Introduction

  • 1  Wong VW, Gurtner GC, Longaker MT. Wound healing: a paradigm for regeneration. Mayo Clin Proc 2013;88:102231. Cross Ref link Pubmed link
  • 2  Albina JE, Reichner JS. Oxygen and the regulation of gene expression in wounds. Wound Repair Regen 2003;11:44551. Cross Ref link Pubmed link
  • 3  Hong WX, Hu MS, Esquivel M, et al. The role of hypoxia‐inducible factor in wound healing. Adv Wound Care (New Rochelle) 2014;3:3909. Cross Ref link Pubmed link
  • 4  Schffer M, Bongartz M, Fischer S, et al. Nitric oxide restores impaired healing in normoglycaemic diabetic rats. J Wound Care 2007;16:31116. Cross Ref link Pubmed link
  • 5  Murad A, Nath AK, Cha ST, et al. Leptin is an autocrine/paracrine regulator of wound healing. FASEB J 2003;17:18957. Pubmed link
  • 6  Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83:83570. Pubmed link
  • 7  Müller AK, Meyer M, Werner S. The roles of receptor tyrosine kinases and their ligands in the wound repair process. Semin Cell Dev Biol 2012;23:96370. Cross Ref link Pubmed link
  • 8  Campbell L, Emmerson E, Davies F, et al. Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities. J Exp Med 2010;207:182533. Cross Ref link Pubmed link
  • 9  Gilliver SC, Ashworth JJ, Ashcroft GS. The hormonal regulation of cutaneous wound healing. Clin Dermatol 2007;25:5662. Cross Ref link Pubmed link
  • 10  Gilliver SC, Ashworth JJ, Mills SJ, et al. Androgens modulate the inflammatory response during acute wound healing. J Cell Sci 2006;119:72232. Cross Ref link Pubmed link
  • 11  Ashcroft GS, Mills SJ. Androgen receptor‐mediated inhibition of cutaneous wound healing. J Clin Invest 2002;110:61524. Cross Ref link Pubmed link
  • 12  Poonawala T, Levay‐Young BK, Hebbel RP, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen 2005;13:16574. Cross Ref link Pubmed link
  • 13  Herrick SE, Ashcroft G, Ireland G, et al. Up‐regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest 1997;77:2818. Pubmed link
  • 14  Pirilä E, Korpi JT, Korkiamäki T, et al. Collagenase‐2 (MMP‐8) and matrilysin‐2 (MMP‐26) expression in human wounds of different etiologies. Wound Repair Regen 2007;15:4757. Cross Ref link Pubmed link
  • 15  Vaalamo M, Leivo T, Saarialho‐Kere U. Differential expression of tissue inhibitors of metalloproteinases (TIMP‐1, ‐2, ‐3, and ‐4) in normal and aberrant wound healing. Hum Pathol 1999;30:795802. Cross Ref link Pubmed link
  • 16  Sundaram GM, Common JE, Gopal FE, et al. ‘See‐saw’ expression of microRNA‐198 and FSTL1 from a single transcript in wound healing. Nature 2013;495:1036. Cross Ref link Pubmed link
  • 17  Ferguson MWJ, Herrick SE, Spencer MJ, et al. The histology of diabetic ulcers. Diabet Med 1996;13:5303.
  • 18  Yannas IV, Kwan MD, Longaker MT. Early fetal healing as a model for adult organ regeneration. Tissue Eng 2007;13:178998. Cross Ref link Pubmed link
  • 19  Gosain A, DiPietro LA. Aging and wound healing. World J Surg 2004;28:3216. Cross Ref link Pubmed link
  • 20  Ebrecht M, Hextall J, Kirtley LG, et al. Perceived stress and cortisol levels predict speed of wound healing in healthy male adults. Psychoneuroendocrinol 2004;29:798809. Cross Ref link

