Advertisement

Physiology and Pathophysiology of Wound Healing in Diabetes

  • Irena Pastar
  • Nkemcho Ojeh
  • George D. Glinos
  • Olivera Stojadinovic
  • Marjana Tomic-Canic
Chapter
Part of the Contemporary Diabetes book series (CDI)

Abstract

Wound healing is a dynamic process comprising of overlapping phases of hemostasis, inflammation, proliferation, and remodeling that involve multiple cell types. This highly organized and coordinated series of processes result in the restoration of tissue integrity. Deregulation in any of these processes leads to a delayed or nonhealing phenotype as seen in diabetic foot ulcers (DFUs). The functions and cell-to-cell communication between different cell types contributing to wound healing (keratinocytes, fibroblasts, endothelial cells, neutrophils, and macrophages) and their deregulation in chronic nonhealing ulcers are discussed in detail. The balance of signaling factors, including growth factors and gene expression regulators such as microRNA, and their spatiotemporal control is indispensable for successful wound healing, while their dysregulation contributes to pathophysiology of DFUs. Additional factors that contribute to the delayed healing seen in diabetes include macro- and microvascular, neuropathic, immune functions, and microbiome abnormalities. Novel therapeutic approaches including cell therapy, stem cells, and micrografting that provide perspective on how to efficiently treat patients with DFUs are also discussed.

Keywords

Chronic wounds Keratinocytes Fibroblasts Endothelial cells Immune response Microbiome 

