Hydrogel microparticles for biomedical applications

Abstract

Hydrogel microparticles (HMPs) are promising for biomedical applications, ranging from the therapeutic delivery of cells and drugs to the production of scaffolds for tissue repair and bioinks for 3D printing. Biologics (cells and drugs) can be encapsulated into HMPs of predefined shapes and sizes using a variety of fabrication techniques (batch emulsion, microfluidics, lithography, electrohydrodynamic spraying and mechanical fragmentation). HMPs can be formulated in suspensions to deliver therapeutics, as aggregates of particles (granular hydrogels) to form microporous scaffolds that promote cell infiltration or embedded within a bulk hydrogel to obtain multiscale behaviours. HMP suspensions and granular hydrogels can be injected for minimally invasive delivery of biologics, and they exhibit modular properties when comprised of mixtures of distinct HMP populations. In this Review, we discuss the techniques that are available for fabricating HMPs, as well as the multiscale behaviours of HMP systems and their functional properties, highlighting their advantages over traditional bulk hydrogels. Furthermore, we discuss applications of HMPs in the fields of cell delivery, drug delivery, scaffold design and biofabrication.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Categories of HMPs.
Fig. 2: Fabrication of HMPs.
Fig. 3: Microfluidic and lithographic templating of compartmentalized HMPs.
Fig. 4: Structure and properties of granular hydrogels.
Fig. 5: Hydrogel microparticle delivery to various tissues in the body.
Fig. 6: Drug release from HMPs.
Fig. 7: Design considerations for building scaffolds from HMPs.
Fig. 8: HMPs in biofabrication.

References

  1. 1.

    Caliari, S. R. & Burdick, J. A. A practical guide to hydrogels for cell culture. Nat. Methods 13, 405–414 (2016).

    CAS  Google Scholar 

  2. 2.

    Van Vlierberghe, S., Dubruel, P. & Schacht, E. Biopolymer-based hydrogels as scaffolds for tissue engineering applications: a review. Biomacromolecules 12, 1387–1408 (2011).

    Google Scholar 

  3. 3.

    Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 16071 (2016).

    CAS  Google Scholar 

  4. 4.

    Annabi, N. et al. Controlling the porosity and microarchitecture of hydrogels for tissue engineering. Tissue Eng. Part B Rev. 16, 371–383 (2010).

    CAS  Google Scholar 

  5. 5.

    Henderson, T. M. A., Ladewig, K., Haylock, D. N., McLean, K. M. & O’Connor, A. J. Cryogels for biomedical applications. J. Mater. Chem. B 1, 2682–2695 (2013).

    CAS  Google Scholar 

  6. 6.

    Wade, R. J., Bassin, E. J., Rodell, C. B. & Burdick, J. A. Protease-degradable electrospun fibrous hydrogels. Nat. Commun. 6, 6639 (2015).

    CAS  Google Scholar 

  7. 7.

    Highley, C. B., Song, K. H., Daly, A. C. & Burdick, J. A. Jammed microgel inks for 3D printing applications. Adv. Sci. 6, 1801076 (2019).

    Google Scholar 

  8. 8.

    Griffin, D. R., Weaver, W. M., Scumpia, P. O., Di Carlo, D. & Segura, T. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015).

    CAS  Google Scholar 

  9. 9.

    Mealy, J. E. et al. Injectable granular hydrogels with multifunctional properties for biomedical applications. Adv. Mater. 30, 1705912 (2018).

    Google Scholar 

  10. 10.

    Sideris, E. et al. Particle hydrogels based on hyaluronic acid building blocks. ACS Biomater. Sci. Eng. 2, 2034–2041 (2016).

    CAS  Google Scholar 

  11. 11.

    Franco, C. L., Price, J. & West, J. L. Development and optimization of a dual-photoinitiator, emulsion-based technique for rapid generation of cell-laden hydrogel microspheres. Acta Biomater. 7, 3267–3276 (2011).

    CAS  Google Scholar 

  12. 12.

    Leong, W., Lau, T. T. & Wang, D. A. A temperature-cured dissolvable gelatin microsphere-based cell carrier for chondrocyte delivery in a hydrogel scaffolding system. Acta Biomater. 9, 6459–6467 (2013).

    CAS  Google Scholar 

  13. 13.

    Liu, A. L. & Garcia, A. J. Methods for generating hydrogel particles for protein delivery. Ann. Biomed. Eng. 44, 1946–1958 (2016).

    Google Scholar 

  14. 14.

    Xu, Q. et al. Preparation of monodisperse biodegradable polymer microparticles using a microfluidic flow-focusing device for controlled drug delivery. Small 5, 1575–1581 (2009).

    CAS  Google Scholar 

  15. 15.

    Truong, N. F., Lesher-Pérez, S. C., Kurt, E. & Segura, T. Pathways governing polyethylenimine polyplex transfection in microporous annealed particle scaffolds. Bioconjug. Chem. 30, 476–486 (2019).

    CAS  Google Scholar 

  16. 16.

    Scott, E. A., Nichols, M. D., Kuntz-Willits, R. & Elbert, D. L. Modular scaffolds assembled around living cells using poly(ethylene glycol) microspheres with macroporation via a non-cytotoxic porogen. Acta Biomater. 6, 29–38 (2010).

    CAS  Google Scholar 

  17. 17.

    Stenekes, R. J. H., Franssen, O., van Bommel, E. M. G., Crommelin, D. J. A. & Hennink, W. E. The preparation of dextran microspheres in an all-aqueous system: effect of the formulation parameters on particle characteristics. Pharm. Res. 15, 557–561 (1998).

    CAS  Google Scholar 

  18. 18.

    Elbert, D. L. Liquid–liquid two-phase systems for the production of porous hydrogels and hydrogel microspheres for biomedical applications: a tutorial review. Acta Biomater. 7, 31–56 (2011).

    CAS  Google Scholar 

  19. 19.

    Nichols, M. D., Scott, E. A. & Elbert, D. L. Factors affecting size and swelling of poly(ethylene glycol) microspheres formed in aqueous sodium sulfate solutions without surfactants. Biomaterials 30, 5283–5291 (2009).

    CAS  Google Scholar 

  20. 20.

    Jeon, O., Wolfson, D. W. & Alsberg, E. In-situ formation of growth-factor-loaded coacervate microparticle-embedded hydrogels for directing encapsulated stem cell fate. Adv. Mater. 27, 2216–2223 (2015).

    CAS  Google Scholar 

  21. 21.

    Thorsen, T., Roberts, R. W., Arnold, F. H. & Quake, S. R. Dynamic pattern formation in a vesicle-generating microfluidic device. Phys. Rev. Lett. 86, 4163–4166 (2001).

    CAS  Google Scholar 

  22. 22.

    Anna, S. L., Bontoux, N. & Stone, H. A. Formation of dispersions using “flow focusing” in microchannels. Appl. Phys. Lett. 82, 364–366 (2003).

    CAS  Google Scholar 

  23. 23.

    De Geest, B. G., Urbanski, J. P., Thorsen, T., Demeester, J. & De Smedt, S. C. Synthesis of monodisperse biodegradable microgels in microfluidic devices. Langmuir 21, 10275–10279 (2005).

    Google Scholar 

  24. 24.

    Pittermannová, A. et al. Microfluidic fabrication of composite hydrogel microparticles in the size range of blood cells. RSC Adv. 6, 103532–103540 (2016).

    Google Scholar 

  25. 25.

    Utada, A. S. et al. Monodisperse double emulsions generated from a microcapillary device. Science 308, 537–541 (2005).

    CAS  Google Scholar 

  26. 26.