Inflammation and the immune response

  • 21  Eming SA, Krieg T. Molecular mechanisms of VEGF‐A action during tissue repair. J Investig Dermatol Symp Proc 2006;11:7986. Cross Ref link Pubmed link
  • 22  Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007;127:51425. Cross Ref link Pubmed link
  • 23  Ishida Y, Kondo T, Kimura A, Matsushima K, Mukaida N. Absence of IL‐1 receptor antagonist impaired wound healing along with aberrant NF‐kappaB activation and a reciprocal suppression of TGF‐beta signal pathway. J Immunol 2006;176:5598606. Cross Ref link Pubmed link
  • 24  Kim MH, Gorouhi F, Ramirez S, et al. Catecholamine stress alters neutrophil trafficking and impairs wound healing byβ2‐adrenergic receptor‐mediated upregulation of IL‐6. J Invest Dermatol 2014;134:80917. Cross Ref link Pubmed link
  • 25  Subramaniam M, Saffaripour S, Van De Water L, et al. Role of endothelial selectins in wound repair. Am J Pathol 1997;150:17019. Pubmed link
  • 26  Szpaderska AM, Egozi EI, Gamelli RL, DiPietro LA. The effect of thrombocytopenia on dermal wound healing. J Invest Dermatol 2003;120:11307. Cross Ref link Pubmed link
  • 27  Peters T, Sindrilaru A, Hinz B, et al. Wound‐healing defect of CD18(–/–) mice due to a decrease in TGF‐beta1 and myofibroblast differentiation. EMBO J 2005;24:340010. Cross Ref link Pubmed link
  • 28  Leibovich SJ, Ross R. The role of the macrophage in wound repair. Am J Pathol 1975;78:71100. Pubmed link
  • 29  Wang XJ, Han G, Owens P, et al. Role of TGF beta‐mediated inflammation in cutaneous wound healing. J Investig Dermatol Symp Proc 2006;11:11217. Cross Ref link Pubmed link
  • 30  Muro AF, Chauhan AK, Gajovic S, et al. Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol 2003;162:4960. Cross Ref link
  • 31  Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001;69:51321. Pubmed link
  • 32  Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg 2004;187:S116. Cross Ref link
  • 33  Yin H, Li X, Hu S, et al. IL‐33 accelerates cutaneous wound healing involved in upregulation of alternatively activated macrophages. Mol Immunol 2013;56:34753. Cross Ref link Pubmed link
  • 34  Sharp LL, Jameson JM, Cauvi G, et al. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin‐like growth factor 1. Nat Immunol 2005;6:739. Cross Ref link Pubmed link
  • 35  Gay D, Kwon O, Zhang Z, et al. Fgf9 from dermal γδT cells induces hair follicle neogenesis after wounding. Nat Med 2013;19:91623. Cross Ref link Pubmed link
  • 36  Jameson JM, Cauvi G, Sharp LL, et al. Gammadelta T cell‐induced hyaluronan production by epithelial cells regulates inflammation. J Exp Med 2005;201:126979. Cross Ref link Pubmed link
  • 37  Melder RJ, Koenig GC, Witver BP, et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 1996;2:9927. Cross Ref link Pubmed link
  • 38  Gallucci RM, Lee EG, Tomasek JJ. IL‐6 modulates alpha‐smooth muscle actin expression in dermal fibroblasts from IL‐6‐deficient mice. J Invest Dermatol 2006;126:5618. Cross Ref link Pubmed link
  • 39  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;13:11228. Cross Ref link Pubmed link
  • 40  Braun S, Hanselmann C, Gassmann MG, et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol 2002;22:5492505. Cross Ref link Pubmed link
  • 41  Chen L, Guo S, Ranzer MJ, DiPietro LA. Toll‐like receptor 4 has an essential role in early skin wound healing. J Invest Dermatol 2013;133:25867. Cross Ref link Pubmed link

