Abstract
Cells reside in a complex and dynamic extracellular matrix where they interact with a myriad of biophysical and biochemical cues that direct their function and regulate tissue homeostasis, wound repair, and even pathophysiological events. There is a desire in the biomaterials community to develop synthetic hydrogels to recapitulate facets of the ECM for in vitro culture platforms and tissue engineering applications. Advances in synthetic hydrogel design and chemistries, including user-tunable platforms, have broadened the field’s understanding of the role of matrix cues in directing cellular processes and enabled the design of improved tissue engineering scaffolds. This review focuses on recent advances in the development and fabrication of hydrogels and discusses what aspects of ECM signals can be incorporated to direct cell function in different contexts.
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Annabi, N., A. Tamayol, J. A. Uquillas, M. Akbari, L. E. Bertassoni, C. Cha, et al. 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Adv. Mater. 26:85–124, 2014.
Azagarsamy, M. A., and K. S. Anseth. Bioorthogonal click chemistry: an indispensable tool to create multifaceted cell culture scaffolds. ACS Macro Lett. 2:5–9, 2013.
Bian, L., M. Guvendiren, R. L. Mauck, and J. A. Burdick. Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proc. Natl. Acad. Sci. USA 110:10117–10122, 2013.
Brennan, A. B., C. M. Kirschner, and Society for Biomaterials. Bio-Inspired Materials for Biomedical Engineering. New York: Wiley, 2014.
Codelli, J. A., J. M. Baskin, N. J. Agard, and C. R. Bertozzi. Second-generation difluorinated cyclooctynes for copper-free click chemistry. J. Am. Chem. Soc. 130:11486–11493, 2008.
Cosgrove, B. D., P. M. Gilbert, E. Porpiglia, F. Mourkioti, S. P. Lee, S. Y. Corbel, et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20:255–264, 2014.
DeForest, C. A., and K. S. Anseth. Cytocompatible click-based hydrogels with dynamically tunable properties through orthogonal photoconjugation and photocleavage reactions. Nat. Chem. 3:925–931, 2011.
DeForest, C. A., and K. S. Anseth. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chem. Int. Edit. 51:1816–1819, 2012.
DeForest, C. A., B. D. Polizzotti, and K. S. Anseth. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat. Mater. 8:659–664, 2009.
DeForest, C. A., E. A. Sims, and K. S. Anseth. Peptide-functionalized click hydrogels with independently tunable mechanics and chemical functionality for 3D cell culture. Chem. Mater. 22:4783–4790, 2010.
DeLong, S. A., J. J. Moon, and J. L. West. Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration. Biomaterials 26:3227–3234, 2005.
Dingal, P. C., and D. E. Discher. Combining insoluble and soluble factors to steer stem cell fate. Nat. Mater. 13:532–537, 2014.
Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006.
Fairbanks, B. D., M. P. Schwartz, A. E. Halevi, C. R. Nuttelman, C. N. Bowman, and K. S. Anseth. A versatile synthetic extracellular matrix mimic via thiol-norbornene photopolymerization. Adv. Mater. 21:5005, 2009.
Faulk, D. M., S. A. Johnson, L. Zhang, and S. F. Badylak. Role of the extracellular matrix in whole organ engineering. J. Cell. Physiol. 229:984–989, 2014.
Gandavarapu, N. R., M. A. Azagarsamy, and K. S. Anseth. Photo-click living strategy for controlled, reversible exchange of biochemical ligands. Adv. Mater. 26:2521–2526, 2014.
Gilbert, P. M., K. L. Havenstrite, K. E. Magnusson, A. Sacco, N. A. Leonardi, P. Kraft, et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329:1078–1081, 2010.
Gould, S. T., N. J. Darling, and 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.
Gupta, N., B. F. Lin, L. M. Campos, M. D. Dimitriou, S. T. Hikita, N. D. Treat, et al. A versatile approach to high-throughput microarrays using thiol-ene chemistry. Nat. Chem. 2:138–145, 2010.
Hern, D. L., and J. A. Hubbell. Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing. J. Biomed. Mater. Res. 39:266–276, 1998.
Hiesinger, W., J. R. Frederick, P. Atluri, R. C. McCormick, N. Marotta, J. R. Muenzer, et al. Spliced stromal cell-derived factor-1 alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction. J. Thorac. Cardiov. Sur. 140:1174–1180, 2010.
Hoyle, C. E., and C. N. Bowman. Thiol-ene click chemistry. Angew. Chem. 49:1540–1573, 2010.
Hubbell, J. A. Biomaterials in tissue engineering. Bio-Technology 13:565–576, 1995.
Hudalla, G. A., T. S. Eng, and W. L. Murphy. An approach to modulate degradation and mesenchymal stem cell behavior in poly(ethylene glycol) networks. Biomacromolecules 9:842–849, 2008.
Humphries, M. J. The molecular-basis and specificity of integrin ligand interactions. J. Cell Sci. 97:585–592, 1990.
Jabbari, E. Bioconjugation of hydrogels for tissue engineering. Curr. Opin. Biotechnol. 22:655–660, 2011.
Karp, G. Cell and Molecular Biology: Concepts and Experiments (3rd ed.). New York: Wiley, 2002.
Kharkar, P. M., K. L. Kiick, and A. M. Kloxin. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem. Soc. Rev. 42:7335–7372, 2013.
Khetan, S., M. Guvendiren, W. R. Legant, D. M. Cohen, C. S. Chen, and J. A. Burdick. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12:458–465, 2013.
Kloxin, A. M., K. J. Lewis, C. A. DeForest, G. Seedorf, M. W. Tibbitt, V. Balasubramaniam, et al. Responsive culture platform to examine the influence of microenvironmental geometry on cell function in 3D. Integr. Biol. 4:1540–1549, 2012.
Kyburz, K. A., and K. S. Anseth. Three-dimensional hMSC motility within peptide-functionalized PEG-based hydrogels of varying adhesivity and crosslinking density. Acta Biomater. 9:6381–6392, 2013.
Lee, S. H., J. J. Moon, J. S. Miller, and J. L. West. Poly(ethylene glycol) hydrogels conjugated with a collagenase-sensitive fluorogenic substrate to visualize collagenase activity during three-dimensional cell migration. Biomaterials 28:3163–3170, 2007.
Legant, W. R., J. S. Miller, B. L. Blakely, D. M. Cohen, G. M. Genin, and C. S. Chen. Measurement of mechanical tractions exerted by cells in three-dimensional matrices. Nat. Methods 7:969–971, 2010.
Leight, J. L., D. L. Alge, A. J. Maier, and K. S. Anseth. Direct measurement of matrix metalloproteinase activity in 3D cellular microenvironments using a fluorogenic peptide substrate. Biomaterials 34:7344–7352, 2013.
Leight, J. L., M. A. Wozniak, S. Chen, M. L. Lynch, and C. S. Chen. Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition. Mol. Biol. Cell 23:781–791, 2012.
Liang, Y. K., and K. L. Kiick. Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications. Acta Biomater. 10:1588–1600, 2014.
Lu, P. F., V. M. Weaver, and Z. Werb. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196:395–406, 2012.
Lutolf, M. P., J. L. Lauer-Fields, H. G. Schmoekel, A. T. Metters, F. E. Weber, G. B. Fields, et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc. Natl. Acad. Sci. USA 100:5413–5418, 2003.
MacArthur, Jr., J. W., B. P. Purcell, Y. Shudo, J. E. Cohen, A. Fairman, A. Trubelja, et al. Sustained release of engineered stromal cell-derived factor 1-alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation 128:S79–S86, 2013.
Madl, C. M., M. Mehta, G. N. Duda, S. C. Heilshorn, and D. J. Mooney. Presentation of BMP-2 mimicking peptides in 3D hydrogels directs cell fate commitment in osteoblasts and mesenchymal stem cells. Biomacromolecules 15:445–455, 2014.
McKinnon, D. D., D. W. Domaille, J. N. Cha, and K. S. Anseth. Bis-aliphatic hydrazone-linked hydrogels form most rapidly at physiological ph: identifying the origin of hydrogel properties with small molecule kinetic studies. Chem. Mater. 26:2382–2387, 2014.
McKinnon, D. D., D. W. Domaille, J. N. Cha, and K. S. Anseth. Biophysically defined and cytocompatible covalently adaptable networks as viscoelastic 3D cell culture systems. Adv. Mater. 26:865–872, 2014.
Moroni, F., and T. Mirabella. Decellularized matrices for cardiovascular tissue engineering. Am. J. Stem Cells 3:1–20, 2014.
Mosiewicz, K. A., L. Kolb, A. J. van der Vlies, M. M. Martino, P. S. Lienemann, J. A. Hubbell, et al. In situ cell manipulation through enzymatic hydrogel photopatterning. Nat. Mater. 12:1072–1078, 2013.
Ott, H. C., T. S. Matthiesen, S. K. Goh, L. D. Black, S. M. Kren, T. I. Netoff, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat. Med. 14:213–221, 2008.
Packard, B. Z., V. V. Artym, A. Komoriya, and K. M. Yamada. Direct visualization of protease activity on cells migrating in three-dimensions. Matrix Biol. 28:3–10, 2009.
Patterson, J., and J. A. Hubbell. Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. Biomaterials 31:7836–7845, 2010.
Perlin, L., S. MacNeil, and S. Rimmer. Production and performance of biomaterials containing RGD peptides. Soft Matter 4:2331–2349, 2008.
Purcell, B. P., D. Lobb, M. B. Charati, S. M. Dorsey, R. J. Wade, K. N. Zellars, et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 13:653–661, 2014.
Rabenstein, D. L. Heparin and heparan sulfate: structure and function. Nat. Prod. Rep. 19:312–331, 2002.
Schultz, K. M., and K. S. Anseth. Monitoring degradation of matrix metalloproteinases-cleavable PEG hydrogels via multiple particle tracking microrheology. Soft Matter 9:1570–1579, 2013.
Schultz, K. M., and E. M. Furst. Microrheology of biomaterial hydrogelators. Soft matter 8:6198–6205, 2012.
Tan, J. L., J. Tien, D. M. Pirone, D. S. Gray, K. Bhadriraju, and C. S. Chen. Cells lying on a bed of microneedles: An approach to isolate mechanical force. Proc. Natl. Acad. Sci. USA 100:1484–1489, 2003.
Tibbitt, M. W., A. M. Kloxin, K. U. Dyamenahalli, and K. S. Anseth. Controlled two-photon photodegradation of PEG hydrogels to study and manipulate subcellular interactions on soft materials. Soft Matter 6:5100–5108, 2010.
Wang, H., M. W. Tibbitt, S. J. Langer, L. A. Leinwand, and K. S. Anseth. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway. Proc. Natl. Acad. Sci. USA 110:19336–19341, 2013.
Watt, F. M., and W. T. S. Huck. Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Bio 14:467–473, 2013.
West, J. L., and J. A. Hubbell. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32(1):241–244, 1999.
Wylie, R. G., S. Ahsan, Y. Aizawa, K. L. Maxwell, C. M. Morshead, and M. S. Shoichet. Spatially controlled simultaneous patterning of multiple growth factors in three-dimensional hydrogels. Nat. Mater. 10:799–806, 2011.
Yang, C., M. W. Tibbitt, L. Basta, and K. S. Anseth. Mechanical memory and dosing influence stem cell fate. Nat. Mater 13:645–652, 2014.
Acknowledgments
The authors would like to especially thank Emily Kyburz for her figure design and illustrations and Sharon Wang for valuable insight and discussion. Funding for this work was provided in part by the Howard Hughes Medical Institute and Grants from the National Institutes of Health (RO1DE016523) and National Science Foundation (CBET 1236662).
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Associate Editor Nadya Lumelsky oversaw the review of this article.
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Kyburz, K.A., Anseth, K.S. Synthetic Mimics of the Extracellular Matrix: How Simple is Complex Enough?. Ann Biomed Eng 43, 489–500 (2015). https://doi.org/10.1007/s10439-015-1297-4
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DOI: https://doi.org/10.1007/s10439-015-1297-4