    Nisisako, T. & Torii, T. Microfluidic large-scale integration on a chip for mass production of monodisperse droplets and particles. Lab Chip 8, 287–293 (2008).

    CAS  Google Scholar 

  27. 27.

    Kim, J.-W., Utada, A. S., Fernández-Nieves, A., Hu, Z. & Weitz, D. A. Fabrication of monodisperse gel shells and functional microgels in microfluidic devices. Angew. Chem. 119, 1851–1854 (2007).

    Google Scholar 

  28. 28.

    Greenwood-Goodwin, M., Teasley, E. S. & Heilshorn, S. C. Dual-stage growth factor release within 3D protein-engineered hydrogel niches promotes adipogenesis. Biomater. Sci. 2, 1627–1639 (2014).

    CAS  Google Scholar 

  29. 29.

    Foster, G. A. et al. Protease-degradable microgels for protein delivery for vascularization. Biomaterials 113, 170–175 (2017).

    CAS  Google Scholar 

  30. 30.

    Deveza, L. et al. Microfluidic synthesis of biodegradable polyethylene-glycol microspheres for controlled delivery of proteins and DNA nanoparticles. ACS Biomater. Sci. Eng. 1, 157–165 (2015).

    CAS  Google Scholar 

  31. 31.

    Jiang, W., Li, M., Chen, Z. & Leong, K. W. Cell-laden microfluidic microgels for tissue regeneration. Lab Chip 16, 4482–4506 (2016).

    CAS  Google Scholar 

  32. 32.

    Selimovic´, Š., Oh, J., Bae, H., Dokmeci, M. & Khademhosseini, A. Microscale strategies for generating cell-encapsulating hydrogels. Polymers 4, 1554–1579 (2012).

    Google Scholar 

  33. 33.

    Headen, D. M., García, J. R. & García, A. J. Parallel droplet microfluidics for high throughput cell encapsulation and synthetic microgel generation. Microsyst. Nanoeng. 4, 17076 (2018).

    CAS  Google Scholar 

  34. 34.

    Krutkramelis, K, Xia, B. & Oakey, J. Monodisperse polyethylene glycol diacrylate hydrogel microsphere formation by oxygen-controlled photopolymerization in a microfluidic device. Lab Chip 16, 1457–1465 (2016).

    CAS  Google Scholar 

  35. 35.

    Cha, C. et al. Microfluidics-assisted fabrication of gelatin-silica core–shell microgels for injectable tissue constructs. Biomacromolecules 15, 283–290 (2014).

    CAS  Google Scholar 

  36. 36.

    Jiang, Z., Xia, B., McBride, R. & Oakey, J. A microfluidic-based cell encapsulation platform to achieve high long-term cell viability in photopolymerized PEGNB hydrogel microspheres. J. Mater. Chem. B 5, 173–180 (2017).

    CAS  Google Scholar 

  37. 37.

    Kumachev, A., Tumarkin, E., Walker, G. C. & Kumacheva, E. Characterization of the mechanical properties of microgels acting as cellular microenvironments. Soft Matter 9, 2959–2965 (2013).

    CAS  Google Scholar 

  38. 38.

    Headen, D. M., Aubry, G., Lu, H. & Garcia, A. J. Microfluidic-based generation of size-controlled, biofunctionalized synthetic polymer microgels for cell encapsulation. Adv. Mater. 26, 3003–3008 (2014).

    CAS  Google Scholar 

  39. 39.

    Allazetta, S., Hausherr, T. C. & Lutolf, M. P. Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. Biomacromolecules 14, 1122–1131 (2013).

    CAS  Google Scholar 

  40. 40.

    Seiffert, S., Thiele, J., Abate, A. R. & Weitz, D. A. Smart microgel capsules from macromolecular precursors. J. Am. Chem. Soc. 132, 6606–6609 (2010).

    CAS  Google Scholar 

  41. 41.

    Seiffert, S. & Weitz, D. A. Microfluidic fabrication of smart microgels from macromolecular precursors. Polymer 51, 5883–5889 (2010).

    CAS  Google Scholar 

  42. 42.

    Chu, L. Y., Utada, A. S., Shah, R. K., Kim, J. W. & Weitz, D. A. Controllable monodisperse multiple emulsions. Angew. Chem. Int. Ed. 46, 8970–8974 (2007).

    CAS  Google Scholar 

  43. 43.

    Seiffert, S., Romanowsky, M. B. & Weitz, D. A. Janus microgels produced from functional precursor polymers. Langmuir 26, 14842–14847 (2010).

    CAS  Google Scholar 

  44. 44.

    Zhao, C. X. Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery. Adv. Drug Deliv. Rev. 65, 1420–1446 (2013).

    CAS  Google Scholar 

  45. 45.

    Duncanson, W. J. et al. Microfluidic synthesis of advanced microparticles for encapsulation and controlled release. Lab Chip 12, 2135–2145 (2012).

    CAS  Google Scholar 

  46. 46.

    Chen, Q. et al. Controlled assembly of heterotypic cells in a core–shell scaffold: organ in a droplet. Lab Chip 16, 1346–1349 (2016).

    CAS  Google Scholar 

  47. 47.

    Zhang, L. et al. Microfluidic templated multicompartment microgels for 3D encapsulation and pairing of single cells. Small 14, 1702955 (2018).

    Google Scholar 

  48. 48.

    Yoshida, S., Takinoue, M. & Onoe, H. Compartmentalized spherical collagen microparticles for anisotropic cell culture microenvironments. Adv. Healthc. Mater. 6, 1601463 (2017).

    Google Scholar 

  49. 49.

    Kamperman, T., Trikalitis, V. D., Karperien, M., Visser, C. W. & Leijten, J. Ultrahigh-throughput production of monodisperse and multifunctional Janus microparticles using in-air microfluidics. ACS Appl. Mater. Interfaces 10, 23433–23438 (2018).

    CAS  Google Scholar 

  50. 50.

    Visser, C. W., Kamperman, T., Karbaat, L. P., Lohse, D. & Karperien, M. In-air microfluidics enables rapid fabrication of emulsions, suspensions, and 3D modular (bio)materials. Science Adv. 4, eaao1175 (2018).

    Google Scholar 

  51. 51.

    Bardin, D., Kendall, M. R., Dayton, P. A. & Lee, A. P. Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow-focusing module. Biomicrofluidics 7, 034112 (2013).

    Google Scholar 

  52. 52.

    Muluneh, M. & Issadore, D. Hybrid soft-lithography/laser machined microchips for the parallel generation of droplets. Lab Chip 13, 4750–4754 (2013).

    CAS  Google Scholar 

  53. 53.

    Li, W., Greener, J., Voicu, D. & Kumacheva, E. Multiple modular microfluidic (M3) reactors for the synthesis of polymer particles. Lab Chip 9, 2715–2721 (2009).

    CAS  Google Scholar 

  54. 54.

    de Rutte, J. M., Koh, J. & Di Carlo, D. Scalable high-throughput production of modular microgels for in situ assembly of microporous tissue scaffolds. Adv. Funct. Mater. 29, 1900071.

  55. 55.

    Helgeson, M. E., Chapin, S. C. & Doyle, P. S. Hydrogel microparticles from lithographic processes: novel materials for fundamental and applied colloid science. Curr. Opin. Colloid Interface Sci. 16, 106–117 (2011).

    CAS  Google Scholar 

  56. 56.

    Lee, S. A., Chung, S. E., Park, W., Lee, S. H. & Kwon, S. Three-dimensional fabrication of heterogeneous microstructures using soft membrane deformation and optofluidic maskless lithography. Lab Chip 9, 1670–1675 (2009).

    CAS  Google Scholar 

  57. 57.