Abbreviations

AGE

Advanced glycation end product

ASC

Adipose-derived stem cell

BM-MNC

Bone marrow-derived mononuclear cell

BM-MSC

Bone marrow-derived mesenchymal stem cell

CEA

Cultured epithelial autograft

DFU

Diabetic foot ulcer

EC

Endothelial cell

ECM

Extracellular matrix

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

EGR3

Early growth response factor 3

En1

Engrailed-1

EPC

Endothelial progenitor cell

FGF

Fibroblast growth factor

GM-CSF

Granulocyte macrophage colony stimulating factor

HB-EGF

Heparin-binding EGF

HBO

Hyperbaric oxygen

IGF-1

Insulin-like growth factor 1

IKBKB

Inhibitor of nuclear factor kappa-B kinase subunit beta

IL-1

Interleukin-1

IL-6

Interleukin-6

iNOS

Inducible nitric oxide synthase

iPSC

Induced pluripotent stem cell

KGF

Keratinocyte growth factor

LepR

Leptin receptor

MAPC

Multipotent adult progenitor cell

miR

Micro-RNA

mKitL

Membrane-bound Kit ligand

MMP

Matrix metalloproteinase

MSC

Mesenchymal stem cell

NET

Neutrophil extracellular trap

NLRP

Nod-like receptor protein

NO

Nitric oxide

Nrf2

Nuclear factor like 2

PDGF

Platelet-derived growth factor

PPARγ

Peroxisome proliferator-activated receptor γ

rhEGF

Recombinant human epidermal growth factor

rhPDGF

Recombinant human platelet-derived growth factor

rhVEGF

Recombinant human vascular endothelial growth factor

sKitL

Soluble Kit ligand

TGF-ß1

Transforming growth factor-beta 1

TGF-α

Transforming growth factor alpha

TIMP

Tissue inhibitor of metalloproteinase

TNF-α

Tumor necrosis factor alpha

VEGF

Vascular endothelial growth factor

WEE1

Wee1-like protein kinase

References

  1. 1.
    Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–22.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010;126(4):1172–80.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Behm B, Babilas P, Landthaler M, Schreml S. Cytokines, chemokines and growth factors in wound healing. J Eur Acad Dermatol Venereol. 2012;26(7):812–20.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83(3):835–70.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007;127(5):998–1008.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Fu X, Li X, Cheng B, Chen W, Sheng Z. Engineered growth factors and cutaneous wound healing: success and possible questions in the past 10 years. Wound Repair Regen. 2005;13(2):122–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG, Sawaya A, et al. Epithelialization in wound healing: a comprehensive review. Adv Wound Care (New Rochelle). 2014;3(7):445–64.CrossRefGoogle Scholar
  10. 10.
    Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen. 2014;22(5):569–78.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Pastar I, Stojadinovic O, Tomic-Canic M. Role of keratinocytes in healing of chronic wounds. Surg Technol Int. 2008;17:105–12.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wikramanayake TC, Stojadinovic O, Tomic-Canic M. Epidermal differentiation in barrier maintenance and wound healing. Adv Wound Care (New Rochelle). 2014;3(3):272–80.CrossRefGoogle Scholar
  13. 13.
    Blumenberg M, Tomic-Canic M. Human epidermal keratinocyte: keratinization processes. EXS. 1997;78:1–29.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Raja, Sivamani K, Garcia MS, Isseroff RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci. 2007;12:2849–68.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Werner S, Smola H. Paracrine regulation of keratinocyte proliferation and differentiation. Trends Cell Biol. 2001;11(4):143–6.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ. Keratinocytes as initiators of inflammation. Lancet. 1991;337(8735):211–4.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Pastar I, Stojadinovic O, Sawaya AP, Stone RC, Lindley LE, Ojeh N, et al. Skin metabolite, farnesyl pyrophosphate, regulates epidermal response to inflammation, oxidative stress, and migration. J Cell Physiol. 2016;231(11):2452–63.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jozic I, Stojadinovic O, Kirsner RS, Tomic-Canic M. Skin under the (spot)-light: cross-talk with the central hypothalamic-pituitary-adrenal (HPA) axis. J Invest Dermatol. 2015;135(6):1469–71.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M. Keratins and the keratinocyte activation cycle. J Invest Dermatol. 2001;116(5):633–40.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Kupper TS. The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J Invest Dermatol. 1990;94(6 Suppl):146S–50S.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015;348(6232):aaa2151.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bainbridge P. Wound healing and the role of fibroblasts. J Wound Care. 2013;22(8):407–8. 10-12CrossRefPubMedGoogle Scholar
  24. 24.
    Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997;276(5309):75–81.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Heng MC. Wound healing in adult skin: aiming for perfect regeneration. Int J Dermatol. 2011;50(9):1058–66.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Brown BN, Badylak SF. Extracellular matrix as an inductive scaffold for functional tissue reconstruction. Transl Res. 2014;163(4):268–85.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol. 2002;13(5):377–83.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Tracy LE, Minasian RA, Caterson EJ. Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care (New Rochelle). 2016;5(3):119–36.CrossRefGoogle Scholar
  29. 29.
    Ffrench-Constant C, Van de Water L, Dvorak HF, Hynes RO. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol. 1989;109(2):903–14.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Desmouliere 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.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Maione AG, Smith A, Kashpur O, Yanez V, Knight E, Mooney DJ, et al. Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair. Wound Repair Regen. 2016;24(4):630–43.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Stone RC, Pastar I, Ojeh N, Chen V, Liu S, Garzon KI, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016;365(3):495–506.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cheng F, Shen Y, Mohanasundaram P, Lindstrom M, Ivaska J, Ny T, et al. Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-slug signaling. Proc Natl Acad Sci U S A. 2016;113(30):E4320–7.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rolin GL, Binda D, Tissot M, Viennet C, Saas P, Muret P, et al. In vitro study of the impact of mechanical tension on the dermal fibroblast phenotype in the context of skin wound healing. J Biomech. 2014;47(14):3555–61.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Junker JP, Kratz C, Tollback A, Kratz G. Mechanical tension stimulates the transdifferentiation of fibroblasts into myofibroblasts in human burn scars. Burns. 2008;34(7):942–6.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol. 2001;159(3):1009–20.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.CrossRefPubMedGoogle Scholar
  38. 38.
    Hinz B. Myofibroblasts. Exp Eye Res. 2016;142:56–70.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Montesano R, Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A. 1988;85(13):4894–7.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Clark RA, Folkvord JM, Hart CE, Murray MJ, McPherson JM. Platelet isoforms of platelet-derived growth factor stimulate fibroblasts to contract collagen matrices. J Clin Invest. 1989;84(3):1036–40.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Jiang H, Rhee S, Ho CH, Grinnell F. Distinguishing fibroblast promigratory and procontractile growth factor environments in 3-D collagen matrices. FASEB J. 2008;22(7):2151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Mia MM, Boersema M, Bank RA. Interleukin-1beta attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-beta1. PLoS One. 2014;9(3):e91559.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Tingstrom A, Heldin CH, Rubin K. Regulation of fibroblast-mediated collagen gel contraction by platelet-derived growth factor, interleukin-1 alpha and transforming growth factor-beta 1. J Cell Sci. 1992;102(Pt 2):315–22.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Lin YC, Grinnell F. Treatment of human fibroblasts with vanadate and platelet-derived growth factor in the presence of serum inhibits collagen matrix contraction. Exp Cell Res. 1995;221(1):73–82.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Akasaka Y, Ono I, Kamiya T, Ishikawa Y, Kinoshita T, Ishiguro S, et al. The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing. J Pathol. 2010;221(3):285–99.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995;146(1):56–66.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer S. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290–5.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study G. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701–5.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264(5158):569–71.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Hynes RO, Bader BL, Hodivala-Dilke K. Integrins in vascular development. Braz J Med Biol Res. 1999;32(5):501–10.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev. 2015;24(14):1635–47.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Wong VW, Crawford JD. Vasculogenic cytokines in wound healing. Biomed Res Int. 2013;2013:190486.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Bauer SM, Bauer RJ, Velazquez OC. Angiogenesis, vasculogenesis, and induction of healing in chronic wounds. Vasc Endovascular Surg. 2005;39(4):293–306.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Sephel GC, Kennedy R, Kudravi S. Expression of capillary basement membrane components during sequential phases of wound angiogenesis. Matrix Biol. 1996;15(4):263–79.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Burbridge MF, Coge F, Galizzi JP, Boutin JA, West DC, Tucker GC. The role of the matrix metalloproteinases during in vitro vessel formation. Angiogenesis. 2002;5(3):215–26.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Czirok A. Endothelial cell motility, coordination and pattern formation during vasculogenesis. Wiley Interdiscip Rev Syst Biol Med. 2013;5(5):587–602.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev. 2013;93(1):327–58.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Cazander G, Jukema GN, Nibbering PH. Complement activation and inhibition in wound healing. Clin Dev Immunol. 2012;2012:534291.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 2011;18(4):581–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819–35.CrossRefGoogle Scholar
  61. 61.
    Winterbourn CC, Kettle AJ. Redox reactions and microbial killing in the neutrophil phagosome. Antioxid Redox Signal. 2013;18(6):642–60.PubMedCrossRefGoogle Scholar
  62. 62.
    Zawrotniak M, Rapala-Kozik M. Neutrophil extracellular traps (NETs) - formation and implications. Acta Biochim Pol. 2013;60(3):277–84.PubMedGoogle Scholar
  63. 63.
    Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14(10):986–95.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332(6035):1284–8.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Jenkins SJ, Ruckerl D, Thomas GD, Hewitson JP, Duncan S, Brombacher F, et al. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J Exp Med. 2013;210(11):2477–91.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Mirza RE, Fang MM, Novak ML, Urao N, Sui A, Ennis WJ, et al. Macrophage PPARgamma and impaired wound healing in type 2 diabetes. J Pathol. 2015;236(4):433–44.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Spiller KL, Anfang RR, Spiller KJ, Ng J, Nakazawa KR, Daulton JW, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials. 2014;35(15):4477–88.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Spiller KL, Nassiri S, Witherel CE, Anfang RR, Ng J, Nakazawa KR, et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials. 2015;37:194–207.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Schafer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008;58(2):165–71.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Sen CK, Roy S. Redox signals in wound healing. Biochim Biophys Acta. 2008;1780(11):1348–61.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Soares MA, Cohen OD, Low YC, Sartor RA, Ellison T, Anil U, et al. Restoration of Nrf2 signaling normalizes the regenerative niche. Diabetes. 2016;65(3):633–46.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Schafer M, Werner S. Nrf2—a regulator of keratinocyte redox signaling. Free Radic Biol Med. 2015;88(Pt B):243–52.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Reichner JS, Meszaros AJ, Louis CA, Henry WL Jr, Mastrofrancesco B, Martin BA, et al. Molecular and metabolic evidence for the restricted expression of inducible nitric oxide synthase in healing wounds. Am J Pathol. 1999;154(4):1097–104.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lee RH, Efron D, Tantry U, Barbul A. Nitric oxide in the healing wound: a time-course study. J Surg Res. 2001;101(1):104–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Lindley LE, Stojadinovic O, Pastar I, Tomic-Canic M. Biology and biomarkers for wound healing. Plast Reconstr Surg. 2016;138(3 Suppl):18S–28S.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Pilcher BK, Wang M, Qin XJ, Parks WC, Senior RM, Welgus HG. Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. Ann N Y Acad Sci. 1999;878:12–24.PubMedCrossRefGoogle Scholar
  79. 79.
    Nagaoka T, Kaburagi Y, Hamaguchi Y, Hasegawa M, Takehara K, Steeber DA, et al. Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression. Am J Pathol. 2000;157(1):237–47.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Madlener M, Parks WC, Werner S. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res. 1998;242(1):201–10.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Parks WC. Matrix metalloproteinases in repair. Wound Repair Regen. 1999;7(6):423–32.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996;4(4):411–20.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    CDC. 2014 National Diabetes Statistics Report. 2014.Google Scholar
  84. 84.
    Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94(3):311–21.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Sargen MR, Hoffstad O, Margolis DJ. Geographic variation in Medicare spending and mortality for diabetic patients with foot ulcers and amputations. J Diabetes Complications. 2013;27(2):128–33.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Goodridge D, Trepman E, Sloan J, Guse L, Strain LA, McIntyre J, et al. Quality of life of adults with unhealed and healed diabetic foot ulcers. Foot Ankle Int. 2006;27(4):274–80.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle). 2015;4(9):560–82.CrossRefGoogle Scholar
  88. 88.
    Noor S, Zubair M, Ahmad J. Diabetic foot ulcer—a review on pathophysiology, classification and microbial etiology. Diabetes Metab Syndr. 2015;9(3):192–9.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Ramirez HA, Liang L, Pastar I, Rosa AM, Stojadinovic O, Zwick TG, et al. Comparative genomic, MicroRNA, and tissue analyses reveal subtle differences between non-diabetic and diabetic foot skin. PLoS One. 2015;10(8):e0137133.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Bettahi I, Sun H, Gao N, Wang F, Mi X, Chen W, et al. Genome-wide transcriptional analysis of differentially expressed genes in diabetic, healing corneal epithelial cells: hyperglycemia-suppressed TGFbeta3 expression contributes to the delay of epithelial wound healing in diabetic corneas. Diabetes. 2014;63(2):715–27.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Sun H, Mi X, Gao N, Yan C, Yu FS. Hyperglycemia-suppressed expression of Serpine1 contributes to delayed epithelial wound healing in diabetic mouse corneas. Invest Ophthalmol Vis Sci. 2015;56(5):3383–92.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Tsourdi E, Barthel A, Rietzsch H, Reichel A, Bornstein SR. Current aspects in the pathophysiology and treatment of chronic wounds in diabetes mellitus. Biomed Res Int. 2013;2013:385641.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Stojadinovic O, Pastar I, Nusbaum AG, Vukelic S, Krzyzanowska A, Tomic-Canic M. Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers. Wound Repair Regen. 2014;22(2):220–7.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Stojadinovic O, Yin N, Lehmann J, Pastar I, Kirsner RS, Tomic-Canic M. Increased number of Langerhans cells in the epidermis of diabetic foot ulcers correlates with healing outcome. Immunol Res. 2013;57(1–3):222–8.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yager DR, Zhang LY, Liang HX, Diegelmann RF, Cohen IK. Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol. 1996;107(5):743–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Liang L, Stone RC, Stojadinovic O, Ramirez H, Pastar I, Maione AG, Smith A, Yanez V, Veves A, Kirsner RS, Garlick JA, Tomic-Canic M. Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions. Wound Repair Regen. 2016;24(6):943–53.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Catrina SB, Zheng X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(Suppl 1):179–85.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Leal EC, Carvalho E, Tellechea A, Kafanas A, Tecilazich F, Kearney C, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol. 2015;185(6):1638–48.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lee B, Vouthounis C, Stojadinovic O, Brem H, Im M, Tomic-Canic M. From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol. 2005;345(5):1083–97.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Brem H, Stojadinovic O, Diegelmann RF, Entero H, Lee B, Pastar I, et al. Molecular markers in patients with chronic wounds to guide surgical debridement. Mol Med. 2007;13(1–2):30–9.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol. 1992;18(7):604–6.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Stojadinovic O, Landon JN, Gordon KA, Pastar I, Escandon J, Vivas A, et al. Quality assessment of tissue specimens for studies of diabetic foot ulcers. Exp Dermatol. 2013;22(3):216–8.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Stojadinovic O, Pastar I, Vukelic S, Mahoney MG, Brennan D, Krzyzanowska A, et al. Deregulation of keratinocyte differentiation and activation: a hallmark of venous ulcers. J Cell Mol Med. 2008;12(6B):2675–90.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167(1):59–69.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Usui ML, Mansbridge JN, Carter WG, Fujita M, Olerud JE. Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds. J Histochem Cytochem. 2008;56(7):687–96.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Velander P, Theopold C, Bleiziffer O, Bergmann J, Svensson H, Feng Y, et al. Cell suspensions of autologous keratinocytes or autologous fibroblasts accelerate the healing of full thickness skin wounds in a diabetic porcine wound healing model. J Surg Res. 2009;157(1):14–20.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Maione AG, Brudno Y, Stojadinovic O, Park LK, Smith A, Tellechea A, et al. Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds. Tissue Eng Part C Methods. 2015;21(5):499–508.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Berlanga-Acosta J, Mendoza-Mari Y, Martinez MD, Valdes-Perez C, Ojalvo AG, Armstrong DG. Expression of cell proliferation cycle negative regulators in fibroblasts of an ischemic diabetic foot ulcer. A clinical case report. Int Wound J. 2013;10(2):232–6.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Yang M, Sheng L, Zhang TR, Li Q. Stem cell therapy for lower extremity diabetic ulcers: where do we stand? Biomed Res Int. 2013;2013:462179.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Pirila E, Korpi JT, Korkiamaki T, Jahkola T, Gutierrez-Fernandez A, Lopez-Otin C, et al. Collagenase-2 (MMP-8) and matrilysin-2 (MMP-26) expression in human wounds of different etiologies. Wound Repair Regen. 2007;15(1):47–57.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993;101(1):64–8.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Liu Y, Min D, Bolton T, Nube V, Twigg SM, Yue DK, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care. 2009;32(1):117–9.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    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(17):2670–81.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY. Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med. 2008;25(4):419–26.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002;45(7):1011–6.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Pastar I, Stojadinovic O, Krzyzanowska A, Barrientos S, Stuelten C, Zimmerman K, et al. Attenuation of the transforming growth factor beta-signaling pathway in chronic venous ulcers. Mol Med. 2010;16(3–4):92–101.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Gras C, Ratuszny D, Hadamitzky C, Zhang H, Blasczyk R, Figueiredo C. miR-145 contributes to hypertrophic scarring of the skin by inducing myofibroblast activity. Mol Med. 2015;21:296–304.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Huang RY, Li L, Wang MJ, Chen XM, Huang QC, Lu CJ. An exploration of the role of MicroRNAs in psoriasis: a systematic review of the literature. Medicine (Baltimore). 2015;94(45):e2030.CrossRefGoogle Scholar
  120. 120.
    Hu G, Drescher KM, Chen XM. Exosomal miRNAs: biological properties and therapeutic potential. Front Genet. 2012;3:56.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Zhang J, Li S, Li L, Li M, Guo C, Yao J, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13(1):17–24.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Pastar I, Ramirez H, Stojadinovic O, Brem H, Kirsner RS, Tomic-Canic M. Micro-RNAs: new regulators of wound healing. Surg Technol Int. 2011;21:51–60.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Moura J, Borsheim E, Carvalho E. The role of MicroRNAs in diabetic complications-special emphasis on wound healing. Genes (Basel). 2014;5(4):926–56.CrossRefGoogle Scholar
  125. 125.
    Pastar I, Khan AA, Stojadinovic O, Lebrun EA, Medina MC, Brem H, et al. Induction of specific microRNAs inhibits cutaneous wound healing. J Biol Chem. 2012;287(35):29324–35.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Sundaram GM, Common JE, Gopal FE, Srikanta S, Lakshman K, Lunny DP, et al. ‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature. 2013;495(7439):103–6.PubMedCrossRefGoogle Scholar
  127. 127.
    Ramirez H, Pastar I, Stojadinovic O, Jozic I, Stone RC, Rosa A, Kirsner RS, Tomic-Canic M. Diabetic foot ulcers versus acute wounds: sub-obtimal inflammatory response regulated by mir-15b-5p. Wound Repair Regen. 2016;24(2):A9.Google Scholar
  128. 128.
    Xu J, Wu W, Zhang L, Dorset-Martin W, Morris MW, Mitchell ME, et al. The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment. Diabetes. 2012;61(11):2906–12.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Nesca V, Guay C, Jacovetti C, Menoud V, Peyot ML, Laybutt DR, et al. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia. 2013;56(10):2203–12.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Ferland-McCollough D, Fernandez-Twinn DS, Cannell IG, David H, Warner M, Vaag AA, et al. Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ. 2012;19(6):1003–12.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Deppe J, Steinritz D, Santovito D, Egea V, Schmidt A, Weber C, et al. Upregulation of miR-203 and miR-210 affect growth and differentiation of keratinocytes after exposure to sulfur mustard in normoxia and hypoxia. Toxicol Lett. 2016;244:81–7.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Demidova-Rice TN, Durham JT, Herman IM. Wound healing angiogenesis: innovations and challenges in acute and chronic wound healing. Adv Wound Care (New Rochelle). 2012;1(1):17–22.CrossRefGoogle Scholar
  133. 133.
    Xu L, Kanasaki K, Kitada M, Koya D. Diabetic angiopathy and angiogenic defects. Fibrogenesis Tissue Repair. 2012;5(1):13.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012;25(7):304–14.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Costa PZ, Soares R. Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci. 2013;92(22):1037–45.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Kota SK, Meher LK, Jammula S, Kota SK, Krishna SV, Modi KD. Aberrant angiogenesis: the gateway to diabetic complications. Indian J Endocrinol Metab. 2012;16(6):918–30.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Boltin D, Kamenetsky Z, Perets TT, Snir Y, Sapoznikov B, Schmilovitz-Weiss H, et al. Circulating bone marrow-derived CD45-/CD34+/CD133+/VEGF+ endothelial progenitor cells in adults with Crohn’s disease. Dig Dis Sci. 2017;62(3):633–8.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Lauer G, Sollberg S, Cole M, Flamme I, Sturzebecher J, Mann K, et al. Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. J Invest Dermatol. 2000;115(1):12–8.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137–48.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Nakagawa T, Sato W, Kosugi T, Johnson RJ. Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy. J Diabetes Res. 2013;2013:184539.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Tecilazich F, Dinh TL, Veves A. Emerging drugs for the treatment of diabetic ulcers. Expert Opin Emerg Drugs. 2013;18(2):207–17.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Georgescu A, Alexandru N, Constantinescu A, Titorencu I, Popov D. The promise of EPC-based therapies on vascular dysfunction in diabetes. Eur J Pharmacol. 2011;669(1–3):1–6.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Liu ZJ, Velazquez OC. Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid Redox Signal. 2008;10(11):1869–82.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, et al. Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes. 2007;56(4):960–7.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Brunner S, Hoellerl F, Schmid-Kubista KE, Zeiler F, Schernthaner G, Binder S, et al. Circulating angiopoietic cells and diabetic retinopathy in type 2 diabetes mellitus, with or without macrovascular disease. Invest Ophthalmol Vis Sci. 2011;52(7):4655–62.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Loomans CJ, van Haperen R, Duijs JM, Verseyden C, de Crom R, Leenen PJ, et al. Differentiation of bone marrow-derived endothelial progenitor cells is shifted into a proinflammatory phenotype by hyperglycemia. Mol Med. 2009;15(5–6):152–9.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Yu CG, Zhang N, Yuan SS, Ma Y, Yang LY, Feng YM, et al. Endothelial progenitor cells in diabetic microvascular complications: friends or foes? Stem Cells Int. 2016;2016:1803989.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Drela E, Stankowska K, Kulwas A, Rosc D. Endothelial progenitor cells in diabetic foot syndrome. Adv Clin Exp Med. 2012;21(2):249–54.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Kim KA, Shin YJ, Kim JH, Lee H, Noh SY, Jang SH, et al. Dysfunction of endothelial progenitor cells under diabetic conditions and its underlying mechanisms. Arch Pharm Res. 2012;35(2):223–34.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Albiero M, Menegazzo L, Boscaro E, Agostini C, Avogaro A, Fadini GP. Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice. Diabetologia. 2011;54(4):945–53.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Hu H, Jiang H, Ren H, Hu X, Wang X, Han C. AGEs and chronic subclinical inflammation in diabetes: disorders of immune system. Diabetes Metab Res Rev. 2015;31(2):127–37.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Aljada A, Friedman J, Ghanim H, Mohanty P, Hofmeyer D, Chaudhuri A, et al. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism. 2006;55(9):1177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab. 2000;85(8):2970–3.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Tellechea A, Kafanas A, Leal EC, Tecilazich F, Kuchibhotla S, Auster ME, et al. Increased skin inflammation and blood vessel density in human and experimental diabetes. Int J Low Extrem Wounds. 2013;12(1):4–11.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes. 2012;61(11):2937–47.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Nassiri S, Zakeri I, Weingarten MS, Spiller KL. Relative expression of proinflammatory and antiinflammatory genes reveals differences between healing and nonhealing human chronic diabetic foot ulcers. J Invest Dermatol. 2015;135(6):1700–3.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Mirza RE, Fang MM, Weinheimer-Haus EM, Ennis WJ, Koh TJ. Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice. Diabetes. 2014;63(3):1103–14.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Mirza RE, Fang MM, Ennis WJ, Koh TJ. Blocking interleukin-1beta induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013;62(7):2579–87.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    van Asten SA, La Fontaine J, Peters EJ, Bhavan K, Kim PJ, Lavery LA. The microbiome of diabetic foot osteomyelitis. Eur J Clin Microbiol Infect Dis. 2016;35(2):293–8.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Pastar I, Nusbaum AG, Gil J, Patel SB, Chen J, Valdes J, et al. Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection. PLoS One. 2013;8(2):e56846.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Messad N, Prajsnar TK, Lina G, O'Callaghan D, Foster SJ, Renshaw SA, et al. Existence of a colonizing Staphylococcus aureus strain isolated in diabetic foot ulcers. Diabetes. 2015;64(8):2991–5.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127(3):514–25.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Wenk J, Foitzik A, Achterberg V, Sabiwalsky A, Dissemond J, Meewes C, et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept. J Invest Dermatol. 2001;116(6):833–9.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Dhall S, Do D, Garcia M, Wijesinghe DS, Brandon A, Kim J, et al. A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity. PLoS One. 2014;9(10):e109848.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Dunnill C, Patton T, Brennan J, Barrett J, Dryden M, Cooke J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J. 2017;14(1):89–96.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Cordova EJ, Martinez-Hernandez A, Uribe-Figueroa L, Centeno F, Morales-Marin M, Koneru H, et al. The NRF2-KEAP1 pathway is an early responsive gene network in arsenic exposed lymphoblastoid cells. PLoS One. 2014;9(2):e88069.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, 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(15):5492–505.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Li H, Wang F, Zhang L, Cao Y, Liu W, Hao J, et al. Modulation of Nrf2 expression alters high glucose-induced oxidative stress and antioxidant gene expression in mouse mesangial cells. Cell Signal. 2011;23(10):1625–32.PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Lee YJ, Kwon SB, An JM, Kim CH, Lee SH, Choi CY, et al. Increased protein oxidation and decreased expression of nuclear factor E2-related factor 2 protein in skin tissue of patients with diabetes. Clin Exp Dermatol. 2015;40(2):192–200.PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Long M, Rojo de la Vega M, Wen Q, Bharara M, Jiang T, Zhang R, et al. An essential role of NRF2 in diabetic wound healing. Diabetes. 2016;65(3):780–93.PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Noor S, Khan RU, Ahmad J. Understanding diabetic foot infection and its management. Diabetes Metab Syndr. 2017;11(2):149–56.PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Richard JL, Lavigne JP, Got I, Hartemann A, Malgrange D, Tsirtsikolou D, et al. Management of patients hospitalized for diabetic foot infection: results of the French OPIDIA study. Diabetes Metab. 2011;37(3):208–15.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187(1):538–52.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Martinod K, Fuchs TA, Zitomersky NL, Wong SL, Demers M, Gallant M, et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood. 2015;125(12):1948–56.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Menegazzo L, Ciciliot S, Poncina N, Mazzucato M, Persano M, Bonora B, et al. NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol. 2015;52(3):497–503.PubMedCrossRefGoogle Scholar
  177. 177.
    Fadini GP, Menegazzo L, Scattolini V, Gintoli M, Albiero M, Avogaro A. A perspective on NETosis in diabetes and cardiometabolic disorders. Nutr Metab Cardiovasc Dis. 2016;26(1):1–8.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Fadini GP, Menegazzo L, Rigato M, Scattolini V, Poncina N, Bruttocao A, et al. NETosis delays diabetic wound healing in mice and humans. Diabetes. 2016;65(4):1061–71.PubMedCrossRefGoogle Scholar
  179. 179.
    Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC, et al. Topographical and temporal diversity of the human skin microbiome. Science. 2009;324(5931):1190–2.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Gao Z, Tseng CH, Pei Z, Blaser MJ. Molecular analysis of human forearm superficial skin bacterial biota. Proc Natl Acad Sci U S A. 2007;104(8):2927–32.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Misic AM, Gardner SE, Grice EA. The wound microbiome: modern approaches to examining the role of microorganisms in impaired chronic wound healing. Adv Wound Care (New Rochelle). 2014;3(7):502–10.CrossRefGoogle Scholar
  182. 182.
    Zeeuwen PL, Boekhorst J, van den Bogaard EH, de Koning HD, van de Kerkhof PM, Saulnier DM, et al. Microbiome dynamics of human epidermis following skin barrier disruption. Genome Biol. 2012;13(11):R101.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Redel H, Gao Z, Li H, Alekseyenko AV, Zhou Y, Perez-Perez GI, et al. Quantitation and composition of cutaneous microbiota in diabetic and nondiabetic men. J Infect Dis. 2013;207(7):1105–14.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Malik A, Mohammad Z, Ahmad J. The diabetic foot infections: biofilms and antimicrobial resistance. Diabetes Metab Syndr. 2013;7(2):101–7.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Schommer NN, Gallo RL. Structure and function of the human skin microbiome. Trends Microbiol. 2013;21(12):660–8.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Group NHW, Peterson J, Garges S, Giovanni M, McInnes P, Wang L, et al. The NIH Human Microbiome Project. Genome Res. 2009;19(12):2317–23.CrossRefGoogle Scholar
  187. 187.
    Gardner SE, Hillis SL, Heilmann K, Segre JA, Grice EA. The neuropathic diabetic foot ulcer microbiome is associated with clinical factors. Diabetes. 2013;62(3):923–30.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Wolcott RD, Hanson JD, Rees EJ, Koenig LD, Phillips CD, Wolcott RA, et al. Analysis of the chronic wound microbiota of 2,963 patients by 16S rDNA pyrosequencing. Wound Repair Regen. 2016;24(1):163–74.PubMedCrossRefGoogle Scholar
  189. 189.
    Ojeh N, Pastar I, Tomic-Canic M, Stojadinovic O. Stem cells in skin regeneration, wound healing, and their clinical applications. Int J Mol Sci. 2015;16(10):25476–501.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Fuchs E. Cell biology: more than skin deep. J Cell Biol. 2015;209(5):629–31.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Braun KM, Prowse DM. Distinct epidermal stem cell compartments are maintained by independent niche microenvironments. Stem Cell Rev. 2006;2(3):221–31.PubMedCrossRefGoogle Scholar
  192. 192.
    Hsu YC, Li L, Fuchs E. Emerging interactions between skin stem cells and their niches. Nat Med. 2014;20(8):847–56.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W. The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract. 2012;96(1):1–9.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648–59.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Potten CS. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 1974;7(1):77–88.PubMedGoogle Scholar
  196. 196.
    Fuchs E. Skin stem cells: rising to the surface. J Cell Biol. 2008;180(2):273–84.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S, Sotiropoulou PA, et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature. 2012;489(7415):257–62.PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Clayton E, Doupe DP, Klein AM, Winton DJ, Simons BD, Jones PH. A single type of progenitor cell maintains normal epidermis. Nature. 2007;446(7132):185–9.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Walker MR, Patel KK, Stappenbeck TS. The stem cell niche. J Pathol. 2009;217(2):169–80.PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118(5):635–48.PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Ciompi L. Affect logic: an integrative model of the psyche and its relations to schizophrenia. Br J Psychiatry Suppl. 1994;23:51–5.CrossRefGoogle Scholar
  202. 202.
    Heublein H, Bader A, Giri S. Preclinical and clinical evidence for stem cell therapies as treatment for diabetic wounds. Drug Discov Today. 2015;20(6):703–17.PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Teng M, Huang Y, Zhang H. Application of stems cells in wound healing--an update. Wound Repair Regen. 2014;22(2):151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  204. 204.
    Yoshikawa T, Mitsuno H, Nonaka I, Sen Y, Kawanishi K, Inada Y, et al. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg. 2008;121(3):860–77.PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Quesenberry P, Colvin G, Lambert JF, Abedi M, Cerny J, Dooner M, et al. Marrow stem cell potential within a continuum. Ann N Y Acad Sci. 2003;996:209–21.PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Altman AM, Matthias N, Yan Y, Song YH, Bai X, Chiu ES, et al. Dermal matrix as a carrier for in vivo delivery of human adipose-derived stem cells. Biomaterials. 2008;29(10):1431–42.PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Rodriguez-Menocal L, Shareef S, Salgado M, Shabbir A, Van Badiavas E. Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing. Stem Cell Res Ther. 2015;6:24.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Ravari H, Hamidi-Almadari D, Salimifar M, Bonakdaran S, Parizadeh MR, Koliakos G. Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix. Cytotherapy. 2011;13(6):705–11.PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009;12(5):359–66.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Kirana S, Stratmann B, Prante C, Prohaska W, Koerperich H, Lammers D, et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int J Clin Pract. 2012;66(4):384–93.PubMedCrossRefPubMedCentralGoogle Scholar
  211. 211.
    Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26–36.PubMedCrossRefPubMedCentralGoogle Scholar
  212. 212.
    Thom SR, Hampton M, Troiano MA, Mirza Z, Malay DS, Shannon S, et al. Measurements of CD34+/CD45-dim stem cells predict healing of diabetic neuropathic wounds. Diabetes. 2016;65(2):486–97.PubMedCrossRefPubMedCentralGoogle Scholar
  213. 213.
    Tanaka R, Masuda H, Kato S, Imagawa K, Kanabuchi K, Nakashioya C, et al. Autologous G-CSF-mobilized peripheral blood CD34+ cell therapy for diabetic patients with chronic nonhealing ulcer. Cell Transplant. 2014;23(2):167–79.PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135–46.PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554–60.PubMedCrossRefGoogle Scholar
  216. 216.
    Gerami-Naini B, Smith A, Maione AG, Kashpur O, Carpinito G, Veves A, et al. Generation of induced pluripotent stem cells from diabetic foot ulcer fibroblasts using a nonintegrative Sendai virus. Cell Reprogram. 2016;18(4):214–23.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Hewitt KJ, Garlick JA. Cellular reprogramming to reset epigenetic signatures. Mol Aspects Med. 2013;34(4):841–8.PubMedCrossRefPubMedCentralGoogle Scholar
  218. 218.
    Shamis Y, Hewitt KJ, Bear SE, Alt-Holland A, Qari H, Margvelashvilli M, et al. iPSC-derived fibroblasts demonstrate augmented production and assembly of extracellular matrix proteins. In Vitro Cell Dev Biol Anim. 2012;48(2):112–22.PubMedCrossRefPubMedCentralGoogle Scholar
  219. 219.
    Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res. 2013;112(3):523–33.PubMedCrossRefPubMedCentralGoogle Scholar
  220. 220.
    Griffiths M, Ojeh N, Livingstone R, Price R, Navsaria H. Survival of Apligraf in acute human wounds. Tissue Eng. 2004;10(7–8):1180–95.PubMedCrossRefPubMedCentralGoogle Scholar
  221. 221.
    Oliveira SM, Reis RL, Mano JF. Towards the design of 3D multiscale instructive tissue engineering constructs: current approaches and trends. Biotechnol Adv. 2015;33(6 Pt 1):842–55.PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299–312.PubMedCrossRefPubMedCentralGoogle Scholar
  223. 223.
    Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol. 2003;139(4):510–6.PubMedCrossRefPubMedCentralGoogle Scholar
  224. 224.
    Hingorani A, LaMuraglia GM, Henke P, Meissner MH, Loretz L, Zinszer KM, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3S–21S.PubMedCrossRefGoogle Scholar
  225. 225.
    Braun LR, Fisk WA, Lev-Tov H, Kirsner RS, Isseroff RR. Diabetic foot ulcer: an evidence-based treatment update. Am J Clin Dermatol. 2014;15(3):267–81.PubMedCrossRefPubMedCentralGoogle Scholar
  226. 226.
    Forsythe RO, Brownrigg J, Hinchliffe RJ. Peripheral arterial disease and revascularization of the diabetic foot. Diabetes Obes Metab. 2015;17(5):435–44.PubMedCrossRefPubMedCentralGoogle Scholar
  227. 227.
    Driver VR, Lavery LA, Reyzelman AM, Dutra TG, Dove CR, Kotsis SV, et al. A clinical trial of integra template for diabetic foot ulcer treatment. Wound Repair Regen. 2015;23(6):891–900.PubMedCrossRefPubMedCentralGoogle Scholar
  228. 228.
    Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. 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):335–46.PubMedCrossRefPubMedCentralGoogle Scholar
  229. 229.
    McCartan BL, Rosenblum BI. Offloading of the diabetic foot: orthotic and pedorthic strategies. Clin Podiatr Med Surg. 2014;31(1):71–88.PubMedCrossRefPubMedCentralGoogle Scholar
  230. 230.
    van Schie CH, Rawat F, Boulton AJ. Reduction of plantar pressure using a prototype pressure-relieving dressing. Diabetes Care. 2005;28(9):2236–7.PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    de Oliveira AL, Moore Z. Treatment of the diabetic foot by offloading: a systematic review. J Wound Care. 2015;24(12):560–70.PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Wound Repair Regen. 2010;18(5):433–8.PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Lebrun E, Kirsner RS. Frequent debridement for healing of chronic wounds. JAMA Dermatol. 2013;149(9):1059.PubMedCrossRefPubMedCentralGoogle Scholar
  234. 234.
    Richmond NA, Vivas AC, Kirsner RS. Topical and biologic therapies for diabetic foot ulcers. Med Clin North Am. 2013;97(5):883–98.PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Yang S, Geng Z, Ma K, Sun X, Fu X. Efficacy of topical recombinant human epidermal growth factor for treatment of diabetic foot ulcer: a systematic review and meta-analysis. Int J Low Extrem Wounds. 2016;15(2):120–5.PubMedCrossRefPubMedCentralGoogle Scholar
  236. 236.
    Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, Fabian-Victoriano MR, Kresch-Tronik NS, et al. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: a randomized double-blinded controlled trial. Wound Repair Regen. 2014;22(4):497–503.PubMedCrossRefPubMedCentralGoogle Scholar
  237. 237.
    Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, et al. Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor. J Vasc Surg. 1995;21(2):314–24. discussion 24-5PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet. 1997;350(9081):855–9.PubMedCrossRefPubMedCentralGoogle Scholar
  239. 239.
    Da Costa RM, Ribeiro Jesus FM, Aniceto C, Mendes M. Randomized, double-blind, placebo-controlled, dose- ranging study of granulocyte-macrophage colony stimulating factor in patients with chronic venous leg ulcers. Wound Repair Regen. 1999;7(1):17–25.PubMedCrossRefPubMedCentralGoogle Scholar
  240. 240.
    Marques da Costa R, Jesus FM, Aniceto C, Mendes M. Double-blind randomized placebo-controlled trial of the use of granulocyte-macrophage colony-stimulating factor in chronic leg ulcers. Am J Surg. 1997;173(3):165–8.PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Green H. Cultured cells for the treatment of disease. Sci Am. 1991;265(5):96–102.PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Kiwanuka E, Hackl F, Philip J, Caterson EJ, Junker JP, Eriksson E. Comparison of healing parameters in porcine full-thickness wounds transplanted with skin micrografts, split-thickness skin grafts, and cultured keratinocytes. J Am Coll Surg. 2011;213(6):728–35.PubMedCrossRefPubMedCentralGoogle Scholar
  243. 243.
    You HJ, Han SK, Lee JW, Chang H. Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes—a pilot study. Wound Repair Regen. 2012;20(4):491–9.PubMedPubMedCentralGoogle Scholar
  244. 244.
    Meek CP. Successful microdermagrafting using the Meek-Wall microdermatome. Am J Surg. 1958;96(4):557–8.PubMedCrossRefPubMedCentralGoogle Scholar
  245. 245.
    Singh M, Nuutila K, Kruse C, Dermietzel A, Caterson EJ, Eriksson E. Pixel grafting: an evolution of mincing for transplantation of full-thickness wounds. Plast Reconstr Surg. 2016;137(1):92e–9e.PubMedCrossRefPubMedCentralGoogle Scholar
  246. 246.
    Hackl F, Bergmann J, Granter SR, Koyama T, Kiwanuka E, Zuhaili B, et al. Epidermal regeneration by micrograft transplantation with immediate 100-fold expansion. Plast Reconstr Surg. 2012;129(3):443e–52e.PubMedCrossRefPubMedCentralGoogle Scholar
  247. 247.
    Mahmoud SM, Mohamed AA, Mahdi SE, Ahmed ME. Split-skin graft in the management of diabetic foot ulcers. J Wound Care. 2008;17(7):303–6.PubMedCrossRefPubMedCentralGoogle Scholar
  248. 248.
    Rose JF, Giovinco N, Mills JL, Najafi B, Pappalardo J, Armstrong DG. Split-thickness skin grafting the high-risk diabetic foot. J Vasc Surg. 2014;59(6):1657–63.PubMedCrossRefPubMedCentralGoogle Scholar
  249. 249.
    Tzeng YS, Deng SC, Wang CH, Tsai JC, Chen TM, Burnouf T. Treatment of nonhealing diabetic lower extremity ulcers with skin graft and autologous platelet gel: a case series. Biomed Res Int. 2013;2013:837620.PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    Wu L, Norman G, Dumville JC, O'Meara S, Bell-Syer SE. Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews. Cochrane Database Syst Rev. 2015;7:CD010471.Google Scholar
  251. 251.
    Waltenberger J. Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. Cardiovasc Res. 2001;49(3):554–60.PubMedCrossRefPubMedCentralGoogle Scholar
  252. 252.
    Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 2003;25(6):513–8.PubMedCrossRefPubMedCentralGoogle Scholar
  253. 253.
    Ma L, Li P, Shi Z, Hou T, Chen X, Du J. A prospective, randomized, controlled study of hyperbaric oxygen therapy: effects on healing and oxidative stress of ulcer tissue in patients with a diabetic foot ulcer. Ostomy Wound Manage. 2013;59(3):18–24.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Harding KG, Moore K, Phillips TJ. Wound chronicity and fibroblast senescence--implications for treatment. Int Wound J. 2005;2(4):364–8.PubMedCrossRefPubMedCentralGoogle Scholar
  255. 255.
    Lazaro JL, Izzo V, Meaume S, Davies AH, Lobmann R, Uccioli L. Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care. 2016;25(5):277–87.PubMedCrossRefPubMedCentralGoogle Scholar
  256. 256.
    Bodnar RJ. Chemokine regulation of angiogenesis during wound healing. Adv Wound Care (New Rochelle). 2015;4(11):641–50.CrossRefGoogle Scholar
  257. 257.
    Kulwas A, Drela E, Jundzill W, Goralczyk B, Ruszkowska-Ciastek B, Rosc D. Circulating endothelial progenitor cells and angiogenic factors in diabetes complicated diabetic foot and without foot complications. J Diabetes Complications. 2015;29(5):686–90.PubMedCrossRefPubMedCentralGoogle Scholar
  258. 258.
    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):822–7.PubMedCrossRefGoogle Scholar
  259. 259.
    Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999;7(4):201–7.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Irena Pastar
    • 1
  • Nkemcho Ojeh
    • 1
    • 2
  • George D. Glinos
    • 1
  • Olivera Stojadinovic
    • 1
  • Marjana Tomic-Canic
    • 1
  1. 1.Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research ProgramUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Faculty of Medical SciencesThe University of the West IndiesSt. MichaelBarbados

Personalised recommendations