non-toxic, and biodegradable. CS has myriad applications, including biocatalysis, as support for immobilized enzymes, drug delivery, and regenerative medicine. Often, CS is modified at the molecular level to increase its solubility preventing it from aggregating. [120] CSbased microspheres are often crosslinked with other monomers (such as acrylates or acrylic acids) to shield them from dissolution and enhance its stability. Chitosan-based microspheres are generally prepared by emulsion cross-linking, precipitation, spray-drying, ionic gelation, and sieving method. [121] Through the use of microreactors, various crosslinked chitosan-based acrylic microspheres were synthesized. Xu et al. [34b] used microfluidics to generate CS/poly acrylic acid-glutaraldehyde (CS/PAA-GLA) microspheres. The microfluidic device used consisted of PMMA plates, a Teflon tube was inserted as a multiphase flow channel in between the plates which were eventually sandwiched together. Additionally, stainless-steel needles were inserted as the dispersed phase and continuous phase inlets. Adding additional acrylic acid, ammonium persulfate, and polyethylene glycol (PEG) to the dispersed CS/PAA-GLA microspheres with subsequent washing made them turn porous. Analysis through an optical microscope confirmed that the microspheres were highly monodisperse with a high degree of sphericity. Figure 22 represents the microspheres formed from the microreactor and the schematic of a microreactor.
Using a coaxial microfluidic device with a multiphase flow channel (made of PTFE), Xu et al. [34c] synthesized CS-PAA microspheres with a compact core and porous structure (confirmed through SEM analysis). Traditionally inverse suspension polymerization coupled with stirring operation was used to produce these microspheres, which were not monodisperse with no control on their size and structure. On the contrary, the use of microfluidics allowed producing monodisperse (PDI of 3.2%) with ease in control over size and structure.

Synthesis through Integrating Microreactors with Photopolymerization
Transition to the integrated photomicroreactor technology is crucial in this age, due to its benefits in the synthesis procedures presented.
Lobry et al. [61b] synthesized linear polymeric nanoparticles in a microreactor with a low-intensity UV fluorescent lamp using MMA/nBA/acrylic acid (49.5/49.5/1 wt%) as monomers. The schematic of the experimental setup utilized is depicted in Figure 23. The two 36 W UV fluorescent lamps used were www.advmatinterfaces.de emitting between 280 and 360 nm and provided an estimated irradiance of 3 mW cm −2 . They claim that their approach of using a photochemical microreactor to synthesize nanoparticles was the first of its kind. The use of visible light as photoinitiator and initiator-less photopolymerization (by click chemistry) were concluded as future research directions.
[61a] achieved a clogging-free, stable performance through the photochemical microreactor. The photochemical effect provided by the UV fluorescent lamp was not causing any thermal effects in the reaction, causing a negligible 3 °C rise for a 3 h irradiation. Effects such as decreasing droplet size, which improved the light penetration, caused the conversion to rise. Quantitatively, for 10 min of UV irradiation, conversion of 74% was observed when the droplet size was 40 nm. The conversion plummeted to 35% when droplets had a size of 90 nm. The rise in the photo-initiator concentration had a modest effect on the conversion, whereas it caused a drastic drop in the molecular weight. Parameters such as diffuse reflectance (R) and diffuse transmittance (T diff ) can be used to observe the effects of droplet size on the irradiated light penetration inside the microreactor. Both R and T diff were close to zero in the wavelength range where the reaction mixture strongly absorbs the light. Where a rise in R and T diff is observed in the range where the photo-initiator moderately absorbs the light. An increase in the residence time (t R ) caused an expected rise in conversion and increased radical generation (due to a rise in absorbed photon flux). However, for longer t R , clogging was observed due to reduced flow rates.
Lapierre et al. [122] synthesized highly porous polymeric beads by creating a stable oil-water emulsion using three acrylatebased monomers (2-ethyl hexyl acrylate, isobornyl acrylate, and dipentaerythritol penta/hexa-acrylate). The stable oil-water emulsion was fed into a microfluidic reactor, which was assembled using micropipette tips and tubing. After the formation of microdroplets containing all the monomers in per-fluorinated oil, the porous microspheres were photocured through UV photopolymerization with Darocur 4265 as the photoinitiator. The excess water from the microspheres was removed via an acetone wash and subsequent drying in an oven (50 °C for 24 h).
Through the use of droplet-based microfluidics with in situ photopolymerization, Kim et al. [123] produced poly (1,10-decane diol dimethacrylate-co-trimethoxysillyl propyl methacrylate) core-shell microspheres. There was a gradual growth of silica nanoparticles as an inorganic shell around the acrylic-based core. Using microfluidics over conventional reactors helped obtain improvements in size uniformity and reduction in the number of processes.
Jachuck and Nekkanti [62] used UV radiation for initiating the polymerization of nBA through a narrow channel reactor (with an internal diameter of 1.5 mm, made of borosilicate). The reaction setup is shown in Figure 24. The UV lamp was let to operate at the peak intensity of 365 nm. Extensive experiments contrasting the effects of UV lamp intensity, initiator concentration, and space-time on conversion and molecular weight distribution were conducted. They concluded that the use of a photoinitiator with 2% w/w of monomer provided the highest monomer conversion; however, it had relatively higher PDI compared to using the mixture with 0.5% w/w photoinitiator. Compared with the thermally initiated micro and macro reactors, the photo-initiated microreactor took about a tenth of the exposure time and gave a relatively similar conversion and a significantly lower PDI. Additionally, the molecular weight was found to be lower compared to the thermally initiated microreactor.
A mathematical model was developed by Jachuck and Nekkanti [62] with the assumption that the reactor operates with a plug flow and has a uniform temperature throughout. The model predicted the monomer conversion for a given reactor geometry, photoinitiator concentration, and parameters influencing   [62] Copyright 2008, ACS.

www.advmatinterfaces.de
kinetics via the mixing/hydrodynamics effects. Individual model correlation (with respect to the % conversion) with the experimental results was found to be weak in the case of pho-toinitiator concentration. However, the prediction of % conversion with respect to UV intensity and exposure time (considered individually) was found to be in good agreement.  [132] Copyright 2015, Wiley-VCH. b) Use of bisepoxy as spacer arm Reproduced with permission. [134] Copyright 2016, MDPI. www.advmatinterfaces.de

Applications of Acrylic Microspheres
Polymeric microspheres have been adopted in chemical, biotechnology, pharmaceutical, and food industries to achieve sustainable growth and ecofriendly development. Polymeric microspheres have been of huge interest in the areas of medical diagnostics, medical therapy, drug delivery, adsorbents, affinity bioseparators, and biocatalysis. [124] Specifically, in the case of acrylic microspheres, due to the diversity in the monomers used for synthesis, a specific set of monomer units can be crafted to suit the expected resultant properties.

Biocatalyst Immobilization
Enzymes are considered the most diverse, naturally available catalysts that can support the chemical reactions with high specificity and stereoselectivity. [125] However, the enzyme alone cannot perform the required catalysis at a commercially viable level. Immobilization of enzymes is essential to enhance the stability and recyclability, which are some of the key aspects of an efficient catalyst. In the synthesis aspect, the immobilized enzymes can be used in both batch and continuous processes with controllable production rates. [126] To avoid the mass transfer limitations, the immobilization is done on the surface of the support material. The essential features of the support material include non-toxicity, biocompatibility (in the case of biochemical reactions), and possessing a large enough surface area to accommodate the enzyme reaction and substrate. It is also desirable to have the ability to transfer products through an unrestricted diffusion process. Naturally available polymers such as alginate, chitosan, collagen, gelatin, cellulose, starch, and pectin have been explored as support materials. [127] Some other commonly used support materials include various synthetic polymers, inorganic magnetic particles, and magnetic polymer microspheres. [128] Of late, acrylic microspheres have proven to be efficient to act as support materials for immobilizing various enzymes. [129] Attributes such as having a large enough surface area via a porous structure are essential to achieve effective diffusion of reaction materials. [11a] The immobilization process primarily involves the reaction between epoxy groups and amino groups present in the enzymes. Hence, acrylic microspheres such as PGMA which inherently contain free epoxy groups become a good choice. [93] Various factors affect the performance of the biocatalyst produced by the immobilization of enzymes with acrylic microspheres as a support material. The presence of substrates or inhibitors enhances activity retention. In addition to that, the pore size of the support material plays a crucial role in the enzyme activity; the larger the pore size, the more diffusion limitation is eradicated which leads to enhanced activity retention. [127] To gain improvements in enzyme stabilization and performance; microspheres are desirable to have a large surface area, greater physical strength, inertness, and resistance to a microbial attack. [130]

Describing Kinetic Behavior of Immobilized Enzymes
To quantitatively compare the results obtained from the enzyme immobilization process, various models and parameters are defined that describe the enzyme-microsphere behavior. The kinetics of immobilized enzymes in an enzyme-inhibited reaction usually follows the Michaelis-Menten model. [131] Whereas the graphical representation is carried out through the use of Lineweaver-Burk plots.
Below mentioned in Table 5 are some of the most widely used parameters used to describe the immobilized enzymes.

Using Acrylic Microspheres for Enzyme Immobilization
The process of enzyme immobilization can be achieved through various methods. [128] Some of the popular methods include physical adsorption, encapsulation, covalent bonding, or use of a spacer arm. A pictorial representation of the different methods is presented in Figure 25. Among these, the covalent bonding mechanism is the one that is widely used for its enhanced stability of the enzyme-support bond, preventing the release of enzymes into the environment. [132] Unlike other methods, covalent bonding method forms new bond between microspheres and enzymes, which improve the immobilization. [133] Below are some of the implementations of enzyme immobilization using a wide variety of acrylic microspheres.
Shevchenko et al. [114] synthesized porous cross-linked poly (styrene-methacrylic acid-divinyl benzene) microspheres which showed impressive sorption of bovine serum albumin (BSA). Designing microspheres with characteristics of mono-dispersity, narrow size distribution, and a porous structure with a specific surface of greater than 200 m 2 g -1 were helpful in the sorption process. This was made possible through the use of a droplet-based microfluidic reactor. However, it could be attributed that; neither using microspheres with a structure having a smooth surface nor the specific surface area below a certain limit (0.7 m 2 g −1 in this case) helps the effective sorption of BSA.
Immobilization of BSA was contrasted between two procedures: physical interaction and covalent interaction. [7a] BSA was immobilized onto poly(styrene)-co-poly(2-acrylanmido-2-methyl propane sulfonic acid) microspheres via physical interaction mechanism whereas PMMA-co-PGMA microspheres were used as support through covalent interaction. The equilibrium amount of BSA immobilized was found to be higher when PMMA-co-PGMA microspheres were used as the supporting material. Immobilization of lipase polyethyleneimine (PEI) grafted PMMA microspheres were found to have enhanced catalytic activity. [135] In the recyclability aspect; even after 4 cycles of reuse, the PEI-crosslinked immobilized lipase retained more than 80% of its maximum residual activity whereas only 60% was retained in the case of directly immobilized lipase.
Leontieș et al. [129a] used chitosan-polyacrylic acid microspheres as a support material with EDC as the crosslinker for the immobilization of laccase via a multi-step approach. The idealistic representation of the immobilization procedure is shown in Figure 26. Laccase enzymes belong to the family of multi-copper oxidases (MCOs), naturally found in various plants, bacteria, and fungi. Characterization of the enzymemicrospheres showed that the PAA played a vital role in the parameters such as size, surface morphology, rheology, and modulation of laccase immobilization. However, it was found that the product with the largest active enzyme amount present was the one with the lowest PAA concentration. Compared to free laccase, the immobilized one was found to provide greater recyclability, faster biocatalytic decomposition rate, and was less prone to a substrate, operation, and thermal inactivation.
Vera et al. [9c] immobilized laccase onto monodisperse PGMA microspheres to enhance the degradation of aziphosmethyl. This operation concluded to find support through PGMA microspheres was found to improve various biochemical properties such as degradation of the pesticide diazinon of the enzyme and help them function efficiently. Similarly, PGMA experienced a change in its surface morphology with the immobilization with laccase, which is evident through the scanning electron micrograph comparison shown in Figure 27.

Functionalized Acrylic Microspheres
Lei et al. [93] used PGMA grafted Fe 3 O 4 /SiO x magnetic microspheres for the immobilization of lipase. SiO x is used to provide biocompatibility and higher specific surface area, both desirable for efficient immobilization. Additionally, the enzymes immobilized on microspheres under the effect of a magnetic field showed higher activity, stability, and easy separation from the reaction medium, promoting recyclability. [137] Immobilization activity of laccase over amine-functionalized poly(GMA-co-nBA) microspheres was observed. [88] Covalent binding immobilization (carried out at room temperature) involved the amino groups over the enzyme surface and the aldehyde groups on the acrylic microspheres, which is schematized in Figure 28. An increase in the epoxy content increased the activity of laccase-immobilized microspheres. The immobilization amount of laccase increases with the increase in the concentration of the cross-linking agent (glutaric dialdehyde) www.advmatinterfaces.de up to a certain limit. The maximum laccase immobilization of 67.62% was obtained at 0.01% glutaric dialdehyde concentration (when concentrations varied within the range of 0-0.03%). It was found that the immobilized laccase was more thermally stable and had a much broader pH profile compared to the free laccase preserving the enzyme in a wide range of environments.
Similarly, Han et al. [138] observed a wider pH profile and thermal stability of immobilized pepsin where modified poly (GMA-co-MMA) monolith was used as the support over free pepsin.
For cellulase immobilization, methacrylamide-co-acrylic acid (PMAAc) copolymer was used with an upper critical solution temperature (UCST) type. [139] UCST-type biocatalyst exists in a soluble state, is accessible to the substrate at temperatures above UCST, and can undergo precipitation below UCST. This ensures higher catalytic activity and easy recovery from the reaction medium. The UCST of a material is usually determined via the cloud point method. The specific enzyme loading (46.6 mg g -1 ) of cellulase was found to be much higher compared to that of non-acrylic microspheres (7.2 mg g -1 ). [140] In addition to that, recyclability was impressive in the case of PMAAc-cellulase. It was found to retain 82.4% of original catalytic activity after being reused for 10 times.
Ling et al. developed a potentiometric formaldehyde biosensor based on alcohol oxidase immobilized onto poly(nBA-Nacryloxysuccinimide) microspheres. [11a] The microspheres used were hydrophobic in nature and were surface functionalized using acryloxysuccinimide.

Metal Catalyst Carrier
Over the last few decades, research on catalytic materials has been focused on enhancing product yield with minimal side reactions. This can be addressed through heterogenous catalysis, but their catalytic performance is generally quite lower compared to their homogenous counterparts. [141] The catalytic performance can be increased by increasing the catalytic activity or loading capacity via an enhanced specific surface area. [142] Compared to the free catalyst, improvements in stability, reusability, and recoverability are obtained through acrylic microspheres as carriers. [143] For the catalytic reduction of 4-nitrophenol, gold nanoparticles were loaded onto magnetic Fe 3 O 4 /poly(GMA-DVB)/ polyamidoamine(PAMAM) microspheres. [143] Wherein Fe 3 O 4 acted as magnetic cores, with grafted poly(GMA-DVB) and PAMAM microspheres as a carrier. The catalyst-microspheres were found to be stable even after ten cycles and could be reused via magnetic separation. The reusability of various catalyst types has been compared in Figure 29.
Du et al. [144] used silica/poly (styrene-co-acrylic acid) (SiO 2 / PSA) core-shell microspheres as support for a hybrid titaniumbased catalyst for the homopolymerization of ethylene. The catalytic activity was found to vary based on the mass ratio of SiO 2 /PSA in the loaded catalysts. A steady kinetic curve, a longer polymerization lifetime was observed with a higher mass ratio (20% SiO 2 /PSA). The resultant polymerized ethylene was found to have desired characteristics such as a higher molecular weight with a broader distribution. Higher overall activity was observed with the polymerization time in the case of 20% SiO 2 /PSA compared to the other variations. The kinetics of polymerization are shown in Figure 30.
Similarly, the catalysis of polyolefins for the production of polyethylene via zirconocene and titanium-based Ziegler-Natta catalysts was improved through the support of acrylic co-polymer core-shell microspheres. [145] Well-disperse SiO 2 /PSA core-shell microspheres were employed wherein, the core part of the microspheres supported (n-BuCp) 2 ZrCl 2 and the shell part carried TiCl 4 .

Conclusion, Challenges, and Future Prospects
This review extensively covered the synthesis of various acrylic microspheres under different reaction conditions, initiation protocols, and various polymerization methods through conventional and process-intensified reactors. Through an intensified reactor, acrylic microspheres are synthesized with greater control over the particle size distribution, particle morphology, molecular weight distribution, porosity, and polydispersity. Compared to conventional reactors, ultrasound and microreactors have a much greener footprint, provide greater polymerization Figure 27. SEM results of PGMA microspheres performed a) before immobilization, and b) after coimmobilization of Agaricus bisporus and Trametes Versicolor laccases. Reproduced with permission. [136] Copyright 2020, Elsevier.

Figure 29.
Describing the quantitative comparison of various catalyst types based on their recyclability. Reproduced with permission. [143] Copyright 2018, Springer Nature.

Figure 30.
Homopolymerization kinetics (activity with respect to the time) of ethylene using different titanium-based catalysts with SiO 2 /PSA core-shell microspheres as support. Reproduced with permission. [144] Copyright 2010, Wiley-VCH. rates, and involve lower operational risks. Additionally, through microreactors, higher heat and mass transfer rates can be obtained due to a miniaturized reactor volume and a variety of flow-mixing patterns. The impact of integrating reactors with an external energy source such as microwaves, light, or ultrasonic waves has been also discussed.

Other Reactor Types
The equipment used for synthesizing polymeric materials influences the product efficiency and its properties (such as size, dispersity, porosity, solubility, and absorption spectra). Slight variation in these types of crucial parameters is expected to greatly impact the application being worked upon. In addition to the above-mentioned process intensification methods, additional strategies are currently being explored suitable to the application. Reactor designs that incorporate flow patterns resulting in efficient mixing of the reaction mixture which hasn't been used to synthesize acrylic microspheres are listed: • The spinning disc reactor is considered to be one of the most important milestones in modernizing the field of process intensification. [146] It has been extensively used for synthesizing nanoparticles with impressive control over size, shape, and surface characteristics. It has also been proven to have dissipated 15% lower power than a conventional reactor. • The use of continuous reactors is helpful in the synthesis of controllable monodisperse nanoparticles over their batch counterparts. An oscillatory baffle reactor was designed as a novel form of the continuous PFR, where the tubular sections are fitted with equally spaced constriction orifice plate baffles. The baffles are designed to oscillate to generate a flow pattern that maintains plug flow while having efficient heat and mass transfer characteristics. [147] OBR has been used to conduct suspension polymerization. [148] The reaction conditions were set in the moderate range(43-45 °C) compared to the batch polymerization operation conditions, which require a constant temperature of over 70 °C. However, batch OBR has been used to produce methyl methacrylate suspensions through suspension polymerization. [149] • For certain polymerization reactions as involvement of external catalysts such as metal halides is crucial. [83] Controllable polymerization procedures, which were found to have improved the monodispersity and molecular weight distribution, often involve an external catalyst. Catalytic plate reactors, which consist of metal plates have channels arranged in a crisscross manner. They are used for enhancing catalytic activity and to gain improvements in the transverse temperature gradients. • Use of helix reactors enhances the mixing aspect of plug flow combined with a reduced pressure drop across the reactor. TNOs' helix reactor demonstrated the use of the polymerization of MMA while preventing coagulation through its gentle mixing characteristics. [150] • A continuous system that uses the Taylor-Couette flow to synthesize wide range of products. Taylor vortex flow reactor was also been used for the continuous production of emulsion polymerization of styrene, [151] polycondensation of polyacrylate. [152] Hence, the use of these reactors might lead to desirable improvements in various characterizing features of the synthesized acrylic microspheres.
Enhancements in catalytic activity using support/carriers have been discussed. The use of acrylic microspheres as support materials for enzymes enhanced their thermal, pH, and operational stability. Additionally, compared with the free enzyme, the immobilized biocatalyst showed improvements in reusability, recyclability, enzymatic activity, and efficiency. Functionalization of the carrier through functional-group modification, porous nature, core-shell structure, or composites was shown to provide additional benefits.

Alternative Support Materials
Cellulose and chitosan are some of the most largely exploitable natural polymeric materials that could be used to carry out enzyme immobilization. Additionally, materials such as metalorganic frameworks (MOFs) and covalent-organic frameworks (COFs) based composite materials have been used as support materials for enzymes specifically due to their organic nanoporous structure. [153] Features such as having a predesignable structure to tune pore size, functional groups, and various physicochemical properties are inherent to MOFs and COFs. Zeolite imidazolate framework-67(Co)/multiwalled carbon nanotube (ZIF-67(Co)/MWCNT) based composite has been used to carry out enzyme immobilization of Horseradish peroxidase. [154] Magnetic COFs used as support material for the immobilization of lipase were found to have maintained good recovery and enzyme activity. [155] Research on MOFs and COFs is still in the initial stages. Acrylic microspheres composites with the abovementioned alternate materials can provide additional benefits through an intensified process.
Additionally, most biocatalysts produced with acrylic microspheres as supporting material through enzyme immobilization have not been synthesized through the process intensification route. Considering all the benefits observed in surface morphology control, monodispersity, and porous nature, resultant activity from materials produced through intensified strategies would probably outshine the ones from a conventional approach. www.advmatinterfaces.de Shirish H. Sonawane is currently working as full professor at National Institute of Technology, Warangal, (NITW), India. He is a prolific, well-cited, and multiple-fellowship-winning scientist. He received his Ph.D. at North Maharashtra University (NMU), Jalgaon, India. His research expertise is in sonoprocess engineering and cavitation-based nanotechnology to synthesize carbon-based 2D materials and polymer nanocomposites in energy conversion, fuel cells, membranes developments, and wastewater treatment applications.