    Chung, S. E., Park, W., Shin, S., Lee, S. A. & Kwon, S. Guided and fluidic self-assembly of microstructures using railed microfluidic channels. Nat. Mater. 7, 581–587 (2008).

    CAS  Google Scholar 

  58. 58.

    Nichol, J. W. et al. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 31, 5536–5544 (2010).

    CAS  Google Scholar 

  59. 59.

    Panda, P. et al. Stop-flow lithography to generate cell-laden microgel particles. Lab Chip 8, 1056–1061 (2008).

    CAS  Google Scholar 

  60. 60.

    Jang, J.-H., Dendukuri, D., Hatton, T. A., Thomas, E. L. & Doyle, P. S. A route to three-dimensional structures in a microfluidic device: stop-flow interference lithography. Angew. Chem. Int. Ed. 119, 9185–9189 (2007).

    Google Scholar 

  61. 61.

    Dendukuri, D., Pregibon, D. C., Collins, J., Hatton, T. A. & Doyle, P. S. Continuous-flow lithography for high-throughput microparticle synthesis. Nat. Mater. 5, 365–369 (2006).

    CAS  Google Scholar 

  62. 62.

    Rolland, J. P. et al. Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials. J. Am. Chem. Soc. 127, 10096–10100 (2005).

    CAS  Google Scholar 

  63. 63.

    Nielson, R., Kaehr, B. & Shear, J. B. Microreplication and design of biological architectures using dynamic-mask multiphoton lithography. Small 5, 120–125 (2009).

    CAS  Google Scholar 

  64. 64.

    Laza, S. C. et al. Two-photon continuous flow lithography. Adv. Mater. 24, 1304–1308 (2012).

    CAS  Google Scholar 

  65. 65.

    Dendukuri, D., Gu, S. S., Pregibon, D. C., Hatton, T. A. & Doyle, P. S. Stop-flow lithography in a microfluidic device. Lab Chip 7, 818–828 (2007).

    CAS  Google Scholar 

  66. 66.

    Merkel, T. J. et al. The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles. J. Control. Release 162, 37–44 (2012).

    CAS  Google Scholar 

  67. 67.

    Khademhosseini, A. et al. Micromolding of photocrosslinkable hyaluronic acid for cell encapsulation and entrapment. J. Biomed. Mater. Res. A 79, 522–532 (2006).

    Google Scholar 

  68. 68.

    Baudis, S. et al. Modular material system for the microfabrication of biocompatible hydrogels based on thiol–ene-modified poly(vinyl alcohol). J. Polym. Sci. Part A Polym. Chem. 54, 2060–2070 (2016).

    CAS  Google Scholar 

  69. 69.

    Qin, X.-H. et al. Enzymatic synthesis of hyaluronic acid vinyl esters for two-photon microfabrication of biocompatible and biodegradable hydrogel constructs. Polym. Chem. 5, 6523–6533 (2014).

    CAS  Google Scholar 

  70. 70.

    Gramlich, W. M., Kim, I. L. & Burdick, J. A. Synthesis and orthogonal photopatterning of hyaluronic acid hydrogels with thiol-norbornene chemistry. Biomaterials 34, 9803–9811 (2013).

    CAS  Google Scholar 

  71. 71.

    Ifkovits, J. L. & Burdick, J. A. Review: photopolymerizable and degradable biomaterials for tissue engineering applications. Tissue Eng. 13, 2369–2385 (2007).

    CAS  Google Scholar 

  72. 72.

    Nguyen, K. T. & West, J. L. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials 23, 4307–4314 (2002).

    CAS  Google Scholar 

  73. 73.

    Bahney, C. S. et al. Visible light photoinitiation of mesenchymal stem cell-laden bioresponsive hydrogels. Eur. Cell Mater. 22, 43–55 (2011).

    CAS  Google Scholar 

  74. 74.

    Bryant, S. J., Nuttelman, C. R. & Anseth, K. S. Cytocompatibility of UV and visible light photoinitiating systems on cultured NIH/3T3 fibroblasts in vitro. J. Biomater. Sci. Polym. Ed. 11, 439–457 (2000).

    CAS  Google Scholar 

  75. 75.

    Le Goff, G. C., Lee, J., Gupta, A., Hill, W. A. & Doyle, P. S. High-throughput contact flow lithography. Adv. Sci. 2, 1500149 (2015).

    Google Scholar 

  76. 76.

    Naqvi, S. M. et al. Living cell factories - electrosprayed microcapsules and microcarriers for minimally invasive delivery. Adv. Mater. 28, 5662–5671 (2016).

    CAS  Google Scholar 

  77. 77.

    Gansau, J., Kelly, L. & Buckley, C. T. Influence of key processing parameters and seeding density effects of microencapsulated chondrocytes fabricated using electrohydrodynamic spraying. Biofabrication 10, 035011 (2018).

    Google Scholar 

  78. 78.

    Pancholi, K., Ahras, N., Stride, E. & Edirisinghe, M. Novel electrohydrodynamic preparation of porous chitosan particles for drug delivery. J. Mater. Sci. Mater. Med. 20, 917–923 (2009).

    CAS  Google Scholar 

  79. 79.

    Qayyum, A. S. et al. Design of electrohydrodynamic sprayed polyethylene glycol hydrogel microspheres for cell encapsulation. Biofabrication 9, 025019 (2017).

    Google Scholar 

  80. 80.

    Young, C. J., Poole-Warren, L. A. & Martens, P. J. Combining submerged electrospray and UV photopolymerization for production of synthetic hydrogel microspheres for cell encapsulation. Biotechnol. Bioeng. 109, 1561–1570 (2012).

    CAS  Google Scholar 

  81. 81.

    Kim, P. H. et al. Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization. J. Control. Release 187, 1–13 (2014).

    CAS  Google Scholar 

  82. 82.

    Gu, Z. et al. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano 7, 6758–6766 (2013).

    CAS  Google Scholar 

  83. 83.

    Jayasinghe, S. N. & Townsend-Nicholson, A. Stable electric-field driven cone-jetting of concentrated biosuspensions. Lab Chip 6, 1086–1090 (2006).

    CAS  Google Scholar 

  84. 84.

    Jayasinghe, S. N., Qureshi, A. N. & Eagles, P. A. Electrohydrodynamic jet processing: an advanced electric-field-driven jetting phenomenon for processing living cells. Small 2, 216–219 (2006).

    CAS  Google Scholar 

  85. 85.

    Sinclair, A. et al. Self-healing zwitterionic microgels as a versatile platform for malleable cell constructs and injectable therapies. Adv. Mater. 30, 1803087 (2018).

    Google Scholar 

  86. 86.

    Hinton, T. J. et al. Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Science Adv. 1, e1500758 (2015).

    Google Scholar 

  87. 87.

    Riley, L., Schirmer, L. & Segura, T. Granular hydrogels: emergent properties of jammed hydrogel microparticles and their applications in tissue repair and regeneration. Curr. Opin. Biotechnol. 60, 1–8 (2018).

    Google Scholar 

  88. 88.

    Behringer, R. P. & Chakraborty, B. The physics of jamming for granular materials: a review. Rep. Prog. Phys. 82, 012601 (2019).

    CAS  Google Scholar 

  89. 89.

    Hurley, R. C., Hall, S. A., Andrade, J. E. & Wright, J. Quantifying interparticle forces and heterogeneity in 3D granular materials. Phys. Rev. Lett. 117, 098005 (2016).

    CAS  Google Scholar 

  90. 90.

    Weeks, E. R. in Statistical Physics of Complex Fluids (eds Maruyama, S. & Tokuyama, M.) 1–53 (Tohoku Univ. Press, 2007).

  91. 91.

    Torquato, S. & Stillinger, F. H. Jammed hard-particle packings: from Kepler to Bernal and beyond. Rev. Mod. Phys. 82, 2633–2672 (2010).

    Google Scholar 

  92. 92.

    Menut, P., Seiffert, S., Sprakel, J. & Weitz, D. A. Does size matter? Elasticity of compressed suspensions of colloidal- and granular-scale microgels. Soft Matter 8, 156–164 (2012).

    CAS  Google Scholar 

  93. 93.

    Liu, A. J. & Nagel, S. R. The jamming transition and the marginally jammed solid. Annu. Rev. Condens. Matter Phys. 1, 347–369 (2010).

    Google Scholar 

  94. 94.

    van Hecke, M. Jamming of soft particles: geometry, mechanics, scaling and isostaticity. J. Phys. Condens. Matter 22, 033101 (2009).

    Google Scholar 

  95. 95.

    Yuan, Y., Liu, L., Zhuang, Y., Jin, W. & Li, S. Coupling effects of particle size and shape on improving the density of disordered polydisperse packings. Phys. Rev. E 98, 042903 (2018).

    CAS  Google Scholar 

  96. 96.

    Haustein, M., Gladkyy, A. & Schwarze, R. Discrete element modeling of deformable particles in YADE. SoftwareX 6, 118–123 (2017).

    Google Scholar 

  97. 97.

    Sun, Q., Jin, F., Liu, J. & Zhang, G. Understanding force chains in dense granular materials. Int. J. Mod. Phys. B 24, 5743–5759 (2010).

    CAS  Google Scholar 

  98. 98.

    Truong, N. F. et al. Microporous annealed particle hydrogel stiffness, void space size, and adhesion properties impact cell proliferation, cell spreading, and gene transfer. Acta Biomater. 94, 160–172 (2019).

    CAS  Google Scholar 

  99. 99.

    Kim, J., Yaszemski, M. J. & Lu, L. Three-dimensional porous biodegradable polymeric scaffolds fabricated with biodegradable hydrogel porogens. Tissue Eng. Part C Methods 15, 583–594 (2009).

    CAS  Google Scholar 

  100. 100.

    Wang, L., Lu, S., Lam, J., Kasper, F. K. & Mikos, A. G. Fabrication of cell-laden macroporous biodegradable hydrogels with tunable porosities and pore sizes. Tissue Eng. Part C Methods 21, 263–273 (2014).

    Google Scholar 

  101. 101.

    Hu, J. et al. Microgel-reinforced hydrogel films with high mechanical strength and their visible mesoscale fracture structure. Macromolecules 44, 7775–7781 (2011).

    CAS  Google Scholar 

  102. 102.

    Shin, H., Olsen, B. D. & Khademhosseini, A. Gellan gum microgel-reinforced cell-laden gelatin hydrogels. J. Mater. Chem. B 2, 2508–2516 (2014).

    CAS  Google Scholar 

  103. 103.

    Nih, L. R., Sideris, E., Carmichael, S. T. & Segura, T. Injection of microporous annealing particle (MAP) hydrogels in the stroke cavity reduces gliosis and inflammation and promotes NPC migration to the lesion. Adv. Mater. 29, 1606471 (2017).

    Google Scholar 

  104. 104.

    Darling, N. J., Sideris, E., Hamada, N., Carmichael, S. T. & Segura, T. Injectable and spatially patterned microporous annealed particle (MAP) hydrogels for tissue repair applications. Adv. Sci. 5, 1801046 (2018).

    Google Scholar 

  105. 105.

    Le, L. V. et al. Injectable hyaluronic acid based microrods provide local micromechanical and biochemical cues to attenuate cardiac fibrosis after myocardial infarction. Biomaterials 169, 11–21 (2018).

    CAS  Google Scholar 

  106. 106.

    Caldwell, A. S., Campbell, G. T., Shekiro, K. M. T. & Anseth, K. S. Clickable microgel scaffolds as platforms for 3D cell encapsulation. Adv. Healthc. Mater. 6, 1700254 (2017).

    Google Scholar 

  107. 107.

    Madl, C. M., Heilshorn, S. C. & Blau, H. M. Bioengineering strategies to accelerate stem cell therapeutics. Nature 557, 335–342 (2018).

    CAS  Google Scholar 

  108. 108.

    Seliktar, D. Designing cell-compatible hydrogels for biomedical applications. Science 336, 1124–1128 (2012).

    CAS  Google Scholar 

  109. 109.

    Wang, C., Varshney, R. R. & Wang, D.-A. Therapeutic cell delivery and fate control in hydrogels and hydrogel hybrids. Adv. Drug Deliv. Rev. 62, 699–710 (2010).

    CAS  Google Scholar 

  110. 110.

    Rosales, A. M. & Anseth, K. S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 1, 15012 (2016).

    CAS  Google Scholar 

  111. 111.

    Prince, E. & Kumacheva, E. Design and applications of man-made biomimetic fibrillar hydrogels. Nat. Rev. Mater. 4, 99–115 (2019).

    Google Scholar 

  112. 112.

    Mao, A. S. et al. Deterministic encapsulation of single cells in thin tunable microgels for niche modelling and therapeutic delivery. Nat. Mater. 16, 236–243 (2016).

    Google Scholar 

  113. 113.

    Daly, A. C., Sathy, B. N. & Kelly, D. J. Engineering large cartilage tissues using dynamic bioreactor culture at defined oxygen conditions. J. Tissue Eng. 9, 2041731417753718 (2018).

    Google Scholar 

  114. 114.

    Sheehy, E. J., Buckley, C. T. & Kelly, D. J. Chondrocytes and bone marrow-derived mesenchymal stem cells undergoing chondrogenesis in agarose hydrogels of solid and channelled architectures respond differentially to dynamic culture conditions. J. Tissue Eng. Regen. Med. 5, 747–758 (2011).

    CAS  Google Scholar 

  115. 115.

    Daly, A. C. & Kelly, D. J. Biofabrication of spatially organised tissues by directing the growth of cellular spheroids within 3D printed polymeric microchambers. Biomaterials 197, 194–206 (2019).

    CAS  Google Scholar 

  116. 116.

    Kolesky, D. B., Homan, K. A., Skylar-Scott, M. A. & Lewis, J. A. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl. Acad. Sci. USA 113, 3179–3184 (2016).

    CAS  Google Scholar 

  117. 117.

    Madl, C. M. & Heilshorn, S. C. Engineering hydrogel microenvironments to recapitulate the stem cell niche. Annu. Rev. Biomed. Eng. 20, 21–47 (2018).

    CAS  Google Scholar 

  118. 118.

    Rapp, T. L., Highley, C. B., Manor, B. C., Burdick, J. A. & Dmochowski, I. J. Ruthenium-crosslinked hydrogels with rapid, visible-light degradation. Chem 24, 2328–2333 (2018).

    CAS  Google Scholar 

  119. 119.

    Mohamed, M. G. A. et al. An integrated microfluidic flow-focusing platform for on-chip fabrication and filtration of cell-laden microgels. Lab Chip 19, 1621–1632 (2019).

    CAS  Google Scholar 

  120. 120.

    Deng, Y. et al. Rapid purification of cell encapsulated hydrogel beads from oil phase to aqueous phase in a microfluidic device. Lab Chip 11, 4117–4121 (2011).

    CAS  Google Scholar 

  121. 121.

    Choi, C. H. et al. One-step generation of cell-laden microgels using double emulsion drops with a sacrificial ultra-thin oil shell. Lab Chip 16, 1549–1555 (2016).

    CAS  Google Scholar 

  122. 122.

