Skip to main content
SpringerLink
Log in

Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine

  • Technical Feature
  • Published:
MRS Bulletin Aims and scope Submit manuscript

Abstract

One of the major challenges in the field of regenerative medicine is how to optimize tissue regeneration in the body by therapeutically manipulating its natural ability to form scar at the time of injury or disease. It is often the balance between tissue regeneration, a process that is activated at the onset of disease, and scar formation, which develops as a result of the disease process that determines the ability of the tissue or organ to be functional. Using biomaterials as scaffolds often can provide a “bridge” for normal tissue edges to regenerate over small distances, usually up to 1 cm. Larger tissue defect gaps typically require both scaffolds and cells for normal tissue regeneration to occur without scar formation. Various strategies can help to modulate the scar response and can potentially enhance tissue regeneration. Understanding the mechanistic basis of such multivariate interactions as the scar microenvironment, the immune system, extracellular matrix, and inflammatory cytokines may enable the design of tissue engineering and wound healing strategies that directly modulate the healing response in a manner favorable to regeneration.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. W.K. Stadelmann, A.G. Digenis, G.R. Tobin, Am. J. Surg. 176, 26S (1998).

    Google Scholar 

  2. J.V. Quinn, Tissue Adhesives in Wound Care. (B.C. Decker, Hamilton, Ontario, 1998).

    Google Scholar 

  3. K.S. Midwood, L.V. Williams, J.E. Schwarzbauer, Int. J. Biochem. Cell Biol. 36, 1031 (2004).

    Google Scholar 

  4. H.Y. Chang, J.B. Sneddon, A.A. Alizadeh, R. Sood, R.B. West, K. Montgomery, J.T. Chi, M. van de Rijn, D. Botstein, P.O. Brown, PLoS Biol. 2, E7 (2004).

    Google Scholar 

  5. H.G. Garg, M. Longaker, Scarless Wound Healing (Marcel Dekker, New York, 2000).

    Google Scholar 

  6. R.P. Dorin, H.G. Pohl, R.E. De Filippo, J.J. Yoo, A. Atala, World J. Urol. 26, 323 (2008).

    Google Scholar 

  7. J.J. Yoo, J. Meng, F. Oberpenning, A. Atala, Urology 51, 221 (1998).

    Google Scholar 

  8. F. Oberpenning, J. Meng, J.J. Yoo, A. Atala, Nat. Biotechnol. 17, 149 (1999).

    Google Scholar 

  9. R.E. De Filippo, C.E. Bishop, L.F. Filho, J.J. Yoo, A. Atala, Transplantation 86, 208 (2008).

    Google Scholar 

  10. D.J. Lee, J. Steen, J.E. Jordan, E.H. Kincaid, N.D. Kon, A. Atala, J. Berry, J.J. Yoo, Tissue Eng. Part A 15, 807 (2009).

    Google Scholar 

  11. K.L. Chen, D. Eberli, J.J. Yoo, A. Atala, Proc. Natl. Acad. Sci. U.S.A. 107, 3346 (2010).

    Google Scholar 

  12. A. Joraku, C.A. Sullivan, J. Yoo, A. Atala, Differentiation 75, 318 (2007).

    Google Scholar 

  13. J. Stitzel, J. Liu, S.J. Lee, M. Komura, J. Berrya, S. Sokerc, G. Limc, M.V. Dykec, C. Richard, J.Y. James, Biomater. 27, 1088 (2006).

    Google Scholar 

  14. B.S. Kim, J.J. Yoo, A. Atala, J. Biomed. Mater. Res. Part A 68, 201 (2004).

    Google Scholar 

  15. R. Medzhitov, Nat. 454, 428 (2008).

    Google Scholar 

  16. M.E. Bianchi, J. Leukocyte Biol. 81, 1 (2007).

    Google Scholar 

  17. J.M. Anderson, A. Rodriguez, D.T. Chang, Semin. Immunol. 20, 86 (2008).

    Google Scholar 

  18. J.E. Babensee, Semin. Immunol. 20, 101 (2008).

    Google Scholar 

  19. S.F. Badylak, T.W. Gilbert, Semin. Immunol. 20, 109 (2008).

    Google Scholar 

  20. J.A. Jones, D.T. Chang, H. Meyerson, E. Colton, K. Kwon, T. Matsuda, M.M. Anderson, J. Biomed. Mater. Res. Part A 83, 585 (2007).

