, Volume 19, Issue 6, pp 363–381

Advances in the Modulation of Cutaneous Wound Healing and Scarring

Mechanisms and Targets


Cutaneous wounds inevitably heal with scars, which can be disfiguring and compromise function. In general, the greater the insult, the worse the scarring, although genetic make up, regional variations and age can influence the final result. Excessive scarring manifests as hypertrophic and keloid scars. At the other end of the spectrum are poorly healing chronic wounds, such as foot ulcers in diabetic patients and pressure sores. Current therapies to minimize scarring and accelerate wound healing rely on the optimization of systemic conditions, early wound coverage and closure of lacerations, and surgical incisions with minimal trauma to the surrounding skin. The possible benefits of topical therapies have also been assessed. Further major improvements in wound healing and scarring require an understanding of the molecular basis of this process. Promising strategies for modulating healing include the local administration of platelet derived growth factor (PDGF)-BB to accelerate the healing of chronic ulcers, and increasing the relative ratio of transforming growth factor (TGF)β-3 to TGFβ-1 and TGFβ-2 in order to minimize scarring.


  1. 1.
    Ferguson MW, O’Kane S. Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci 2004; 359(1445): 839–50PubMedCrossRefGoogle Scholar
  2. 2.
    Martin P. Wound healing: aiming for perfect skin regeneration. Science 1997; 276(5309): 75–81PubMedCrossRefGoogle Scholar
  3. 3.
    Clark RAF. Wound repair: overview and general considerations. In: Clark RAF, editor. The molecular and cellular biology of wound repair. 2nd ed. New York: Plenum Press, 1996: 3–50Google Scholar
  4. 4.
    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999; 341(10): 738–46PubMedCrossRefGoogle Scholar
  5. 5.
    Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326(12): 800–6PubMedCrossRefGoogle Scholar
  6. 6.
    Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69(4): 513–21PubMedGoogle Scholar
  7. 7.
    Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76(2): 301–14PubMedCrossRefGoogle Scholar
  8. 8.
    Grose R, Hutter C, Bloch W, et al. A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development 2002; 129(9): 2303–15PubMedGoogle Scholar
  9. 9.
    Grondahl-Hansen J, Lund LR, Ralfkiaer E, et al. Urokinase- and tissue-type plasminogen activators in keratinocytes during wound reepithelialization in vivo. J Invest Dermatol 1988; 90(6): 790–5PubMedCrossRefGoogle Scholar
  10. 10.
    Steffensen B, Hakkinen L, Larjava H. Proteolytic events of wound-healing: coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med 2001; 12(5): 373–98PubMedCrossRefGoogle Scholar
  11. 11.
    Saarialho-Kere UK, Chang ES, Welgus HG, et al. Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest 1992; 90(5): 1952–7PubMedCrossRefGoogle Scholar
  12. 12.
    Salo T, Makela M, Kylmaniemi M, et al. Expression of matrix metalloproteinase-2 and -9 during early human wound healing. Lab Invest 1994; 70(2): 176–82PubMedGoogle Scholar
  13. 13.
    Saarialho-Kere UK, Pentland AP, Birkedal-Hansen H, et al. Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest 1994; 94(1): 79–88PubMedCrossRefGoogle Scholar
  14. 14.
    Pilcher BK, Sudbeck BD, Dumin JA, et al. Collagenase-1 and collagen in epidermal repair. Arch Dermatol Res 1998; 290Suppl.: S37–46PubMedCrossRefGoogle Scholar
  15. 15.
    Madlener M, Mauch C, Conca W, et al. Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing. Biochem J 1996 Dec 1; 320(Pt 2): 659–64PubMedGoogle Scholar
  16. 16.
    Midwood KS, Williams LV, Schwarzbauer JE. Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol 2004; 36(6): 1031–7PubMedCrossRefGoogle Scholar
  17. 17.
    Midwood KS, Valenick LV, Hsia HC, et al. Coregulation of fibronectin signaling and matrix contraction by tenascin-C and syndecan-4. Mol Biol Cell 2004; 15(12): 5670–7PubMedCrossRefGoogle Scholar
  18. 18.
    Yamamoto N, Kiyosawa T, Arai K, et al. Dermal neoformation during skin wound healing as demonstrated using scanning electron microscopy. Ann Plast Surg 2004; 52(4): 398–406PubMedCrossRefGoogle Scholar
  19. 19.
    Tonnesen MG, Feng X, Clark RA. Angiogenesis in wound healing. J Investig Dermatol Symp Proc 2000; 5(1): 40–6PubMedCrossRefGoogle Scholar
  20. 20.
    Desmouliere A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995; 146(1): 56–66PubMedGoogle Scholar
  21. 21.
    Greenhalgh DG. The role of apoptosis in wound healing. Int J Biochem Cell Biol 1998; 30(9): 1019–30PubMedCrossRefGoogle Scholar
  22. 22.
    Akasaka Y, Ono I, Yamashita T, et al. Basic fibroblast growth factor promotes apoptosis and suppresses granulation tissue formation in acute incisional wounds. J Pathol 2004; 203(2): 710–20PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou Z, Wang J, Cao R, et al. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 2004; 64(14): 4699–702PubMedCrossRefGoogle Scholar
  24. 24.