    Zhu, K. et al. All-aqueous-phase microfluidics for cell encapsulation. ACS Appl. Mater. Interfaces 11, 4826–4832 (2019).

    CAS  Google Scholar 

  123. 123.

    Maeda, K., Onoe, H., Takinoue, M. & Takeuchi, S. Controlled synthesis of 3D multi-compartmental particles with centrifuge-based microdroplet formation from a multi-barrelled capillary. Adv. Mater. 24, 1340–1346 (2012).

    CAS  Google Scholar 

  124. 124.

    Ma, C., Tian, C., Zhao, L. & Wang, J. Pneumatic-aided micro-molding for flexible fabrication of homogeneous and heterogeneous cell-laden microgels. Lab Chip 16, 2609–2617 (2016).

    CAS  Google Scholar 

  125. 125.

    Allazetta, S., Kolb, L., Zerbib, S., Bardy, J. & Lutolf, M. P. Cell-instructive microgels with tailor-made physicochemical properties. Small 11, 5647–5656 (2015).

    CAS  Google Scholar 

  126. 126.

    Blaeser, A. et al. Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity. Adv. Healthc. Mater. 5, 326–333 (2016).

    CAS  Google Scholar 

  127. 127.

    Chen, M. H. et al. Methods to assess shear-thinning hydrogels for application as injectable biomaterials. ACS Biomater. Sci. Eng. 3, 3146–3160 (2017).

    CAS  Google Scholar 

  128. 128.

    Aguado, B. A., Mulyasasmita, W., Su, J., Lampe, K. J. & Heilshorn, S. C. Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. Tissue Eng. Part A 18, 806–815 (2011).

    Google Scholar 

  129. 129.

    Zhao, X. et al. Injectable stem cell-laden photocrosslinkable microspheres fabricated using microfluidics for rapid generation of osteogenic tissue constructs. Adv. Funct. Mater. 26, 2809–2819 (2016).

    CAS  Google Scholar 

  130. 130.

    Annamalai, R. T. et al. Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical-size defects. Biomaterials 208, 32–44 (2019).

    CAS  Google Scholar 

  131. 131.

    Wise, J. K., Alford, A. I., Goldstein, S. A. & Stegemann, J. P. Synergistic enhancement of ectopic bone formation by supplementation of freshly isolated marrow cells with purified MSC in collagen–chitosan hydrogel microbeads. Connect. Tissue Res. 57, 516–525 (2016).

    CAS  Google Scholar 

  132. 132.

    Wang, L., Rao, R. R. & Stegemann, J. P. Delivery of mesenchymal stem cells in chitosan/collagen microbeads for orthopedic tissue repair. Cells Tissues Organs 197, 333–343 (2013).

    CAS  Google Scholar 

  133. 133.

    Daley, E. L. H., Coleman, R. M. & Stegemann, J. P. Biomimetic microbeads containing a chondroitin sulfate/chitosan polyelectrolyte complex for cell-based cartilage therapy. J. Mater. Chem. B 3, 7920–7929 (2015).

    CAS  Google Scholar 

  134. 134.

    Li, F. et al. Cartilage tissue formation through assembly of microgels containing mesenchymal stem cells. Acta Biomater. 77, 48–62 (2018).

    CAS  Google Scholar 

  135. 135.

    Yin, H. et al. Functional tissue-engineered microtissue derived from cartilage extracellular matrix for articular cartilage regeneration. Acta Biomater. 77, 127–141 (2018).

    CAS  Google Scholar 

  136. 136.

    Wang, Y. et al. Fabrication of nanofibrous microcarriers mimicking extracellular matrix for functional microtissue formation and cartilage regeneration. Biomaterials 171, 118–132 (2018).

    CAS  Google Scholar 

  137. 137.

    Feyen, D. A. M. et al. Gelatin microspheres as vehicle for cardiac progenitor cells delivery to the myocardium. Adv. Healthc. Mater. 5, 1071–1079 (2016).

    CAS  Google Scholar 

  138. 138.

    Shrestha, P., Regmi, S. & Jeong, J.-H. Injectable hydrogels for islet transplantation: a concise review. Int. J. Pharm. Investig. 1-17 (2019).

  139. 139.

    Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    CAS  Google Scholar 

  140. 140.

    Headen, D. M. et al. Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nat. Mater. 17, 732–739 (2018).

    CAS  Google Scholar 

  141. 141.

    Hoare, T. R. & Kohane, D. S. Hydrogels in drug delivery: Progress and challenges. Polymer 49, 1993–2007 (2008).

    CAS  Google Scholar 

  142. 142.

    Guvendiren, M., Lu, H. D. & Burdick, J. A. Shear-thinning hydrogels for biomedical applications. Soft Matter 8, 260–272 (2012).

    CAS  Google Scholar 

  143. 143.

    Dimatteo, R., Darling, N. J. & Segura, T. In situ forming injectable hydrogels for drug delivery and wound repair. Adv. Drug Deliv. Rev. 127, 167–184 (2018).

    CAS  Google Scholar 

  144. 144.

    Chen, W., Palazzo, A., Hennink, W. E. & Kok, R. J. Effect of particle size on drug loading and release kinetics of gefitinib-loaded PLGA microspheres. Mol. Pharm. 14, 459–467 (2017).

    CAS  Google Scholar 

  145. 145.

    Freiberg, S. & Zhu, X. X. Polymer microspheres for controlled drug release. Int. J. Pharm. 282, 1–18 (2004).

    CAS  Google Scholar 

  146. 146.

    Nguyen, A. H., McKinney, J., Miller, T., Bongiorno, T. & McDevitt, T. C. Gelatin methacrylate microspheres for controlled growth factor release. Acta Biomater. 13, 101–110 (2015).

    CAS  Google Scholar 

  147. 147.

    Solorio, L. D., Dhami, C. D., Dang, P. N., Vieregge, E. L. & Alsberg, E. Spatiotemporal regulation of chondrogenic differentiation with controlled delivery of transforming growth factor-β1 from gelatin microspheres in mesenchymal stem cell aggregates. Stem Cells Transl. Med. 1, 632–639 (2012).

    CAS  Google Scholar 

  148. 148.

    Censi, R., Di Martino, P., Vermonden, T. & Hennink, W. E. Hydrogels for protein delivery in tissue engineering. J. Control. Release 161, 680–692 (2012).

    CAS  Google Scholar 

  149. 149.

    Hettiaratchi, M. H., Miller, T., Temenoff, J. S., Guldberg, R. E. & McDevitt, T. C. Heparin microparticle effects on presentation and bioactivity of bone morphogenetic protein-2. Biomaterials 35, 7228–7238 (2014).

    CAS  Google Scholar 

  150. 150.

    Feng, Q. et al. Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy. Acta Biomater. 53, 329–342 (2017).

    CAS  Google Scholar 

  151. 151.

    Öztürk, E. et al. Sulfated hydrogel matrices direct mitogenicity and maintenance of chondrocyte phenotype through activation of FGF signaling. Adv. Funct. Mater. 26, 3649–3662 (2016).

    Google Scholar 

  152. 152.

    Freeman, I., Kedem, A. & Cohen, S. The effect of sulfation of alginate hydrogels on the specific binding and controlled release of heparin-binding proteins. Biomaterials 29, 3260–3268 (2008).

    CAS  Google Scholar 

  153. 153.

    Buket Basmanav, F., Kose, G. T. & Hasirci, V. Sequential growth factor delivery from complexed microspheres for bone tissue engineering. Biomaterials 29, 4195–4204 (2008).

    CAS  Google Scholar 

  154. 154.

    Jaklenec, A. et al. Sequential release of bioactive IGF-I and TGF-β1 from PLGA microsphere-based scaffolds. Biomaterials 29, 1518–1525 (2008).

    CAS  Google Scholar 

  155. 155.

    Wang, Y., Cooke, M. J., Sachewsky, N., Morshead, C. M. & Shoichet, M. S. Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke. J. Control. Release 172, 1–11 (2013).

    CAS  Google Scholar 

  156. 156.

    McGillicuddy, F. C. et al. Novel “plum pudding” gels as potential drug-eluting stent coatings: controlled release of fluvastatin. J. Biomed. Mater. Res. A 79, 923–933 (2006).

    CAS  Google Scholar 

  157. 157.

    Sivakumaran, D., Maitland, D. & Hoare, T. Injectable microgel-hydrogel composites for prolonged small-molecule drug delivery. Biomacromolecules 12, 4112–4120 (2011).

    CAS  Google Scholar 

  158. 158.

    Almeida, H. V. et al. Controlled release of transforming growth factor-β3 from cartilage-extra-cellular-matrix-derived scaffolds to promote chondrogenesis of human-joint-tissue-derived stem cells. Acta Biomater. 10, 4400–4409 (2014).

    CAS  Google Scholar 

  159. 159.

    Bian, L. et al. Enhanced MSC chondrogenesis following delivery of TGF-β3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo. Biomaterials 32, 6425–6434 (2011).

    CAS  Google Scholar 

  160. 160.

    Patel, Z. S., Yamamoto, M., Ueda, H., Tabata, Y. & Mikos, A. G. Biodegradable gelatin microparticles as delivery systems for the controlled release of bone morphogenetic protein-2. Acta Biomater. 4, 1126–1138 (2008).

    CAS  Google Scholar 

  161. 161.

    Kavanaugh, T. E., Werfel, T. A., Cho, H., Hasty, K. A. & Duvall, C. L. Particle-based technologies for osteoarthritis detection and therapy. Drug Deliv. Transl. Res. 6, 132–147 (2016).

    CAS  Google Scholar 

  162. 162.

    Li, M., Liu, X., Liu, X. & Ge, B. Calcium phosphate cement with BMP-2-loaded gelatin microspheres enhances bone healing in osteoporosis: a pilot study. Clin. Orthop. Relat. Res. 468, 1978–1985 (2010).

    Google Scholar 

  163. 163.

    Patel, Z. S. et al. Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model. Bone 43, 931–940 (2008).

    CAS  Google Scholar 

  164. 164.

    Cai, B. et al. Injectable gel constructs with regenerative and anti-infective dual effects based on assembled chitosan microspheres. ACS Appl. Mater. Interfaces 10, 25099–25112 (2018).

    CAS  Google Scholar 

  165. 165.

    DeFail, A. J., Chu, C. R., Izzo, N. & Marra, K. G. Controlled release of bioactive TGF-β1 from microspheres embedded within biodegradable hydrogels. Biomaterials 27, 1579–1585 (2006).

    CAS  Google Scholar 

  166. 166.

    Holland, T. A., Tabata, Y. & Mikos, A. G. Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. J. Control. Release 101, 111–125 (2005).

    CAS  Google Scholar 

  167. 167.

    Park, H., Temenoff, J. S., Holland, T. A., Tabata, Y. & Mikos, A. G. Delivery of TGF-β1 and chondrocytes via injectable, biodegradable hydrogels for cartilage tissue engineering applications. Biomaterials 26, 7095–7103 (2005).

    CAS  Google Scholar 

  168. 168.

    Kang, M. L., Ko, J.-Y., Kim, J. E. & Im, G.-I. Intra-articular delivery of kartogenin-conjugated chitosan nano/microparticles for cartilage regeneration. Biomaterials 35, 9984–9994 (2014).

    CAS  Google Scholar 

  169. 169.

    Hoshino, K. et al. Three catheter-based strategies for cardiac delivery of therapeutic gelatin microspheres. Gene Ther. 13, 1320–1327 (2006).

    CAS  Google Scholar 

  170. 170.

    Iwakura, A. et al. Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model. Heart Vessels 18, 93–99 (2003).

    Google Scholar 

  171. 171.

    Liu, Y., Sun, L., Huan, Y., Zhao, H. & Deng, J. Effects of basic fibroblast growth factor microspheres on angiogenesis in ischemic myocardium and cardiac function: analysis with dobutamine cardiovascular magnetic resonance tagging. Eur. J. Cardiothorac. Surg. 30, 103–107 (2006).

    CAS  Google Scholar 

  172. 172.

    Uitterdijk, A. et al. VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function. Am. J. Physiol. Heart Circ. Physiol. 309, H396–H406 (2015).

    CAS  Google Scholar 

  173. 173.

    Chen, M. H. et al. Injectable supramolecular hydrogel/microgel composites for therapeutic delivery. Macromol. Biosci. 19, e1800248 (2019).

    Google Scholar 

  174. 174.

    Du, J., Du, P. & Smyth, H. D. Hydrogels for controlled pulmonary delivery. Ther. Deliv. 4, 1293–1305 (2013).

    CAS  Google Scholar 

  175. 175.

    Qurrat, ul-Ain, Sharma, S., Khuller, G. K. & Garg, S. K. Alginate-based oral drug delivery system for tuberculosis: pharmacokinetics and therapeutic effects. J. Antimicrob. Chemother. 51, 931–938 (2003).

    Google Scholar 

  176. 176.

    Selvam, P., El-Sherbiny, I. M. & Smyth, H. D. Swellable hydrogel particles for controlled release pulmonary administration using propellant-driven metered dose inhalers. J. Aerosol. Med. Pulm. Drug Deliv. 24, 25–34 (2011).

    CAS  Google Scholar 

  177. 177.

    El-Sherbiny, I. M., McGill, S. & Smyth, H. D. Swellable microparticles as carriers for sustained pulmonary drug delivery. J. Pharm. Sci. 99, 2343–2356 (2010).

    CAS  Google Scholar 

  178. 178.

    Hwang, S. M., Kim, D. D., Chung, S. J. & Shim, C. K. Delivery of ofloxacin to the lung and alveolar macrophages via hyaluronan microspheres for the treatment of tuberculosis. J. Control. Release 129, 100–106 (2008).

    CAS  Google Scholar 

  179. 179.

    Secret, E., Crannell, K. E., Kelly, S. J., Villancio-Wolter, M. & Andrew, J. S. Matrix metalloproteinase-sensitive hydrogel microparticles for pulmonary drug delivery of small molecule drugs or proteins. J. Mater. Chem. B 3, 5629–5634 (2015).

    CAS  Google Scholar 

  180. 180.

    Secret, E., Kelly, S. J., Crannell, K. E. & Andrew, J. S. Enzyme-responsive hydrogel microparticles for pulmonary drug delivery. ACS Appl. Mater. Interfaces 6, 10313–10321 (2014).

    CAS  Google Scholar 

  181. 181.

    Chaturvedi, K., Ganguly, K., Nadagouda, M. N. & Aminabhavi, T. M. Polymeric hydrogels for oral insulin delivery. J. Control. Release 165, 129–138 (2013).

    CAS  Google Scholar 

  182. 182.

    Bell, C. L. & Peppas, N. A. Water, solute and protein diffusion in physiologically responsive hydrogels of poly(methacrylic acid-g-ethylene glycol). Biomaterials 17, 1203–1218 (1996).

    CAS  Google Scholar 

  183. 183.

    Mundargi, R. C., Rangaswamy, V. & Aminabhavi, T. M. Poly(N-vinylcaprolactam-co-methacrylic acid) hydrogel microparticles for oral insulin delivery. J. Microencapsul. 28, 384–394 (2011).