    Google Scholar 

  21. G. Guarda, C. Dostert, F. Staehli, K. Cabalzar, R. Castillo, A. Tardivel, P. Schneider, J. Tschopp, Nat. 460, 269 (2009).

    Google Scholar 

  22. C.N. Serhan, J. Savill, Nat. Immunol. 6, 1191 (2005).

    Google Scholar 

  23. S. Sozzani, M. Rusnati, E. Riboldi, S. Mitola, M. Presta, Trends Immunol. 28, 385 (2007).

    Google Scholar 

  24. R. Mirza, L.A. DiPietro, T.J. Koh, Am. J. Pathol. 175, 2454 (2009).

    Google Scholar 

  25. A.S. Chung, H. Waldeck, D.R. Schmidt, W.J. Kao, J. Biomed. Mater. Res. Part A 91, 742 (2009).

    Google Scholar 

  26. P. Batten, P. Sarathchandra, J.W. Antoniw, S.S. Tay, M.W. Lowdell, P.M. Taylor, M.H. Yacoub, Tissue Eng. 12, 2263 (2006).

    Google Scholar 

  27. M.C. Walsh, N. Kim, Y. Kadono, J. Rho, S.Y. Lee, J. Lorenzo, Y. Choi, Annu. Rev. Immunol. 24, 33 (2006).

    Google Scholar 

  28. V.M. Paralkar, F. Borovecki, H.Z. Ke, K.O. Cameron, B. Lefker, W.A. Grasser, T.A. Owen, M. Li, P. DaSilva-Jardine, M. Zhou, R.L. Dunn, F. Dumount, R. Korsmeyer, P. Krasney, T.A. Brown, D. Plowchalk, S. Vukicevic, D.D. Thompson, Proc. Natl. Acad. Sci. U.S.A. 100, 6736 (2003).

    Google Scholar 

  29. L.C. Gerstenfeld, T.-J. Cho, T. Kon, T. Aizawa, A. Tsay, J. Fitch, G.L. Barnes, D.T. Graves, T.A. Einhorn, J. Bone Miner. Res. 18, 1584 (2003).

    Google Scholar 

  30. Y. Yin, M.T. Henzl, B. Lorber, T. Nakazawa, T.T. Thomas, F. Jiang, R. Langer, L.I. Benowitz, Nat. Neurosci. 9, 843 (2006).

    Google Scholar 

  31. X. Lu, P.M. Richardson, J. Neurosci. 11, 972 (1991).

    Google Scholar 

  32. S.J. Greco, P. Rameshwar, J. Immunol. 179, 3342 (2007).

    Google Scholar 

  33. G.K. Michalopoulos, M.C. DeFrances, Science 276, 60 (1997).

    Google Scholar 

  34. J.A. Andrades, M.E. Nimni, J. Becerra, R. Eisenstein, M. Davis, N. Sorgente, Exp. Cell Res. 227, 208 (1996).

    Google Scholar 

  35. K. Del Rio-Tsonis, P.A. Tsonis, I.K. Zarkadis, A.G. Tsagas, J.D. Lambris, J. Immunol. 161, 6819 (1998).

    Google Scholar 

  36. D. Mastellos, J.C. Papadimitriou, S. Franchini, P.A. Tsonis, J.D. Lambris, J. Immunol. 166, 2479 (2001).

    Google Scholar 

  37. G. Chan, D.J. Mooney, Trends Biotechnol. 26, 382 (2008).

    Google Scholar 

  38. N.L. Lumelsky, Tissue Eng. 13, 1393 (2007).

    Google Scholar 

  39. P.M. Mountziaris, A.G. Mikos, Tissue Eng. Part B Rev. (Apr 30, 2008).

  40. M. Harty, A.W. Neff, M.W. King, A.L. Mescher, Dev. Dyn. 226, 268 (2003).

    Google Scholar 

  41. T.P. Richardson, M.C. Peters, A.B. Ennett, D.J. Mooney, Nat. Biotechnol. 19, 1029 (2001).

    Google Scholar 

  42. A.H. Zisch, M.P. Lutolf, M. Ehrbar, G.P. Raeber, S.C. Rizzi, N. Davies, H. Schmökel, D. Bezuidenhout, V. Djonov, P. Zilla, J.A. Hubbell, FASEB J. 17, 2260 (2003).

    Google Scholar 

  43. M.P. Lutolf, J.A. Hubbell, Nat. Biotechnol. 23, 47 (2005).

    Google Scholar 

  44. D. Lauffenburger, B. Farrell, R. Tranquillo, A. Kistler, S. Zigmond, J. Cell Sci. 88 (Pt 4), 415 (1987).

    Google Scholar 

  45. S.H. Zigmond, J. Cell. Biol. 75, 606 (1977).

    Google Scholar 

  46. T. Kumamoto, E.K. Huang, H.J. Paek, A. Morita, H. Matsue, R.F. Valentini, A. Takashima, Nat. Biotechnol. 20, 64 (2002).

    Google Scholar 

  47. X. Zhao, S. Jain, H. Benjamin Larman, S. Gonzalez, D.J. Irvine, Biomater. 26, 5048 (2005).

    Google Scholar 

  48. A.N. Stachowiak, D.J. Irvine, J. Biomed. Mater. Res. Part A 85, 815 (2008).

    Google Scholar 

  49. O.A. Ali, N. Huebsch, L. Cao, G. Dranoff, D.J. Mooney, Nat. Mater. 8, 151 (2009).

    Google Scholar 

  50. A. Singh, S. Suri, K. Roy, Biomater. 30, 5187 (2009).

    Google Scholar 

  51. M.C. Poznansky, I.T. Olszak, R. Foxall, R.H. Evans, A.D. Luster, D.T. Scadden, Nat. Med. 6, 543 (2000).

    Google Scholar 

  52. M.C. Poznansky, I.T. Olszak, R.H. Evans, Z. Wang, R.B. Foxall, D.P. Olson, K. Weibrecht, A.D. Luster, D.T. Scadden, J. Clin. Invest. 109, 1101 (2002).

    Google Scholar 

  53. W.G. Tharp, R. Yadav, D. Irimia, A. Upadhyaya, A. Samadani, O. Hurtado, S.-Y. Liu, S. Munisamy, D.M. Brainard, M.J. Mahon, S. Nourshargh, A. van Oudenaarden, M.G. Toner, M.C. Poznansky. J. Leukocyte Biol. 79, 539 (2006).

    Google Scholar 

  54. K.W. Christopherson, 2nd, J.J. Campbell, J.B. Travers, R.A. Hromas, J. Pharmacol. Exp. Ther. 302, 290 (2002).

    Google Scholar 

  55. M. Perretti, C.P. Page, Gut 47, 14 (2000).

    Google Scholar 

  56. D.D. Patel, W. Koopmann, T. Imai, L.P. Whichard, O. Yoshie, M.S. Krangel, Clin. Immunol. 99, 43 (2001).

    Google Scholar 

  57. A.E. Proudfoot, T.M. Handel, Z. Johnson, E.K. Lau, P.L. Wang, I. Clark-Lewis, F. Borlat, T.N.C. Wells, M.H. Kosco-Vilbois, Proc. Natl. Acad. Sci. U.S.A. 100, 1885 (2003).

    Google Scholar 

  58. D.H. Barouch, P.F. McKay, S.M. Sumida, S. Santra, S.S. Jackson, D.A. Gorgone, M.A. Lifton, B.K. Chakrabarti, L. Xu, G.J. Nabel, N.L. Letvin, J. Virol. 77, 8729 (2003).

    Google Scholar 

  59. R.J. Song, K.W. Leong, Mol. Ther. 7, S257 (2003).

    Google Scholar 

  60. A. Haisch, F. Wanjura, C. Radke, K. Leder-Jöhrens, A. Gröger, M. Endres, S. Klaering, A. Loch, M. Sittinger, Eur. Arch. Otorhinolaryngol. 261, 216 (2004).

    Google Scholar 

  61. M.L. Ho, J.K. Chang, G.J. Wang, Clin. Orthop. Relat. Res., 270 (1995).

  62. F.A. Sharp, D. Ruane, B. Claass, E. Creagh, J. Harris, P. Malyala, M. Singh, D.T. O’Hagan, V. Pétrilli, J. Tschopp, L.A.J. O’Neill, E.C. Lavelle, Proc. Natl. Acad. Sci. U.S.A. 106, 870 (2009).

    Google Scholar 

  63. C. Dostert, V. Pétrilli, R. Van Bruggen, C. Steele, B.T. Mossman, J. Tschopp, Science 320, 674 (2008).

    Google Scholar 

  64. V. Hornung, F. Bauernfeind, A. Halle, E.O. Samstad, H. Kono, K.L. Rock, K.A. Fitzgerald, E. Latz, Nat. Immunol. 9, 847 (2008).

    Google Scholar 

  65. C. Termeer, F. Benedix, J. Sleeman, C. Fieber, U. Voith, T. Ahrens, K. Miyake, M. Freudenberg, C. Galanos, J.C. Simon, J. Exp. Med. 195, 99 (2002).

    Google Scholar 

  66. C.A. Da Silva, C. Chalouni, A. Williams, D. Hartl, C.G. Lee, J.A. Elias, J. Immunol. 182, 3573 (2009).

    Google Scholar 

  67. D. Yang, K.S. Jones, J. Biomed. Mater. Res. Part A 90, 411 (2009).

    Google Scholar 

  68. S.K. Tam, J. Dusseault, S. Polizu, M. Menard, J.P. Halle, L. Yahia, Biomater. 27, 1296 (2006).

    Google Scholar 

  69. G. Klock, A. Pfeffermann, C. Ryser, P. Grohn, B. Kuttler, J.J. Hahn, U. Zimmermann, Biomater. 18, 707 (1997).

    Google Scholar 

  70. J.S. Pieper, P.B. Van Wachem, M.J.A. Van Luyn, L.A. Brouwer, T. Hafmans, J.H. Veerkamp, T.H. Van Kuppevelt, Biomater. 21, 1689 (2000).

    Google Scholar 

  71. H. Sterling, C. Saginario, A. Vignery, J. Cell Biol. 143, 837 (1998).

    Google Scholar 

  72. S.J. Yoon, S.H. Kim, H.J. Ha, Y.K. Ko, J.W. So, M.S. Kim, Y. Yang, G. Khang, J.M. Rhee, H.B. Lee, Tissue Eng. Part A 14, 539 (2008).

    Google Scholar 

  73. S.M. van Putten, M. Wubben, W.E. Hennink, M.J. van Luyn, M.C. Harmsen, Biomater. 30, 730 (2009).

    Google Scholar 

  74. S.T. Reddy, A.J. van der Vlies, E. Simeoni, V. Angeli, G.J. Randolph, C.P. O’Neil, L.K. Lee, M.A. Swartz, J.A. Hubbell, Nat. Biotechnol. 25, 1159 (2007).

    Google Scholar 

  75. D.A. Rothenfluh, H. Bermudez, C.P. O’Neil, J.A. Hubbell, Nat. Mater. 7, 248 (2008).

    Google Scholar 

  76. R. Roy, B. Zhang, M.A. Moses, Exp. Cell Res. 312, 608 (2006).

    Google Scholar 

  77. L.M. Matrisian, Trends Genet. 6, 121 (1990).

    Google Scholar 

  78. H. Nagase, J.F. Woessner, Jr., J. Biol. Chem. 274, 21491 (1999).

    Google Scholar 

  79. W. Bode, Biochem. Soc. Symp. 1 (2003).

  80. R. Visse, H. Nagase, Circ. Res. 92, 827 (2003).

    Google Scholar 

  81. J.F. Woessner, Jr., H. Nagase, Matrix Metalloproteinases and TIMPs (Oxford University Press, New York, 2000).

    Google Scholar 

  82. W. Bode, K. Maskos, Methods Mol. Biol. 151, 45 (2001).

    Google Scholar 

  83. A. Buckley-Sturrock, S.C. Woodward, R.M. Senior, G.L. Griffin, M. Klagsbrun, J.M. Davidson, J. Cell Physiol. 138, 70 (1989).

    Google Scholar 

  84. A.N. Neely, C.E. Clendening, J. Gardner, D.G. Greenhalgh, G.D. Warden, Wound Repair Regen. 7, 166 (1999).

    Google Scholar 

  85. S.D. Shapiro, D.K. Kobayashi, H.G. Welgus, J. Biol. Chem. 267, 13890 (1992).

    Google Scholar 

  86. U.A. Stock, D. Wiederschain, S.M. Kilroy, D. Shum-Tim, P.N. Khalil, J.P. Vacanti, J.E. Mayer, M.A. Moses, J. Cell Biochem. 81, 220 (2001).

    Google Scholar 

  87. M.A. Karim, A.G. Ferguson, B.T. Wakim, A.M. Samarel, Am. J. Physiol. 260, C316 (1991).

    Google Scholar 

  88. C.A. Peters, M.R. Freeman, C.A. Fernandez, J. Shepard, D.G. Wiederschain, M.A. Moses, Am. J. Physiol. 272, R1960 (1997).

    Google Scholar 

  89. A.B. Wysocki, L. Staiano-Coico, F. Grinnell, J. Invest. Dermatol. 101, 64 (1993).

    Google Scholar 

  90. A.B. Wysocki, L. Staiano-Coico, F. Grinnell, J. Cell Biol. 115, 137a (1993).

    Google Scholar 

  91. M.A. Moses, J. Harper, Cancer: Cell Structures, Carcinogens and Tumor Pathogenesis, EXS 96, 223 (2005).

    Google Scholar 

  92. A.K. Greene, M. Puder, R. Roy, S. Kilroy, G. Louis, J. Folkman, M.A. Moses, Transplant. 78, 1139 (2004).

    Google Scholar 

  93. I.P. Alwayn, J.E. Verbesey, S. Kim, R. Roy, D.A. Arsenault, A.K. Greene, K. Novak, A. Laforme, S. Lee, M.A. Moses, M. Puder, J. Surg. Res. 145, 192 (2008).

    Google Scholar 

  94. I. Bellayr, X. Mu, Y. Li, Future Med. Chem. 1, 1095 (2009).

    Google Scholar 

  95. M.A. Moses, M. Marikovsky, J.W. Harper, P. Vogt, E. Eriksson, M. Klagsbrun, R. Langer, J. Cell Biochem. 60, 379 (1996).

    Google Scholar 

  96. M.J. Reiss, Y.P. Han, E. Garcia, M. Goldberg, H. Yu, W.L. Garner, Surgery 147, 295 (2010).

    Google Scholar 

  97. F. Grinnell, C.H. Ho, A. Wysocki, J. Invest. Dermatol. 98, 410 (1992).

    Google Scholar 

  98. U.K. Saarialho-Kere, E.S. Chang, H.G. Welgus, W.C. Parks, J. Clin. Invest. 90, 1952 (1992).

    Google Scholar 

  99. P.J. Hennessey, C.T. Black, R.J. Andrassy, Arch. Surg. 125, 926 (1990).

    Google Scholar 

  100. T. Hasebe, S. Harasawa, T. Miwa, T. Shibata, S. Inayama, Tokai J. Exp. Clin. Med. 12, 147 (1987).

    Google Scholar 

  101. C. Zuany-Amorim, J. Hastewell, C. Walker, Nat. Rev. Drug Discov. 1, 797 (2002).

    Google Scholar 

  102. U. Ohto, K. Fukase, K. Miyake, Y. Satow, Science 316, 1632 (2007).

    Google Scholar 

  103. B.S. Park, D.H. Song, H.M. Kim, B.-S. Choi, H. Lee, J.-O. Lee, Nature 458, 1191 (2009).

    Google Scholar 

  104. H.M. Kim, B.S. Park, J.I. Kim, S.E. Kim, J. Lee, S.C. Oh, P. Enkhbayar, N. Matsushima, H. Lee, O.J. Yoo, Cell 130, 906 (2007).

    Google Scholar 

  105. J.C. Kagan, T. Su, T. Horng, A. Chow, S. Akira, R. Medzhitov, Nat. Immunol. 9, 361 (2008).

    Google Scholar 

  106. P. Boros, J. S. Bromberg, Am. J. Transplant. 6, 652 (2006).

    Google Scholar 

  107. D. Jiang, J. Liang, J. Fan, S. Yu, S. Chen, Y. Luo, G.D. Prestwich, M.M. Mascarenhas, H.G. Garg, D.A. Quinn, Nat. Med. 11, 1173 (2005).

    Google Scholar 

  108. K.A. Scheibner, M.A. Lutz, S. Boodoo, M.J. Fenton, J.D. Powell, M.R. Horton, J. Immunol. 177, 1272 (2006).

    Google Scholar 

  109. S. Benhamron, H. Nechushtan, I. Verbovetski, A. Krispin, G. Abboud-Jarrous, E. Zcharia, E. Edovitsky, E. Nahari, T. Peretz, I. Vlodavsky, D. Mevorach, J. Immunol. 176, 6417 (2006).

    Google Scholar 

  110. B.M. Tesar, D. Jiang, J. Liang, S.M. Palmer, P.W. Noble, Am. J. Transplant. 6, 2622 (2006).

    Google Scholar 

  111. Y. Takahashi, L. Li, M. Kamiryo, T. Asteriou, A. Moustakas, H. Yamashita, P. Heldin, J. Biol. Chem. 280, 24195 (2005).

    Google Scholar 

  112. S.I. Miller, R.K. Ernst, M.W. Bader, Nat. Rev. Microbiol. 3, 36 (2005).

    Google Scholar 

  113. C.R. Parish, Nat. Rev. Immunol. 6, 633 (2006).

    Google Scholar 

  114. T.H. Flo, L. Ryan, E. Latz, O. Takeuchi, B.G. Monks, E. Lien, O. Halaas, S. Akira, J. Biol. Chem. 277, 35489 (2002).

    Google Scholar 

  115. S. Svenson, D.A. Tomalia, Adv. Drug Deliv. Rev. 57, 2106 (2005).

    Google Scholar 

  116. J.W. Dear, K. Hisataka, S.-K. Jo, M.K. Holly, X. Hu, P.S.T. Yuen, M.W. Brechbiel, R.A. Star, Kidney Int. 67, 2159 (2005).

    Google Scholar 

  117. S. Shaunak, S. Thomas, E. Gianasi, A. Godwin, E. Jones, Nat. Biotechnol. 22, 977 (2004).

    Google Scholar 

Download references

Authors
  1. Anthony Atala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darrell J. Irvine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marsha Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sunil Shaunak
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atala, A., Irvine, D.J., Moses, M. et al. Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine. MRS Bulletin 35, 597–606 (2010). https://doi.org/10.1557/mrs2010.528

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1557/mrs2010.528

Search

Navigation