Re‐epithelialization

  • 42  Rotty JD, Coulombe PA. A wound‐induced keratin inhibits Src activity during keratinocyte migration and tissue repair. J Cell Biol 2012;197:3819. Cross Ref link Pubmed link
  • 43  Satish L, Blair HC, Glading A, Wells A. Interferon‐inducible protein 9 (CXCL11)‐induced cell motility in keratinocytes requires calcium flux‐dependent activation of mu‐calpain. Mol Cell Biol 2005;25:192241. Cross Ref link Pubmed link
  • 44  Jiang CK, Magnaldo T, Ohtsuki M, et al. Epidermal growth factor and transforming growth factor‐α specifically induce the activation‐ and hyperproliferation‐associated keratins 6 and 16. Proc Natl Acad Sci USA 1993;90:67869. Cross Ref link Pubmed link
  • 45  Ponugoti B, Xu F, Zhang C, Tian C, Pacios S, Graves DT. FOXO1 promotes wound healing through the up‐regulation of TGF‐β1 and prevention of oxidative stress. J Cell Biol 2013;203:32743. Cross Ref link Pubmed link
  • 46  Chmielowiec J, Borowiak M, Morkel M, et al. c‐Met is essential for wound healing in the skin. J Cell Biol 2007;177:15162. Cross Ref link Pubmed link
  • 47  Tscharntke M, Pofahl R, Chrostek‐Grashoff A, et al. Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1. J Cell Sci 2007;120:148090. Cross Ref link Pubmed link
  • 48  Miao Q, Ku AT, Nishino Y, et al. Tcf3 promotes cell migration and wound repair through regulation of lipocalin 2. Nat Commun 2014;5:4088. Pubmed link
  • 49  Li W, Nadelman C, Henry G, et al. The p38‐MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen. J Invest Dermatol 2001;117:160111. Cross Ref link Pubmed link
  • 50  Sano S, Itami S, Takeda K, et al. Keratinocyte specific ablation of Stat3 exhibits impaired skin remodelling but does not affect skin morphogenesis. EMBO J 1999;18:465768. Cross Ref link Pubmed link
  • 51  Yates S, Rayner TE. Transcription factor activation in response to cutaneous injury: role of AP‐1 in re‐epithelialization. Wound Repair Regen 2002;10:515. Cross Ref link Pubmed link
  • 52  Di‐Poi N, Tan NS, Michalik L, et al. Anti‐apoptotic role of PPARβ in keratinocytes via transcriptional control of the Akt1 pathway. Mol Cell 2002;10:72133. Cross Ref link Pubmed link
  • 53  Zanet J, Pibre S, Jacquet C, et al. Endogenous Myc controls mammalian epidermal cell size, hyperproliferation, endoreplication and stem cell amplification. J Cell Sci 2005;118:1693704. Cross Ref link Pubmed link
  • 54  Morris VL, Chan BM. Interaction of epidermal growth factor, Ca2+, and matrix metalloproteinase‐9 in primary keratinocyte migration. Wound Repair Regen 2007;15:90715. Cross Ref link Pubmed link
  • 55  Romer J, Lund LR, Eriksen J, et al. Differential expression of urokinase‐type plasminogen activator and its type‐1 inhibitor during healing of mouse skin wounds. J Invest Dermatol 1991;97:80311. Cross Ref link Pubmed link
  • 56  O'Toole EA, van Koningsveld R, Chen M, Woodley DT. Hypoxia induces epidermal keratinocyte matrix metalloproteinase‐9 secretion via the protein kinase C pathway. J Cell Physiol 2008;214:4755. Cross Ref link Pubmed link
  • 57  Daniel RJ, Groves RW. Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator. J Invest Dermatol 2002;119:13049. Cross Ref link Pubmed link
  • 58  Romer J, Bugge TH, Pyke C, et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996;2:28792. Cross Ref link Pubmed link
  • 59  Ojeh N, Hiilesvuo K, Wärri A, et al. Ectopic expression of syndecan‐1 in basal epidermis affects keratinocyte proliferation and wound re‐epithelialization. J Invest Dermatol 2008;128:2634. Cross Ref link Pubmed link
  • 60  Clark RAF. Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 1990;94:12834. Cross Ref link
  • 61  Gailit G, Welch MP, Clark RAF. TGF‐β1 stimulates expression of keratinocyte integrins during re‐epithelialization of cutaneous wounds. J Invest Dermatol 1994;103:2217. Cross Ref link Pubmed link
  • 62  Clark RAF, Ashcroft GS, Spencer MJ, et al. Re‐epithelialization of normal excisional wounds is associated with a switch from αVβ5 to αVβ6 integrins. Br J Dermatol 1996;13:4651. Cross Ref link
  • 63  Kubo M, Van De Water L, Plantefaber LC, et al. Fibrinogen and fibrin are anti‐adhesive for keratinocytes: a mechanism for fibrin eschar slough during wound repair. J Invest Dermatol 2001;117:136981. Cross Ref link Pubmed link
  • 64  Li Y, Fan J, Chen M, Li W, Woodley DT. Transforming growth factor‐alpha: a major human serum factor that promotes human keratinocyte migration. J Invest Dermatol 2006;126:2096105. Cross Ref link Pubmed link
  • 65  Bandyopadhyay B, Fan J, Guan S, et al. A ‘traffic control’ role for TGFbeta3: orchestrating dermal and epidermal cell motility during wound healing. J Cell Biol 2006;172:1093105. Cross Ref link Pubmed link
  • 66  Shirakata Y, Kimura R, Nanba D, et al. Heparin‐binding EGF‐like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci 2005;118:236370. Cross Ref link Pubmed link
  • 67  Biggs LC, Naridze RL, DeMali KA, et al. Interferon regulatory factor 6 regulates keratinocyte migration. J Cell Sci 2014;127:28408. Cross Ref link Pubmed link
  • 68  Karvinen S, Pasonen‐Seppanen S, Hyttinen JM, et al. Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3. J Biol Chem 2003;278:49495504. Cross Ref link Pubmed link
  • 69  Niyonsaba F, Ushio H, Nakano N, et al. Antimicrobial peptides human beta‐defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol 2007;127:594604. Cross Ref link Pubmed link
  • 70  Cheng CF, Fan J, Fedesco M, et al. Transforming growth factor alpha (TGFalpha)‐stimulated secretion of HSP90alpha: using the receptor LRP‐1/CD91 to promote human skin cell migration against a TGFbeta‐rich environment during wound healing. Mol Cell Biol 2008;28:334458. Cross Ref link Pubmed link
  • 71  Werner S, Peters KG, Lonkager MT, et al. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 1992;89:6896900. Cross Ref link Pubmed link
  • 72  Henry G, Li W, Garner W, et al. Migration of human keratinocytes in plasma and serum and wound re‐epithelialization. Lancet 2003;361:5746. Cross Ref link Pubmed link
  • 73  Nyström A, Velati D, Mittapalli VR, Fritsch A, Kern JS, Bruckner‐Tuderman L. Collagen VII plays a dual role in wound healing. J Clin Invest 2013;123:3498509. Cross Ref link Pubmed link
  • 74  Fleischmajer R, Utani A, MacDonald ED, et al. Initiation of skin basement membrane formation at the epidermo‐dermal interface involves assembly of laminins through binding to cell membrane receptors. J Cell Sci 1998;111:192940. Pubmed link
  • 75  Compton CC, Press W, Gill JM, et al. The generation of anchoring fibrils by epidermal keratinocytes: a quantitative long‐term study. Epithelial Cell Biol 1995;4:93103. Pubmed link
  • 76  Martins VL, Caley M, O'Toole EA. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res 2013;351:25568. Cross Ref link Pubmed link
  • 77  Czekay RP, Wilkins‐Port CE, Higgins SP, et al. PAI‐1: an integrator of cell signaling and migration. Int J Cell Biol 2011;2011:article ID 562481, doi:10.1155/2011/562481. Cross Ref link Pubmed link

Angiogenesis

  • 78  Baldassarre G, Papa G, Zorzet S, et al. C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc Natl Acad Sci USA 2014;111:420914. Cross Ref link Pubmed link
  • 79  Tassi E, McDonnell K, Gibby KA, et al. Impact of fibroblast growth factor‐binding protein‐1 expression on angiogenesis and wound healing. Am J Pathol 2011;179:222032. Cross Ref link Pubmed link
  • 80  Greaves NS, Ashcroft KJ, Baguneid M, Bayat A. Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing. J Dermatol Sci 2013;72:20617. Cross Ref link Pubmed link
  • 81  Matthies AM, Low QE, Lingen MW, DiPietro LA. Neuropilin‐1 participates in wound angiogenesis. Am J Pathol 2002;160:28996. Cross Ref link Pubmed link
  • 82  Roy S, Patel D, Khanna S, et al. Transcriptome‐wide analysis of blood vessels laser captured from human skin and chronic wound‐edge tissue. Proc Natl Acad Sci USA 2007;104:144727. Cross Ref link Pubmed link
  • 83  Schafer M, Werner S. Transcriptional control of wound repair. Annu Rev Cell Dev Biol 2007;23:6992. Cross Ref link Pubmed link
  • 84  Sen CK, Khanna S, Babior BM, et al. Oxidant‐induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem 2002;277:3328490. Cross Ref link Pubmed link
  • 85  Grunewald M, Avraham I, Dor Y, et al. VEGF‐induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006;124:17589. Cross Ref link Pubmed link
  • 86  Li J, Zhou L, Tran HT, et al. Overexpression of laminin 8 in human dermal microvascular cells promotes angiogenesis‐related functions. J Invest Dermatol 2006;126:43240. Cross Ref link Pubmed link
  • 87  Feng X, Clark RA, Galanakis D, et al. Fibrin and collagen differentially regulate human dermal microvascular endothelial cell integrins: stabilization of alphaV/beta3 mRNA by fibrin 1. J Invest Dermatol 1999;113:91319. Cross Ref link Pubmed link
  • 88  Cornelius LA, Nehring LC, Roby JE, et al. Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. J Invest Dermatol 1995;105:1706. Cross Ref link Pubmed link
  • 89  Cheng N, Brantley DM, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 2002;13:7585. Cross Ref link Pubmed link
  • 90  Paquet‐Fifield S, Schlüter H, Li A, et al. A role for pericytes as microenvironmental regulators of human skin tissue regeneration. J Clin Invest 2009;119:2795806. Pubmed link
  • 91  Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl‐2 and A1 in vascular endothelial cells. J Biol Chem 1998;273:1331316. Cross Ref link Pubmed link

Fibroblast recruitment, matrix synthesis and scarring

  • 92  Schmidt BA, Horsley V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 2013;140:151727 Cross Ref link Pubmed link
  • 93  Driskell RR, Lichtenberger BM, Hoste E, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 2013;504:27781. Cross Ref link Pubmed link
  • 94  Clark RA, An JQ, Greiling D, et al. Fibroblast migration on fibronectin requires three distinct functional domains. J Invest Dermatol 2003;121:695705. Cross Ref link Pubmed link
  • 95  Werner S, Krieg T, Smola H. Keratinocyte–fibroblast interactions in wound healing. J Inv Dermatol 2007;127:9981008. Cross Ref link
  • 96  Müller AK, Meyer M, Werner S. The roles of receptor tyrosine kinases and their ligands in the wound repair process. Semin Cell Dev Biol 2012;23:96370. Cross Ref link Pubmed link
  • 97  Li W, Fan J, Chen M, et al. Mechanism of human dermal fibroblast migration driven by type I collagen and platelet‐derived growth factor‐BB. Mol Biol Cell 2004;15:294309. Cross Ref link Pubmed link
  • 98  Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127:52637. Cross Ref link Pubmed link
  • 99  Borensztajn K, Stiekema J, Nijmeijer S, et al. Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via protease‐activated receptor‐2 activation. Am J Pathol 2008;172:30920. Cross Ref link Pubmed link
  • 100  Sumiyoshi K, Nakao A, Setoguchi Y, et al. Smads regulate collagen gel contraction by human dermal fibroblasts. Br J Dermatol 2003;149:46470. Cross Ref link Pubmed link
  • 101  Martins VL, Caley M, O'Toole EA. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res 2013;351:25568. Cross Ref link Pubmed link
  • 102  Young PK, Grinell F. Metalloproteinase activation cascade after burn injury: a longitudinal analysis of the human wound environment. J Invest Dermatol 1994;103:6604. Cross Ref link Pubmed link
  • 103  Luckett LR, Gallucci RM. Interleukin‐6 (IL‐6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL‐6KO mice. Br J Dermatol 2007;156:116371. Cross Ref link Pubmed link
  • 104  King A, Balaji S, Le LD, Crombleholme TM, Keswani SG. Regenerative wound healing: the role of interleukin‐10. Adv Wound Care (New Rochelle) 2014;3:31523. Cross Ref link Pubmed link
  • 105  Xie J, Bian H, Qi S, et al. Effects of basic fibroblast growth factor on the expression of extracellular matrix and matrix metalloproteinase‐1 in wound healing. Clin Exp Dermatol 2008;33:17682. Cross Ref link Pubmed link
  • 106  Bayat A, McGrouther DA, Ferguson MW. Skin scarring. BMJ 2003;326:8892. Cross Ref link Pubmed link
  • 107  Ashcroft GS, Kielty CM, Horan MA, Ferguson MWJ. Age‐related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. J Pathol 1997;183:809. Cross Ref link Pubmed link
  • 108  Jahoda CA, Reynolds AJ, Oliver RF. Induction of hair growth in ear wounds by cultured dermal papilla cells. J Invest Dermatol 1993;101:58490. Cross Ref link Pubmed link
  • 109  Ito M, Yang Z, Andl T, et al. Wnt‐dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 2007;447:31620. Cross Ref link Pubmed link
  • 110  Hakkinen L, Koivisto L, Gardner H, et al. Increased expression of β6‐integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol 2004;164:22942. Cross Ref link Pubmed link
  • 111  Cha J, Kwak T, Butmarc J, et al. Fibroblasts from non‐healing human chronic wounds show decreased expression of beta ig‐h3, a TGF‐beta inducible protein. J Dermatol Sci 2008;50:1523. Cross Ref link Pubmed link
  • 112  Cowin AJ, Holmes TM, Brosnan P, Ferguson MW. Expression of TGF‐β and its receptors in murine fetal and adult dermal wounds. Eur J Dermatol 2001;11:42431. Pubmed link
  • 113  Beausang E, Floyd H, Dunn KW, et al. A new quantitative scale for clinical scar assessment. Plast Reconstr Surg 1998;102:195461. Cross Ref link Pubmed link
  • 114  Bond JS, Duncan JA, Mason T, et al. Scar redness in humans: how long does it persist after incisional and excisional wounding? Plast Reconstr Surg 2008;121:48796. Cross Ref link Pubmed link
  • 115  Shah M, Foreman DM, Ferguson MWJ. Neutralizing antibody to TGF‐β1,2 reduces scarring in adult rodents. J Cell Sci 1994;107:113757. Pubmed link
  • 116  Shah M, Foreman DM, Ferguson MWJ. Neutralization of TGF‐β1 and TGF‐β2 or exogenous addition of TGF‐β3 to cutaneous rat wounds reduces scarring. J Cell Sci 1995;108:9851002. Pubmed link
  • 117  Arany PR, Flanders KC, Kobayashi T, et al. Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure. Proc Natl Acad Sci USA 2006;103:92505. Cross Ref link Pubmed link
  • 118  Finnson KW, McLean S, Di Guglielmo GM, Philip A. Dynamics of transforming growth factor beta signaling in wound healing and scarring. Adv Wound Care (New Rochelle) 2013;2:195214. Cross Ref link Pubmed link
  • 119  Mori R, Power KT, Wang CM, et al. Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci 2006;119:5193203. Cross Ref link Pubmed link
  • 120  Coutinho P, Qiu C, Frank S, et al. Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury. Br J Plast Surg 2005;58:65867. Cross Ref link Pubmed link
  • 121  Ongstad EL, O'Quinn MP, Ghatnekar GS, Yost MJ, Gourdie RG. A connexin43 mimetic peptide promotes regenerative healing and improves mechanical properties in skin and heart. Adv Wound Care (New Rochelle) 2013;2:5562. Cross Ref link Pubmed link
  • 122  Greaves NS, Ashcroft KJ, Baguneid M, Bayat A. Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing. J Dermatol Sci 2013;72:20617. Cross Ref link Pubmed link

Abnormal wound healing and scarring

  • 123  Claudy AI, Mirshahi M, Soria C, Soria J. Detection of undegraded fibrin and tumour necrosis factor‐α in venous leg ulcers. J Am Acad Dermatol 1991;25:6237. Cross Ref link Pubmed link
  • 124  Falanga V. Growth factors and chronic wounds: the need to understand the microenvironment. J Dermatol 1992;19:66772. Cross Ref link Pubmed link
  • 125  Petreaca ML, Do D, Dhall S, et al. Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans. Wound Repair Regen 2012;20:35366. Cross Ref link Pubmed link
  • 126  Willenborg S, Eming SA. Macrophages – sensors and effectors coordinating skin damage and repair. J Dtsch Dermatol Ges 2014;12(3):21421. Pubmed link
  • 127  Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation by chronic wound fluid. Wound Repair Regen 1993;1:1816. Cross Ref link Pubmed link
  • 128  De Mattei M, Ongaro A, Magaldi S, et al. Time‐ and dose‐dependent effects of chronic wound fluid on human adult dermal fibroblasts. Dermatol Surg 2008;34:34756. Pubmed link
  • 129  Seah CC, Phillips TJ, Howard CE, et al. Chronic wound fluid suppresses proliferation of dermal fibroblasts through a Ras‐mediated signaling pathway. J Invest Dermatol 2005;124:46674. Cross Ref link Pubmed link
  • 130  Raffetto JD, Vasquez R, Goodwin DG, Menzoian JO. Mitogen‐activated protein kinase pathway regulates cell proliferation in venous ulcer fibroblasts. Vasc Endovascular Surg 2006;40:5966. Cross Ref link
  • 131  Katz MH, Alvarez AF, Kirsner RS, et al. Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth. J Am Acad Dermatol 1991;25:10548. Cross Ref link Pubmed link
  • 132  Eming SA, Koch M, Krieger A, et al. Differential proteomic analysis distinguishes tissue repair biomarker signatures in wound exudates obtained from normal healing and chronic wounds. J Proteome Res 2010;9:475866. Cross Ref link Pubmed link
  • 133  Martins VL, Caley M, O'Toole EA. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res 2013;351:25568. Cross Ref link Pubmed link
  • 134  Saarialho‐Kere UK. Patterns of matrix metalloproteinase and TIMP expression in chronic ulcers. Arch Dermatol Res 1998;290(Suppl.): S4754. Cross Ref link Pubmed link
  • 135  Gutiérrez‐Fernández A, Inada M, Balbín M, et al. Increased inflammation delays wound healing in mice deficient in collagenase‐2 (MMP‐8). FASEB J 2007;21:258091. Cross Ref link Pubmed link
  • 136  O'Toole EA. Extracellular matrix and keratinocyte migration. Clin Exp Dermatol 2001;26:52530. Cross Ref link Pubmed link
  • 137  Grice EA, Segre JA. Interaction of the microbiome with the innate immune response in chronic wounds. Adv Exp Med Biol 2012;946:5568. Cross Ref link Pubmed link
  • 138  Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther 2014;31:81736. Cross Ref link Pubmed link
  • 139  Pepe D, Elliott CG, Forbes TL, Hamilton DW. Detection of galectin‐3 and localization of advanced glycation end products (AGE) in human chronic skin wounds. Histol Histopathol 2014;29:2518. Pubmed link
  • 140  Krisp C, Jacobsen F, McKay MJ, Molloy MP, Steinstraesser L, Wolters DA. Proteome analysis reveals antiangiogenic environments in chronic wounds of diabetes mellitus type 2 patients. Proteomics 2013;13:267081. Cross Ref link Pubmed link
  • 141  Bannon P, Wood S, Restivo T, Campbell L, Hardman MJ, Mace KA. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. Dis Model Mech 2013;6:143447. Cross Ref link Pubmed link
  • 142  Kim KA, Shin YJ, Kim JH, et al. Dysfunction of endothelial progenitor cells under diabetic conditions and its underlying mechanisms. Arch Pharm Res 2012;35:22334. Cross Ref link Pubmed link
  • 143  Ekstrand AJ, Cao R, Bjorndahl M, et al. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY‐induced angiogenesis and delayed wound healing. Proc Natl Acad Sci USA 2003;100:60338. Cross Ref link Pubmed link
  • 144  Cheng CF, Sahu D, Tsen F, et al. A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice. J Clin Invest 2011;121:434861. Cross Ref link Pubmed link
  • 145  Marneros AG, Norris JEC, Watanabe S, et al. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 2004;122:112632. Cross Ref link Pubmed link
  • 146  Nakashima M, Chung S, Takahashi A, et al. A genome‐wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat Genet 2010;42:76871. Cross Ref link Pubmed link
  • 147  Diegelmann RF, Cohen IK, McCoy BJ. Growth kinetics and collagen synthesis of normal skin, normal scar and keloid fibroblasts in vitro. J Cell Physiol 1979;98:3416. Cross Ref link Pubmed link
  • 148  Russell JD, Witt WS. Cell size and growth characteristics of cultured fibroblasts isolated from normal and keloid tissue. Plast Reconstr Surg 1976;57:20712. Cross Ref link Pubmed link
  • 149  Szulgit G, Rudolph R, Wandel A, et al. Alterations in fibroblast α1β1 integrin collagen receptor expression in keloids and hypertrophic scars. J Invest Dermatol 2002;118:40915. Cross Ref link Pubmed link
  • 150  Akasaka Y, Fujita K, Ishikawa Y, et al. Detection of apoptosis in keloids and a comparative study on apoptosis between keloids, hypertrophic scars, normal healed flat scars, and dermatofibroma. Wound Repair Regen 2001;9:5016. Cross Ref link Pubmed link
  • 151  Lim IJ, Phan TT, Bay BH, et al. Fibroblasts cocultured with keloid keratinocytes: normal fibroblasts secrete collagen in a keloid‐like manner. Am J Physiol Cell Physiol 2002;283:C21222. Cross Ref link Pubmed link
  • 152  Hahn JM, Glaser K, McFarland KL, Aronow BJ, Boyce ST, Supp DM. Keloid‐derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology. Wound Repair Regen 2013;21:53044. Cross Ref link Pubmed link
  • 153  Bagabir R, Byers RJ, Chaudhry IH, Müller W, Paus R, Bayat A. Site‐specific immunophenotyping of keloid disease demonstrates immune upregulation and the presence of lymphoid aggregates. Br J Dermatol 2012;167:105366. Cross Ref link Pubmed link

Age‐related changes in wound healing

  • 154  Martin P. Wound healing: aiming for perfect skin regeneration. Science 1997;276:7581. Cross Ref link Pubmed link
  • 155  Ferguson MWJ, Whitby DJ, Shah M, et al. Scar formation: the spectral nature of fetal and adult wound repair. Plast Reconstr Surg 1996;97:85460. Cross Ref link Pubmed link
  • 156  Helmo FR, Machado JR, Guimarães CS, Teixeira V de P, dos Reis MA, Corrêa RR. Fetal wound healing biomarkers. Dis Markers 2013;35:93944. Cross Ref link Pubmed link
  • 157  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;132:45865. Cross Ref link Pubmed link
  • 158  Whitby DJ, Ferguson MWJ. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol 1991;147:20715. Cross Ref link Pubmed link
  • 159  Shah M, Foreman DM, Ferguson MWJ. Control of scarring in adult wounds by neutralizing antibodies to transforming growth factor‐β (TGF‐β). Lancet 1992;339:21314. Cross Ref link Pubmed link
  • 160  Shyh‐Chang N, Zhu H, Yvanka de Soysa T, et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 2013;155:77892. Cross Ref link Pubmed link
  • 161  Ashcroft GS, Horan MA, Ferguson MWJ. The effect of ageing on cutaneous wound healing. J Anat 1995;187:126. Pubmed link
  • 162  Fleming TH, Theilen TM, Masania J, et al. Aging‐dependent reduction in glyoxalase 1 delays wound healing. Gerontology 2013;59:42737. Cross Ref link Pubmed link
  • 163  Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J Immunol 2013;190:17465. Cross Ref link Pubmed link
  • 164  Ashcroft GS, Herrick SE, Tarnuzzer RW, et al. Human ageing impairs injury induced in vivo expression of tissue inhibitor of matrix metalloproteinases (TIMP)‐1 and ‐2 proteins and mRNA. J Pathol 1997;183:16976. Cross Ref link Pubmed link
  • 165  Emmerson E, Hardman MJ. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology 2012;13:320. Cross Ref link Pubmed link
  • 166  Gilliver SC, Ruckshanthi JP, Atkinson SJ, Ashcroft GS. Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing. Lab Invest 2007;87:87181. Cross Ref link Pubmed link
  • 167  Ashcroft GS, Dodsworth J, Van Boxtel E, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF‐β1 levels. Nat Med 1997;3:120915. Cross Ref link Pubmed link
  • 168  Hardman MJ, Emmerson E, Campbell L, Ashcroft GS. Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology 2008;149:5517. Cross Ref link Pubmed link
  • 169  Midgley AC, Bowen T, Phillips AO, Steadman R. MicroRNA‐7 inhibition rescues age‐associated loss of epidermal growth factor receptor and hyaluronan‐dependent differentiation in fibroblasts. Aging Cell 2014;13:23544. Cross Ref link Pubmed link

Physiological basis of the treatment of wounds

  • 170  Dunphy JE, Jackson DS. Practical applications of experimental studies in the care of the primarily closed wound. Am J Surg 1982;104:27382. Cross Ref link
  • 171  Driskell RR, Lichtenberger BM, Hoste E, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 2013;504:27781. Cross Ref link Pubmed link
  • 172  Jonkman MF, Hoeksma EA, Niewenhuis P. Accelerated epithelialization under a highly water vapour permeable wound dressing is associated with increased precipitation of fibrin (ogen) and fibronectin. J Invest Dermatol 1990;94:47784. Cross Ref link Pubmed link

Novel therapies for wound healing

    Growth factors to augment wound healing

    • 173  Leahy PJ, Lawrence WT. Biologic enhancement of wound healing. Clin Plast Surg 2007;34:65971. Cross Ref link Pubmed link
    • 174  Braund R, Hook S, Medlicott NJ. The role of topical growth factors in chronic wounds. Curr Drug Deliv 2007;4:195204. Cross Ref link Pubmed link
    • 175  Wong T, McGrath JA, Navsaria H. The role of fibroblasts in tissue engineering and regeneration. Br J Dermatol 2007;156:114955. Cross Ref link Pubmed link
    • 176  Trengove NJ, Stacey MC, MacAuley S, et al. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen 1999;7:44252. Cross Ref link Pubmed link
    • 177  Huiyong Z, Yong L, Yunxiao S, Wuling Z, Jingjing L, Taiming L. Generation of a chimeric plasmin‐resistant VEGF165/VEGF183 (132‐158) protein and its comparative activity. Protein Pept Lett 2013;20:94754. Cross Ref link Pubmed link
    • 178  Schweigerer L. Basic fibroblast growth factor as a wound healing hormone. Trends Pharmacol Sci 1988;9:4278. Cross Ref link Pubmed link
    • 179  Mustoe TA, Pierce GF, Thomason A, et al. Accelerated healing of incisional wounds in rats induced by transforming growth factor β. Science 1987;237:13336. Cross Ref link Pubmed link
    • 180  Brown GL, Nanney LB, Griffen J, et al. Enhancement of healing by topical treatment with epidermal growth factor. N Engl J Med 1989;321:769. Cross Ref link Pubmed link
    • 181  Laato N, Niinikoski J, Gerbin B, et al. Stimulation of wound healing by epidermal growth factor. Ann Surg 1986;203:37981. Cross Ref link Pubmed link
    • 182  Schultz GS, White MW, Mitchell R, et al. Epithelial wound healing enhanced by transforming growth factor‐α and vaccinia growth factor. Science 1987;235:3502. Cross Ref link Pubmed link
    • 183  Robson MC, Phillips TJ, Falanga V, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor‐2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001;9:34752. Cross Ref link Pubmed link
    • 184  Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant 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;21:8227. Cross Ref link Pubmed link
    • 185  Ziyadeh N, Fife D, Walker AM, Wilkinson GS, Seeger JD. A matched cohort study of the risk of cancer in users of becaplermin. Adv Skin Wound Care 2011;24:319. Cross Ref link Pubmed link
    • 186  Cheng CF, Sahu D, Tsen F, et al. A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice. J Clin Invest 2011;121:434861. Cross Ref link Pubmed link

    Stem cell therapy

    • 187  Hsu YC, Li L, Fuchs E. Emerging interactions between skin stem cells and their niches. Nat Med 2014;20:84756. Cross Ref link Pubmed link
    • 188  Teng M, Huang Y, Zhang H. Application of stems cells in wound healing‐an update. Wound Repair Regen 2014;22:15160. Cross Ref link Pubmed link
    • 189  Tamai K, Yamazaki T, Chino T, et al. PDGFRalpha‐positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci USA 2011;108:660914. Cross Ref link Pubmed link
    • 190  Wagner JE, Ishida‐Yamamoto A, McGrath JA, et al. Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 2010;363:62939. Cross Ref link Pubmed link
    • 191  Nishimura Y, Li M, Qin G, et al. CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Invest Dermatol 2012;132:71120. Cross Ref link Pubmed link
    • 192  Lin Q, Wesson RN, Maeda H et al. Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full‐thickness excision: the synergistic activity of AMD3100 and tacrolimus. J Invest Dermatol 2014;134:245868. Cross Ref link Pubmed link
    • 193  Tolar J, McGrath JA. Augmentation of cutaneous wound healing by pharmacologic mobilization of endogenous bone marrow stem cells. J Invest Dermatol 2014;134:231214. Cross Ref link Pubmed link

    Skin grafting and biomaterials

    • 194  Oien RF, Hakansson A, Hansen BU, Bjellerup M. Pinch grafting of chronic leg ulcers in primary care: fourteen years' experience. Acta Derm Venereol (Stockh) 2002;82:2758. Cross Ref link
    • 195  Rheinwald J, Green H. Serial cultivation of strains of human epidermal keratinocytes: formation of keratinizing colonies from single cells. Cell 1975;6:3314. Cross Ref link Pubmed link
    • 196  Green H, Kehinde O, Thomas J. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc Natl Acad Sci USA 1979;76:56658. Cross Ref link Pubmed link
    • 197  Chapman S, Liu X, Meyers C, Schlegel R, McBride AA. Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor. J Clin Invest 2010;120:261926. Cross Ref link Pubmed link
    • 198  O'Connor NE, Mulliken JB, Banks‐Schlegel S, et al. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet 1981;i:758. Cross Ref link
    • 199  Compton CC, Gill JM, Bradford DA, et al. Skin regenerated from cultured epithelial autografts on full thickness burn wounds from 6 days to 5 years after grafting: a light, electron microscopic and immunohistochemical study. Lab Invest 1989;60:60012. Pubmed link
    • 200  Cuono C, Langdon R, McGuire J. Use of cultured epidermal autograft and dermal allografts as skin replacement after burn injury. Lancet 1986;i:11234. Cross Ref link
    • 201  Collin B, Balderson D, Papini R, Marsden J, Moss C. Cultured autologous keratinocyte grafting of chronic erosions in three patients with epidermolysis bullosa. Clin Exp Dermatol 2006;31:71819. Cross Ref link Pubmed link
    • 202  Gallico GG, O'Connor NE, Compton CC, et al. Cultured epithelial autografts for giant congenital naevi. Plast Reconstr Surg 1989;84:19. Cross Ref link Pubmed link
    • 203  Limova M, Mauro T. Treatment of leg ulcers with cultured epithelial autografts: clinical study and case reports. Osteotomy Wound Manage 1995;41:5460.
    • 204  Scuderi N, Onesti MG, Bistoni G, et al. The clinical application of autologous bioengineered skin based on a hyaluronic acid scaffold. Biomaterials 2008;29:16209. Cross Ref link Pubmed link
    • 205  Magnusson M, Papini RP, Rea SM, et al. Cultured autologous keratinocytes in suspension accelerate epithelial maturation in an in vivo wound model as measured by surface electrical capacitance. Plast Reconstr Surg 2007;119:4959. Cross Ref link Pubmed link
    • 206  Brain A, Purkis PE, Coates P, et al. Survival of cultured allogeneic keratinocytes transplanted to deep dermal bed assessed with probe specific for Y chromosome. BMJ 1989;298:91719. Cross Ref link Pubmed link
    • 207  Karawach WF, Oliver AM, Weiler‐Mithoff E, et al. Survival assessment of cultured epidermal allografts applied over partial thickness burn wounds. Br J Plast Surg 1991;44:3214. Cross Ref link Pubmed link
    • 208  Leigh IM, Purkis PE, Navsaria HA, Phillips TJ. Treatment of chronic venous ulcers with sheets of cultured allogeneic keratinocytes. Br J Dermatol 1987;117:5917. Cross Ref link Pubmed link
    • 209  Kamel RA, Ong JF, Eriksson E, Junker JP, Caterson EJ. Tissue engineering of skin. J Am Coll Surg 2013;217:53355. Cross Ref link Pubmed link
    • 210  Sasaki M, Abe R, Fujita Y, et al. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 2008;180:25817. Cross Ref link Pubmed link
    • 211  Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:264859. Cross Ref link Pubmed link
    • 212  Laverdet B, Micallef L, Lebreton C, et al. Use of mesenchymal stem cells for cutaneous repair and skin substitute elaboration. Pathol Biol (Paris) 2014;62:10817. Cross Ref link Pubmed link
    • 213  Driskell RR, Lichtenberger BM, Hoste E, et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 2013;504:27781. Cross Ref link Pubmed link
    • 214  Wang X, Ghasri P, Amir M, et al. Topical application of recombinant type VII collagen incorporates into the dermal‐epidermal junction and promotes wound closure. Mol Ther 2013;21:133544. Cross Ref link Pubmed link
    • 215  Connelly JT, Gautrot JE, Trappmann B, et al. Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat Cell Biol 2010;12:71118. Cross Ref link Pubmed link