    CAS  Google Scholar 

  184. 184.

    Sajeesh, S., Bouchemal, K., Marsaud, V., Vauthier, C. & Sharma, C. P. Cyclodextrin complexed insulin encapsulated hydrogel microparticles: An oral delivery system for insulin. J. Control. Release 147, 377–384 (2010).

    CAS  Google Scholar 

  185. 185.

    Bravo-Osuna, I., Vauthier, C., Farabollini, A., Palmieri, G. F. & Ponchel, G. Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials 28, 2233–2243 (2007).

    CAS  Google Scholar 

  186. 186.

    Zhang, Y., Wei, W., Lv, P., Wang, L. & Ma, G. Preparation and evaluation of alginate–chitosan microspheres for oral delivery of insulin. Eur. J. Pharm. Biopharm. 77, 11–19 (2011).

    CAS  Google Scholar 

  187. 187.

    He, P., Davis, S. S. & Illum, L. In vitro evaluation of the mucoadhesive properties of chitosan microspheres. Int. J. Pharm. 166, 75–88 (1998).

    CAS  Google Scholar 

  188. 188.

    Solorio, L. D., Fu, A. S., Hernández-Irizarry, R. & Alsberg, E. Chondrogenic differentiation of human mesenchymal stem cell aggregates via controlled release of TGF-β1 from incorporated polymer microspheres. J. Biomed. Mater. Res. A 92A, 1139–1144 (2010).

    CAS  Google Scholar 

  189. 189.

    Solorio, L. D., Vieregge, E. L., Dhami, C. D., Dang, P. N. & Alsberg, E. Engineered cartilage via self-assembled hMSC sheets with incorporated biodegradable gelatin microspheres releasing transforming growth factor-β1. J. Control. Release 158, 224–232 (2012).

    CAS  Google Scholar 

  190. 190.

    Bratt-Leal, A. M., Nguyen, A. H., Hammersmith, K. A., Singh, A. & McDevitt, T. C. A microparticle approach to morphogen delivery within pluripotent stem cell aggregates. Biomaterials 34, 7227–7235 (2013).

    CAS  Google Scholar 

  191. 191.

    Collins, M. N. & Birkinshaw, C. Hyaluronic acid based scaffolds for tissue engineering—A review. Carbohydr. Polym. 92, 1262–1279 (2013).

    CAS  Google Scholar 

  192. 192.

    Chan, B. P. & Leong, K. W. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur. Spine J. 17, 467–479 (2008).

    CAS  Google Scholar 

  193. 193.

    Ahmed, E. M. Hydrogel: Preparation, characterization, and applications: a review. J. Adv. Res. 6, 105–121 (2015).

    CAS  Google Scholar 

  194. 194.

    Sheikhi, A. et al. Microfluidic-enabled bottom-up hydrogels from annealable naturally-derived protein microbeads. Biomaterials 192, 560–568 (2019).

    CAS  Google Scholar 

  195. 195.

    Xin, S., Wyman, O. M. & Alge, D. L. Assembly of PEG microgels into porous cell-instructive 3D scaffolds via thiol-ene click chemistry. Adv. Healthc. Mater. 7, e1800160 (2018).

    Google Scholar 

  196. 196.

    Hsu, R. S. et al. Adaptable microporous hydrogels of propagating NGF-gradient by injectable building blocks for accelerated axonal outgrowth. Adv. Sci. 6, 1900520 (2019).

    Google Scholar 

  197. 197.

    McWhorter, F. Y., Wang, T., Nguyen, P., Chung, T. & Liu, W. F. Modulation of macrophage phenotype by cell shape. Proc. Natl Acad. Sci. USA 110, 17253–17258 (2013).

    CAS  Google Scholar 

  198. 198.

    Werner, M. et al. Surface curvature differentially regulates stem cell migration and differentiation via altered attachment morphology and nuclear deformation. Adv. Sci. 4, 1600347 (2017).

    Google Scholar 

  199. 199.

    Mitra, A. et al. Cell geometry dictates TNFα-induced genome response. Proc. Natl Acad. Sci. USA 114, E3882–E3891 (2017).

    CAS  Google Scholar 

  200. 200.

    Li, S. et al. Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability. Nat. Mater. 16, 953–961 (2017).

    CAS  Google Scholar 

  201. 201.

    Bae, M.-S., Lee, K. Y., Park, Y. J. & Mooney, D. J. RGD island spacing controls phenotype of primary human fibroblasts adhered to ligand-organized hydrogels. Macromol. Res. 15, 469–472 (2007).

    CAS  Google Scholar 

  202. 202.

    Cruz, D. M. et al. Chitosan microparticles as injectable scaffolds for tissue engineering. J. Tissue Eng. Regen. Med. 2, 378–380 (2008).

    CAS  Google Scholar 

  203. 203.

    Malafaya, P. B., Santos, T. C., van Griensven, M. & Reis, R. L. Morphology, mechanical characterization and in vivo neo-vascularization of chitosan particle aggregated scaffolds architectures. Biomaterials 29, 3914–3926 (2008).

    CAS  Google Scholar 

  204. 204.

    Kucharska, M. et al. Fabrication and characterization of chitosan microspheres agglomerated scaffolds for bone tissue engineering. Mater. Lett. 64, 1059–1062 (2010).

    CAS  Google Scholar 

  205. 205.

    Dumont, C. M. et al. Aligned hydrogel tubes guide regeneration following spinal cord injury. Acta Biomater. 86, 312–322 (2019).

    CAS  Google Scholar 

  206. 206.

    Hu, Z., Ma, C., Rong, X., Zou, S. & Liu, X. Immunomodulatory ECM-like microspheres for accelerated bone regeneration in diabetes mellitus. ACS Appl. Mater. Interfaces 10, 2377–2390 (2018).

    CAS  Google Scholar 

  207. 207.

    Roam, J. L., Nguyen, P. K. & Elbert, D. L. Controlled release and gradient formation of human glial-cell derived neurotrophic factor from heparinated poly(ethylene glycol) microsphere-based scaffolds. Biomaterials 35, 6473–6481 (2014).

    CAS  Google Scholar 

  208. 208.

    Roam, J. L. et al. A modular, plasmin-sensitive, clickable poly(ethylene glycol)-heparin-laminin microsphere system for establishing growth factor gradients in nerve guidance conduits. Biomaterials 72, 112–124 (2015).

    CAS  Google Scholar 

  209. 209.

    Custódio, C. A. et al. Functionalized microparticles producing scaffolds in combination with cells. Adv. Funct. Mater. 24, 1391–1400 (2014).

    Google Scholar 

  210. 210.

    Jgamadze, D., Liu, L., Vogler, S., Chu, L. Y. & Pautot, S. Thermoswitching microgel carriers improve neuronal cell growth and cell release for cell transplantation. Tissue Eng. C Methods 21, 65–76 (2015).

    CAS  Google Scholar 

  211. 211.

    Moroni, L. et al. Biofabrication strategies for 3D in vitro models and regenerative medicine. Nat. Rev. Mater. 3, 21–37 (2018).

    CAS  Google Scholar 

  212. 212.

    Groll, J. et al. Biofabrication: reappraising the definition of an evolving field. Biofabrication 8, 013001 (2016).

    Google Scholar 

  213. 213.

    Xu, F. et al. Three-dimensional magnetic assembly of microscale hydrogels. Adv. Mater. 23, 4254–4260 (2011).

    CAS  Google Scholar 

  214. 214.

    Tasoglu, S., Diller, E., Guven, S., Sitti, M. & Demirci, U. Untethered micro-robotic coding of three-dimensional material composition. Nat. Commun. 5, 3124 (2014).

    CAS  Google Scholar 

  215. 215.

    Xu, F. et al. The assembly of cell-encapsulating microscale hydrogels using acoustic waves. Biomaterials 32, 7847–7855 (2011).

    CAS  Google Scholar 

  216. 216.

    Kamperman, T. et al. Single cell microgel based modular bioinks for uncoupled cellular micro- and macroenvironments. Adv. Healthc. Mater. 6, 1600913 (2017).

    Google Scholar 

  217. 217.

    Xin, S., Chimene, D., Garza, J. E., Gaharwar, A. K. & Alge, D. L. Clickable PEG hydrogel microspheres as building blocks for 3D bioprinting. Biomater. Sci. 7, 1179–1187 (2019).

    CAS  Google Scholar 

  218. 218.

    Highley, C. B., Rodell, C. B. & Burdick, J. A. Direct 3D printing of shear-thinning hydrogels into self-healing hydrogels. Adv. Mater. 27, 5075–5079 (2015).

    CAS  Google Scholar 

  219. 219.

    Bhattacharjee, T. et al. Writing in the granular gel medium. Sci. Adv. 1, e1500655 (2015).

    Google Scholar 

  220. 220.

    Bhattacharjee, T. et al. Liquid-like solids support cells in 3D. ACS Biomater. Sci. Eng. 2, 1787–1795 (2016).

    CAS  Google Scholar 

  221. 221.

    Gilbert, E., Hui, A. & Waldorf, H. A. The basic science of dermal fillers: past and present part I: background and mechanisms of action. J. Drugs Dermatol. 11, 1059–1068 (2012).

    CAS  Google Scholar 

  222. 222.

    Tezel, A. & Fredrickson, G. H. The science of hyaluronic acid dermal fillers. J. Cosmet. Laser Ther. 10, 35–42 (2008).

    Google Scholar 

  223. 223.

    Rose, J. C. et al. Nerve cells decide to orient inside an injectable hydrogel with minimal structural guidance. Nano Lett. 17, 3782–3791 (2017).

    CAS  Google Scholar 

  224. 224.

    Le, L. V., Mkrtschjan, M. A., Russell, B. & Desai, T. A. Hang on tight: reprogramming the cell with microstructural cues. Biomed. Microdevices 21, 43 (2019).

    Google Scholar 

  225. 225.

    Tan, H. et al. Heterogeneous multi-compartmental hydrogel particles as synthetic cells for incompatible tandem reactions. Nat. Commun. 8, 663 (2017).

    Google Scholar 

  226. 226.

    Yadavali, S., Jeong, H. H., Lee, D. & Issadore, D. Silicon and glass very large scale microfluidic droplet integration for terascale generation of polymer microparticles. Nat. Commun. 9, 1222 (2018).

    Google Scholar 

  227. 227.

    Andrade, J. E., Avila, C. F., Hall, S. A., Lenoir, N. & Viggiani, G. Multiscale modeling and characterization of granular matter: from grain kinematics to continuum mechanics. J. Mech. Phys. Solids 59, 237–250 (2011).

    Google Scholar 

  228. 228.

    Liu, J., Bosco, E. & Suiker, A. S. J. Multi-scale modelling of granular materials: numerical framework and study on micro-structural features. Comput. Mech. 63, 409–427 (2019).

    Google Scholar 

  229. 229.

    Zhu, H. et al. Spatial control of in vivo CRISPR–Cas9 genome editing via nanomagnets. Nat. Biomed. Eng. 3, 126–136 (2019).

    CAS  Google Scholar 

  230. 230.

    Lu, L., Stamatas, G. N. & Mikos, A. G. Controlled release of transforming growth factor β1 from biodegradable polymer microparticles. J. Biomed. Mater. Res. 50, 440–451 (2000).

    CAS  Google Scholar 

  231. 231.

    Pregibon, D. C., Toner, M. & Doyle, P. S. Multifunctional encoded particles for high-throughput biomolecule analysis. Science 315, 1393–1396 (2007).

    CAS  Google Scholar 

  232. 232.

    Wang, S. et al. An in-situ photocrosslinking microfluidic technique to generate non-spherical, cytocompatible, degradable, monodisperse alginate microgels for chondrocyte encapsulation. Biomicrofluidics 12, 014106 (2018).

    Google Scholar 

  233. 233.

    Wang, H. et al. One-step generation of core–shell gelatin methacrylate (GelMA) microgels using a droplet microfluidic system. Adv. Mater. Technol. 4, 1800632 (2019).

    Google Scholar 

  234. 234.

    Jha, A. K., Malik, M. S., Farach-Carson, M. C., Duncan, R. L. & Jia, X. Hierarchically structured, hyaluronic acid-based hydrogel matrices via the covalent integration of microgels into macroscopic networks. Soft Matter 6, 5045–5055 (2010).

    CAS  Google Scholar 

  235. 235.

    Loebel, C., Broguiere, N., Alini, M., Zenobi-Wong, M. & Eglin, D. Microfabrication of photo-cross-linked hyaluronan hydrogels by single- and two-photon tyramine oxidation. Biomacromolecules 16, 2624–2630 (2015).

    CAS  Google Scholar 

  236. 236.

    Ma, T., Gao, X., Dong, H., He, H. & Cao, X. High-throughput generation of hyaluronic acid microgels via microfluidics-assisted enzymatic crosslinking and/or Diels–Alder click chemistry for cell encapsulation and delivery. Appl. Mater. Today 9, 49–59 (2017).

    Google Scholar 

  237. 237.

    Jia, X. et al. Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration. Biomacromolecules 7, 3336–3344 (2006).

    CAS  Google Scholar 

  238. 238.

    Chen, J. et al. Tailor-making fluorescent hyaluronic acid microgels via combining microfluidics and photoclick chemistry for sustained and localized delivery of herceptin in tumors. ACS Appl. Mater. Interfaces 10, 3929–3937 (2018).

    CAS  Google Scholar 

  239. 239.

    Sonnet, C. et al. Rapid healing of femoral defects in rats with low dose sustained BMP2 expression from PEGDA hydrogel microspheres. J. Orthop. Res. 31, 1597–1604 (2013).

    CAS  Google Scholar 

  240. 240.

    Chung, S. E. et al. Optofluidic maskless lithography system for real-time synthesis of photopolymerized microstructures in microfluidic channels. Appl. Phys. Lett. 91, 041106 (2007).

    Google Scholar 

  241. 241.

    Ryu, S. et al. Dual mode gelation behavior of silk fibroin microgel embedded poly(ethylene glycol) hydrogels. J. Mater. Chem. B 4, 4574–4584 (2016).

    CAS  Google Scholar 

  242. 242.

    Kumachev, A. et al. High-throughput generation of hydrogel microbeads with varying elasticity for cell encapsulation. Biomaterials 32, 1477–1483 (2011).

    CAS  Google Scholar 

Download references

Acknowledgements

J.A.B. acknowledges funding through the National Science Foundation through the PENN MRSEC (DMR-1720530) and STC Program (CMMI: 15-48571). T.S. acknowledges funding from the National Institutes of Health (R01NS094599) and Duke Biomedical Engineering. The authors would like to thank their laboratories for the helpful input and suggestions on the manuscript.

Author information

Affiliations

Authors

Contributions

All authors contributed equally to the preparation of this manuscript.

Corresponding authors

Correspondence to Tatiana Segura or Jason A. Burdick.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Daly, A.C., Riley, L., Segura, T. et al. Hydrogel microparticles for biomedical applications. Nat Rev Mater 5, 20–43 (2020). https://doi.org/10.1038/s41578-019-0148-6

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing