Advertisement

Advances in Therapy

, Volume 31, Issue 8, pp 817–836 | Cite as

Pathogenesis and Treatment of Impaired Wound Healing in Diabetes Mellitus: New Insights

  • Dimitrios Baltzis
  • Ioanna Eleftheriadou
  • Aristidis VevesEmail author
Review

Abstract

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.

Keywords

Diabetes mellitus Foot ulceration Ulcer treatment strategies Wound healing 

Notes

Acknowledgments

Sponsorship for this study was funded by the National Institute of Health Grants 1R01DK091949 (AV), 1R01NS066205 (AV, LPN) 1R01DK076937 (AV), 1R01NS046710 (AV) and 1R24DK091210-01 (AV). All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Conflict of interest

Dimitrios Baltzis, Ioanna Eleftheriadou and Aristidis Veves declare that they have no conflict of interest.

Compliance with ethics guidelines

The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

Funding

Sponsorship for this study was funded by the National Institute of Health Grants.

Supplementary material

12325_2014_140_MOESM1_ESM.pdf (191 kb)
Supplementary material 1 (PDF 191 kb)

References

  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Boulton AJ. The pathway to foot ulceration in diabetes. Med Clin North Am. 2013;97(5):775–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Mulder GD, Patt LM, Sanders L, Rosenstock J, Altman MI, Hanley ME, et al. Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. Wound Repair Regen. 1994;2(4):259–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Dinh TL, Veves A. A review of the mechanisms implicated in the pathogenesis of the diabetic foot. Int J Low Extrem Wounds. 2005;4(3):154–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med. 2009;11:e2.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Blakytny R, Jude E. The molecular biology of chronic wounds and delayed healing in diabetes. Diabet Med. 2006;23(6):594–608.PubMedCrossRefGoogle Scholar
  7. 7.
    Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Dovi JV, Szpaderska AM, DiPietro LA. Neutrophil function in the healing wound: adding insult to injury? Thromb Haemost. 2004;92(2):275–80.PubMedGoogle Scholar
  10. 10.
    Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Weller K, Foitzik K, Paus R, Syska W, Maurer M. Mast cells are required for normal healing of skin wounds in mice. Faseb J. 2006;20(13):2366–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Egozi EI, Ferreira AM, Burns AL, Gamelli RL, Dipietro LA. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regen. 2003;11(1):46–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Investig. 2007;117(5):1219–22.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Fadini GP, Sartore S, Agostini C, Avogaro A. Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care. 2007;30(5):1305–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Drela E, Stankowska K, Kulwas A, Rosc D. Endothelial progenitor cells in diabetic foot syndrome. Adv Clin Exp Med. 2012;21(2):249–54.PubMedGoogle Scholar
  16. 16.
    Lobmann R, Schultz G, Lehnert H. Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care. 2005;28(2):461–71.PubMedCrossRefGoogle Scholar
  17. 17.
    Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26(6):1879–82.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Pradhan Nabzdyk L, Kuchibhotla S, Guthrie P, Chun M, Auster ME, Nabzdyk C, et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J Vasc Surg. 2013;58(3):766–75 e12.Google Scholar
  20. 20.
    Ochoa O, Torres FM, Shireman PK. Chemokines and diabetic wound healing. Vascular. 2007;15(6):350–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Desta T, Li J, Chino T, Graves DT. Altered fibroblast proliferation and apoptosis in diabetic gingival wounds. J Dent Res. 2010;89(6):609–14.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Jude EB, Blakytny R, Bulmer J, Boulton AJ, Ferguson MW. Transforming growth factor-beta 1, 2, 3 and receptor type I and II in diabetic foot ulcers. Diabet Med. 2002;19(6):440–7.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    Menghini R, Uccioli L, Vainieri E, Pecchioli C, Casagrande V, Stoehr R, et al. Expression of tissue inhibitor of metalloprotease 3 is reduced in ischemic but not neuropathic ulcers from patients with type 2 diabetes mellitus. Acta Diabetol. 2013;50(6):907–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Martins VL, Caley M, O’Toole EA. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res. 2013;351(2):255–68.PubMedCrossRefGoogle Scholar
  27. 27.
    Tecilazich F, Dinh TL, Veves A. Emerging drugs for the treatment of diabetic ulcers. Expert Opin Emerg Drugs. 2013;18(2):207–17.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    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 Pharmacal Res. 2012;35(2):223–34.CrossRefGoogle Scholar
  29. 29.
    Greenman RL, Panasyuk S, Wang X, Lyons TE, Dinh T, Longoria L, et al. Early changes in the skin microcirculation and muscle metabolism of the diabetic foot. Lancet. 2005;366(9498):1711–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Donaghue VM, Chrzan JS, Rosenblum BI, Giurini JM, Habershaw GM, Veves A. Evaluation of a collagen-alginate wound dressing in the management of diabetic foot ulcers. Adv Wound Care. 1998;11(3):114–9.PubMedGoogle Scholar
  31. 31.
    Dinh T, Veves A. Microcirculation of the diabetic foot. Curr Pharm Des. 2005;11(18):2301–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol. 2003;139(11):1479–88.PubMedGoogle Scholar
  33. 33.
    Ekstrand AJ, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander AC, Hassani H, 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(10):6033–8.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Toda M, Suzuki T, Hosono K, Kurihara Y, Kurihara H, Hayashi I, et al. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother. 2008;62(6):352–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Gordon KA, Lebrun EA, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Skinmed. 2012;10(1):24–6.PubMedGoogle Scholar
  36. 36.
    Cavanagh PR, Bus SA. Off-loading the diabetic foot for ulcer prevention and healing. J Vasc Surg. 2010;52(3 Suppl):37S–43S.PubMedCrossRefGoogle Scholar
  37. 37.
    Moura LI, Dias AM, Carvalho E, de Sousa HC. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—a review. Acta Biomater. 2013;9(7):7093–114.PubMedCrossRefGoogle Scholar
  38. 38.
    Dumville JC, Deshpande S, O’Meara S, Speak K. Hydrocolloid dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev (Online). 2013;8:CD009099.Google Scholar
  39. 39.
    Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers. Cochrane Database Syst Rev (Online). 2013;1:CD002302.Google Scholar
  40. 40.
    Albayati MA, Shearman CP. Peripheral arterial disease and bypass surgery in the diabetic lower limb. Med Clin North Am. 2013;97(5):821–34.PubMedCrossRefGoogle Scholar
  41. 41.
    Mendes JJ, Neves J. Diabetic foot infectios: current diagnosis and treatment. J Diabet Foot Complicat. 2012;4(2):26–45.Google Scholar
  42. 42.
    Lipsky BA, Peters EJ, Berendt AR, Senneville E, Bakker K, Embil JM, et al. Specific guidelines for the treatment of diabetic foot infections 2011. Diabetes Metabol Res Rev. 2012;28(Suppl 1):234–5.CrossRefGoogle Scholar
  43. 43.
    Uchi H, Igarashi A, Urabe K, Koga T, Nakayama J, Kawamori R, et al. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol. 2009;19(5):461–8.PubMedGoogle Scholar
  44. 44.
    Maier HM, Ilich JZ, Kim JS, Spicer MT. Nutrition supplementation for diabetic wound healing: a systematic review of current literature. Skinmed. 2013;11(4):217–24 (quiz 24–25).PubMedGoogle Scholar
  45. 45.
    Steed DL, Attinger C, Colaizzi T, Crossland M, Franz M, Harkless L, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680–92.PubMedCrossRefGoogle Scholar
  46. 46.
    Villar G, Graham AD, Bayley H. A tissue-like printed material. Science. 2013;340(6128):48–52.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Michael S, Sorg H, Peck CT, Koch L, Deiwick A, Chichkov B, et al. Tissue engineered skin substitutes created by laser-assisted bioprinting form skin-like structures in the dorsal skin fold chamber in mice. PLoS One. 2013;8(3):e57741.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Perrier A, Vuillerme N, Luboz V, Bucki M, Cannard F, Diot B, et al. Smart diabetic shocks: embedded device for diabetic foot prevention. Innov Res Biomed Eng. 2014;32(2):72–6.Google Scholar
  49. 49.
    Shen JT, Falanga V. Innovative therapies in wound healing. J Cutan Med Surg. 2003;7(3):217–24.PubMedCrossRefGoogle Scholar
  50. 50.
    Dinh TL, Veves A. The efficacy of Apligraf in the treatment of diabetic foot ulcers. Plast Reconstr Surg. 2006;117(7 Suppl):152S–7S (discussion 8S–9S).PubMedCrossRefGoogle Scholar
  51. 51.
    Marston WA. Dermagraft, a bioengineered human dermal equivalent for the treatment of chronic nonhealing diabetic foot ulcer. Expert Rev Med Devices. 2004;1(1):21–31.PubMedCrossRefGoogle Scholar
  52. 52.
    Veves A, Giurini JM, LoGerfo FW. The diabetic foot: medical and surgical management. Heidelberg: Springer; 2012. p. 279.CrossRefGoogle Scholar
  53. 53.
    Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: a prospective 16-week pilot study. Int Wound J. 2006;3(3):181–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Ehrenreich M, Ruszczak Z. Update on tissue-engineered biological dressings. Tissue Eng. 2006;12(9):2407–24.PubMedCrossRefGoogle Scholar
  55. 55.
    Caselli A, Rich J, Hanane T, Uccioli L, Veves A. Role of C-nociceptive fibers in the nerve axon reflex-related vasodilation in diabetes. Neurology. 2003;60(2):297–300.PubMedCrossRefGoogle Scholar
  56. 56.
    Niezgoda JA, Van Gils CC, Frykberg RG, Hodde JP. Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care. 2005;18(5 Pt 1):258–66.PubMedCrossRefGoogle Scholar
  57. 57.
    Veves A, Sheehan P, Pham HT. A randomized, controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg. 2002;137(7):822–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Hong JP, Jung HD, Kim YW. Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg. 2006;56(4):394–8 (discussion 9–400).PubMedCrossRefGoogle Scholar
  59. 59.
    Saad Setta H, Elshahat A, Elsherbiny K, Massoud K, Safe I. Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: a comparative study. Int Wound J. 2011;8(3):307–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Margolis DJ, Bartus C, Hoffstad O, Malay S, Berlin JA. Effectiveness of recombinant human platelet-derived growth factor for the treatment of diabetic neuropathic foot ulcers. Wound Repair Regen. 2005;13(6):531–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Galiano RD, Tepper OM, Pelo CR, Bhatt KA, Callaghan M, Bastidas N, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;164(6):1935–47.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Tiaka EK, Papanas N, Manolakis AC, Maltezos E. The role of nerve growth factor in the prophylaxis and treatment of diabetic foot ulcers. Int J Burns Trauma. 2011;1(1):68–76.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, et al. A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metabol Res Rev. 2012;28(Suppl 1):119–41.CrossRefGoogle Scholar
  64. 64.
    Londahl M. Hyperbaric oxygen therapy as adjunctive treatment of diabetic foot ulcers. Med Clin North Am. 2013;97(5):957–80.PubMedCrossRefGoogle Scholar
  65. 65.
    Liu R, Li L, Yang M, Boden G, Yang G. Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers. Mayo Clin Proc. 2013;88(2):166–75.PubMedCrossRefGoogle Scholar
  66. 66.
    O’Reilly D, Pasricha A, Campbell K, Burke N, Assasi N, Bowen JM, et al. Hyperbaric oxygen therapy for diabetic ulcers: systematic review and meta-analysis. Int J Technol Assess Health Care. 2013;29(3):269–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Margolis DJ, Gupta J, Hoffstad O, Papdopoulos M, Glick HA, Thom SR, et al. Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study. Diabetes Care. 2013;36(7):1961–6.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Isaac AL, Armstrong DG. Negative pressure wound therapy and other new therapies for diabetic foot ulceration: the current state of play. Med Clin North Am. 2013;97(5):899–909.PubMedCrossRefGoogle Scholar
  69. 69.
    Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997;38(6):563–76 (discussion 77).PubMedCrossRefGoogle Scholar
  70. 70.
    Plikaitis CM, Molnar JA. Subatmospheric pressure wound therapy and the vacuum-assisted closure device: basic science and current clinical successes. Expert Rev Med Devices. 2006;3(2):175–84.PubMedCrossRefGoogle Scholar
  71. 71.
    Seo SG, Yeo JH, Kim JH, Kim JB, Cho TJ, Lee DY. Negative-pressure wound therapy induces endothelial progenitor cell mobilization in diabetic patients with foot infection or skin defects. Exp Mol Med. 2013;45:e62.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Vig S, Dowsett C, Berg L, Caravaggi C, Rome P, Birke-Sorensen H, et al. Evidence-based recommendations for the use of negative pressure wound therapy in chronic wounds: steps towards an international consensus. J Tissue Viability. 2011;20(Suppl 1):S1–18.PubMedCrossRefGoogle Scholar
  73. 73.
    Thakral G, Lafontaine J, Najafi B, Talal TK, Kim P, Lavery LA. Electrical stimulation to accelerate wound healing. Diabet Foot Ankle. 2013;4:22081.Google Scholar
  74. 74.
    Moretti B, Notarnicola A, Maggio G, Moretti L, Pascone M, Tafuri S, et al. The management of neuropathic ulcers of the foot in diabetes by shock wave therapy. BMC Musculoskelet Disord. 2009;10:54.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. 2005;28(9):2155–60.PubMedCrossRefGoogle Scholar
  76. 76.
    Dubsky M, Jirkovska A, Bem R, Fejfarova V, Pagacova L, Sixta B, et al. Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. Diabetes Metabol Res Rev. 2013;29(5):369–76.CrossRefGoogle Scholar
  77. 77.
    Humpert PM, Bartsch U, Konrade I, Hammes HP, Morcos M, Kasper M, et al. Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient. Exp Clin Endocrinol Diabetes. 2005;113(9):538–40.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    O’Loughlin A, Kulkarni M, Creane M, Vaughan EE, Mooney E, Shaw G, et al. Topical administration of allogeneic mesenchymal stromal cells seeded in a collagen scaffold augments wound healing and increases angiogenesis in the diabetic rabbit ulcer. Diabetes. 2013;62(7):2588–94.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Mulder G, Tallis AJ, Marshall VT, Mozingo D, Phillips L, Pierce GF, et al. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair Regen. 2009;17(6):772–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Brem H, Kodra A, Golinko MS, Entero H, Stojadinovic O, Wang VM, et al. Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. J Invest Dermatol. 2009;129(9):2275–87.PubMedCrossRefGoogle Scholar
  82. 82.
    Steckelings UM, Henz BM, Wiehstutz S, Unger T, Artuc M. Differential expression of angiotensin receptors in human cutaneous wound healing. Br J Dermatol. 2005;153(5):887–93.PubMedCrossRefGoogle Scholar
  83. 83.
    Steckelings UM, Wollschlager T, Peters J, Henz BM, Hermes B, Artuc M. Human skin: source of and target organ for angiotensin II. Exp Dermatol. 2004;13(3):148–54.PubMedCrossRefGoogle Scholar
  84. 84.
    Rodgers K, Verco S, Bolton L, Dizerega G. Accelerated healing of diabetic wounds by NorLeu(3)-angiotensin (1-7). Expert Opin Investig Drugs. 2011;20(11):1575–81.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Rodgers KE, Roda N, Felix JE, Espinoza T, Maldonado S, diZerega G. Histological evaluation of the effects of angiotensin peptides on wound repair in diabetic mice. Exp Dermatol. 2003;12(6):784–90.PubMedCrossRefGoogle Scholar
  86. 86.
    Rodgers KE, Espinoza T, Felix J, Roda N, Maldonado S, diZerega G. Acceleration of healing, reduction of fibrotic scar, and normalization of tissue architecture by an angiotensin analogue, NorLeu3-A(1-7). Plast Reconstr Surg. 2003;111(3):1195–206.PubMedCrossRefGoogle Scholar
  87. 87.
    Balingit PP, Armstrong DG, Reyzelman AM, Bolton L, Verco SJ, Rodgers KE, et al. NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial. Wound Repair Regen. 2012;20(4):482–90.PubMedGoogle Scholar
  88. 88.
    Kant V, Gopal A, Kumar D, Bag S, Kurade NP, Kumar A, et al. Topically applied substance P enhanced healing of open excision wound in rats. Eur J Pharmacol. 2013;715(1–3):345–53.PubMedCrossRefGoogle Scholar
  89. 89.
    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.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Healthcare 2014

Authors and Affiliations

  • Dimitrios Baltzis
    • 1
  • Ioanna Eleftheriadou
    • 1
  • Aristidis Veves
    • 2
    Email author
  1. 1.Joslin-Beth Israel Deaconess Foot Center and Microcirculation labBostonUSA
  2. 2.Beth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations