Annals of Biomedical Engineering

, Volume 43, Issue 3, pp 489–500 | Cite as

Synthetic Mimics of the Extracellular Matrix: How Simple is Complex Enough?

  • Kyle A. Kyburz
  • Kristi S. Anseth


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.


Hydrogels Extracellular matrix Three-dimensional culture Peptides 



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).


  1. 1.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Brennan, A. B., C. M. Kirschner, and Society for Biomaterials. Bio-Inspired Materials for Biomedical Engineering. New York: Wiley, 2014.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    DeForest, C. A., and K. S. Anseth. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chem. Int. Edit. 51:1816–1819, 2012.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    Dingal, P. C., and D. E. Discher. Combining insoluble and soluble factors to steer stem cell fate. Nat. Mater. 13:532–537, 2014.CrossRefPubMedGoogle Scholar
  13. 13.
    Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    Hoyle, C. E., and C. N. Bowman. Thiol-ene click chemistry. Angew. Chem. 49:1540–1573, 2010.CrossRefGoogle Scholar
  23. 23.
    Hubbell, J. A. Biomaterials in tissue engineering. Bio-Technology 13:565–576, 1995.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Humphries, M. J. The molecular-basis and specificity of integrin ligand interactions. J. Cell Sci. 97:585–592, 1990.PubMedGoogle Scholar
  26. 26.
    Jabbari, E. Bioconjugation of hydrogels for tissue engineering. Curr. Opin. Biotechnol. 22:655–660, 2011.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Karp, G. Cell and Molecular Biology: Concepts and Experiments (3rd ed.). New York: Wiley, 2002.Google Scholar
  28. 28.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Liang, Y. K., and K. L. Kiick. Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications. Acta Biomater. 10:1588–1600, 2014.CrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    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.CrossRefGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    Moroni, F., and T. Mirabella. Decellularized matrices for cardiovascular tissue engineering. Am. J. Stem Cells 3:1–20, 2014.PubMedCentralPubMedGoogle Scholar
  44. 44.
    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.CrossRefPubMedGoogle Scholar
  45. 45.
    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.CrossRefPubMedGoogle Scholar
  46. 46.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    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.CrossRefPubMedGoogle Scholar
  48. 48.
    Perlin, L., S. MacNeil, and S. Rimmer. Production and performance of biomaterials containing RGD peptides. Soft Matter 4:2331–2349, 2008.CrossRefGoogle Scholar
  49. 49.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Rabenstein, D. L. Heparin and heparan sulfate: structure and function. Nat. Prod. Rep. 19:312–331, 2002.CrossRefPubMedGoogle Scholar
  51. 51.
    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.CrossRefGoogle Scholar
  52. 52.
    Schultz, K. M., and E. M. Furst. Microrheology of biomaterial hydrogelators. Soft matter 8:6198–6205, 2012.CrossRefGoogle Scholar
  53. 53.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    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.CrossRefGoogle Scholar
  57. 57.
    West, J. L., and J. A. Hubbell. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32(1):241–244, 1999.CrossRefGoogle Scholar
  58. 58.
    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.CrossRefPubMedGoogle Scholar
  59. 59.
    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.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  1. 1.Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderUSA
  2. 2.The BioFrontiers InstituteUniversity of ColoradoBoulderUSA
  3. 3.The Howard Hughes Medical InstituteUniversity of ColoradoBoulderUSA

Personalised recommendations