Skip to main content
Log in

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

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Brennan, A. B., C. M. Kirschner, and Society for Biomaterials. Bio-Inspired Materials for Biomedical Engineering. New York: Wiley, 2014.

    Book  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. DeForest, C. A., and K. S. Anseth. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chem. Int. Edit. 51:1816–1819, 2012.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  12. Dingal, P. C., and D. E. Discher. Combining insoluble and soluble factors to steer stem cell fate. Nat. Mater. 13:532–537, 2014.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  22. Hoyle, C. E., and C. N. Bowman. Thiol-ene click chemistry. Angew. Chem. 49:1540–1573, 2010.

    Article  CAS  Google Scholar 

  23. Hubbell, J. A. Biomaterials in tissue engineering. Bio-Technology 13:565–576, 1995.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  25. Humphries, M. J. The molecular-basis and specificity of integrin ligand interactions. J. Cell Sci. 97:585–592, 1990.

    CAS  PubMed  Google Scholar 

  26. Jabbari, E. Bioconjugation of hydrogels for tissue engineering. Curr. Opin. Biotechnol. 22:655–660, 2011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Karp, G. Cell and Molecular Biology: Concepts and Experiments (3rd ed.). New York: Wiley, 2002.

    Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  43. Moroni, F., and T. Mirabella. Decellularized matrices for cardiovascular tissue engineering. Am. J. Stem Cells 3:1–20, 2014.

    PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  48. Perlin, L., S. MacNeil, and S. Rimmer. Production and performance of biomaterials containing RGD peptides. Soft Matter 4:2331–2349, 2008.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Rabenstein, D. L. Heparin and heparan sulfate: structure and function. Nat. Prod. Rep. 19:312–331, 2002.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  52. Schultz, K. M., and E. M. Furst. Microrheology of biomaterial hydrogelators. Soft matter 8:6198–6205, 2012.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kristi S. Anseth.

Additional information

Associate Editor Nadya Lumelsky oversaw the review of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-015-1297-4

Keywords

Navigation