Induction of the Fetal Scarless Phenotype in Adult Wounds: Impossible?

  • Michael S. HuEmail author
  • Mimi R. Borrelli
  • Michael T. Longaker
  • H. Peter Lorenz


Adult cutaneous wounds repair through a fibroproliferative response which results in a scar. Early-gestation fetal skin has the ability to regenerate damaged skin without the formation of a scar in a process that resembles regeneration. The fetal and adult wound healing phenotypes are characterized by differences in the degree of inflammation, molecular signaling, extracellular matrix composition, and biomechanical properties. Significant advancements in understanding scarless fetal mammalian wound healing have led to the development of therapeutic applications with the potential to reduce scarring in the healing of adult cutaneous wounds. This chapter outlines the molecular and cellular processes involved in scarless fetal wound healing and the progress that has been made in recapitulating this process in adult wounds.


Wound healing Scarring Regeneration Fibrosis 


  1. 1.
    Beanes SR, Hu FY, Soo C, Dang CM, Urata M, Ting K, Atkinson JB, Benhaim P, Hedrick MH, Lorenz HP. Confocal microscopic analysis of scarless repair in the fetal rat: defining the transition. Plast Reconstr Surg. 2002;109(1):160–70.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.CrossRefGoogle Scholar
  4. 4.
    Rowlatt U. Intrauterine wound healing in a 20 week human fetus. Virchows Arch. 1979;381(3):353–61.CrossRefGoogle Scholar
  5. 5.
    Lorenz HP, Longaker MT, Perkocha LA, Jennings RW, Harrison MR, Adzick NS. Scarless wound repair: a human fetal skin model. Development. 1992;114(1):253–9.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Adzick NS, Longaker MT. Animal models for the study of fetal tissue repair. J Surg Res. 1991;51(3):216–22.CrossRefGoogle Scholar
  7. 7.
    Adzick NS, Longaker MT. Scarless fetal healing. Therapeutic implications. Ann Surg. 1992;215(1):3.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Longaker MT, Whitby DJ, Ferguson MW, Lorenz HP, Harrison MR, Adzick NS. Adult skin wounds in the fetal environment heal with scar formation. Ann Surg. 1994;219(1):65–72.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Cass DL, Bullard KM, Sylvester KG, Yang EY, Longaker MT, Adzick NS. Wound size and gestational age modulate scar formation in fetal wound repair. J Pediatr Surg. 1997;32(3):411–5.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Colwell AS, Krummel TM, Longaker MT, Lorenz HP. An in vivo mouse excisional wound model of scarless healing. Plast Reconstr Surg. 2006;117(7):2292–6.CrossRefGoogle Scholar
  11. 11.
    Ihara S, Motobayashi Y, Nagao E, Kistler A. Ontogenetic transition of wound healing pattern in rat skin occurring at the fetal stage. Development. 1990;110(3):671–80.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wong JW, Gallant-Behm C, Wiebe C, Mak K, Hart DA, Larjava H, Häkkinen L. Wound healing in oral mucosa results in reduced scar formation as compared with skin: evidence from the red Duroc pig model and humans. Wound Repair Regen. 2009;17(5):717–29.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Szpaderska AM, Zuckerman JD, DiPietro LA. Differential injury responses in oral mucosal and cutaneous wounds. J Dent Res. 2003;82(8):621–6.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Sciubba JJ, Waterhouse JP, Meyer J. A fine structural comparison of the healing of incisional wounds of mucosa and skin. J Oral Pathol Med. 1978;7(4):214–27.CrossRefGoogle Scholar
  15. 15.
    Häkkinen L, Uitto VJ, Larjava H. Cell biology of gingival wound healing. Periodontology. 2000;24:127.CrossRefGoogle Scholar
  16. 16.
    Szpaderska AM, Walsh CG, Steinberg MJ, DiPietro LA. Distinct patterns of angiogenesis in oral and skin wounds. J Dent Res. 2005;84(4):309–14.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Ferguson MW, O'Kane S. Scar–free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond Ser B Biol Sci. 2004;359(1445):839–50.CrossRefGoogle Scholar
  18. 18.
    Arnardottir HH, Freysdottir J, Hardardottir I. Two circulating neutrophil populations in acute inflammation in mice. Inflamm Res. 2012;61(9):931–9.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Olutoye OO, Alaish SM, Carr ME Jr, Paik M, Yager DR, Cohen IK, Diegelmann RF. Aggregatory characteristics and expression of the collagen adhesion receptor in fetal porcine platelets. J Pediatr Surg. 1995;30(12):1649–53.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Olutoye OO, Barone EJ, Yager DR, Cohen IK, Diegelmann RF. Collagen induces cytokine release by fetal platelets: implications in scarless healing. J Pediatr Surg. 1997;32(6):827–30.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Naik-Mathuria B, Gay AN, Zhu X, Yu L, Cass DL, Olutoye OO. Age-dependent recruitment of neutrophils by fetal endothelial cells: implications in scarless wound healing. J Pediatr Surg. 2007;42(1):166–71.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Olutoye OO, Zhu X, Cass DL, Smith CW. Neutrophil recruitment by fetal porcine endothelial cells: implications in scarless fetal wound healing. Pediatr Res. 2005;58(6):1290–4.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Satish L, Kathju S. Cellular and molecular characteristics of scarless versus fibrotic wound healing. Dermatol Res Pract. 2010;2010:790234.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002;183(4):406–12.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Robson MC, Barnett RA, Leitch IO, Hayward PG. Prevention and treatment of postburn scars and contracture. World J Surg. 1992;16(1):87–96.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Hopkinson-Woolley J, Hughes D, Gordon S, Martin P. Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci. 1994;107(5):1159–67.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Soo C, Hu FY, Zhang X, Wang Y, Beanes SR, Lorenz HP, Hedrick MH, Mackool RJ, Plaas A, Kim SJ, Longaker MT, Freymiller E, Ting K. Differential expression of fibromodulin, a transforming growth factor-β modulator, in fetal skin development and scarless repair. Am J Pathol. 2000;157(2):423–33.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Woolf N. Pathology: basic and systemic. London: WB Saunders; 1998.Google Scholar
  29. 29.
    Garbuzenko E, Nagler A, Pickholtz D, Gillery P, Reich R, Maquart FX, Levi-Schaffer F. Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis. Clin Exp Allergy. 2002;32(2):237–46.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Abe M, Kurosawa M, Ishikawa O, Miyachi Y. Effect of mast cell-derived mediators and mast cell-related neutral proteases on human dermal fibroblast proliferation and type I collagen production. J Allergy Clin Immunol. 2000;106(1):S78–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Nauta AC, Grova M, Montoro DT, Zimmermann A, Tsai M, Gurtner GC, Galli SJ, Longaker MT. Evidence that mast cells are not required for healing of splinted cutaneous excisional wounds in mice. PLoS One. 2013;8(3):e59167.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA. Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol. 2012;132(2):458–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, 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. 1986;83(12):4167–71.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Nall AV, Brownlee RE, Colvin CP, Schultz G, Fein D, Cassisi NJ, Nguyen T, Kalra A. Transforming growth factor β1 improves wound healing and random flap survival in normal and irradiated rats. Arch Otolaryngol Head Neck Surg. 1996;122(2):171–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Bullard KM, Longaker MT, Lorenz HP. Fetal wound healing: current biology. World J Surg. 2003;27(1):54–61.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Soo C, Beanes SR, Hu FY, Zhang X, Dang C, Chang G, Wang Y, Nishimura I, Freymiller E, Longaker MT, Lorenz HP, Ting K. Ontogenetic transition in fetal wound transforming growth factor-β regulation correlates with collagen organization. Am J Pathol. 2003;163(6):2459–76.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, Post M. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3. J Clin Invest. 2000;105(5):577–87.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Eslami A, Gallant-Behm CL, Hart DA, Wiebe C, Honardoust D, Gardner H, Häkkinen L, Larjava HS. Expression of integrin αvβ6 and TGF-β in scarless vs. scar-forming wound healing. J Histochem Cytochem. 2009;57(6):543–57.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hsu M, Peled ZM, Chin GS, Liu W, Longaker MT. 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):1787–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Sporn MB, Roberts AB. Transforming growth factor-beta: recent progress and new challenges. J Cell Biol. 1992;119(5):1017–21.CrossRefGoogle Scholar
  42. 42.
    Krummel TM, Michna BA, Thomas BL, Sporn MB, Nelson JM, Salzberg AM, Cohen IK, Diegelmann RF. Transforming growth factor beta (TGF-β) induces fibrosis in a fetal wound model. J Pediatr Surg. 1988;23(7):647–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Shah M, Rorison P, Ferguson MW. The role of transforming growth factors beta in cutaneous scarring. In: Garg HG, Longaker MT, editors. Scarless wound healing. New York, NY: Marcel Dekker; 2000. p. 213–26.CrossRefGoogle Scholar
  44. 44.
    Rolfe KJ, Irvine LM, Grobbelaar AO, Linge C. Differential gene expression in response to transforming growth factor-β1 by fetal and postnatal dermal fibroblasts. Wound Repair Regen. 2007;15(6):897–906.PubMedCrossRefGoogle Scholar
  45. 45.
    Scheid A, Wenger RH, Schäffer L, Camenisch I, Distler O, Ferenc A, Cristina H, Ryan HE, Johnson RS, Wagner KF, Stauffer UG, Bauer C, Gassmann M, Meuli M. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-β3. FASEB J. 2002;16(3):411–3.PubMedCrossRefGoogle Scholar
  46. 46.
    Liechty KW, Adzick NS, Crombleholme TM. Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair. Cytokine. 2000;12(6):671–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Peranteau WH, Zhang L, Muvarak N, Badillo AT, Radu A, Zoltick PW, Liechty KW. IL-10 overexpression decreases inflammatory mediators and promotes regenerative healing in an adult model of scar formation. J Invest Dermatol. 2008;128(7):1852–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Liechty KW, Kim HB, Adzick NS, Crombleholme TM. Fetal wound repair results in scar formation in interleukin-10–deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg. 2000;35(6):866–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Colwell AS, Beanes SR, Soo C, Dang C, Ting K, Longaker MT, Atkinson JB, Lorenz HP. Increased angiogenesis and expression of vascular endothelial growth factor during scarless repair. Plast Reconstr Surg. 2005;115(1):204–12.PubMedGoogle Scholar
  50. 50.
    Amadeu T, Braune A, Mandarim-de-Lacerda C, Porto LC, Desmoulière A, Costa A. Vascularization pattern in hypertrophic scars and keloids: a stereological analysis. Pathol Res Pract. 2003;199(7):469–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Mak K, Manji A, Gallant-Behm C, Wiebe C, Hart DA, Larjava H, Häkkinen L. Scarless healing of oral mucosa is characterized by faster resolution of inflammation and control of myofibroblast action compared to skin wounds in the red Duroc pig model. J Dermatol Sci. 2009;56(3):168–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Mogili NS, Krishnaswamy VR, Jayaraman M, Rajaram R, Venkatraman A, Korrapati PS. Altered angiogenic balance in keloids: a key to therapeutic intervention. Transl Res. 2012;159(3):182–9.CrossRefGoogle Scholar
  53. 53.
    van der Veer WM, Niessen FB, Ferreira JA, Zwiers PJ, de Jong EH, Middelkoop E, Molema G. Time course of the angiogenic response during normotrophic and hypertrophic scar formation in humans. Wound Repair Regen. 2011;19(3):292–301.PubMedCrossRefGoogle Scholar
  54. 54.
    Wilgus TA. Immune cells in the healing skin wound: influential players at each stage of repair. Pharmacol Res. 2008;58(2):112–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Wilgus TA, Ferreira AM, Oberyszyn TM, Bergdall VK, Dipietro LA. Regulation of scar formation by vascular endothelial growth factor. Lab Investig. 2008;88(6):579–90.CrossRefGoogle Scholar
  56. 56.
    Mast BA, Diegelmann RF, Krummel TM, Cohen IK. Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. Matrix. 1993;13(6):441–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Clark R. Wound repair. In: Clark R, editor. The molecular and cellular biology of wound repair. New York: Springer; 1988. p. 3–50.CrossRefGoogle Scholar
  58. 58.
    Longaker MT, Chiu ES, Adzick NS, Stern M, Harrison MR, Stern R. Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid. Ann Surg. 1991;213(4):292.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hu MS, Maan ZN, Wu JC, Rennert RC, Hong WX, Lai TS, Cheung AT, Walmsley GG, Chung MT, McArdle A, Longaker MT, Lorenz HP. Tissue engineering and regenerative repair in wound healing. Ann Biomed Eng. 2014;42(7):1494–507.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Alaish SM, Yager D, Diegelmann RF, Cohen IK. Biology of fetal wound healing: hyaluronate receptor expression in fetal fibroblasts. J Pediatr Surg. 1994;29(8):1040–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Longaker MT, Adzick NS, Hall JL, Stair SE, Crombleholme TM, Duncan BW, Bradley SM, Harrison MR, Stern R. Studies in fetal wound healing VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation. J Pediatr Surg. 1990;25(1):63–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Kennedy CI, Diegelmann RF, Haynes JH, Yager DR. Proinflammatory cytokines differentially regulate hyaluronan synthase isoforms in fetal and adult fibroblasts. J Pediatr Surg. 2000;35(6):874–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Whitby D, Ferguson M. The extracellular matrix of lip wounds in fetal, neonatal and adult mice. Development. 1991;112(2):651–68.PubMedGoogle Scholar
  64. 64.
    Coolen NA, Schouten KC, Middelkoop E, Ulrich MM. Comparison between human fetal and adult skin. Arch Dermatol Res. 2010;302(1):47–55.PubMedCrossRefGoogle Scholar
  65. 65.
    Whitby DJ, Longaker MT, Harrison MR, Adzick NS, Ferguson MW. Rapid epithelialisation of fetal wounds is associated with the early deposition of tenascin. J Cell Sci. 1991;99(3):583–6.PubMedGoogle Scholar
  66. 66.
    Longaker MT, Whitby DJ, Jennings RW, Duncan BW, Ferguson MW, Harrison MR, Adzick NS. Fetal diaphragmatic wounds heal with scar formation. J Surg Res. 1991;50(4):375–85.PubMedCrossRefGoogle Scholar
  67. 67.
    Cass DL, Bullard KM, Sylvester KG, Yang EY, Sheppard D, Herlyn M, Adzick NS. Epidermal integrin expression is upregulated rapidly in human fetal wound repair. J Pediatr Surg. 1998;33(2):312–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Beanes SR, Dang C, Soo C, Wang Y, Urata M, Ting K, Fonkalsrud EW, Benhaim P, Hedrick MH, Atkinson JB, Lorenz HP. Down-regulation of decorin, a transforming growth factor–beta modulator, is associated with scarless fetal wound healing. J Pediatr Surg. 2001;36(11):1666–71.PubMedCrossRefGoogle Scholar
  69. 69.
    Burd DAR, Longaker MT, Adzick NS, Harrison MR, Ehrlich HP. Foetal wound healing in a large animal model: the deposition of collagen is confirmed. Br J Plast Surg. 1990;43(5):571–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Merkel JR, DiPaolo BR, Hallock GG, Rice DC. Type I and type III collagen content of healing wounds in fetal and adult rats. Proc Soc Exp Biol Med. 1988;187(4):493–7.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Carter R, Jain K, Sykes V, Lanning D. Differential expression of procollagen genes between mid-and late-gestational fetal fibroblasts. J Surg Res. 2009;156(1):90–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Lovvorn HN 3rd, Cheung DT, Nimni ME, Perelman N, Estes JM, Adzick NS. Relative distribution and crosslinking of collagen distinguish fetal from adult sheep wound repair. J Pediatr Surg. 1999;34(1):218–23.PubMedCrossRefGoogle Scholar
  73. 73.
    Dang CM, Beanes SR, Lee H, Zhang X, Soo C, Ting K. Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metalloproteinase ratio. Plast Reconstr Surg. 2003;111(7):2273–85.PubMedCrossRefGoogle Scholar
  74. 74.
    Huang C, Leavitt T, Bayer LR, Orgill DP. Effect of negative pressure wound therapy on wound healing. Curr Probl Surg. 2014;51(7):301–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Wong VW, Beasley B, Zepeda J, Dauskardt RH, Yock PG, Longaker MT, Gurtner GC. A mechanomodulatory device to minimize incisional scar formation. Adv Wound Care (New Rochelle). 2013;2(4):185–94.CrossRefGoogle Scholar
  76. 76.
    Junker JP, Kratz C, Tollbäck A, Kratz G. Mechanical tension stimulates the transdifferentiation of fibroblasts into myofibroblasts in human burn scars. Burns. 2008;34(7):942–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Baur P, Larson D, Stacey T. The observation of myofibroblasts in hypertrophic scars. Surg Gynecol Obstet. 1975;141(1):22–6.PubMedGoogle Scholar
  78. 78.
    Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122(1):103–11.PubMedCrossRefGoogle Scholar
  79. 79.
    Estes JM, Vande Berg JS, Adzick NS, MacGillivray TE, Desmoulière A, Gabbiani G. Phenotypic and functional features of myofibroblasts in sheep fetal wounds. Differentiation. 1994;56(3):173–81.PubMedCrossRefGoogle Scholar
  80. 80.
    Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J Cell Biol. 2007;179(6):1311–23.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ferdman AG, Yannas LV. Scattering of light from histologic sections: a new method for the analysis of connective tissue. J Invest Dermatol. 1993;100(5):710–6.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Yannas IV. Similarities and differences between induced organ regeneration in adults and early foetal regeneration. J R Soc Interface. 2005;2(5):403–17.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Rolfe KJ, Richardson J, Vigor C, Irvine LM, Grobbelaar AO, Linge C. A role for TGF-β1-induced cellular responses during wound healing of the non-scarring early human fetus? J Invest Dermatol. 2007;127(11):2656–67.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Martin P, Lewis J. Actin cables and epidermal movement in embryonic wound healing. Nature. 1992;360(6400):179–83.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Brock J, Midwinter K, Lewis J, Martin P. Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation. J Cell Biol. 1996;135(4):1097–107.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Yates CC, Hebda P, Wells A. Skin wound healing and scarring: fetal wounds and regenerative restitution. Birth Defects Res Part C Embryo Today. 2012;96(4):325–33.CrossRefGoogle Scholar
  87. 87.
    Ridge M, Wright V. The directional effects of skin: a bio-engineering study of skin with particular reference to Langer’s lines. J Invest Dermatol. 1966;46(4):341–6.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Cox H. The cleavage lines of the skin. Br J Surg. 1941;29(114):234–40.CrossRefGoogle Scholar
  89. 89.
    Piérard GE, Lapière CM. Microanatomy of the dermis in relation to relaxed skin tension lines and Langer's lines. Am J Dermatopathol. 1987;9(3):219–24.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Wong VW, Rustad KC, Akaishi S, Sorkin M, Glotzbach JP, Januszyk M, Nelson ER, Levi K, Paterno J, Vial IN, Kuang IA, Longaker MT, Gurtner GC. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med. 2012;18(1):148–52.CrossRefGoogle Scholar
  91. 91.
    Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.PubMedCentralCrossRefGoogle Scholar
  92. 92.
    Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010;126(4):1172–80.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Nodder S, Martin P. Wound healing in embryos: a review. Anat Embryol. 1997;195(3):215–28.CrossRefGoogle Scholar
  94. 94.
    Falanga V, Kirsner RS. Low oxygen stimulates proliferation of fibroblasts seeded as single cells. J Cell Physiol. 1993;154(3):506–10.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1(1):13–23.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Chin GS, Lee S, Hsu M, Liu W, Kim WJ, Levinson H, Longaker MT. Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro. Plast Reconstr Surg. 2001;107(3):769–76.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Ellis IR, Schor SL. Differential effects of TGF-β1 on hyaluronan synthesis by fetal and adult skin fibroblasts: implications for cell migration and wound healing. Exp Cell Res. 1996;228(2):326–33.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K, Simons BD, Charalambous M, Ferron SR, Herault Y, Pavlovic G, Ferguson-Smith AC, Watt FM. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature. 2013;504(7479):277–81.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, Januszyk M, Krampitz GW, Gurtner GC, Lorenz HP, Weissman IL, Longaker MT. Skin fibrosis: identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015;348(6232):aaa2151.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med. 2012;18(8):1262–70.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Degen KE, Gourdie RG. Embryonic wound healing: a primer for engineering novel therapies for tissue repair. Birth Defects Res C Embryo Today. 2012;96(3):258–70.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Mackenzie TC, Flake AW. Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep. Blood Cells Mol Dis. 2001;27(3):601–4.CrossRefGoogle Scholar
  103. 103.
    Klein JD, Turner CG, Steigman SA, Ahmed A, Zurakowski D, Eriksson E, Fauza DO. Amniotic mesenchymal stem cells enhance normal fetal wound healing. Stem Cells Dev. 2010;20(6):969–76.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Wu SC, Marston W, Armstrong DG. Wound care: the role of advanced wound healing technologies. J Vasc Surg. 2010;52(3 Suppl):59S–66S.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Gauglitz GG, Jeschke MG. Combined gene and stem cell therapy for cutaneous wound healing. Mol Pharm. 2011;8(5):1471–9.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Chung HJ, Steplewski A, Chung KY, Uitto J, Fertala A. Collagen fibril formation: a new target to limit fibrosis. J Biol Chem. 2008;283(38):25879–86.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Iocono JA, Ehrlich HP, Keefer KA, Krummel TM. Hyaluronan induces scarless repair in mouse limb organ culture. J Pediatr Surg. 1998;33(4):564–7.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Frank S, Madlener M, Werner S. Transforming growth factors 1, 2, and 3 and their receptors are differentially regulated during normal and impaired wound healing. J Biol Chem. 1996;271(17):10188–93.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Chen X, Peng LH, Li N, Li QM, Li P, Fung KP, Leung PC, Gao JQ. The healing and anti-scar effects of astragaloside IV on the wound repair in vitro and in vivo. J Ethnopharmacol. 2012;139(3):721–7.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Li HL, Chen LP, Hu YH, Qin Y, Liang G, Xiong YX, Chen QX. Crocodile oil enhances cutaneous burn wound healing and reduces scar formation in rats. Acad Emerg Med. 2012;19(3):265–73.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Jia S, Xie P, Hong SJ, Galiano R, Singer A, Clark RA, Mustoe TA. Intravenous curcumin efficacy on healing and scar formation in rabbit ear wounds under nonischemic, ischemic, and ischemia–reperfusion conditions. Wound Repair Regen. 2014;22(6):730–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Choi BM, Kwak HJ, Jun CD, Park SD, Kim KY, Kim HR, Chung HT. Control of scarring in adult wounds using antisense transforming growth factor-β1 oligodeoxynucleotides. Immunol Cell Biol. 1996;74(2):144–50.PubMedCrossRefGoogle Scholar
  113. 113.
    Shah M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor β. Lancet. 1992;339(8787):213–4.PubMedCrossRefGoogle Scholar
  114. 114.
    Shah M, Foreman DM, Ferguson M. 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(3):985–1002.PubMedGoogle Scholar
  115. 115.
    Shah M, Foreman DM, Ferguson M. Neutralising antibody to TGF-beta 1, 2 reduces cutaneous scarring in adult rodents. J Cell Sci. 1994;107(5):1137–57.PubMedGoogle Scholar
  116. 116.
    Rhett JM, Ghatnekar GS, Palatinus JA, O'Quinn M, Yost MJ, Gourdie RG. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol. 2008;26(4):173–80.PubMedCrossRefGoogle Scholar
  117. 117.
    Diridollou S, Vabre V, Berson M, Vaillant L, Black D, Lagarde JM, Grégoire JM, Gall Y, Patat F. Skin ageing: changes of physical properties of human skin in vivo. Int J Cosmet Sci. 2001;23(6):353–62.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Ashcroft GS, Dodsworth J, van Boxtel E, Tarnuzzer RW, Horan MA, Schultz GS, Ferguson MW. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels. Nat Med. 1997;3(11):1209–15.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Nelson L. The role of oestrogen in skin. PhD Thesis. Bradford: School of Life Sciences, University of Bradford; 2006.Google Scholar
  120. 120.
    Hu D, Hughes MA, Cherry GW. Topical tamoxifen—a potential therapeutic regime in treating excessive dermal scarring? Br J Plast Surg. 1998;51(6):462–9.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, Green CR, Becker DL. Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol. 2003;13(19):1697–703.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Davis NG, Phillips A, Becker DL. Connexin dynamics in the privileged wound healing of the buccal mucosa. Wound Repair Regen. 2013;21(4):571–8.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Debels H, Hamdi M, Abberton K, Morrison W. Dermal matrices and bioengineered skin substitutes: a critical review of current options. Plast Reconstr Surg Global Open. 2015;3(1):e284.CrossRefGoogle Scholar
  124. 124.
    Hodgkinson T, Bayat A. Dermal substitute-assisted healing: enhancing stem cell therapy with novel biomaterial design. Arch Dermatol Res. 2011;303(5):301–15.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Ziade M, Domergue S, Batifol D, Jreige R, Sebbane M, Goudot P, Yachouh J. Use of botulinum toxin type A to improve treatment of facial wounds: a prospective randomised study. J Plast Reconstr Aesthet Surg. 2013;66(2):209–14.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Gauglitz G, Bureik D, Dombrowski Y, Pavicic T, Ruzicka T, Schauber J. Botulinum toxin A for the treatment of keloids. Skin Pharmacol Physiol. 2012;25(6):313–8.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Atkinson JA, McKenna KT, Barnett AG, McGrath DJ, Rudd M. A randomized, controlled trial to determine the efficacy of paper tape in preventing hypertrophic scar formation in surgical incisions that traverse Langer’s skin tension lines. Plast Reconstr Surg. 2005;116(6):1648–56.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Rosengren H, Askew DA, Heal C, Buettner PG, Humphreys WO, Semmens LA. Does taping torso scars following dermatologic surgery improve scar appearance? Dermatol Pract Conceptual. 2013;3(2):75–83.Google Scholar
  129. 129.
    Lo DD, Zimmermann AS, Nauta A, Longaker MT, Lorenz HP. Scarless fetal skin wound healing update. Birth Defects Res C Embryo Today. 2012;96(3):237–47.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Aarabi S, Bhatt KA, Shi Y, Paterno J, Chang EI, Loh SA, Holmes JW, Longaker MT, Yee H, Gurtner GC. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 2007;21(12):3250–61.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Puri N, Talwar A. The efficacy of silicone gel for the treatment of hypertrophic scars and keloids. J Cutan Aesthet Surg. 2009;2(2):104–6.PubMedCentralCrossRefPubMedGoogle Scholar
  132. 132.
    Fulton JE. Silicone gel sheeting for the prevention and management of evolving hypertrophic and keloid scars. Dermatol Surg. 1995;21(11):947–51.CrossRefGoogle Scholar
  133. 133.
    O’Brien L, Jones DJ. Silicone gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2013;(9):CD003826.Google Scholar
  134. 134.
    Lim AF, Weintraub J, Kaplan EN, Januszyk M, Cowley C, McLaughlin P, Beasley B, Gurtner GC, Longaker MT. The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial. Plast Reconstr Surg. 2014;133(2):398–405.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Longaker MT, Rohrich RJ, Greenberg L, Furnas H, Wald R, Bansal V, Seify H, Tran A, Weston J, Korman JM, Chan R, Kaufman D, Dev VR, Mele JA, Januszyk M, Cowley C, McLaughlin P, Beasley B, Gurtner GC. A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation. Plast Reconstr Surg. 2014;134(3):536–46.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michael S. Hu
    • 1
    • 2
    • 3
    • 4
    Email author
  • Mimi R. Borrelli
    • 2
    • 3
  • Michael T. Longaker
    • 2
    • 3
    • 4
  • H. Peter Lorenz
    • 3
    • 4
  1. 1.Department of Plastic SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Stanford Institute for Stem Cell Biology and Regenerative MedicineStanford University School of MedicineStanfordUSA
  3. 3.Division of Plastic and Reconstructive Surgery, Department of SurgeryStanford School of MedicineStanfordUSA
  4. 4.Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of SurgeryStanford University School of MedicineStanfordUSA

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