Annals of Biomedical Engineering

, Volume 42, Issue 7, pp 1413–1423 | Cite as

Microstructured Extracellular Matrices in Tissue Engineering and Development: An Update

  • Joe Tien
  • Celeste M. Nelson


Microstructured extracellular matrix (ECM), which contains heterogeneous features of the same size scale (5–100 μm) as tissue organoids, has become an important material for the engineering of functional tissues and for the study of tissue-level biology. This review describes methods to generate this class of ECM, and highlights recent advances in the application of microstructured ECM to problems in basic and applied biology. It also discusses computational techniques to analyze and optimize the microstructural patterns for a desired functional output.


Biomimicry Bio-inspired design Micropatterning Soft lithography Multi-scale biomaterials 


  1. 1.
    Affolter, M., S. Bellusci, N. Itoh, B. Shilo, J.-P. Thiery, and Z. Werb. Tube or not tube: remodeling epithelial tissues by branching morphogenesis. Dev. Cell 4:11–18, 2003.PubMedCrossRefGoogle Scholar
  2. 2.
    Barocas, V. H., A. G. Moon, and R. T. Tranquillo. The fibroblast-populated collagen microsphere assay of cell traction force—part 2: measurement of the cell traction parameter. J. Biomech. Eng. 117:161–170, 1995.PubMedCrossRefGoogle Scholar
  3. 3.
    Bellamkonda, R. V. Peripheral nerve regeneration: an opinion on channels, scaffolds and anisotropy. Biomaterials 27:3515–3518, 2006.PubMedGoogle Scholar
  4. 4.
    Bettinger, C. J., K. M. Cyr, A. Matsumoto, R. Langer, J. T. Borenstein, and D. L. Kaplan. Silk fibroin microfluidic devices. Adv. Mater. 19:2847–2850, 2007.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Cabodi, M., N. W. Choi, J. P. Gleghorn, C. S. Lee, L. J. Bonassar, and A. D. Stroock. A microfluidic biomaterial. J. Am. Chem. Soc. 127:13788–13789, 2005.PubMedCrossRefGoogle Scholar
  6. 6.
    Choi, N. W., M. Cabodi, B. Held, J. P. Gleghorn, L. J. Bonassar, and A. D. Stroock. Microfluidic scaffolds for tissue engineering. Nat. Mater. 6:908–915, 2007.PubMedCrossRefGoogle Scholar
  7. 7.
    Chrobak, K. M., D. R. Potter, and J. Tien. Formation of perfused, functional microvascular tubes in vitro. Microvasc. Res. 71:185–196, 2006.PubMedCrossRefGoogle Scholar
  8. 8.
    Cui, X., and T. Boland. Human microvasculature fabrication using thermal inkjet printing technology. Biomaterials 30:6221–6227, 2009.PubMedCrossRefGoogle Scholar
  9. 9.
    Du, Y., E. Lo, S. Ali, and A. Khademhosseini. Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs. Proc. Natl. Acad. Sci. U.S.A. 105:9522–9527, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Engelmayr, Jr., G. C., M. Cheng, C. J. Bettinger, J. T. Borenstein, R. Langer, and L. E. Freed. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat. Mater. 7:1003–1010, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Gjorevski, N., and C. M. Nelson. Endogenous patterns of mechanical stress are required for branching morphogenesis. Integr. Biol. 2:424–434, 2010.CrossRefGoogle Scholar
  12. 12.
    Gjorevski, N., and C. M. Nelson. Mapping of mechanical strains and stresses around quiescent engineered three-dimensional epithelial tissues. Biophys. J. 103:152–162, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Golden, A. P., and J. Tien. Fabrication of microfluidic hydrogels using molded gelatin as a sacrificial element. Lab Chip 7:720–725, 2007.PubMedCrossRefGoogle Scholar
  14. 14.
    Guo, C.-L., M. Ouyang, J.-Y. Yu, J. Maslov, A. Price, and C.-Y. Shen. Long-range mechanical force enables self-assembly of epithelial tubular patterns. Proc. Natl. Acad. Sci. U.S.A. 109:5576–5582, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Guo, L., and J. J. Pribaz. Clinical flap prefabrication. Plast. Reconstr. Surg. 124:340e–350e, 2009.CrossRefGoogle Scholar
  16. 16.
    Hahn, M. S., J. S. Miller, and J. L. West. Three-dimensional biochemical and biomechanical patterning of hydrogels for guiding cell behavior. Adv. Mater. 18:2679–2684, 2006.CrossRefGoogle Scholar
  17. 17.
    Hay, E. D. Collagen and other matrix glycoproteins in embryogenesis. In: Cell Biology of Extracellular Matrix, edited by E. D. Hay. New York: Plenum Press, 1991, pp. 419–462.CrossRefGoogle Scholar
  18. 18.
    Ilina, O., G.-J. Bakker, A. Vasaturo, R. M. Hofmann, and P. Friedl. Two-photon laser-generated microtracks in 3D collagen lattices: principles of MMP-dependent and -independent collective cancer cell invasion. Phys. Biol. 8:015010, 2011.PubMedCrossRefGoogle Scholar
  19. 19.
    Khademhosseini, A., R. Langer, J. Borenstein, and J. P. Vacanti. Microscale technologies for tissue engineering and biology. Proc. Natl. Acad. Sci. U.S.A. 103:2480–2487, 2006.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Kloxin, A. M., A. M. Kasko, C. N. Salinas, and K. S. Anseth. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324:59–63, 2009.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Koh, W.-G., A. Revzin, and M. V. Pishko. Poly(ethylene glycol) hydrogel microstructures encapsulating living cells. Langmuir 18:2459–2462, 2002.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee, K., N. Gjorevski, E. Boghaert, D. C. Radisky, and C. M. Nelson. Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis. EMBO J. 30:2662–2674, 2011.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ling, Y., J. Rubin, Y. Deng, C. Huang, U. Demirci, J. M. Karp, and A. Khademhosseini. A cell-laden microfluidic hydrogel. Lab Chip 7:756–762, 2007.PubMedCrossRefGoogle Scholar
  24. 24.
    Mak, A. F. Unconfined compression of hydrated viscoelastic tissues: a biphasic poroviscoelastic analysis. Biorheology 23:371–383, 1986.PubMedGoogle Scholar
  25. 25.
    Miller, J. S., K. R. Stevens, M. T. Yang, B. M. Baker, D.-H. T. Nguyen, D. M. Cohen, E. Toro, A. A. Chen, P. A. Galie, X. Yu, R. Chaturvedi, S. N. Bhatia, and C. S. Chen. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11:768–774, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Mow, V. C., S. C. Kuei, W. M. Lai, and C. G. Armstrong. Biphasic creep and stress relaxation of articular cartilage in compression: theory and experiments. J. Biomech. Eng. 102:73–84, 1980.PubMedCrossRefGoogle Scholar
  27. 27.
    Nelson, C. M., and M. J. Bissell. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22:287–309, 2006.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Nelson, C. M., J. L. Inman, and M. J. Bissell. Three-dimensional lithographically defined organotypic tissue arrays for quantitative analysis of morphogenesis and neoplastic progression. Nat. Protoc. 3:674–678, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Nelson, C. M., and J. Tien. Microstructured extracellular matrices in tissue engineering and development. Curr. Opin. Biotechnol. 17:518–523, 2006.PubMedCrossRefGoogle Scholar
  30. 30.
    Nelson, C. M., M. M. VanDuijn, J. L. Inman, D. A. Fletcher, and M. J. Bissell. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 314:298–300, 2006.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Nguyen, D.-H. T., S. C. Stapleton, M. T. Yang, S. S. Cha, C. K. Choi, P. A. Galie, and C. S. Chen. Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc. Natl. Acad. Sci. U.S.A. 110:6712–6717, 2013.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Nichol, J. W., S. T. Koshy, H. Bae, C. M. Hwang, S. Yamanlar, and A. Khademhosseini. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 31:5536–5544, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ott, H. C., B. Clippinger, C. Conrad, C. Schuetz, I. Pomerantseva, L. Ikonomou, D. Kotton, and J. P. Vacanti. Regeneration and orthotopic transplantation of a bioartificial lung. Nat. Med. 16:927–933, 2010.PubMedCrossRefGoogle Scholar
  34. 34.
    Ott, H. C., T. S. Matthiesen, S.-K. Goh, L. D. Black, S. M. Kren, T. I. Netoff, and D. A. Taylor. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat. Med. 14:213–221, 2008.PubMedCrossRefGoogle Scholar
  35. 35.
    Pavlovich, A. L., E. Boghaert, and C. M. Nelson. Mammary branch initiation and extension are inhibited by separate pathways downstream of TGFβ in culture. Exp. Cell Res. 317:1872–1884, 2011.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Petersen, T. H., E. A. Calle, L. Zhao, E. J. Lee, L. Gui, M. B. Raredon, K. Gavrilov, T. Yi, Z. W. Zhuang, C. Breuer, E. Herzog, and L. E. Niklason. Tissue-engineered lungs for in vivo implantation. Science 329:538–541, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Polacheck, W. J., R. Li, S. G. M. Uzel, and R. D. Kamm. Microfluidic platforms for mechanobiology. Lab Chip 13:2252–2267, 2013.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Price, G. M., K. K. Chu, J. G. Truslow, M. D. Tang-Schomer, A. P. Golden, J. Mertz, and J. Tien. Bonding of macromolecular hydrogels using perturbants. J. Am. Chem. Soc. 130:6664–6665, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Price, G. M., K. H. K. Wong, J. G. Truslow, A. D. Leung, C. Acharya, and J. Tien. Effect of mechanical factors on the function of engineered human blood microvessels in microfluidic collagen gels. Biomaterials 31:6182–6189, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Reiffel, A. J., P. W. Henderson, D. D. Krijgh, D. A. Belkin, Y. Zheng, L. J. Bonassar, A. D. Stroock, and J. A. Spector. Mathematical modeling and frequency gradient analysis of cellular and vascular invasion into Integra and Strattice: toward optimal design of tissue regeneration scaffolds. Plast. Reconstr. Surg. 129:89–99, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Schumacher, K. M., S. C. Phua, A. Schumacher, and J. Y. Ying. Controlled formation of biological tubule systems in extracellular matrix gels in vitro. Kidney Int. 73:1187–1192, 2008.PubMedCrossRefGoogle Scholar
  42. 42.
    Simian, M., Y. Hirai, M. Navre, Z. Werb, A. Lochter, and M. J. Bissell. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development 128:3117–3131, 2001.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Song, J. J., J. P. Guyette, S. E. Gilpin, G. Gonzalez, J. P. Vacanti, and H. C. Ott. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat. Med. 19:646–651, 2013.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Sung, J. H., J. Yu, D. Luo, M. L. Shuler, and J. C. March. Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. Lab Chip 11:389–392, 2011.PubMedCrossRefGoogle Scholar
  45. 45.
    Tang, M. D., A. P. Golden, and J. Tien. Molding of three-dimensional microstructures of gels. J. Am. Chem. Soc. 125:12988–12989, 2003.PubMedCrossRefGoogle Scholar
  46. 46.
    Tang, M. D., A. P. Golden, and J. Tien. Fabrication of collagen gels that contain patterned, micrometer-scale cavities. Adv. Mater. 16:1345–1348, 2004.CrossRefGoogle Scholar
  47. 47.
    Tien, J., J. G. Truslow, and C. M. Nelson. Modulation of invasive phenotype by interstitial pressure-driven convection in aggregates of human breast cancer cells. PLoS ONE 7:e45191, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Truslow, J. G., G. M. Price, and J. Tien. Computational design of drainage systems for vascularized scaffolds. Biomaterials 30:4435–4443, 2009.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Truslow, J. G., and J. Tien. Perfusion systems that minimize vascular volume fraction in engineered tissues. Biomicrofluidics 5:022201, 2011.PubMedCentralCrossRefGoogle Scholar
  50. 50.
    Uygun, B. E., A. Soto-Gutierrez, H. Yagi, M.-L. Izamis, M. A. Guzzardi, C. Shulman, J. Milwid, N. Kobayashi, A. Tilles, F. Berthiaume, M. Hertl, Y. Nahmias, M. L. Yarmush, and K. Uygun. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat. Med. 16:814–820, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Vernon, R. B., M. D. Gooden, S. L. Lara, and T. N. Wight. Native fibrillar collagen membranes of micron-scale and submicron thicknesses for cell support and perfusion. Biomaterials 26:1109–1117, 2005.PubMedCrossRefGoogle Scholar
  52. 52.
    Vracko, R., and E. P. Benditt. Basal lamina: the scaffold for orderly cell replacement. Observations on regeneration of injured skeletal muscle fibers and capillaries. J. Cell Biol. 55:406–419, 1972.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Wang, H. F. Theory of Linear Poroelasticity with Applications to Geomechanics and Hydrogeology. Princeton, NJ: Princeton University Press, 2000, 287 pp.Google Scholar
  54. 54.
    Wong, K. H. K., J. M. Chan, R. D. Kamm, and J. Tien. Microfluidic models of vascular functions. Annu. Rev. Biomed. Eng. 14:205–230, 2012.PubMedCrossRefGoogle Scholar
  55. 55.
    Wong, K. H. K., J. G. Truslow, A. H. Khankhel, K. L. S. Chan, and J. Tien. Artificial lymphatic drainage systems for vascularized microfluidic scaffolds. J. Biomed. Mater. Res. A 101:2181–2190, 2013.PubMedCrossRefGoogle Scholar
  56. 56.
    Wong, K. H. K., J. G. Truslow, and J. Tien. The role of cyclic AMP in normalizing the function of engineered human blood microvessels in microfluidic collagen gels. Biomaterials 31:4706–4714, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Zheng, Y., J. Chen, M. Craven, N. W. Choi, S. Totorica, A. Diaz-Santana, P. Kermani, B. Hempstead, C. Fischbach-Teschl, J. A. López, and A. D. Stroock. In vitro microvessels for the study of angiogenesis and thrombosis. Proc. Natl. Acad. Sci. U.S.A. 109:9342–9347, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Zheng, Y., P. W. Henderson, N. W. Choi, L. J. Bonassar, J. A. Spector, and A. D. Stroock. Microstructured templates for directed growth and vascularization of soft tissue in vivo. Biomaterials 32:5391–5401, 2011.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringBoston UniversityBostonUSA
  2. 2.Division of Materials Science and EngineeringBoston UniversityBrooklineUSA
  3. 3.Department of Chemical and Biological EngineeringPrinceton UniversityPrincetonUSA
  4. 4.Department of Molecular BiologyPrinceton UniversityPrincetonUSA

Personalised recommendations