    Levenson SM, Geever EF, Crowley LV, et al. The healing of rat skin wounds. Ann Surg 1965; 161: 293–308PubMedCrossRefGoogle Scholar
  25. 25.
    Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 2005; 13(1): 7–12PubMedCrossRefGoogle Scholar
  26. 26.
    Darby I, Skalli O, Gabbiani G. Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 1990; 63(1): 21–9PubMedGoogle Scholar
  27. 27.
    Berry DP, Harding KG, Stanton MR, et al. Human wound contraction: collagen organization, fibroblasts, and myofibroblasts. Plast Reconstr Surg 1998; 102(1): 124–31PubMedCrossRefGoogle Scholar
  28. 28.
    Men YD, Han YP, Tawil B, et al. Fibrinogen inhibits fibroblast-mediated contraction of collagen. Wound Repair Regen 2003; 11(5): 380–5CrossRefGoogle Scholar
  29. 29.
    Efron PA, Moldawer LL. Cytokines and wound healing: the role of cytokine and anticytokine therapy in the repair response. J Burn Care Rehabil 2004; 25(2): 149–60PubMedCrossRefGoogle Scholar
  30. 30.
    Ross R. Platelet-derived growth factor. Annu Rev Med 1987; 38: 71–9PubMedCrossRefGoogle Scholar
  31. 31.
    Rumalla VK, Borah GL. Cytokines, growth factors, and plastic surgery. Plast Reconstr Surg 2001; 108(3): 719–33PubMedCrossRefGoogle Scholar
  32. 32.
    Marneros AG, Norris JE, Watanabe S, et al. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7pll. J Invest Dermatol 2004; 122(5): 1126–32PubMedCrossRefGoogle Scholar
  33. 33.
    Higgins PJ, Slack JK, Diegelmann RF, et al. Differential regulation of PAI-1 gene expression in human fibroblasts predisposed to a fibrotic phenotype. Exp Cell Res 1999; 248(2): 634–42PubMedCrossRefGoogle Scholar
  34. 34.
    Tuan TL, Zhu JY, Sun B, et al. Elevated levels of plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts. J Invest Dermatol 1996 May; 106(5): 1007–11PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang Q, Wu Y, Ann DK, et al. Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts. J Invest Dermatol 2003; 121(5): 1005–12PubMedCrossRefGoogle Scholar
  36. 36.
    Beer TW, Baldwin HC, Goddard JR, et al. Angiogenesis in pathological and surgical scars. Hum Pathol 1998; 29(11): 1273–8PubMedCrossRefGoogle Scholar
  37. 37.
    Kischer CW, Thies AC, Chvapil M. Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum Pathol 1982 Sep; 13(9): 819–24PubMedCrossRefGoogle Scholar
  38. 38.
    Lee TY, Chin GS, Kim WJ, et al. Expression of transforming growth factor beta 1, 2, and 3 proteins in keloids. Ann Plast Surg 1999; 43(2): 179–84PubMedGoogle Scholar
  39. 39.
    Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg 2001; 108(2): 423–9PubMedCrossRefGoogle Scholar
  40. 40.
    Younai S, Nichter LS, Wellisz T, et al. Modulation of collagen synthesis by transforming growth factor-beta in keloid and hypertrophic scar fibroblasts. Ann Plast Surg 1994; 33(2): 148–51PubMedCrossRefGoogle Scholar
  41. 41.
    Smith P, Mosiello G, Deluca L, et al. TGF-beta2 activates proliferative scar fibroblasts. J Surg Res 1999; 82(2): 319–23PubMedCrossRefGoogle Scholar
  42. 42.
    Haisa M, Okochi H, Grotendorst GR. Elevated levels of PDGF alpha receptors in keloid fibroblasts contribute to an enhanced response to PDGF. J Invest Dermatol 1994; 103(4): 560–3PubMedCrossRefGoogle Scholar
  43. 43.
    Hasegawa T, Nakao A, Sumiyoshi K, et al. IFN-gamma fails to antagonize fibrotic effect of TGF-beta on keloid-derived dermal fibroblasts. J Dermatol Sci 2003; 32(1): 19–24PubMedCrossRefGoogle Scholar
  44. 44.
    Calderon M, Lawrence WT, Banes AJ. Increased proliferation in keloid fibroblasts wounded in vitro. J Surg Res 1996; 61(2): 343–7PubMedCrossRefGoogle Scholar
  45. 45.
    Nakaoka H, Miyauchi S, Miki Y. Proliferating activity of dermal fibroblasts in keloids and hypertrophic scars. Acta Derm Venereol 1995; 75(2): 102–4PubMedGoogle Scholar
  46. 46.
    Ladin DA, Hou Z, Patel D, et al. p53 and apoptosis alterations in keloids and keloid fibroblasts. Wound Repair Regen 1998; 6(1): 28–37PubMedCrossRefGoogle Scholar
  47. 47.
    Saed GM, Ladin D, Olson J, et al. Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol 1998; 134(8): 963–7PubMedCrossRefGoogle Scholar
  48. 48.
    Chodon T, Sugihara T, Igawa HH, et al. Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance. Am J Pathol 2000; 157(5): 1661–9PubMedCrossRefGoogle Scholar
  49. 49.
    Funayama E, Chodon T, Oyama A, et al. Keratinocytes promote proliferation and inhibit apoptosis of the underlying fibroblasts: an important role in the patho-genesis of keloid. J Invest Dermatol 2003; 121(6): 1326–31PubMedCrossRefGoogle Scholar
  50. 50.
    Phan TT, Lim IJ, Bay BH, et al. Differences in collagen production between normal and keloid-derived fibroblasts in serum-media co-culture with keloid-derived keratinocytes. J Dermatol Sci 2002; 29(1): 26–34PubMedCrossRefGoogle Scholar
  51. 51.
    Lim IJ, Phan TT, Song C, et al. Investigation of the influence of keloid-derived keratinocytes on fibroblast growth and proliferation in vitro. Plast Reconstr Surg 2001; 107(3): 797–808PubMedCrossRefGoogle Scholar
  52. 52.
    Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92(8): 827–39PubMedCrossRefGoogle Scholar
  53. 53.
    Uchida G, Yoshimura K, Kitano Y, et al. Tretinoin reverses upregulation of matrix metalloproteinase-13 in human keloid-derived fibroblasts. Exp Dermatol 2003; 12 Suppl. 2: 35–42CrossRefGoogle Scholar
  54. 54.
    Yoshimoto H, Ishihara H, Ohtsuru A, et al. Overexpression of insulin-like growth factor-1 (IGF-I) receptor and the invasiveness of cultured keloid fibroblasts. Am J Pathol 1999; 154(3): 883–9PubMedCrossRefGoogle Scholar
  55. 55.
    Wang R, Ghahary A, Shen Q, et al. Hypertrophie scar tissues and fibroblasts produce more transforming growth factor-betal mRNA and protein than normal skin and cells. Wound Repair Regen 2000; 8(2): 128–37PubMedCrossRefGoogle Scholar
  56. 56.
    Akimoto S, Ishikawa O, Iijima C, et al. Expression of basic fibroblast growth factor and its receptor by fibroblast, macrophages and mast cells in hypertrophie scar. Eur J Dermatol 1999; 9(5): 357–62PubMedGoogle Scholar
  57. 57.
    Ghahary A, Shen YJ, Nedelec B, et al. Enhanced expression of mRNA for insulinlike growth factor-1 in post-burn hypertrophie scar tissue and its fibrogenic role by dermal fibroblasts. Mol Cell Biochem 1995; 148(1): 25–32PubMedCrossRefGoogle Scholar
  58. 58.
    Yamamoto T, Hartmann K, Eckes B, et al. Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. J Dermatol Sci 2001; 26(2): 106–11PubMedCrossRefGoogle Scholar
  59. 59.
    Dasu MR, Hawkins HK, Barrow RE, et al. Gene expression profiles from hypertrophic scar fibroblasts before and after IL-6 stimulation. J Pathol 2004; 202(4): 476–85PubMedCrossRefGoogle Scholar
  60. 60.
    Ghahary A, Shen YJ, Nedelec B, et al. Collagenase production is lower in post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-like growth factor-1. J Invest Dermatol 1996; 106(3): 476–81PubMedCrossRefGoogle Scholar
  61. 61.
    Garner WL. Epidermal regulation of dermal fibroblast activity. Plast Reconstr Surg 1998; 102(1): 135–9PubMedCrossRefGoogle Scholar
  62. 62.
    Messen FB, Andriessen MP, Schalkwijk J, et al. Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars. J Pathol 2001; 194(2): 207–16CrossRefGoogle Scholar
  63. 63.
    Garg HG, Siebert JW, Garg A, et al. Inseparable iduronic acid-containing proteog-lycan PG (IdoA) preparations of human skin and post-burn scar tissues: evidence for elevated levels of PG (IdoA)-I in hypertrophie scar by N-terminal sequencing. Carbohydr Res 1996; 284(2): 223–8PubMedCrossRefGoogle Scholar
  64. 64.
    Scott PG, Dodd CM, Tredget EE, et al. Chemical characterization and quantification of proteoglycans in human post-burn hypertrophie and mature scars. Clin Sci (Lond) 1996; 90(5): 417–25Google Scholar
  65. 65.
    Scott PG, Dodd CM, Tredget EE, et al. Immunohistochemical localization of the proteoglycans decorin, biglycan and versican and transforming growth factor-beta in human post-burn hypertrophie and mature scars. Histopathology 1995; 26(5): 423–31PubMedCrossRefGoogle Scholar
  66. 66.
    Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990 Jul 19; 346(6281): 281–4PubMedCrossRefGoogle Scholar
  67. 67.
    Sayani K, Dodd CM, Nedelec B, et al. Delayed appearance of decorin in healing burn scars. Histopathology 2000; 36(3): 262–72PubMedCrossRefGoogle Scholar
  68. 68.
    Castagnoli C, Trombotto C, Ariotti S, et al. Expression and role of IL-15 in postburn hypertrophic scars. J Invest Dermatol 1999; 113(2): 238–45PubMedCrossRefGoogle Scholar
  69. 69.
    Younai S, Venters G, Vu S, et al. Role of growth factors in scar contraction: an in vitro analysis. Ann Plast Surg 1996; 36(5): 495–501PubMedCrossRefGoogle Scholar
  70. 70.
    Nedelec B, Ghahary A, Scott PG, et al. Control of wound contraction: basic and clinical features. Hand Clin 2000; 16(2): 289–302PubMedGoogle Scholar
  71. 71.
    Moulin V, Larochelle S, Langlois C, et al. Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol 2004; 198(3): 350–8PubMedCrossRefGoogle Scholar
  72. 72.
    Fausto N. Liver regeneration. J Hepatol 2000; 32(1 Suppl.): 19–31PubMedCrossRefGoogle Scholar
  73. 73.
    Cowin AJ, Brosnan MP, Holmes TM, et al. Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Dev Dyn 1998; 212(3): 385–93PubMedCrossRefGoogle Scholar
  74. 74.
    Martin P, D’Souza D, Martin J, et al. Wound healing in the PU.1 null mouse: tissue repair is not dependent on inflammatory cells. Curr Biol 2003; 13(13): 1122–8PubMedCrossRefGoogle Scholar
  75. 75.
    Lorenz HP, Whitby DJ, Longaker MT, et al. Fetal wound healing: the ontogeny of scar formation in the non-human primate. Ann Surg 1993; 217(4): 391–6PubMedCrossRefGoogle Scholar
  76. 76.
    Longaker MT, Whitby DJ, Jennings RW, et al. Fetal diaphragmatic wounds heal with scar formation. J Surg Res 1991; 50(4): 375–85PubMedCrossRefGoogle Scholar
  77. 77.
    Lin RY, Adzick NS. The role of the fetal fibroblast and transforming growth factor-beta in a model of human fetal wound repair. Semin Pediatr Surg 1996; 5(3): 165–74PubMedGoogle Scholar
  78. 78.
    de Larco JE, Todaro GJ. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A 1978; 75(8): 4001–5PubMedCrossRefGoogle Scholar
  79. 79.
    Roberts AB, Lamb LC, Newton DL, et al. Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci U S A 1980; 77(6): 3494–8PubMedCrossRefGoogle Scholar
  80. 80.
    Anzano MA, Roberts AB, Smith JM, et al. Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci U S A 1983; 80(20): 6264–8PubMedCrossRefGoogle Scholar
  81. 81.
    Massague J. The TGF-beta family of growth and differentiation factors. Cell 1987; 49(4): 437–8PubMedCrossRefGoogle Scholar
  82. 82.
    Sporn MB, Roberts AB, Wakefield LM, et al. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 1987; 105(3): 1039–45PubMedCrossRefGoogle Scholar
  83. 83.
    Piez KA, Sporn MB. The transforming growth factor-βs: past, present and future. In: Piez KA, Sporn MB, editors. Transforming growth factor-βs: chemistry, biology and therapeutics. Annals NY Acad Sciences 1990; 593: 1–6Google Scholar
  84. 84.
    O’Kane S, Ferguson MW. Transforming growth factor betas and wound healing. Int J Biochem Cell Biol 1997; 29(1): 63–78PubMedCrossRefGoogle Scholar
  85. 85.
    Sporn MB, Roberts AB, Shull JH, et al. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 1983; 219(4590): 1329–31PubMedCrossRefGoogle Scholar
  86. 86.
    Roberts AB, Sporn MB, Assoian RK, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 1986; 83(12): 4167–71PubMedCrossRefGoogle Scholar
  87. 87.
    Whitby DJ, Ferguson MW. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol 1991; 147(1): 207–15PubMedCrossRefGoogle Scholar
  88. 88.
    Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci 1995; 108(Pt 3): 985–1002PubMedGoogle Scholar
  89. 89.
    Lin RY, Sullivan KM, Argenta PA, et al. Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair. Ann Surg 1995; 222(2): 146–54PubMedCrossRefGoogle Scholar
  90. 90.
    Hsu M, Peled ZM, Chin GS, et al. Ontogeny of expression of transforming growth factor-beta 1 (TGF-beta 1), TGF-beta 3, and TGF-beta receptors I and II in fetal rat fibroblasts and skin. Plast Reconstr Surg 2001; 107(7): 1787–94PubMedCrossRefGoogle Scholar
  91. 91.
    Soo C, Beanes SR, Hu FY, et al. Ontogenetic transition in fetal wound transforming growth factor-beta regulation correlates with collagen organization. Am J Pathol 2003; 163(6): 2459–76PubMedCrossRefGoogle Scholar
  92. 92.
    Martin P, Dickson MC, Millan FA, et al. Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo. Dev Genet 1993; 14(3): 225–38PubMedCrossRefGoogle Scholar
  93. 93.
    Massague J, Cheifetz S, Boyd FT, et al. TGF-beta receptors and TGF-beta binding proteoglycans: recent progress in identifying their functional properties. Ann N Y Acad Sci 1990; 593: 59–72PubMedCrossRefGoogle Scholar
  94. 94.
    Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67: 753–91PubMedCrossRefGoogle Scholar
  95. 95.
    Cowin AJ, Holmes TM, Brosnan P, et al. Expression of TGF-beta and its receptors in murine fetal and adult dermal wounds. Eur J Dermatol 2001; 11(5): 424–31PubMedGoogle Scholar
  96. 96.
    Lovvorn III HN, Cheung DT, Nimni ME, et al. Relative distribution and cross-linking of collagen distinguish fetal from adult sheep wound repair. J Pediatr Surg 1999; 34(1): 218–23PubMedCrossRefGoogle Scholar
  97. 97.
    Moulin V, Plamondon M. Differential expression of collagen integrin receptor on fetal vs adult skin fibroblasts: implication in wound contraction during healing. Br J Dermatol 2002; 147(5): 886–92PubMedCrossRefGoogle Scholar
  98. 98.
    Park JC, Park BJ, Suh H, et al. Comparative study on motility of the cultured fetal and neonatal dermal fibroblasts in extracellular matrix. Yonsei Med J 2001; 42(6): 587–94PubMedGoogle Scholar
  99. 99.
    Dang CM, Beanes SR, Lee H, et al. Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metal-loproteinase ratio. Plast Reconstr Surg 2003; 111(7): 2273–85PubMedCrossRefGoogle Scholar
  100. 100.
    Lee HG, Eun HC. Differences between fibroblasts cultured from oral mucosa and normal skin: implication to wound healing. J Dermatol Sci 1999; 21(3): 176–82PubMedCrossRefGoogle Scholar
  101. 101.
    Sumi Y, Muramatsu H, Hata K, et al. Secretory leukocyte protease inhibitor is a novel inhibitor of fibroblast-mediated collagen gel contraction. Exp Cell Res 2000; 256(1): 203–12PubMedCrossRefGoogle Scholar
  102. 102.
    Shah M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 1992; 339(8787): 213–4PubMedCrossRefGoogle Scholar
  103. 103.
    Shah M, Foreman DM, Ferguson MW. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 1994; 107(Pt 5): 1137–57PubMedGoogle Scholar
  104. 104.
    Brahmatewari J, Serafini A, Serralta V, et al. The effects of topical transforming growth factor-beta 2 and anti-transforming growth factor-beta 2,3 on scarring in pigs. J Cutan Med Surg 2000; 4(3): 126–31PubMedGoogle Scholar
  105. 105.
    Choi BM, Kwak HJ, Jun CD, et al. Control of scarring in adult wounds using antisense transforming growth factor-beta 1 oligodeoxynucleotides. Immunol Cell Biol 1996; 74(2): 144–50PubMedCrossRefGoogle Scholar
  106. 106.
    Shah M, Revis D, Herrick S, et al. Role of elevated plasma transforming growth factor-betal levels in wound healing. Am J Pathol 1999; 154(4): 1115-24PubMedCrossRefGoogle Scholar
  107. 107.
    Liu W, Chua C, Wu X, et al. Inhibiting scar formation in rat wounds by adenovirus-mediated overexpression of truncated TGF-beta receptor II. Plast Reconstr Surg 2005; 115(3): 860–70PubMedCrossRefGoogle Scholar
  108. 108.
    Soo C, Hu FY, Zhang X, et al. Differential expression of fibromodulin, a transforming growth factor-beta modulator, in fetal skin development and scarless repair. Am J Pathol 2000; 157(2): 423–33PubMedCrossRefGoogle Scholar
  109. 109.
    Beanes SR, Dang C, Soo C, et al. Down-regulation of decorin, a transforming growth factor-beta modulator, is associated with scarless fetal wound healing. J Pediatr Surg 2001; 36(11): 1666–71PubMedCrossRefGoogle Scholar
  110. 110.
    Scheid A, Wenger RH, Schaffer L, et al. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J 2002; 16(3): 411–3PubMedGoogle Scholar
  111. 111.
    Ono I, Yamashita T, Hida T, et al. Combined administration of basic fibroblast growth factor protein and the hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds. Wound Repair Regen 2004; 12(1): 67–79PubMedCrossRefGoogle Scholar
  112. 112.
    Ono I, Yamashita T, Hida T, et al. Local administration of hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds. J Surg Res 2004; 120(1): 47–55PubMedCrossRefGoogle Scholar
  113. 113.
    Ha X, Li Y, Lao M, et al. Effect of human hepatocyte growth factor on promoting wound healing and preventing scar formation by adenovirus-mediated gene transfer. Chin Med J (Engl) 2003; 116(7): 1029–33Google Scholar
  114. 114.
    Wilgus TA, Vodovotz Y, Vittadini E, et al. Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regen 2003; 11(1): 25–34PubMedCrossRefGoogle Scholar
  115. 115.
    Kossi J, Peltonen J, Uotila P, et al. Differential effects of hexoses and sucrose, and platelet-derived growth factor isoforms on cyclooxygenase-1 and -2 mRNA expression in keloid, hypertrophic scar and granulation tissue fibroblasts. Arch Dermatol Res 2001; 293(3): 126–32PubMedCrossRefGoogle Scholar
  116. 116.
    Tanaka H, Okada T, Konishi H, et al. The effect of reactive oxygen species on the biosynthesis of collagen and glycosaminoglycans in cultured human dermal fibroblasts. Arch Dermatol Res 1993; 285(6): 352–5PubMedCrossRefGoogle Scholar
  117. 117.
    Baumann LS, Spencer J. The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg 1999; 25(4): 311–5PubMedCrossRefGoogle Scholar
  118. 118.
    Jenkins M, Alexander JW, MacMillan BG, et al. Failure of topical steroids and vitamin E to reduce postoperative scar formation following reconstructive surgery. J Burn Care Rehabil 1986; 7(4): 309–12PubMedCrossRefGoogle Scholar
  119. 119.
    Mustoe TA, Cooter RD, Gold MH, et al. International clinical recommendations on scar management. Plast Reconstr Surg 2002; 110(2): 560–71PubMedCrossRefGoogle Scholar
  120. 120.
    Kischer CW, Shetlar MR, Shetlar CL. Alteration of hypertrophic scars induced by mechanical pressure. Arch Dermatol 1975; 111(1): 60–4PubMedCrossRefGoogle Scholar
  121. 121.
    Reno F, Sabbatini M, Lombardi F, et al. In vitro mechanical compression induces apoptosis and regulates cytokines release in hypertrophic scars. Wound Repair Regen 2003; 11(5): 331–6PubMedCrossRefGoogle Scholar
  122. 122.
    Berman B, Flores F. The treatment of hypertrophic scars and keloids. Eur J Dermatol 1998; 8(8): 591–6PubMedGoogle Scholar
  123. 123.
    Malaker K, Vijayraghavan K, Hodson I, et al. Retrospective analysis of treatment of unresectable keloids with primary radiation over 25 years. Clin Oncol (R Coll Radiol) 2004 Jun; 16(4): 290–8.CrossRefGoogle Scholar
  124. 124.
    Simman R, Alani H, Williams F. Effect of mitomycin C on keloid fibroblasts: an in vitro study. Ann Plast Surg 2003; 50(1): 71–6PubMedCrossRefGoogle Scholar
  125. 125.
    Uppal RS, Khan U, Kakar S, et al. The effects of a single dose of 5-fluorouracil on keloid scars: a clinical trial of timed wound irrigation after extralesional excision. Plast Reconstr Surg 2001; 108(5): 1218–24PubMedCrossRefGoogle Scholar
  126. 126.
    Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. Arch Dermatol 2002; 138(9): 1149–55PubMedCrossRefGoogle Scholar
  127. 127.
    Nanda S, Reddy BS. Intralesional 5-fluorouracil as a treatment modality of keloids. Dermatol Surg 2004; 30(1): 54–6PubMedCrossRefGoogle Scholar
  128. 128.
    Muzaffar AR, Rafols F, Masson J, et al. Keloid formation after syndactyly reconstruction: associated conditions, prevalence, and preliminary report of a treatment method. J Hand Surg [Am] 2004; 29(2): 201–8CrossRefGoogle Scholar
  129. 129.
    Ahn ST, Monafo WW, Mustoe TA. Topical silicone gel: a new treatment for hypertrophic scars. Surgery 1989; 106(4): 781–6PubMedGoogle Scholar
  130. 130.
    Dockery GL, Nilson RZ. Treatment of hypertrophic and keloid scars with SILAS-TIC Gel Sheeting. J Foot Ankle Surg 1994; 33(2): 110–9PubMedGoogle Scholar
  131. 131.
    Gold MH, Foster TD, Adair MA, et al. Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg 2001; 27(7): 641–4PubMedCrossRefGoogle Scholar
  132. 132.
    Hanasono MM, Lum J, Carroll LA, et al. The effect of silicone gel on basic fibroblast growth factor levels in fibroblast cell culture. Arch Facial Plast Surg 2004; 6(2): 88–93PubMedCrossRefGoogle Scholar
  133. 133.
    Ricketts CH, Martin L, Faria DT, et al. Cytokine mRNA changes during the treatment of hypertrophic scars with silicone and nonsilicone gel dressings. Dermatol Surg 1996; 22(11): 955–9PubMedCrossRefGoogle Scholar
  134. 134.
    Hinman CD, Maibach H. Effect of air exposure and occlusion on experimental human skin wounds. Nature 1963; 200: 377–8PubMedCrossRefGoogle Scholar
  135. 135.
    Chang CC, Kuo YF, Chiu HC, et al. Hydration, not silicone, modulates the effects of keratinocytes on fibroblasts. J Surg Res 1995; 59(6): 705–11PubMedCrossRefGoogle Scholar
  136. 136.
    Nowak KC, McCormack M, Koch RJ. The effect of superpulsed carbon dioxide laser energy on keloid and normal dermal fibroblast secretion of growth factors: a serum-free study. Plast Reconstr Surg 2000; 105(6): 2039–48PubMedCrossRefGoogle Scholar
  137. 137.
    Wittenberg GP, Fabian BG, Bogomilsky JL, et al. Prospective, single-blind, randomized, controlled study to assess the efficacy of the 585-nm flashlamp-pumped pulsed-dye laser and silicone gel sheeting in hypertrophic scar treatment. Arch Dermatol 1999; 135(9): 1049–55PubMedCrossRefGoogle Scholar
  138. 138.
    Dalkowski A, Fimmel S, Beutler C, et al. Cryotherapy modifies synthetic activity and differentiation of keloidal fibroblasts in vitro. Exp Dermatol 2003; 12(5): 673–81PubMedCrossRefGoogle Scholar
  139. 139.
    Zouboulis CC, Blume U, Buttner P, et al. Outcomes of cryosurgery in keloids and hypertrophic scars: a prospective consecutive trial of case series. Arch Dermatol 1993; 129(9): 1146–51CrossRefGoogle Scholar
  140. 140.
    Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 1999; 250(2): 273–83PubMedCrossRefGoogle Scholar
  141. 141.
    Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue my-ofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993; 122(1): 103–11CrossRefGoogle Scholar
  142. 142.
    Hinz B, Mastrangelo D, Iselin CE, et al. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 2001; 159(3): 1009–20PubMedCrossRefGoogle Scholar
  143. 143.
    Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3(5): 349–63PubMedCrossRefGoogle Scholar
  144. 144.
    van Zuijlen PP, Ruurda JJ, van Veen HA, et al. Collagen morphology in human skin and scar tissue: no adaptations in response to mechanical loading at joints. Burns 2003; 29(5): 423–31PubMedCrossRefGoogle Scholar
  145. 145.
    Waiden JL, Garcia H, Hawkins H, et al. Both dermal matrix and epidermis contribute to an inhibition of wound contraction. Ann Plast Surg 2000; 45(2): 162–6CrossRefGoogle Scholar
  146. 146.
    Waldorf H, Fewkes J. Wound healing. Adv Dermatol 1995; 10: 77–96PubMedGoogle Scholar
  147. 147.
    Atiyeh BS, Ioannovich J, Al-Amm CA, et al. Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing. Curr Pharm Biotechnol 2002; 3(3): 179–95PubMedCrossRefGoogle Scholar
  148. 148.
    Wiechula R. The use of moist wound-healing dressings in the management of split-thickness skin graft donor sites: a systematic review. Int J Nurs Pract 2003; 9(2): S9–S17PubMedCrossRefGoogle Scholar
  149. 149.
    Svensjo T, Pomahac B, Yao F, et al. Accelerated healing of full-thickness skin wounds in a wet environment. Plast Reconstr Surg 2000; 106(3): 602–12PubMedCrossRefGoogle Scholar
  150. 150.
    Lobmann R, Ambrosch A, Schultz G, et al. Expression of matrix-metal-loproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 2002; 45(7): 1011–6PubMedCrossRefGoogle Scholar
  151. 151.
    Ladwig GP, Robson MC, Liu R, et al. Ratios of activated matrix metal-loproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen 2002; 10(1): 26–37PubMedCrossRefGoogle Scholar
  152. 152.
    Loots MA, Renter SB, Au FL, et al. Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls. Eur J Cell Biol 2002; 81(3): 153–60CrossRefGoogle Scholar
  153. 153.
    Xue M, Thompson P, Kelso I, et al. Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. Exp Cell Res 2004; 299(1): 119–27PubMedCrossRefGoogle Scholar
  154. 154.
    Jackson CJ, Xue M, Thompson P, et al. Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing. Wound Repair Regen 2005; 13(3): 284–94PubMedCrossRefGoogle Scholar
  155. 155.
    Antony S, Terrazas S. A retrospective study: clinical experience using vacuum-assisted closure in the treatment of wounds. J Natl Med Assoc 2004; 96(8): 1073–7PubMedGoogle Scholar
  156. 156.
    Dieu T, Leung M, Leong J, et al. Too much vacuum-assisted closure. ANZ J Surg 2003; 73(12): 1057–60PubMedCrossRefGoogle Scholar
  157. 157.
    Loree S, Dompmartin A, Penven K, et al. Is vacuum assisted closure a valid technique for debriding chronic leg ulcers? J Wound Care 2004; 13(6): 249–52PubMedGoogle Scholar
  158. 158.
    Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg 1997; 38(6): 563–76PubMedCrossRefGoogle Scholar
  159. 159.
    Morykwas MJ, Argenta LC, Shelton-Brown El, et al. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann Plast Surg 1997; 38(6): 553–62PubMedCrossRefGoogle Scholar
  160. 160.
    Saxena V, Hwang CW, Huang S, et al. Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plast Reconstr Surg 2004; 114(5): 1086–96PubMedGoogle Scholar
  161. 161.
    Ross R. Platelet-derived growth factor. Lancet 1989; I(8648): 1179–82CrossRefGoogle Scholar
  162. 162.
    Greenhalgh DG. The role of growth factors in wound healing. J Trauma 1996; 41(1): 159–67PubMedCrossRefGoogle Scholar
  163. 163.
    Meyer-Ingold W, Eichner W. Platelet-derived growth factor. Cell Biol Int 1995; 19(5): 389–98PubMedCrossRefGoogle Scholar
  164. 164.
    Hart CE, Forstrom JW, Kelly JD, et al. Two classes of PDGF receptor recognize different isoforms of PDGF. Science 1988; 240(4858): 1529–31PubMedCrossRefGoogle Scholar
  165. 165.
    LeGrand EK. Preclinical promise of becaplermin (rhPDGF-BB) in wound healing. Am J Surg 1998; 176(2A Suppl.): 48S–54SPubMedCrossRefGoogle Scholar
  166. 166.
    Pierce GF, Mustoe TA, Senior RM, et al. In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins. J Exp Med 1988; 167(3): 974–87PubMedCrossRefGoogle Scholar
  167. 167.
    Greenhalgh DG, Sprugel KH, Murray MJ, et al. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol 1990; 136(6): 1235–46PubMedGoogle Scholar
  168. 168.
    Grotendorst GR, Martin GR, Pencev D, et al. Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest 1985; 76(6): 2323–9PubMedCrossRefGoogle Scholar
  169. 169.
    Pierce GF, Mustoe TA, Altrock BW, et al. Role of platelet-derived growth factor in wound healing. J Cell Biochem 1991; 45(4): 319–26PubMedCrossRefGoogle Scholar
  170. 170.
    Pierce GF, Brown D, Mustoe TA. Quantitative analysis of inflammatory cell influx, procollagen type I synthesis, and collagen cross-linking in incisional wounds: influence of PDGF-BB and TGF-beta 1 therapy. J Lab Clin Med 1991; 117(5): 373–82PubMedGoogle Scholar
  171. 171.
    Breitbart AS, Laser J, Parrett B, et al. Accelerated diabetic wound healing using cultured dermal fibroblasts retrovirally transduced with the platelet-derived growth factor B gene. Ann Plast Surg 2003; 51(4): 409–14PubMedCrossRefGoogle Scholar
  172. 172.
    Uhl E, Rosken F, Sirsjo A, et al. Influence of platelet-derived growth factor on microcirculation during normal and impaired wound healing. Wound Repair Regen 2003; 11(5): 361–7PubMedCrossRefGoogle Scholar
  173. 173.
    Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg 1995; 21(1): 71–8Google Scholar
  174. 174.
    Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers: a phase III randomized placebo-controlled double-blind study. Diabetes Care 1998; 21(5): 822–7PubMedCrossRefGoogle Scholar
  175. 175.
    d’Hemecourt PA, Smiell JM, Karim MR. Sodium carboxymethylcellulose aqueous-based gel vs becaplermin gel in patients with nonhealing lower extremity diabetic foot ulcers. Wounds 1998; 10: 69–75Google Scholar
  176. 176.
    Smiell JM, Wieman TJ, Steed DL, et al. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen 1999; 7(5): 335–46PubMedCrossRefGoogle Scholar
  177. 177.
    Perry BH, Sampson AR, Schwab BH, et al. A meta-analytic approach to an integrated summary of efficacy: a case study of becaplermin gel. Control Clin Trials 2002; 23(4): 389–408PubMedCrossRefGoogle Scholar
  178. 178.
    Balfour JA. Becaplermin. Biodrugs 1999; 11(5): 359–64PubMedCrossRefGoogle Scholar
  179. 179.
    Mustoe TA, Cutler NR, Allman RM, et al. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg 1994; 129(2): 213–9PubMedCrossRefGoogle Scholar
  180. 180.
    Robson MC, Phillips LG, Thomason A, et al. Recombinant human platelet-derived growth factor-BB for the treatment of chronic pressure ulcers. Ann Plast Surg 1992; 29(3): 193–201PubMedCrossRefGoogle Scholar
  181. 181.
    Keswani SG, Katz AB, Lim FY, et al. Adenoviral mediated gene transfer of PDGF-B enhances wound healing in type I and type II diabetic wounds. Wound Repair Regen 2004; 12(5): 497–504PubMedCrossRefGoogle Scholar
  182. 182.
    Yao F, Eriksson E. Gene therapy in wound repair and regeneration. Wound Repair Regen 2000; 8(6): 443–51PubMedCrossRefGoogle Scholar
  183. 183.
    Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg 1998; 28(6): 964–73PubMedCrossRefGoogle Scholar
  184. 184.
    Woodley DT, Peterson HD, Herzog SR, et al. Burn wounds resurfaced by cultured epidermal autografts show abnormal reconstitution of anchoring fibrils. JAMA 1988; 259(17): 2566–71PubMedCrossRefGoogle Scholar
  185. 185.
    Nanchahal J, Dover R, Otto WR. Allogeneic skin substitutes applied to burns patients. Burns 2002; 28(3): 254–7PubMedCrossRefGoogle Scholar
  186. 186.
    Jones I, James SE, Rubin P, et al. Upward migration of cultured autologous keratinocytes in Integra artificial skin: a preliminary report. Wound Repair Regen 2003; 11(2): 132–8PubMedCrossRefGoogle Scholar
  187. 187.
    Jones I, Currie L, Martin R. A guide to biological skin substitutes. Br J Plast Surg 2002 Apr; 55(3): 185–93PubMedCrossRefGoogle Scholar
  188. 188.
    Phillips TJ, Manzoor J, Rojas A, et al. The longevity of a bilayered skin substitute after application to venous ulcers. Arch Dermatol 2002; 138(8): 1079–81PubMedCrossRefGoogle Scholar
  189. 189.
    Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF®) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 1999 Jul–Aug; 7(4): 201–7PubMedCrossRefGoogle Scholar
  190. 190.
    Otto WR, Nanchahal J, Lu QL, et al. Survival of allogeneic cells in cultured organotypic skin grafts. Plast Reconstr Surg 1995; 96(1): 166–76PubMedCrossRefGoogle Scholar
  191. 191.
    Falanga V. The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol Dis 2004; 32(1): 88–94PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Kennedy Institute of RheumatologyImperial CollegeLondonUK
  2. 2.Department of Hand SurgeryRoyal North Shore HospitalNew South WalesAustralia

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