Advertisement

Engineered microscale hydrogels for drug delivery, cell therapy, and sequencing

  • Marissa E. Wechsler
  • Regan E. Stephenson
  • Andrew C. Murphy
  • Heidi F. Oldenkamp
  • Ankur Singh
  • Nicholas A. PeppasEmail author
Article
Part of the following topical collections:
  1. Biomedical Micro-Nanotechnologies toward Translation

Abstract

Engineered microscale hydrogels have emerged as promising therapeutic approaches for the treatment of various diseases. These microgels find wide application in the biomedical field because of the ease of injectability, controlled release of therapeutics, flexible means of synthesis, associated tunability, and can be engineered as stimuli-responsive. While bulk hydrogels of several length-scale dimensions have been used for over two decades in drug delivery applications, their use as microscale carriers of drug and cell-based therapies is relatively new. Herein, we critically summarize the fundamentals of hydrogels based on their equilibrium and dynamics of their molecular structure, as well as solute diffusion as it relates to drug delivery. In addition, examples of common microgel synthesis techniques are provided. The ability to tune microscale hydrogels to obtain controlled release of therapeutics is discussed, along with microgel considerations for cell encapsulation as it relates to the development of cell-based therapies. We conclude with an outlook on the use of microgels for cell sequencing, and the convergence of the use of microscale hydrogels for drug delivery, cell therapy, and cell sequencing based systems.

Keywords

Cell therapy Drug delivery Hydrogels Sequencing 

Notes

Acknowledgements

This work is submitted in honor of Professor Mauro Ferrari’s 60th birthday. Mauro has been an inspirational force in the fields of nanotechnology and bionanotechnology. His writings have been extremely important in defining these fields, and the senior authors who have known him and worked with him appreciate all the contributions he has made to their research, directly and indirectly.

We acknowledge financial support from the National Institutes of Health (R01-AI132738-01A1 and 5R33CA212968-02 awarded to AS; R01-EB022025 awarded to NAP), the National Science Foundation CAREER award (DMR-1554275 awarded to AS), Department of Defense CDMRP and Cancer Career Development Award (W81XWH-17-1-0215 awarded to AS). In addition, NAP acknowledges support from the Cockrell Family Chair Foundation and the office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine. We acknowledge financial support from the National Science Foundation Graduate Research Fellowship Program (DGE-1610403 awarded to MEW; DGE-1650441 awarded to RES). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the funding agencies.

References

  1. S. Allazetta, T.C. Hausherr, M.P. Lutolf, Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. Biomacromolecules 14, 1122–1131 (2013).  https://doi.org/10.1021/bm4000162 CrossRefGoogle Scholar
  2. D. Aydın, S. Kızılel, Water-in-water emulsion based synthesis of hydrogel Nanospheres with tunable release kinetics. JOM 69, 1185 (2017).  https://doi.org/10.1007/s11837-016-1969-z CrossRefGoogle Scholar
  3. C. Berkland, K. Kim, D.W. Pack, PLG Microsphere Size Controls Drug Release Rate Through Several Competing Factors. Pharm. Res. 20, 1055–1062 (2003).  https://doi.org/10.1023/A:1024466407849 CrossRefGoogle Scholar
  4. M.A. Bochenek, O. Veiseh, A.J. Vegas, et al., Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat Biomed Eng 2, 810 (2018)CrossRefGoogle Scholar
  5. L. Brannon-Peppas, N.A. Peppas, Dynamic and equilibrium swelling behaviour of pH-sensitive hydrogels containing 2-hydroxyethyl methacrylate. Biomaterials 11, 635–644 (1990)CrossRefGoogle Scholar
  6. M. Caldorera-Moore, M.K. Kang, Z. Moore, et al., Swelling behavior of nanoscale, shape- and size-specific, hydrogel particles fabricated using imprint lithography. Soft Matter 7, 2879 (2011).  https://doi.org/10.1039/c0sm01185a CrossRefGoogle Scholar
  7. D.A. Carr, N.A. Peppas, Assessment of poly(methacrylic acid- co - N -vinyl pyrrolidone) as a carrier for the oral delivery of therapeutic proteins using Caco-2 and HT29-MTX cell lines. J. Biomed. Mater. Res. Part A 9999A, NA-NA (2009).  https://doi.org/10.1002/jbm.a.32395 CrossRefGoogle Scholar
  8. F. Cayrol, M.C. Diaz Flaque, T. Fernando, et al., Integrin v 3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells. Blood 125, 841–851 (2015).  https://doi.org/10.1182/blood-2014-07-587337 CrossRefGoogle Scholar
  9. J.C. Chang, A. Wysocki, K.M. Tchou-Wong, et al., Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases. Thorax 51, 306–311 (1996)CrossRefGoogle Scholar
  10. Q. Chen, D. Chen, J. Wu, J.M. Lin, Flexible control of cellular encapsulation, permeability, and release in a droplet-templated bifunctional copolymer scaffold. Biomicrofluidics 10, 1–9 (2016a).  https://doi.org/10.1063/1.4972107 CrossRefGoogle Scholar
  11. Q. Chen, S. Utech, D. Chen, et al., Controlled assembly of heterotypic cells in a core-shell scaffold: Organ in a droplet. Lab Chip 16, 1346 (2016b).  https://doi.org/10.1039/c6lc00231e CrossRefGoogle Scholar
  12. C.-H. Choi, H. Wang, H. Lee, 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).  https://doi.org/10.1039/C6LC00261G CrossRefGoogle Scholar
  13. J. Crank, The Mathematics of Diffusion, 2nd edn. (Oxford University Press, New York, 1975)Google Scholar
  14. H.R. Culver, N.A. Peppas, Protein-imprinted polymers: The shape of things to come? Chem. Mater. 29, 5753–5761 (2017).  https://doi.org/10.1021/acs.chemmater.7b01936 CrossRefGoogle Scholar
  15. C.A. Deforest, B.D. Polizzotti, K.S. Anseth, Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat. Mater. 8, 659 (2009).  https://doi.org/10.1038/nmat2473 CrossRefGoogle Scholar
  16. B. Demaree, D. Weisgerber, F. Lan, A.R. Abate, An ultrahigh-throughput microfluidic platform for single-cell genome sequencing. J. Vis. Exp. 57598 (2018).  https://doi.org/10.3791/57598
  17. I.K. Demedts, A. Morel-Montero, S. Lebecque, et al., Elevated MMP-12 protein levels in induced sputum from patients with COPD. Thorax 61, 196–201 (2006).  https://doi.org/10.1136/thx.2005.042432 CrossRefGoogle Scholar
  18. M. Durán-Lobato, B. Carrillo-Conde, Y. Khairandish, N.A. Peppas, Surface-modified P(HEMA- co -MAA) Nanogel carriers for Oral vaccine delivery: Design, characterization, and in vitro targeting evaluation. Biomacromolecules 15, 2725–2734 (2014).  https://doi.org/10.1021/bm500588x CrossRefGoogle Scholar
  19. L.K. Fiddes, V.N. Luk, S.H. Au, et al., Hydrogel discs for digital microfluidics. Biomicrofluidics 6, 14112 (2012).  https://doi.org/10.1063/1.3687381 CrossRefGoogle Scholar
  20. P.J. Flory, J. Rehner, Statistical mechanics of cross-linked polymer networks I. rubberlike elasticity. J. Chem. Phys. 11, 512–520 (1943).  https://doi.org/10.1063/1.1723791 CrossRefGoogle Scholar
  21. G.A. Foster, D.M. Headen, C. González-García, et al., Protease-degradable microgels for protein delivery for vascularization. Biomaterials 113, 170–175 (2017).  https://doi.org/10.1016/j.biomaterials.2016.10.044 CrossRefGoogle Scholar
  22. J. Fu, Y.K. Wang, M.T. Yang, et al., Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat. Methods 7, 733 (2010).  https://doi.org/10.1038/nmeth.1487 CrossRefGoogle Scholar
  23. J. Fukuda, A. Khademhosseini, Y. Yeo, et al., Micromolding of photocrosslinkable chitosan hydrogel for spheroid microarray and co-cultures. Biomaterials 27, 5259 (2006).  https://doi.org/10.1016/j.biomaterials.2006.05.044 CrossRefGoogle Scholar
  24. M.I. González-Sánchez, J. Rubio-Retama, E. López-Cabarcos, E. Valero, Development of an acetaminophen amperometric biosensor based on peroxidase entrapped in polyacrylamide microgels. Biosens. Bioelectron. 26, 1883 (2011).  https://doi.org/10.1016/j.bios.2010.03.024 CrossRefGoogle Scholar
  25. S.T. Gould, N.J. Darling, K.S. Anseth, Small peptide functionalized thiol–ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition. Acta Biomater. 8, 3201–3209 (2012).  https://doi.org/10.1016/j.actbio.2012.05.009 CrossRefGoogle Scholar
  26. S.E.A. Gratton, P.D. Pohlhaus, J. Lee, et al., Nanofabricated particles for engineered drug therapies: A preliminary biodistribution study of PRINT™ nanoparticles. J. Control. Release 121, 10 (2007).  https://doi.org/10.1016/j.jconrel.2007.05.027 CrossRefGoogle Scholar
  27. D.R. Griffin, W.M. Weaver, P.O. Scumpia, et al., Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015).  https://doi.org/10.1038/nmat4294 CrossRefGoogle Scholar
  28. A.E. Guttmacher, F.S. Collins, Welcome to the genomic era. N. Engl. J. Med. 349, 996 (2003).  https://doi.org/10.1056/NEJMe038132 CrossRefGoogle Scholar
  29. D.M. Headen, G. Aubry, H. Lu, A.J. García, Microfluidic-based generation of size-controlled, biofunctionalized synthetic polymer microgels for cell encapsulation. Adv. Mater. 26, 3003–3008 (2014).  https://doi.org/10.1002/adma.201304880 CrossRefGoogle Scholar
  30. D.M. Headen, J.R. García, A.J. García, Parallel droplet microfluidics for high throughput cell encapsulation and synthetic microgel generation. Microsyst. Nanoeng. 4, 17076 (2018a).  https://doi.org/10.1038/micronano.2017.76 CrossRefGoogle Scholar
  31. D.M. Headen, K.B. Woodward, M.M. Coronel, et al., Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nat. Mater. 17, 732–739 (2018b).  https://doi.org/10.1038/s41563-018-0099-0 CrossRefGoogle Scholar
  32. D.E. Heath, A.R.M. Sharif, C.P. Ng, et al., Regenerating the cell resistance of micromolded PEG hydrogels. Lab Chip 15, 2073 (2015).  https://doi.org/10.1039/c4lc01416b CrossRefGoogle Scholar
  33. H. Hirama, T. Kambe, K. Aketagawa, et al., Hyper alginate gel microbead formation by molecular diffusion at the hydrogel/droplet Interface. Langmuir 29, 519–524 (2012).  https://doi.org/10.1021/la303827u CrossRefGoogle Scholar
  34. J.C. Hoffmann, J.L. West, Three-dimensional photolithographic patterning of multiple bioactive ligands in poly(ethylene glycol) hydrogels. Soft Matter 6, 5056 (2010).  https://doi.org/10.1039/c0sm00140f CrossRefGoogle Scholar
  35. S. Jung, H. Yi, Facile micromolding-based fabrication of biopolymeric - synthetic hydrogel microspheres with controlled structures for improved protein conjugation. Chem. Mater. 27, 3988 (2015).  https://doi.org/10.1021/acs.chemmater.5b00920 CrossRefGoogle Scholar
  36. S. Kawata, H.-B. Sun, T. Tanaka, K. Takada, Finer features for functional microdevices. Nature 412, 697–698 (2001).  https://doi.org/10.1038/35089130 CrossRefGoogle Scholar
  37. A. Khademhosseini, G. Eng, J. Yeh, et al., Micromolding of photocrosslinkable hyaluronic acid for cell encapsulation and entrapment. J. Biomed. Mater. Res. Part A. 79A, 522 (2006).  https://doi.org/10.1002/jbm.a.30821 CrossRefGoogle Scholar
  38. S.W. Kim, Y.H.O.T. Bae, Hydrogels: swelling, drug loading, and release. Pharm. Res. 9, 283–290 (1992)CrossRefGoogle Scholar
  39. P.-H. Kim, H.-G. Yim, Y.-J. Choi, et al., Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization. J. Control. Release 187, 1–13 (2014).  https://doi.org/10.1016/j.jconrel.2014.05.010 CrossRefGoogle Scholar
  40. A.M. Klein, D.A. Weitz, M.W. Kirschner, et al., Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187–1201 (2015).  https://doi.org/10.1016/j.cell.2015.04.044 CrossRefGoogle Scholar
  41. M.C. Koetting, J.F. Guido, M. Gupta, et al., pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J. Control. Release 221, 18–25 (2016).  https://doi.org/10.1016/j.jconrel.2015.11.023 CrossRefGoogle Scholar
  42. R.W. Korsmeyer, R. Gurny, E. Doelker, et al., Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 15, 25–35 (1983).  https://doi.org/10.1016/0378-5173(83)90064-9 CrossRefGoogle Scholar
  43. F. Lan, B. Demaree, N. Ahmed, A.R. Abate, Single-cell genome sequencing at ultra-high-throughput with microfluidic droplet barcoding. Nat. Biotechnol. 35, 640–646 (2017).  https://doi.org/10.1038/nbt.3880 CrossRefGoogle Scholar
  44. D. Lee, C. Cha, Combined effects of co-culture and substrate mechanics on 3D tumor spheroid formation within microgels prepared via flow-focusing microfluidic fabrication. Pharmaceutics 10, 1–14 (2018).  https://doi.org/10.3390/pharmaceutics10040229 CrossRefGoogle Scholar
  45. S.-H. Lee, J.S. Miller, J.J. Moon, J.L. West, Proteolytically degradable hydrogels with a Fluorogenic substrate for studies of cellular proteolytic activity and migration. Biotechnol. Prog. 21, 1736–1741 (2005).  https://doi.org/10.1021/bp0502429 CrossRefGoogle Scholar
  46. T.T. Lee, J.R. García, J.I. Paez, et al., Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials. Nat. Mater. 14, 352–360 (2015).  https://doi.org/10.1038/nmat4157 CrossRefGoogle Scholar
  47. T. Leinonen, R. Pirinen, J. Böhm, et al., Expression of matrix metalloproteinases 7 and 9 in non-small cell lung cancer: Relation to clinicopathological factors, β-catenin and prognosis. Lung Cancer 51, 313–321 (2006).  https://doi.org/10.1016/J.LUNGCAN.2005.11.002 CrossRefGoogle Scholar
  48. B. Li, L. Wang, F. Xu, et al., Hydrosoluble, UV-crosslinkable and injectable chitosan for patterned cell-laden microgel and rapid transdermal curing hydrogel in vivo. Acta Biomater. 22, 59 (2015).  https://doi.org/10.1016/j.actbio.2015.04.026 CrossRefGoogle Scholar
  49. B. Li, M. He, L. Ramirez, et al., Multifunctional hydrogel microparticles by polymer-assisted photolithography. ACS Appl. Mater. Interfaces 8, 4158 (2016).  https://doi.org/10.1021/acsami.5b11883 CrossRefGoogle Scholar
  50. W.B. Liechty, D.R. Kryscio, B.V. Slaughter, N.A. Peppas, Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. Eng. 1, 149–173 (2010).  https://doi.org/10.1146/annurev-chembioeng-073009-100847 CrossRefGoogle Scholar
  51. P.S. Lienemann, T. Rossow, A.S. Mao, et al., Single cell-laden protease-sensitive microniches for long-term culture in 3D. Lab Chip 17, 727–737 (2017).  https://doi.org/10.1039/C6LC01444E CrossRefGoogle Scholar
  52. F. Lim, A.M. Sun, Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–910 (1980)CrossRefGoogle Scholar
  53. A.M. Lowman, T.D. Dziubla, P. Bures, N.A. Peppas, Structural and dynamic response of neutral and intelligent networks in biomedical environments. Adv. Chem. Eng. 29, 75–130 (2004).  https://doi.org/10.1016/S0065-2377(03)29004-9 CrossRefGoogle Scholar
  54. V.N. Luk, L.K. Fiddes, V.M. Luk, et al., Digital microfluidic hydrogel microreactors for proteomics. Proteomics 12, 1310–1318 (2012).  https://doi.org/10.1002/pmic.201100608 CrossRefGoogle Scholar
  55. M.P. Lutolf, J.A. Hubbell, Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 23, 47–55 (2005).  https://doi.org/10.1038/nbt1055 CrossRefGoogle Scholar
  56. E.Z. Macosko, A. Basu, A. Regev, et al., Highly parallel genome-wide expression profiling of individual cells using Nanoliter droplets Resource Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161, 1202–1214 (2015).  https://doi.org/10.1016/j.cell.2015.05.002 CrossRefGoogle Scholar
  57. A.S. Mao, J.-W. Shin, S. Utech, et al., Deterministic encapsulation of single cells in thin tunable microgels for niche modelling and therapeutic delivery. Nat. Mater. 16, 236–243 (2017).  https://doi.org/10.1038/nmat4781 CrossRefGoogle Scholar
  58. A.P. McGuigan, D.A. Bruzewicz, A. Glavan, et al., Cell encapsulation in sub-mm sized gel modules using replica molding. PLoS One 3, e2258 (2008).  https://doi.org/10.1371/journal.pone.0002258 CrossRefGoogle Scholar
  59. I. Mironi-Harpaz, L. Hazanov, G. Engel, et al., In-situ architectures designed in 3D cell-laden hydrogels using microscopic laser photolithography. Adv. Mater. 27, 1933 (2015).  https://doi.org/10.1002/adma.201404185 CrossRefGoogle Scholar
  60. S. Morelli, R.G. Holdich, M.M. Dragosavac, Chitosan and poly (vinyl alcohol) microparticles produced by membrane emulsification for encapsulation and pH controlled release. Chem. Eng. J. 288, 451 (2016).  https://doi.org/10.1016/j.cej.2015.12.024 CrossRefGoogle Scholar
  61. T.W. Murphy, Y.-P. Hsieh, S.S. Ma, et al., Microfluidic low-input fluidized-bed enabled ChIP-seq device for automated and parallel analysis of histone modifications. Anal. Chem. 90, 7666–7674 (2018).  https://doi.org/10.1021/acs.analchem.8b01541 CrossRefGoogle Scholar
  62. M.I. Neves, M.E. Wechsler, M.E. Gomes, et al., Molecularly imprinted intelligent scaffolds for tissue engineering applications. Tissue Eng. B Rev. 23, 27–43 (2017).  https://doi.org/10.1089/ten.TEB.2016.0202 CrossRefGoogle Scholar
  63. M. Nikkhah, N. Eshak, P. Zorlutuna, et al., Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels. Biomaterials 33, 9009 (2012).  https://doi.org/10.1016/j.biomaterials.2012.08.068 CrossRefGoogle Scholar
  64. M.H.M. Oudshoorn, R. Penterman, R. Rissmann, et al., Preparation and characterization of structured hydrogel microparticles based on cross-linked hyperbranched polyglycerol. Langmuir 23, 11819 (2007).  https://doi.org/10.1021/la701910d CrossRefGoogle Scholar
  65. J.H. Park, S.O. Choi, R. Kamath, et al., Polymer particle-based micromolding to fabricate novel microstructures. Biomed. Microdevices 9, 223 (2007).  https://doi.org/10.1007/s10544-006-9024-4 CrossRefGoogle Scholar
  66. R.G. Patel, A. Purwada, L. Cerchietti, et al., Microscale bioadhesive hydrogel arrays for cell engineering applications. Cell. Mol. Bioeng. 7, 394 (2014).  https://doi.org/10.1007/s12195-014-0353-8 CrossRefGoogle Scholar
  67. N.A. Peppas, Hydrogels in Medicine and Pharmacy (CRC Press, Boca Raton, 1986)Google Scholar
  68. N.A. Peppas, E.W. Merrill, Crosslinked poly(vinyl alcohol) hydrogels as swollen elastic networks. J. Appl. Polym. Sci. 21, 1763–1770 (1977).  https://doi.org/10.1002/app.1977.070210704 CrossRefGoogle Scholar
  69. N.A. Peppas, B. Narasimhan, Mathematical models in drug delivery: How modeling has shaped the way we design new drug delivery systems. J. Control. Release 190, 75–81 (2014).  https://doi.org/10.1016/j.jconrel.2014.06.041 CrossRefGoogle Scholar
  70. N.A. Peppas, P. Bures, W. Leobandung, H. Ichikawa, Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm. 50, 27–46 (2000).  https://doi.org/10.1016/S0939-6411(00)00090-4 CrossRefGoogle Scholar
  71. N.A. Peppas, J.Z. Hilt, A. Khademhosseini, R. Langer, Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Adv. Mater. 18, 1345–1360 (2006).  https://doi.org/10.1002/adma.200501612 CrossRefGoogle Scholar
  72. E.A. Phelps, N.O. Enemchukwu, V.F. Fiore, et al., Maleimide cross-linked bioactive PEG hydrogel exhibits improved reaction kinetics and cross-linking for cell encapsulation and in situ delivery. Adv. Mater. 24(64–70), 2 (2012).  https://doi.org/10.1002/adma.201103574 CrossRefGoogle Scholar
  73. E. Piacentini, M. Yan, L. Giorno, Development of enzyme-loaded PVA microspheres by membrane emulsification. J. Membr. Sci. 524, 79 (2017).  https://doi.org/10.1016/j.memsci.2016.11.008 CrossRefGoogle Scholar
  74. M.R. Pinezich, L.N. Russell, N.P. Murphy, K.J. Lampe, Encapsulated oligodendrocyte precursor cell fate is dependent on PDGF-AA release kinetics in a 3D microparticle-hydrogel drug delivery system. J. Biomed. Mater. Res. A 106, 2402–2411 (2018).  https://doi.org/10.1002/jbm.a.36432 CrossRefGoogle Scholar
  75. A. Purwada, S.B. Shah, W. Béguelin, et al., Ex vivo synthetic immune tissues with T cell signals for differentiating antigen-specific, high affinity germinal center B cells. Biomaterials (2018).  https://doi.org/10.1016/j.biomaterials.2018.06.034 CrossRefGoogle Scholar
  76. G.P. Raeber, M.P. Lutolf, J.A. Hubbell, Molecularly engineered PEG hydrogels: A novel model system for Proteolytically mediated cell migration. Biophys. J. 89, 1374–1388 (2005).  https://doi.org/10.1529/biophysj.104.050682 CrossRefGoogle Scholar
  77. A. Revzin, R.J. Russell, V.K. Yadavalli, et al., Fabrication of poly(ethylene glycol) hydrogel microstructures using photolithography. Langmuir 17, 5440 (2001).  https://doi.org/10.1021/la010075w CrossRefGoogle Scholar
  78. T. Rossow, J.A. Heyman, A.J. Ehrlicher, et al., Controlled synthesis of cell-laden microgels by radical-free gelation in droplet microfluidics. J. Am. Chem. Soc. (2012).  https://doi.org/10.1021/ja300460p CrossRefGoogle Scholar
  79. A. Rotem, O. Ram, N. Shoresh, et al., Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state HHS public access author manuscript. Nat. Biotechnol. 33, 1165–1172 (2015).  https://doi.org/10.1038/nbt.3383 CrossRefGoogle Scholar
  80. D.K. Sahana, G. Mittal, V. Bhardwaj, M.N.V.R. Kumar, PLGA nanoparticles for oral delivery of hydrophobic drugs: Influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug. J. Pharm. Sci. 97, 1530 (2008).  https://doi.org/10.1002/jps.21158 CrossRefGoogle Scholar
  81. R. Salem, R.J. Lewandowski, B. Atassi, et al., Treatment of Unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): Safety, tumor response, and survival. J. Vasc. Interv. Radiol. 16, 1627–1639 (2005).  https://doi.org/10.1097/01.RVI.0000184594.01661.81 CrossRefGoogle Scholar
  82. K.M. Schultz, K.S. Anseth, Monitoring degradation of matrix metalloproteinases-cleavable PEG hydrogels via multiple particle tracking microrheology. Soft Matter 9, 1570–1579 (2013).  https://doi.org/10.1039/C2SM27303A CrossRefGoogle Scholar
  83. K.M. Schultz, K.A. Kyburz, K.S. Anseth, Measuring dynamic cell–material interactions and remodeling during 3D human mesenchymal stem cell migration in hydrogels. Proc. Natl. Acad. Sci. 112, E3757–E3764 (2015).  https://doi.org/10.1073/pnas.1511304112 CrossRefGoogle Scholar
  84. T.F. Scott, B.A. Kowalski, A.C. Sullivan, et al., Two-color single photon Photoinitiation and Photoinhibition for subdiffraction photolithography. Science 324, 913–917 (2009).  https://doi.org/10.1126/science.116761 CrossRefGoogle Scholar
  85. E. Secret, S.J. Kelly, K.E. Crannell, J.S. Andrew, Enzyme-responsive hydrogel microparticles for pulmonary drug delivery. ACS Appl. Mater. Interfaces 6, 10313–10321 (2014).  https://doi.org/10.1021/am501754s CrossRefGoogle Scholar
  86. L.A. Sharpe, J.E. Vela Ramirez, O.M. Haddadin, et al., pH-responsive microencapsulation Systems for the Oral Delivery of Polyanhydride nanoparticles. Biomacromolecules 19, 793–802 (2018).  https://doi.org/10.1021/acs.biomac.7b01590 CrossRefGoogle Scholar
  87. C. Siltanen, M. Yaghoobi, A. Haque, et al., Microfluidic fabrication of bioactive microgels for rapid formation and enhanced differentiation of stem cell spheroids. Acta Biomater. 34, 125–132 (2016).  https://doi.org/10.1016/J.ACTBIO.2016.01.012 CrossRefGoogle Scholar
  88. B.V. Slaughter, S.S. Khurshid, O.Z. Fisher, et al., Hydrogels in regenerative medicine. Adv. Mater. 21, 3307–3329 (2009).  https://doi.org/10.1002/adma.200802106 CrossRefGoogle Scholar
  89. B.V. Sridhar, J.L. Brock, J.S. Silver, et al., Development of a cellularly degradable PEG hydrogel to promote articular cartilage extracellular matrix deposition. Adv. Healthc. Mater. 4, 702–713 (2015).  https://doi.org/10.1002/adhm.201400695 CrossRefGoogle Scholar
  90. S. Steichen, C. O’Connor, N.A. Peppas, Development of a P((MAA-co-NVP)-g-EG) hydrogel platform for Oral protein delivery: Effects of hydrogel composition on environmental response and protein partitioning. Macromol. Biosci. 17, 1600266 (2016).  https://doi.org/10.1002/mabi.201600266 CrossRefGoogle Scholar
  91. D. Steinhilber, T. Rossow, S. Wedepohl, et al., Angewandte Chemie stimuli-responsive microgels a microgel construction kit for bioorthogonal encapsulation and pH-controlled release of living cells. Angew. Chem. Int. Ed. 52, 13538 (2013).  https://doi.org/10.1002/anie.201308005 CrossRefGoogle Scholar
  92. M. Stoeckius, C. Hafemeister, W. Stephenson, et al., Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017).  https://doi.org/10.1038/nmeth.4380 CrossRefGoogle Scholar
  93. K. Subramani, M.A. Birch, Micropatterning of Poly (Ethylene Glycol)-Diacrylate (PEG-DA) Hydrogel by Soft-Photolithography for Analysis of Cell-Biomaterial interactions. J. Biomimetics Biomater. Tissue Eng. (2009).  https://doi.org/10.4028/www.scientific.net/JBBTE.2.3 CrossRefGoogle Scholar
  94. S. Suri, C.E. Schmidt, Photopatterned collagen-hyaluronic acid interpenetrating polymer network hydrogels. Acta Biomater. 5, 2385 (2009).  https://doi.org/10.1016/j.actbio.2009.05.004 CrossRefGoogle Scholar
  95. W.-H. Tan, S. Takeuchi, Monodisperse alginate hydrogel microbeads for cell encapsulation. Adv. Mater. 19, 2696–2701 (2007).  https://doi.org/10.1002/adma.200700433 CrossRefGoogle Scholar
  96. Y.F. Tian, H. Ahn, R.S. Schneider, et al., Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells. Biomaterials 73, 110–119 (2015).  https://doi.org/10.1016/j.biomaterials.2015.09.007 CrossRefGoogle Scholar
  97. H. Tokuyama, Y. Kato, Preparation of poly(N-isopropylacrylamide) emulsion gels and their drug release behaviors. Colloids Surf. B: Biointerfaces 67, 92 (2008).  https://doi.org/10.1016/j.colsurfb.2008.08.003 CrossRefGoogle Scholar
  98. M. Torres-Lugo, M. García, R. Record, N.A. Peppas, Physicochemical behavior and cytotoxic effects of p(methacrylic acid–g-ethylene glycol) nanospheres for oral delivery of proteins. J. Control. Release 80, 197–205 (2002).  https://doi.org/10.1016/S0168-3659(02)00027-5 CrossRefGoogle Scholar
  99. C. Trapnell, Defining cell types and states with single-cell genomics. Genome Res. 25, 1491 (2015)CrossRefGoogle Scholar
  100. M.F. Ullah, M. Aatif, The footprints of cancer development: Cancer biomarkers. Cancer Treat. Rev. 35, 193–200 (2009).  https://doi.org/10.1016/J.CTRV.2008.10.004 CrossRefGoogle Scholar
  101. O. Veiseh, J.C. Doloff, M. Ma, 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).  https://doi.org/10.1038/nmat4290 CrossRefGoogle Scholar
  102. T. Vermonden, R. Censi, W.E. Hennink, Hydrogels for Protein Delivery. Chem. Rev. 112, 2853–2888 (2012).  https://doi.org/10.1021/cr200157d CrossRefGoogle Scholar
  103. C. Vollmers, R.V. Sit, J.A. Weinstein, et al., Genetic measurement of memory B-cell recall using antibody repertoire sequencing. Proc. Natl. Acad. Sci. 110, 13463 (2013).  https://doi.org/10.1073/pnas.1312146110 CrossRefGoogle Scholar
  104. L. Wang, R.R. Rao, J.P. Stegemann, Delivery of mesenchymal stem cells in chitosan/collagen microbeads for orthopedic tissue repair. Cells Tissues Organs 197, 333 (2013).  https://doi.org/10.1159/000348359 CrossRefGoogle Scholar
  105. G. Wang, D. Chen, L. Zhang, et al., A mild route to entrap papain into cross-linked PEG microparticles via visible light-induced inverse emulsion polymerization. J. Mater. Sci. 53, 880 (2018).  https://doi.org/10.1007/s10853-017-1484-9 CrossRefGoogle Scholar
  106. U. Wattendorf, G. Coullerez, J. Vörös, et al., Mannose-based molecular patterns on stealth microspheres for receptor-specific targeting of human antigen-presenting cells. Langmuir 24, 11790–11802 (2008).  https://doi.org/10.1021/la801085d CrossRefGoogle Scholar
  107. A.R. Wu, J.B. Hiatt, R. Lu, et al., Automated microfluidic chromatin immunoprecipitation from 2,000 cells. Lab Chip 9, 1365–1370 (2009).  https://doi.org/10.1039/b819648f CrossRefGoogle Scholar
  108. Y. Xia, D.W. Pack, Uniform biodegradable microparticle systems for controlled release. Chem. Eng. Sci. 125, 129–143 (2015).  https://doi.org/10.1016/J.CES.2014.06.049 CrossRefGoogle Scholar
  109. F. Xu, C.M. Wu, V. Rengarajan, et al., Three-dimensional magnetic assembly of microscale hydrogels. Adv. Mater. 23, 4254–4260 (2011).  https://doi.org/10.1002/adma.201101962 CrossRefGoogle Scholar
  110. X. Yan, R.A. Gemeinhart, Cisplatin delivery from poly(acrylic acid-co-methyl methacrylate) microparticles. J. Control. Release 106, 198 (2005).  https://doi.org/10.1016/j.jconrel.2005.05.005 CrossRefGoogle Scholar
  111. J.O. You, D.T. Auguste, Feedback-regulated paclitaxel delivery based on poly(N,N-dimethylaminoethyl methacrylate-co-2-hydroxyethyl methacrylate) nanoparticles. Biomaterials 29, 1950 (2008).  https://doi.org/10.1016/j.biomaterials.2007.12.041 CrossRefGoogle Scholar
  112. L. Zhang, K. Chen, H. Zhang, et al., Microfluidic templated multicompartment microgels for 3D encapsulation and pairing of single cells. Small 14, 1–8 (2018).  https://doi.org/10.1002/smll.201702955 CrossRefGoogle Scholar
  113. R. Zilionis, J. Nainys, A. Veres, et al., Single-cell barcoding and sequencing using droplet microfluidics. Nat. Protoc. 12, 44–73 (2017).  https://doi.org/10.1038/nprot.2016.154 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Marissa E. Wechsler
    • 1
    • 2
  • Regan E. Stephenson
    • 3
  • Andrew C. Murphy
    • 2
    • 4
  • Heidi F. Oldenkamp
    • 2
    • 4
  • Ankur Singh
    • 3
    • 5
    • 6
  • Nicholas A. Peppas
    • 1
    • 2
    • 4
    • 7
    • 8
    Email author
  1. 1.Department of Biomedical EngineeringThe University of Texas at AustinAustinUSA
  2. 2.Institute for Biomaterials, Drug Delivery, and Regenerative MedicineThe University of Texas at AustinAustinUSA
  3. 3.Meinig School of Biomedical EngineeringCornell UniversityIthacaUSA
  4. 4.McKetta Department of Chemical EngineeringThe University of Texas at AustinAustinUSA
  5. 5.Sibley School of Mechanical and Aerospace EngineeringCornell UniversityIthacaUSA
  6. 6.Englander Institute for Precision MedicineWeill Cornell Medical CollegeNew YorkUSA
  7. 7.Division of Molecular Pharmaceutics and Drug Delivery, College of PharmacyThe University of Texas at AustinAustinUSA
  8. 8.Department of Surgery and Perioperative Care, and Department of Pediatrics, Dell Medical SchoolThe University of Texas at AustinAustinUSA

Personalised recommendations