Hydrogel Microspheres: Preparation and Application
- 1. Instrumental Analysis Center, Dalian Polytechnic University, China
- 2. School of Biological Engineering, Dalian Polytechnic University, China
- 3. School of Light Industry and Chemical Engineering, Dalian Polytechnic University, China
- #. School of Light Industry and Chemical Engineering, Dalian Polytechnic University, China
Abstract
There are many studies on hydrogel microspheres due to their good biocompatibility and tunable physicochemical properties. This mini review summarizes the synthesis methods and applications of various functional hydrogel microspheres. The common preparation techniques of hydrogel microspheres are first briefly introduced, including emulsion polymerization, microfluidics, photolithography, electrospray and 3D printing. Besides, the related research progress of hydrogel microspheres in various fields was reviewed and focused on the application of hydrogel microspheres as delivery platforms, enzyme immobilized microcarriers, antibacterial agent and some new fields. Finally, the limitations and future prospects of the development of hydrogel microspheres were presented. It is hoped that this review can provide a beneficial reference for the development of hydrogel microspheres and foster the application in a wider range of fields.
KEYWORDS
- Hydrogel microspheres; Drug carrier; Immobilized enzyme carriers; Antibacterial agent.
CITATION
Wang H, Yu X, Wei X, Tian J, Li Y, et al. (2024) Hydrogel Microspheres: Preparation and Application. J Materials Applied Sci 5(1): 1011.
INTRODUCTION
Hydrogel microsphere is a type of spherical material crosslinked by hydrophilic or amphiphilic polymer networks with a diameter of micron. In recent studies, hydrogel microspheres have gained considerable attention because of its variety of unique properties such as high water content, good biocompatibility [1,2], degradability [3,4], stimulus responsiveness [5,6], temperature and pH sensitivity [7,8], porousness [7,9], and controllable particle size [10,11]. With the technological advances, hydrogel microspheres are widely used in drug carriers [12,13], immobilized enzyme carriers [14,15], antibacterial agent [16,17] and improvement of the hydrogel mechanical properties [18] and so on. Here, the research progress in the preparation and modification of hydrogel microspheres are summarized. The various functions of hydrogel microspheres on related biomedical applications are detailed. Finally, we discuss the limitations faced by hydrogel microspheres and prospects of the new strategies for expanding the application. Overall, this mini review aims to provide a solid theoretical foundation for the further development of hydrogel microspheres research.
Preparation of hydrogel microspheres
At present, the main techniques for preparing of hydrogel microspheres include emulsion polymerization [19], microfluidics [20], photolithography [21], electrospray [22,23] and 3D printing [24,25] etc. The emulsion polymerization method is to use a stable emulsion as a reaction system, introduce monomers, initiators and surfactants into the emulsion, and polymerize under certain conditions to generate hydrogel microspheres. This is the most widely used method for preparing hydrogel microspheres, which can be prepared with different sizes, shapes and surface properties [26]. The microfluidic method relies on microfluidic chips to control the flow of polymer materials and the reaction process through microchannels and microvalves, which can prepare hydrogel microspheres with uniform size, regular shape, and controllability [27,28]. In contrast, photolithography and electrospray methods avoid the use of oil phases and surfactants, improve the bioactivity of cells, and are suitable for cell encapsulation. Hydrogel microspheres with complex shapes and structures can be prepared using 3D printing technology.
Modification of hydrogel microspheres
Hydrogel microspheres can be functionalized by different polymers or monomers to meet the needs of different applications. There are two main ways: (1) Hydrogel microspheres with specific functional groups on the surface were prepared by using different functional monomers [29]. (2) The surface of the prepared hydrogel microspheres was treated by various chemical modifications to to endow the microspheres with specific functions functions [30]. Meanwhile, the special selection and design of biomaterials can adjust the biocompatibility and physicochemical property of functional hydrogel microspheres and expand their application range [31].
THE APPLICATION OF MICROSPHERES
Delivery platforms
Systemic and frequent administration of the drugs may result in organ toxicity and anaphylactic reaction. Hydrogel microspheres are characterized by their high porosity and easy injectability, which is conducive to the minimally invasive delivery of drugs [32,33]. Wang et al. [34], loaded sorafenib (SOR) and doxorubicin (DOX) into the skeleton made of hyaluronic acid methacrylate and gelatin methacrylate, and phase-changing hydrogel consisting of fish gelatin and agarose, respectively. The drugs exhibited varied release profiles upon near-infrared irradiation, including rapid release of DOX and sustained release of SOR. The spatiotemporal responsive hydrogel microspheres realized on-demand release of different drugs and improved the treatment efficiency of gastric cancer (Figure 1).
Figure 1: Application of spatio-temporal responsive hydrogel microspheres in the synergistic treatment of gastric cancer with SOR and DOX [35].
Lin et al. [35], designed an injectable double positively charged functional hydrogel microsphere. Positively charged poly-lysine on the surface of hydrogel microspheres could target and adsorb onto cartilage with negative charge. Meanwhile, positively charged polyamidoamine loaded inside the hydrogel microspheres could realize cartilage penetration with the function of electrical charge, achieving in situ drug delivery. Ling et al. [36], designed a novel alginate hydrogel supported with hollow silica microsphere as a drug delivery platform by ion crosslinking. Research results showed the hydrogel microspheres had broad-spectrum controlled-release performance and the controlled-release time could exceed 40 h.
Enzyme immobilized microcarriers
Hydrogel microspheres have a porous structure with adjustable pore size and can also introduce different functional groups through chemical modification, such as carboxyl, amino, hydroxyl, which can form covalent or non-covalent interactions with specific parts of the enzyme, improving the immobilization efficiency and stability of the enzyme [37,38]. Ma et al. [39], combined papain with the size-controlled hydrogel microsphere through strong hydrogen bonds. The enzymatic activity of immobilized papain was increased to 106.41% of free papain and remained 59.60% after 10 cycles. The traditional lipase catalytic methods cannot provide the “micro water environment” for highly efficient catalysis of lipase. Qin et al. [40] , designed a porous polyacrylamide hydrogel microsphere by inverse emulsion polymerization. This hydrogel microsphere and the oil phase successfully created oil-water interface to contribute the open of the unique “lid” structure of lipase, greatly enhancing the catalytic efficiency of lipase (Figure 2).
Figure 2: An oil-water interface for the “interfacial activation” of lipase provided by porous polyacrylamide hydrogel microspheres [40].
Jo et al. [41], prepared cellulose hydrogel microspheres with inherent biocompatibility and biodegradability for the immobilization of lipase, which showed higher loading efficiency than that on microcrystalline cellulose and millimeter-sized hydrogel beads. This hydrogel microsphere also had potential for immobilization of other enzymes.
Antibacterial agent
Antibacterial hydrogel microspheres have large surface area for efficient antimicrobial drug storage and potent resistance of the aggregation of bacterial cells, which can effectively prevent the invasion of harmful bacteria [42,43]. Gwon and the team [44] constructed a uniform micro-sized hydrogel spheres (Si@Ni- GelMA) by encapsulating the antibacterial silicon-based nickel nanoflowers in gelatin methacryloyl through microfluidic and photo-crosslink methods. Si@Ni-GelMA of 2 mg mL-1 exhibited an excellent bactericidal rate as high as 99.9% of three bacteria strains such as Klebsiella pneumonia (Figure 3).
Figure 3: Illustrations of hydrogen microspheres (Si@Ni-GelMA) prepared for antibacterial applications [44].
In another study, Mohammed et al. [45], synthesized chitosan hydrogel microspheres that were doped with silver nanoparticles (CS- AgNPs) and compared the antibacterial activity of them with commercial antibiotics. The result showed the outstanding antimicrobial activity of CS-AgNPs for both Gram-positive and Gram-negative bacteria and could be considered as potential candidates for antimicrobial agents in the medical field.
Hydrogel microspheres in new fields
In the field of hydrogel microspheres, scientists are also constantly exploring new methods to enhance the comprehensive properties of materials. As demonstrated by Zhao et al. [18], the mechanical properties of hydrogels were significantly enhanced by importing micron-scale microspheres into the hydrogels as physical crosslinkers. This multi-scale structure design improved the compressive strength of the hydrogel from 0.17 MPa to 1.37 MPa (Figure 4).
Figure 4: Mechanism of multi-scale hydrogel synthesis. [18].
This improvement was attributed to the enhanced interaction between the microspheres and polymer chains, allowing stress could be efficiently transferred from the continuous network to the entangled microregions.
He et al. [46], specifically developed a point-of-care testing device that integrated hydrogel microsphere-based immunoassays with smart phone Fourier analysis for detecting the chloramphenicol (CAP) residues in milk (Figure 5).
Figure 5: The schematic illustration of working principle of device and its promising applications in milk quality monitoring [46].
By using the mechanical deformation of hydrogel microspheres to accelerate the immunofluorescence reaction, the technology could efficiently detect not only CAP in milk, but also other low- concentration harmful substances in the food field, showing its wide application potential in food safety monitoring.
Taking inspiration from the structure of petunia powder, Hua and his team [47], successfully prepared sodium alginate hydrogel beads that mimic the structure of petunia pollen and encapsulate magnetic hydroxyapatite nanoparticles (Figure 6).
Figure 6: The synthesis process and adsorption mechanism of sodium alginate hydrogel beads [47].
The addition of sodium alginate hydrogel could not only prevent the powdered magnetic hydroxyapatite nanoparticles from falling off, but also chelate with heavy meal ions through hydroxyl and carboxyl groups, which was beneficial to the improvement of the adsorption capacity. The adsorption capacity of hydrogel beards for Pb2+ reached 757.92 mg/g, which was far above that of magnetic hydroxyapatite nanoparticles (400 mg/g). The sodium alginate hydrogel beads were considered as a promising composite material for the adsorption and removal of dyes and heavy metal contaminants.
DISCUSSION & CONCLUSION
In summary, the present study overviewed the recent advance of hydrogel microspheres, including preparation, modification, and wide applications. The fabrication technology of hydrogel microspheres remains limited, where it is difficult to precisely control the size and uniformity of the hydrogel microspheres. Besides, the transformation from laboratory research to clinical application still faces challenges such as overcoming production scale and clinical trials [48,49]. However, with the continuous progress of materials science, we can foresee that hydrogel microspheres will play a key role in more fields in the future, and their application prospects are broad and their potential is unlimited [8,50]. The continuous exploration and innovation of these versatile, high-performance materials by scientists will provide new solutions to many real-world challenges.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science Foundation of China (22278045, 22278048), Foundation of SKL of Marine Food Processing & Safety Control (SKL 202302, SKL 202312), Natural Science Foundation of Liaoning province (2022-MS-344).
REFERENCES
- Gai T, Zhang Y, Li G, Zhou F, He C, Wang X, et al. Engineered hydrogel microspheres for spheroids and organoids construction. Chem Eng J. 2024; 498: 155131.
- Jia J, Liu J, Shi W, Yao F, Wu C, Liu X, et al. Microalgae-loaded biocompatible alginate microspheres for tissue repair. Int J Biol Macromol. 2024; 271: 132534.
- Wijk AE, Georgakopoulou T, Steendam R, Zuidema J, Hordijk PL, Bavel E, et al. Extravasation of biodegradable microspheres in the rat brain. Drug Deliv. 2023; 30: 2194579.
- Thaarup IC, Gummesson C, Bjarnsholt T. Measuring enzymatic degradation of degradable starch microspheres using confocal laser scanning microscopy. Acta Biomater. 2021; 131: 464-471.
- Li S, Xiao L, Deng H, Shi X, Cao Q. Remote controlled drug release from multi-functional Fe3O4/GO/chitosan microspheres fabricated by an electrospray method. Colloids Surf B Biointerfaces. 2017; 151: 354-362.
- Zhang Z, Li Q, Sun N, Liu Y, Ge S, Che H. The preparation of stimulus- responsive pickering emulsion and its application in preparing microspheres. J Dispersion Sci Technol. 2021; 44: 1537-1548.
- Fan H, Sun Y, Bao Y, Guo H, Fan L, Cheng L. Polymer microsphere integrated with fiber bragg grating for simultaneous monitoring of relative humidity and temperature. Measurement. 2024; 225: 113990.
- Wang N, Wei Y, Hu Y, Sun X, Wang X. Microfluidic preparation of pH-responsive microsphere fibers and their controlled drug release properties. Molecules. 2023; 29: 193.
- Song W, Zhang Q, Guan Y, Li W, Xie S, Tong J, et al. Synthesis and Characterization of Porous Chitosan/Saccharomycetes Adsorption Microspheres. Polymers. 2022; 14: 2292.
- Yu H, Zhou C, Wang L, Yang C, Li S, Wang W. Enhancing optical performance of LED light diffusing plates through particle size and distribution control of organosilicone microspheres. Opt Mater. 2024; 151. 115317
- Ren Q, Xue Y, Cui Z, Lu Y, Li W, Zhang W, et al. Preparation of lignin based phenolic resin microspheres with controllable particle size and its application in capacitors. Diam Relat Mater. 2022; 125; 109000.
- Megan H, Stephen H, Prajnaparamita D. Hyaluronic Acid Hydrogel Microspheres for Slow Release Stem Cell Delivery. ACS Biomater Sci Eng. 2021; 7: 3754-3763.
- Li Y, Zha Y, Hu W, Chen J, Liu S, Zhang S, et al. Monoporous microsphere as a dynamically movable drug carrier for osteoporotic bone remodeling. Adv Healthc Mater. 2023; 12: 2201242.
- Wu J, Gao D, Wang L. Bioremediation of 2,4,6-trichlorophenol by extracellular enzymes of white rot fungi immobilized with sodium alginate/hydroxyapatite/chitosan microspheres. Environ Res. 2024; 252: 118937.
- Ben C, Zhao S, Wu Q, He H, Yu M, Liu D, et al. Hydrophobic ionic liquid gel microspheres as bi-component carriers with a liquid phase to immobilize enzymes for enhanced performance. Adv Funct Mater. 2024; 2407913.
- Lei L, Wang X, Zhu Y, Su Y, Lv Q, Li D. Antimicrobial hydrogel microspheres for protein capture and wound healing. Mater Des. 2022; 215: 10478.
- Xin C, Cheng Z, Liu W, Li W, Zhu H. The antibacterial and hemostatic activity of gastrodiaelata polysaccharide-based hydrogel embedded with drug-carrying microspheres accelerates diabetic wound healing. Chem Eng J. 2024; 492: 152403.
- Zhao W, Li Y, Tian J, Tang C, Fei X, Xu L, et al. A novel multi-scale pressure sensing hydrogel for monitoring the physiological signals of long-term bedridden patients. J Mater Chem B. 2023; 11: 8541-8552.
- Kim PH, Yim HG, Choi YJ, kang BJ, kim J, kwon SM, et al. Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization. J Control Release. 2014; 187: 1-13.
- Zhao Z, Li G, Ruan H, Chen K, Cai Z, Lu G, et al. Capturing magnesium ions via microfluidic hydrogel microspheres for promoting cancellous bone regeneration. ACS nano. 2021; 15: 13041-13054.
- Glangchai LC, Caldorera-Moore M, Shi L, Roy K. Nanoimprint lithography based fabrication of shape-specific, enzymatically- triggered smart nanoparticles. J Control Release. 2008; 125: 263-272.
- Pawar A, Thakkar S, Misra M. A bird’s eye view of nanoparticles prepared by electrospraying: advancements in drug delivery field. J Control Release. 2018; 286: 179-200.
- Xu H, Sun M, Wang C, Xia K, Xiao S, Wang Y, et al. Growth differentiation factor-5–gelatin methacryloyl injectable microspheres laden with adipose-derived stem cells for repair of disc degeneration. Biofabrication. 2020; 13: 015010.
- Xie C, Liang R, Ye J, Peng Z, Sun H, Zhu Q, et al. High-efficient engineering of osteo-callus organoids for rapid bone regeneration within one month. Biomaterials. 2022; 288: 121741.
- Wang P, Zhang J, Chen J, Ren J, Liu J, Wang F, et al. Internal and external co-induction pineal 3D printed scaffolds for bone and blood vessel regeneration. Mater Today Adv. 2024; 21: 100456.
- Wang T, Li Y, Fang Y, Guo W, Li X, Li G, et al. Intraarticularly injectable silk hydrogel microspheres with enhanced mechanical and structural stability to attenuate osteoarthritis. Biomaterials. 2022; 286: 121611.
- Bian J, Cai F, Chen H, Tang Z, Xi K, Tang J, et al. Modulation of local overactive inflammation via injectable hydrogel microspheres. Nano Lett. 2021; 21: 2690-2698.
- Chen Z, Lv Z, Zhang Z, Zhang H, Zhang Y, Cui W, et al. Advanced microfluidic devices for fabricating multi-structural hydrogel microsphere. Exploration. 2021; 1: 20210036.
- Suzuki D, Horigome K, Kureha T, Matsui S, Watanabe T. Polymeric hydrogel microspheres: Design, synthesis, characterization, assembly and applications. Polym J. 2017; 49: 695-702.
- He Y, Sun M, Wang J, Yang X, Lin C, Ge L, et al. Chondroitin sulfate microspheres anchored with drug-loaded liposomes play a dual antioxidant role in the treatment of osteoarthritis. Acta Biomater. 2022; 151: 512-527.
- Jung S, Abel JH, Stranger JL, Yi H. Porosity-tuned chitosan– polyacrylamide hydrogel microspheres for improved protein conjugation. Biomacromolecules. 2016; 17: 2427-2436.
- Yang J, Xia P, Meng F, Li X, Xu X. Bio-functional hydrogel microspheres for musculoskeletal regeneration. Adv Funct Materials. 2024; 34: 2400257.
- Yawalkar AN, Pawar MA, Vavia PR. Microspheres for targeted drug delivery- a review on recent applications. J Drug Deliv Sci. 2022; 75: 103659.
- Wang L, Fan L, Filppula AM, Wang Y, Shang L, Zhang H. Spatiotemporal responsive hydrogel microspheres for the treatment of gastric cancer. Aggregate. 2024.
- Lin J, Chen L, Yang J, Li X, Wang J, Zhu Y, et al. Injectable double positively charged hydrogel microspheres for targeting-penetration- phagocytosis. Small. 2022; 18: 2202156.
- Ling X, Zhang M, Zhou H, Han G. Preparation of a novel alginate hydrogel microspheres covered by hollow silica for controlled- release application. Eur Polym J. 2024; 204: 112716.
- Yin Y, Fei X, Tian J, Xu L, Li Y, Wang Y. Synthesis of lipase-hydrogel microspheres and their application in deacidification of high-acid rice bran oil. New J Chem. 2022; 46: 21287-21300.
- Tan B, Li Y, Fei X, Tian J, Xu L, Wang Y. Lipase-polydopamine magnetic hydrogel microspheres for the synthesis of octenyl succinic anhydride starch. Int J Biol Macromol. 2022; 219: 482-490.
- Hu C, Su TR, Lin TJ, Chang CW, Tung KL. Yellowish and blue luminescent graphene oxide quantum dots prepared via a microwave-assisted hydrothermal route using H2O2 and KMnO4 as oxidizing agents. New J Chem. 2018; 42: 3999-4007.
- Qin Z, Feng N, Li Y, Fei X, Tian J, Xu L, et al. Hydrogen-bonded lipase- hydrogel microspheres for esterification application. J Colloid Interface Sci. 2022; 606: 1229-1238.
- Jo S, Park S, Oh Y, Hong J, Kim HJ, Kim KJ, et al. Development of cellulose hydrogel microspheres for lipase immobilization. Biotechnol Bioproc E. 2019; 24: 145-154.
- Chi H, Qiu Y, Ye X, Shi J, Li Z. Preparation strategy of hydrogel microsphere and its application in skin repair. Front Bioeng Biotechnol. 2023; 11: 1239183
- Liu J, Du C, Chen H, Huang W, Lei Y. Nano-micron combined hydrogel microspheres: Novel answer for minimal invasive biomedical applications. Macromol Rapid Commun. 2024; 45: 2300670
- Gwon, K, Park, JD, Lee S, Yu JS, Lee DN. Fabrication of silicon-based nickel nanoflower-encapsulated gelatin microspheres as an active antimicrobial carrier. Int J Biol Macromol. 2024; 264: 130617.
- Mohammed AM, Hassan KT, Hassan OM. Assessment of antimicrobial activity of chitosan/silver nanoparticles hydrogel and cryogel microspheres. Int J Biol Macromol. 2023; 233: 123580.
- He G, Zhao S, Yang C, Che L, Liu Y, Hu Q, et al. Point-of-care monitoring of milk quality by rapid immunofluorescence with mechanical deformation of the hydrogel microspheres. Sensor Actuat B-Chem. 2024; 417: 136160.
- Hua Y, Xu D, Liu Z, Zhou J, Han J, Lin Z, et al. Effective adsorption and removal of malachite green and Pb2+ from aqueous samples and fruit juices by pollen–inspired magnetic hydroxyapatite nanoparticles/ hydrogel beads. J Clean Prod. 2023; 411: 137233.
- Lei Y, Wang Y, Shen J, Cai Z, Zhao C, Chen H, et al. Injectable hydrogel microspheres with self-renewable hydration layers alleviate osteoarthritis. Sci Adv. 2022; 6449
- Wang Y, He L, Ding L, Zhao X, Ma H, Luo Y, et al. Fabrication of cyclodextrin-based hydrogels for wound healing: Progress, limitations, and prospects. Chem Mater. 2023; 35: 5723-5743.
- Huan Cao, Lixia Duan, Yan Zhang, Jun Cao, Kun Zhang. Current hydrogel advances in physicochemical and biological response- driven biomedical application diversity. Signal Transduction Targeted Therap. 2021; 6: 426.