Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering

Abstract

New generations of synthetic biomaterials are being developed at a rapid pace for use as three-dimensional extracellular microenvironments to mimic the regulatory characteristics of natural extracellular matrices (ECMs) and ECM-bound growth factors, both for therapeutic applications and basic biological studies. Recent advances include nanofibrillar networks formed by self-assembly of small building blocks, artificial ECM networks from protein polymers or peptide-conjugated synthetic polymers that present bioactive ligands and respond to cell-secreted signals to enable proteolytic remodeling. These materials have already found application in differentiating stem cells into neurons, repairing bone and inducing angiogenesis. Although modern synthetic biomaterials represent oversimplified mimics of natural ECMs lacking the essential natural temporal and spatial complexity, a growing symbiosis of materials engineering and cell biology may ultimately result in synthetic materials that contain the necessary signals to recapitulate developmental processes in tissue- and organ-specific differentiation and morphogenesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The behavior of individual cells and the dynamic state of multicellular tissues is regulated by intricate reciprocal molecular interactions between cells and their surroundings.
Figure 2: Design strategies for the creation of synthetic biomolecular materials that mimic the complexity of natural ECMs.
Figure 3: Examples of complex synthetic ECM mimetics proposed in Figure 2.
Figure 4: Morphogenetic steps and underlying regulatory molecules involved in endothelial cell assembly into capillary tube structures, and subsequent stabilization of tubes into mature blood vessels.

References

  1. Peppas, N.A. & Langer, R. New challenges in biomaterials. Science 263, 1715–1720 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Hubbell, J.A. Biomaterials in tissue engineering. Bio/Technology 13, 565–576 (1995).

    CAS  Google Scholar 

  3. Langer, R. & Tirrell, D.A. Designing materials for biology and medicine. Nature 428, 487–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Yang, C. et al. The application of recombinant human collagen in tissue engineering. BioDrugs 18, 103–119 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Griffith, L.G. & Naughton, G. Tissue engineering–current challenges and expanding opportunities. Science 295, 1009–1014 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Chaikof, E.L. et al. Biomaterials and scaffolds in reparative medicine. Ann. N. Y. Acad. Sci. 961, 96–105 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Kleinman, H.K., Philp, D. & Hoffman, M.P. Role of the extracellular matrix in morphogenesis. Curr. Opin. Biotechnol. 14, 526–532 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Friedl, P. & Brèocker, E.B. The biology of cell locomotion within three-dimensional extracellular matrix. Cell. Mol. Life Sci. 57, 41–64 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Cukierman, E., Pankov, R., Stevens, D.R. & Yamada, K.M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Cukierman, E., Pankov, R. & Yamada, K.M. Cell interactions with three-dimensional matrices. Curr. Opin. Cell Biol. 14, 633–639 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Grinnell, F. Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol. 13, 264–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Abbott, A. Cell culture: Biology's new dimension. Nature 424, 870–872 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Schmeichel, K.L. & Bissell, M.J. Modeling tissue-specific signaling and organ function in three dimensions. J. Cell Sci. 116, 2377–2388 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Hubbell, J.A. Materials as morphogenetic guides in tissue engineering. Curr. Opin. Biotechnol. 14, 551–558 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Bell, E., Ehrlich, H.P., Buttle, D.J. & Nakatsuji, T. Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science 211, 1052–1054 (1981).

    Article  CAS  PubMed  Google Scholar 

  16. Yannas, I.V., Lee, E., Orgill, D.P., Skrabut, E.M. & Murphy, G.F. Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc. Natl. Acad. Sci. USA 86, 933–937 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Patino, M.G., Neiders, M.E., Andreana, S., Noble, B. & Cohen, R.E. Collagen as an implantable material in medicine and dentistry. J. Oral Implantol. 28, 220–225 (2002).

    Article  PubMed  Google Scholar 

  18. Currie, L.J., Sharpe, J.R. & Martin, R. The use of fibrin glue in skin grafts and tissue-engineered skin replacements: A review. Plast. Reconstr. Surg. 108, 1713–1726 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Hubbell, J.A. Bioactive biomaterials. Curr. Opin. Biotechnol. 10, 123–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Griffith, L.G. Emerging design principles in biomaterials and scaffolds for tissue engineering. Ann. N. Y. Acad. Sci. 961, 83–95 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Galbraith, C.G. & Sheetz, M.P. Forces on adhesive contacts affect cell function. Curr. Opin. Cell Biol. 10, 566–571 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K.M. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol. 2, 793–805 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Maheshwari, G., Brown, G., Lauffenburger, D.A., Wells, A. & Griffith, L.G. Cell adhesion and motility depend on nanoscale RGD clustering. J. Cell Sci. 113, 1677–1686 (2000).

    CAS  PubMed  Google Scholar 

  24. Friedl, P. Prespecification and plasticity: Shifting mechanisms of cell migration. Curr. Opin. Cell Biol. 16, 14–23 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Oberpenning, F., Meng, J., Yoo, J.J. & Atala, A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat. Biotechnol. 17, 149–155 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Park, K.I., Teng, Y.D. & Snyder, E.Y. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat. Biotechnol. 20, 1111–1117 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Kenawy el, R. et al. Electrospinning of poly(ethylene-co-vinyl alcohol) fibers. Biomaterials 24, 907–913 (2003).

    Article  PubMed  Google Scholar 

  28. Zhang, S. Fabrication of novel biomaterials through molecular self-assembly. Nat. Biotechnol. 21, 1171–1178 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Menger, F.M. Supramolecular chemistry and self-assembly. Proc. Natl. Acad. Sci. USA 99, 4818–4822 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Estroff, L.A. & Hamilton, A.D. Water gelation by small organic molecules. Chem. Rev. 104, 1201–1218 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Holmes, T.C. et al. Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc. Natl. Acad. Sci. USA 97, 6728–6733 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kisiday, J. et al. Self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: Implications for cartilage tissue repair. Proc. Natl. Acad. Sci. USA 99, 9996–10001 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Semino, C.E., Merok, J.R., Crane, G.G., Panagiotakos, G. & Zhang, S. Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. Differentiation 71, 262–270 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Nowak, A.P. et al. Rapidly recovering hydrogel scaffolds from self-assembling diblock copolypeptide amphiphiles. Nature 417, 424–428 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Pakstis, L.M. et al. Effect of chemistry and morphology on the biofunctionality of self-assembling diblock copolypeptide hydrogels. Biomacromolecules 5, 312–318 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Ryadnov, M.G. & Woolfson, D.N. Engineering the morphology of a self-assembling protein fibre. Nat. Mater. 2, 329–332 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Niece, K.L., Hartgerink, J.D., Donners, J.J. & Stupp, S.I. Self-assembly combining two bioactive peptide-amphiphile molecules into nanofibers by electrostatic attraction. J. Am. Chem. Soc. 125, 7146–7147 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Silva, G.A. et al. Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 303, 1352–1355 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Peppas, N.A., Huang, Y., Torres-Lugo, M., Ward, J.H. & Zhang, J. Physicochemical foundations and structural design of hydrogels in medicine and biology. Annu. Rev. Biomed. Eng. 2, 9–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Hoffman, A.S. Hydrogels for biomedical applications. Adv. Drug Deliv. Rev. 54, 3–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Drury, J.L. & Mooney, D.J. Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials 24, 4337–4351 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Hennink, W.E. & van Nostrum, C.F. Novel crosslinking methods to design hydrogels. Adv. Drug Deliv. Rev. 54, 13–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Howe, A., Aplin, A.E., Alahari, S.K. & Juliano, R.L. Integrin signaling and cell growth control. Curr. Opin. Cell Biol. 10, 220–231 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Giancotti, F.G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Ruoslahti, E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12, 697–715 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Hersel, U., Dahmen, C. & Kessler, H. RGD modified polymers: Biomaterials for stimulated cell adhesion and beyond. Biomaterials 24, 4385–4415 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Shin, H., Jo, S. & Mikos, A.G. Biomimetic materials for tissue engineering. Biomaterials 24, 4353–4364 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Massia, S.P. & Hubbell, J.A. An RGD spacing of 440 nm is sufficient for integrin alpha v beta 3-mediated fibroblast spreading and 140 nm for focal contact and stress fiber formation. J. Cell Biol. 114, 1089–1100 (1991).

    Article  CAS  PubMed  Google Scholar 

  49. DiMilla, P.A., Barbee, K. & Lauffenburger, D.A. Mathematical model for the effects of adhesion and mechanics on cell migration speed. Biophys. J. 60, 15–37 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Palecek, S.P., Loftus, J.C., Ginsberg, M.H., Lauffenburger, D.A. & Horwitz, A.F. Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness. Nature 385, 537–540 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Kuntz, R.M. & Saltzman, W.M. Neutrophil motility in extracellular matrix gels: Mesh size and adhesion affect speed of migration. Biophys. J. 72, 1472–1480 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Burgess, B.T., Myles, J.L. & Dickinson, R.B. Quantitative analysis of adhesion-mediated cell migration in three-dimensional gels of RGD-grafted collagen. Ann. Biomed. Eng. 28, 110–118 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Schense, J.C. & Hubbell, J.A. Three-dimensional migration of neurites is mediated by adhesion site density and affinity. J. Biol. Chem. 275, 6813–6818 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Gobin, A.S. & West, J.L. Cell migration through defined, synthetic ECM analogs. FASEB J. 16, 751–753 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Lutolf, M.P. 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  CAS  PubMed  PubMed Central  Google Scholar 

  56. Irvine, D.J., Hue, K.A., Mayes, A.M. & Griffith, L.G. Simulations of cell-surface integrin binding to nanoscale-clustered adhesion ligands. Biophys. J. 82, 120–132 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brandley, B.K. & Schnaar, R.L. Tumor cell haptotaxis on covalently immobilized linear and exponential gradients of a cell adhesion peptide. Dev. Biol. 135, 74–86 (1989).

    Article  CAS  PubMed  Google Scholar 

  58. Maheshwari, G., Wells, A., Griffith, L.G. & Lauffenburger, D.A. Biophysical integration of effects of epidermal growth factor and fibronectin on fibroblast migration. Biophys. J. 76, 2814–2823 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koo, L.Y., Irvine, D.J., Mayes, A.M., Lauffenburger, D.A. & Griffith, L.G. Co-regulation of cell adhesion by nanoscale RGD organization and mechanical stimulus. J. Cell Sci. 115, 1423–1433 (2002).

    CAS  PubMed  Google Scholar 

  60. Ramirez, F. & Rifkin, D.B. Cell signaling events: A view from the matrix. Matrix Biol. 22, 101–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Chen, R.R. & Mooney, D.J. Polymeric growth factor delivery strategies for tissue engineering. Pharm. Res. 20, 1103–1112 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Boontheekul, T. & Mooney, D.J. Protein-based signaling systems in tissue engineering. Curr. Opin. Biotechnol. 14, 559–565 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Zisch, A.H., Lutolf, M.P. & Hubbell, J.A. Biopolymeric delivery matrices for angiogenic growth factors. Cardiovasc. Pathol. 12, 295–310 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Richardson, T.P., Peters, M.C., Ennett, A.B. & Mooney, D.J. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19, 1029–1034 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Zisch, A.H. et al. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth. FASEB J. 17, 2260–2262 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Zisch, A.H., Schenk, U., Schense, J.C., Sakiyama-Elbert, S.E. & Hubbell, J.A. Covalently conjugated VEGF–fibrin matrices for endothelialization. J. Control. Release 72, 101–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Sakiyama-Elbert, S.E., Panitch, A. & Hubbell, J.A. Development of growth factor fusion proteins for cell-triggered drug delivery. FASEB J. 15, 1300–1302 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Basbaum, C.B. & Werb, Z. Focalized proteolysis: Spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr. Opin. Cell Biol. 8, 731–738 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Miyata, T., Uragami, T. & Nakamae, K. Biomolecule-sensitive hydrogels. Adv. Drug Deliv. Rev. 54, 79–98 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Ulbrich, K., Zacharieva, E.I., Obereigner, B. & Kopecek, J. Polymers containing enzymatically degradable bonds v. Hydrophilic polymers degradable by papain. Biomaterials 1, 199–204 (1980).

    Article  CAS  PubMed  Google Scholar 

  71. Halstenberg, S., Panitch, A., Rizzi, S., Hall, H. & Hubbell, J.A. Biologically engineered protein-graft-poly(ethylene glycol) hydrogels: A cell adhesive and plasmin-degradable biosynthetic material for tissue repair. Biomacromolecules 3, 710–723 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Pratt, A.B., Weber, F.E., Schmoekel, H.G., Mèuller, R. & Hubbell, J.A. Synthetic extracellular matrices for in situ tissue engineering. Biotechnol. Bioeng. 86, 27–36 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, S. & Healy, K.E. Synthesis and characterization of injectable poly(n-isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links. Biomacromolecules 4, 1214–1223 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. West, J.L. & Hubbell, J.A. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32, 241–244 (1999).

    Article  CAS  Google Scholar 

  75. Mann, B.K., Gobin, A.S., Tsai, A.T., Schmedlen, R.H. & West, J.L. Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: Synthetic ECM analogs for tissue engineering. Biomaterials 22, 3045–3051 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Stocum, D.L. Stem cells in regenerative biology and medicine. Wound Repair Regen. 9, 429–442 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Stocum, D.L. Regenerative biology and engineering: Strategies for tissue restoration. Wound Repair Regen. 6, 276–290 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Caplan, A.I. & Bruder, S.P. Mesenchymal stem cells: Building blocks for molecular medicine in the 21st century. Trends Mol. Med. 7, 259–264 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Nakashima, M. & Reddi, A.H. The application of bone morphogenetic proteins to dental tissue engineering. Nat. Biotechnol. 21, 1025–1032 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Lutolf, M.P., Raeber, G.P., Zisch, A.H., Tirelli, N. & Hubbell, J.A. Cell-responsive synthetic hydrogels. Advanced Materials 15, 888–892 (2003).

    Article  CAS  Google Scholar 

  81. Wang, C., Stewart, R.J. & Kopecek, J. Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains. Nature 397, 417–420 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. van Hest, J.C. & Tirrell, D.A. Protein-based materials, toward a new level of structural control. Chem Commun (Cams), 1897–1904 (2001).

  83. Urry, D.W. Elastic molecular machines in metabolism and soft-tissue restoration. Trends Biotechnol. 17, 249–257 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Kopecek, J. Smart and genetically engineered biomaterials and drug delivery systems. Eur. J. Pharm. Sci. 20, 1–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, J.C., Heilshorn, S.C. & Tirrell, D.A. Comparative cell response to artificial extracellular matrix proteins containing the RGD and CS5 cell-binding domains. Biomacromolecules 5, 497–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Welsh, E.R. & Tirrell, D.A. Engineering the extracellular matrix: A novel approach to polymeric biomaterials. I. Control of the physical properties of artificial protein matrices designed to support adhesion of vascular endothelial cells. Biomacromolecules 1, 23–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Urry, D.W. et al. Elastic protein-based polymers in soft tissue augmentation and generation. J. Biomater. Sci. Polym. Ed. 9, 1015–1048 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Petka, W.A., Harden, J.L., McGrath, K.P., Wirtz, D. & Tirrell, D.A. Reversible hydrogels from self-assembling artificial proteins. Science 281, 389–392 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Sternlicht, M.D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ridley, A.J. et al. Cell migration: Integrating signals from front to back. Science 302, 1704–1709 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Wolf, K. et al. Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160, 267–277 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Behravesh, E. & Mikos, A.G. Three-dimensional culture of differentiating marrow stromal osteoblasts in biomimetic poly(propylene fumarate-co-ethylene glycol)-based macroporous hydrogels. J. Biomed. Mater. Res. 66A, 698–706 (2003).

    Article  CAS  Google Scholar 

  93. Weissman, I.L. Translating stem and progenitor cell biology to the clinic: Barriers and opportunities. Science 287, 1442–1446 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Snyder, E.Y., Daley, G.Q. & Goodell, M. Taking stock and planning for the next decade: Realistic prospects for stem cell therapies for the nervous system. J. Neurosci. Res. 76, 157–168 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Watt, F.M. & Hogan, B.L. Out of eden: Stem cells and their niches. Science 287, 1427–1430 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: Stem cells and their niche. Cell 116, 769–778 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Lin, H. The stem-cell niche theory: Lessons from flies. Nat. Rev. Genet. 3, 931–940 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Mahoney, M.J. & Saltzman, W.M. Transplantation of brain cells assembled around a programmable synthetic microenvironment. Nat. Biotechnol. 19, 934–939 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, C.Y., Apuzzo, M.L. & Tirrell, D.A. Engineering of the extracellular matrix: Working toward neural stem cell programming and neurorestoration–concept and progress report. Neurosurgery 52, 1154–1165; discussion 1165–1157 (2003).

    PubMed  Google Scholar 

  100. Liu, C.Y. et al. Artificial niches for human adult neural stem cells: Possibility for autologous transplantation therapy. J. Hematother. Stem Cell Res. 12, 689–699 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Levenberg, S. et al. Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl. Acad. Sci. USA 100, 12741–12746 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Brocchini, S., James, K., Tangpasuthadol, V. & Kohn, J. A combinatorial approach for polymer design. J. Am. Chem. Soc. 119, 4553–4554 (1997).

    Article  CAS  Google Scholar 

  103. Smith, J.R. et al. Integration of combinatorial synthesis, rapid screening, and computational modeling in biomaterials development. Macromol. Rapid Commun. 25, 127–140 (2004).

    Article  CAS  Google Scholar 

  104. Anderson, D.G., Levenberg, S. & Langer, R. Rapid, nanoliter-scale synthesis and screening of arrayed biomaterials: Applications to human embryonic stem cells. Nat. Biotechnol. 22, 863–866 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Kiyonaka, S. et al. Semi-wet peptide/protein array using supramolecular hydrogel. Nat. Mater. 3, 58–64 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Lutolf, M.P. et al. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nat. Biotechnol. 21, 513–518 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Ennett, A.B. & Mooney, D.J. Tissue engineering strategies for in vivo neovascularisation. Expert Opin. Biol. Ther. 2, 805–818 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Carmeliet, P. Manipulating angiogenesis in medicine. J. Intern. Med. 255, 538–561 (2004).

    Article  PubMed  Google Scholar 

  109. Davis, G.E., Bayless, K.J. & Mavila, A. Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat. Rec. 268, 252–275 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Ehrbar, M. et al. Cell-demanded liberation of VEGF121 from fibrin implants induces local and controlled blood vessel growth. Circ. Res. 94, 1124–1132 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Ozawa, C.R. et al. Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J. Clin. Invest. 113, 516–527 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bottaro, D.P., Liebmann-Vinson, A. & Heidaran, M.A. Molecular signaling in bioengineered tissue microenvironments. Ann. NY Acad. Sci. 961, 143–153 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to our collaborators in angiogenesis, including V. Djornov, M. Ehrbar, H. Hall and A. Zisch, in bone regeneration, including J. Schense, H. Schmökel, F. Weber, and cell-matrix biomechanics, including G. Raeber. We thank P. Raeber for excellent work on illustrations. We apologize to all the scientists whose work we could not cite due to space restrictions.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to M P Lutolf or J A Hubbell.

Ethics declarations

Competing interests

Some of the materials referenced in this work are the subject of patents and patent applications by the authors. J.A.H. holds equity in the company that has licensed these applications.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lutolf, M., Hubbell, J. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 23, 47–55 (2005). https://doi.org/10.1038/nbt1055

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1055

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing