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Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing

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A Letter to the Editor to this article was published on 17 February 2022

A Letter to the Editor to this article was published on 17 February 2022

Abstract

Historically, there has been a scarcity of evidence-based topical therapy to hasten the healing of diabetic foot ulcers. But recently new evidence-based treatments have emerged from multicentre, randomised, controlled trials. This article highlights those trials, and describes the current pharmacological management of the diabetic foot ulcer and the advances that have been made in wound therapy to date. It provides an overview of topical and systemic pharmacotherapies in current use and those in development for future use in managing the diabetic foot. For each treatment, proposed mechanisms of action and evidence available to support their clinical use are presented. There is supporting randomised, controlled evidence for sucrose octasulfate in the treatment of neuro-ischaemic ulcers, and multi-layered patch of autologous leucocytes, platelets and fibrin in ulcers with or without ischaemia. There is also evidence for placentally derived products and for topical and systemic oxygen therapy in the healing of diabetic foot ulcers. Growth factors, bio-engineered tissues, stem cell therapy, gene therapy and peptide therapy also have some supporting evidence in the healing of diabetic foot ulcers. Nonsurgical debriding agents may be useful when the optimum approach of sharp debridement is not possible, and immunomodulators may be helpful for their antimicrobial effects, but robust data is still required to strengthen the case for general use. The review does not cover antimicrobials as their primary role are as anti-infectives and not in wound healing. The development of nanotechnology has created a means of prolonging the bioavailability of target molecules at the wound site, with the use of glass/hydrogel nanoparticles, polyethylene glycol and hyaluronic acid. Looking forward, novel therapies, including traction force-activated payloads, local delivery of short-interfering RNA and finally hydrogels incorporating bioactive agents or cells may provide possibilities for pharmacotherapy in the future.

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References

  1. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.

  2. Petrova N, Edmonds M. Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006;11(4):709–24.

    CAS  PubMed  Google Scholar 

  3. Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ. 2017;359:j5064.

    PubMed  PubMed Central  Google Scholar 

  4. Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.

    CAS  PubMed  Google Scholar 

  5. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43.

    PubMed  Google Scholar 

  6. Berlanga-Acosta J, Valdéz-Pérez C, Savigne-Gutiérrez W, Mendoza-Marí Y, Franco-Pérez N, Vargas-Machiran E, et al. Cellular and molecular insights into the wound healing mechanism in diabetes. Biotecnol Apl. 2010;27(4):255–61.

  7. Clayton W, Elasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic patients. Clin Diabetes. 2009;27(2):52–8.

    Google Scholar 

  8. Braun L, Kim PJ, Margolis D, Peters EJ, Lavery LA. What’s new in the literature: an update of new research since the original WHS diabetic foot ulcer guidelines in 2006. Wound Repair Regener. 2014;22(5):594–604.

    Google Scholar 

  9. Markuson M, Hanson D, Anderson J, et al. The relationship between hemoglobin A(1c) values and healing time for lower extremity ulcers in individuals with diabetes. Adv Skin Wound Care. 2009;22(8):365–72.

    PubMed  Google Scholar 

  10. Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018;1411(1):153–65.

    PubMed  PubMed Central  Google Scholar 

  11. Atkin L, Rippon M. Autolysis: mechanisms of action in the removal of devitalised tissue. Br J Nurs. 2016;25(20 Suppl):S40–7.

    PubMed  Google Scholar 

  12. Gray D, Acton C, Chadwick P, Fumarola S, Leaper DJ, Morris C, et al. Consensus guidance for the use of debridement techniques in the UK. Wounds UK. 2011;7:77–85.

    Google Scholar 

  13. Dumville JC, O’Meara S, Deshpande S, Speak K. Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2011;9:CD009101 (published 2011 Sep 7).

  14. Smith RG. Enzymatic debriding agents: an evaluation of the medical literature. Ostomy Wound Manage. 2008;54(8):16–34.

    PubMed  Google Scholar 

  15. Shi L, Ermis R, Garcia A, Telgenhoff D, Aust D. Degradation of human collagen isoforms by Clostridium collagenase and the effects of degradation products on cell migration. Int Wound J. 2010;7(2):87–95.

    PubMed  PubMed Central  Google Scholar 

  16. Lantis Ii JC, Gordon I. Clostridial collagenase for the management of diabetic foot ulcers: results of four randomized controlled trials. Wounds. 2017;29(10):297–305.

    PubMed  Google Scholar 

  17. Tallis A, Motley TA, Wunderlich RP, et al. Clinical and economic assessment of diabetic foot ulcer debridement with collagenase: results of a randomized controlled study. Clin Ther. 2013;35(11):1805–20.

    PubMed  Google Scholar 

  18. Jimenez JC, Agnew PS, Mayer P, et al. Enzymatic debridement of chronic nonischemic diabetic foot ulcers: results of a randomized, controlled trial. Wounds. 2017;29(5):133–9.

    PubMed  Google Scholar 

  19. Balasubrahmanya KS, Pawar PM, Srinidhi M, Shruthi S, Jinumon KV, Rahul D, Kunju RD. A prospective study on effectiveness of use of papain urea based preparation in dressings compared with regular conventional dressings in diabetic foot ulcers. Int Surg J. 2017;4(6):1984–1987S.

  20. van der Plas MJ, Jukema GN, Wai SW, et al. Maggot excretions/secretions are differentially effective against biofilms of Staphylococcus aureus and Pseudomonas aeruginosa. J Antimicrob Chemother. 2008;61(1):117–22.

    PubMed  Google Scholar 

  21. van der Plas MJ, Baldry M, van Dissel JT, Jukema GN, Nibbering PH. Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP. Diabetologia. 2009;52(9):1962–70.

    PubMed  PubMed Central  Google Scholar 

  22. Abela G. Benefits of maggot debridement therapy on leg ulcers: a literature review. Br J Community Nurs. 2017;22(Sup6):S14–9.

    PubMed  Google Scholar 

  23. Linger RJ, Belikoff EJ, Yan Y, et al. Towards next generation maggot debridement therapy: transgenic Lucilia sericata larvae that produce and secrete a human growth factor. BMC Biotechnol. 2016;16:30. https://doi.org/10.1186/s12896-016-0263-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nigam Y, Morgan C. Does maggot therapy promote wound healing? The clinical and cellular evidence. J Eur Acad Dermatol Venereol. 2016;30(5):776–82.

    CAS  PubMed  Google Scholar 

  25. Majtan J. Honey: an immunomodulator in wound healing. Wound Repair Regen. 2014;22(2):187–92.

    PubMed  Google Scholar 

  26. Molan PC. The evidence supporting the use of honey as a wound dressing [published correction appears in Int J Low Extrem Wounds. 2006 Jun;5(2):122]. Int J Low Extrem Wounds. 2006;5(1):40–54.

  27. Wang C, Guo M, Zhang N, Wang G. Effectiveness of honey dressing in the treatment of diabetic foot ulcers: a systematic review and meta-analysis. Compl Ther Clin Pract. 2019;34:123–31.

    Google Scholar 

  28. Greener B, Hughes AA, Bannister NP, Douglass J. Proteases and pH in chronic wounds. J Wound Care. 2005;14(2):59–61.

    CAS  PubMed  Google Scholar 

  29. Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2015;3:CD005083 (published 2015 Mar 6).

  30. Edmonds ME, Bodansky HJ, Boulton AJM, et al. Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study. Wound Repair Regen. 2018;26(2):228–37.

    PubMed  Google Scholar 

  31. Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002;183(4):406–12.

    CAS  PubMed  Google Scholar 

  32. Friedman AJ, Han G, Navati MS, et al. Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide. 2008;19(1):12–20.

    CAS  PubMed  Google Scholar 

  33. Schwentker A, Vodovotz Y, Weller R, Billiar TR. Nitric oxide and wound repair: role of cytokines? Nitric Oxide. 2002;7(1):1–10.

    CAS  PubMed  Google Scholar 

  34. 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.

    CAS  PubMed  Google Scholar 

  35. Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell. 1986;46(2):155–69.

    CAS  PubMed  Google Scholar 

  36. Ross R, Bowen-Pope DF, Raines EW. Platelet-derived growth factor and its role in health and disease. Philos Trans R Soc Lond B Biol Sci. 1990;327(1239):155–69.

    CAS  PubMed  Google Scholar 

  37. Grotendorst GR, Martin GR, Pencev D, Sodek J, Harvey AK. Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest. 1985;76(6):2323–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mehendale F, Martin P. The cellular and molecular events of wound healing. Cutaneous wound healing. London: Martin Dunitz; 2001. p. 15–38.

    Google Scholar 

  39. Buchberger B, Follmann M, Freyer D, Huppertz H, Ehm A, Wasem J. The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers. GMS Health Technol Assess. 2010;6:Doc12 (published 2010 Sep 1).

  40. 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):822–827.

  41. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg. 1995;21(1):71–81.

  42. Zhao XH, Gu HF, Xu ZR, et al. Efficacy of topical recombinant human platelet-derived growth factor for treatment of diabetic lower-extremity ulcers: systematic review and meta-analysis. Metabolism. 2014;63(10):1304–13.

    CAS  PubMed  Google Scholar 

  43. Khandelwal S, Chaudhary P, Poddar DD, Saxena N, Singh RA, Biswal UC. Comparative study of different treatment options of grade III and IV diabetic foot ulcers to reduce the incidence of amputations. Clin Pract. 2013;3(1):e9 (published 2013 Feb 21).

  44. Papanas N, Maltezos E. Benefit-risk assessment of becaplermin in the treatment of diabetic foot ulcers. Drug Saf. 2010;33(6):455–61.

    CAS  PubMed  Google Scholar 

  45. Bowlby M, Blume P, Schmidt B, Donegan R. Safety and efficacy of Becaplermin gel in the treatment of diabetic foot ulcers. Chronic Wound Care Manag Res. 2014;1(1):11–14.

  46. 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(1):31–9.

    PubMed  Google Scholar 

  47. Okabe K, Hayashi R, Aramaki-Hattori N, Sakamoto Y, Kishi K. Wound treatment using growth factors. Mod Plast Surg. 2013;3(3):108–12.

    Google Scholar 

  48. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C. Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA. 1998;95(10):5672–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Richard JL, Parer-Richard C, Daures JP, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study. Diabetes Care. 1995;18(1):64–69.

  50. Uchi H, Igarashi A, Urabe K, et al. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol. 2009;19(5):461–8.

    PubMed  Google Scholar 

  51. Martí-Carvajal AJ, Gluud C, Nicola S, et al. Growth factors for treating diabetic foot ulcers. Cochrane Database Syst Rev. 2015;10:CD008548.

  52. ClinicalTrials.gov Identifier: NCT01217476 The TRAfermin in neuropathic diabetic foot ulcer study—Northern Europe the TRANS-North Study [NCT01217476]. Last update 2014.

  53. Sridharan K, Sivaramakrishnan G. Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials. Br J Clin Pharmacol. 2018;84(3):434–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou K, Ma Y, Brogan MS. Chronic and non-healing wounds: the story of vascular endothelial growth factor. Med Hypothes. 2015;85(4):399–404.

    CAS  Google Scholar 

  55. Li G, Zou X, Zhu Y, et al. Expression and influence of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor in diabetic foot ulcers. Int J Low Extrem Wounds. 2017;16(1):6–13.

    CAS  PubMed  Google Scholar 

  56. Yang Q, Zhang Y, Yin H, Lu Y. Topical recombinant human epidermal growth factor for diabetic foot ulcers: a meta-analysis of randomized controlled clinical trials. Ann Vasc Surg. 2020;62:442–51.

    PubMed  Google Scholar 

  57. Robson MC, Payne WG. Growth factor therapy to aid wound healing. Wound healing. Boca Raton: CRC Press; 2005. p. 521–32.

    Google Scholar 

  58. Rayman G, Vas P, Dhatariya K, et al. Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3283. https://doi.org/10.1002/dmrr.3283.

    Article  PubMed  Google Scholar 

  59. Vas P, Rayman G, Dhatariya K, et al. Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review. Diabetes Metab Res Rev. 2020;36(Suppl 1):e3284. https://doi.org/10.1002/dmrr.3284.

    Article  PubMed  Google Scholar 

  60. Rohani MG, Parks WC. Matrix remodeling by MMPs during wound repair. Matrix Biol. 2015;44–46:113–21.

    PubMed  Google Scholar 

  61. Opdenakker G, Van Damme J, Vranckx JJ. Immunomodulation as rescue for chronic atonic skin wounds. Trends Immunol. 2018;39(4):341–54.

    CAS  PubMed  Google Scholar 

  62. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu Y, Min D, Bolton T, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care. 2009;32(1):117–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Edmonds M, Lázaro-Martínez JL, Alfayate-García JM, et al. Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial [published correction appears in Lancet Diabetes Endocrinol. 2018 Mar 6;:]. Lancet Diabetes Endocrinol. 2018;6(3):186–196.

  65. Volkin DB, Verticelli AM, Marfia KE, Burke CJ, Mach H, Middaugh CR. Sucralfate and soluble sucrose octasulfate bind and stabilize acidic fibroblast growth factor. Biochim Biophys Acta. 1993;1203(1):18–26.

    CAS  PubMed  Google Scholar 

  66. 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.

    CAS  PubMed  Google Scholar 

  67. Cullen B, Smith R, McCulloch E, Silcock D, Morrison L. Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers. Wound Repair Regen. 2002;10(1):16–25.

    PubMed  Google Scholar 

  68. Akingboye AA, Giddins S, Gamston P, Tucker A, Navsaria H, Kyriakides C. Application of autologous derived-platelet rich plasma gel in the treatment of chronic wound ulcer: diabetic foot ulcer. J Extra Corpor Technol. 2010;42(1):20–9.

    PubMed  PubMed Central  Google Scholar 

  69. Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2016;5:CD006899 (published 2016 May 25).

  70. Hirase T, Ruff E, Surani S, Ratnani I. Topical application of platelet-rich plasma for diabetic foot ulcers: a systematic review. World J Diabetes. 2018;9(10):172–9.

    PubMed  PubMed Central  Google Scholar 

  71. Del Pino-Sedeño T, Trujillo-Martín MM, Andia I, et al. Platelet-rich plasma for the treatment of diabetic foot ulcers: a meta-analysis. Wound Rep Regen. 2019;27(2):170–82.

    Google Scholar 

  72. Game F, Jeffcoate W, Tarnow L, et al. LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(11):870–8.

    PubMed  Google Scholar 

  73. Game F, Jeffcoate W, Tarnow L, Day F, Fitzsimmons D, Jacobsen J. The LeucoPatch® system in the management of hard-to-heal diabetic foot ulcers: study protocol for a randomised controlled trial. Trials. 2017;18(1):469 (published 2017 Oct 10).

  74. Veves A, Falanga V, Armstrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. 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):290–295.

  75. Edmonds M; European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009;8(1):11-18.

  76. Marston WA, Hanft J, Norwood P, Pollak R; Dermagraft Diabetic Foot Ulcer Study Group. 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):1701–1705.

  77. Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs. 1997;21(11):1203–10.

    CAS  PubMed  Google Scholar 

  78. Luck J, Rodi T, Geierlehner A, Mosahebi A. Allogeneic Skin substitutes versus human placental membrane products in the management of diabetic foot ulcers: a narrative comparative evaluation of the literature. Int J of Low Extrem Wounds. 2019;18(1):10–22.

    Google Scholar 

  79. Haugh AM, Witt JG, Hauch A, et al. Amnion membrane in diabetic foot wounds: a meta-analysis. Plast Reconstr Surg Glob Open. 2017;5(4):e1302 (published 2017 Apr).

  80. Tettelbach W, Cazzell S, Reyzelman AM, Sigal F, Caporusso JM, Agnew PS. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: a prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics. Int Wound J. 2019;16(1):19–29.

    PubMed  Google Scholar 

  81. Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix(®) 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.

    PubMed  PubMed Central  Google Scholar 

  82. Moustafa M, Simpson C, Glover M, et al. A new autologous keratinocyte dressing treatment for non-healing diabetic neuropathic foot ulcers. Diabet Med. 2004;21(7):786–9.

    CAS  PubMed  Google Scholar 

  83. ISRCTN14871374. Development of wound healing therapies: a randomised controlled single-blind prospective pilot study for the use of autologous keratinocytes on a transfer dressing [TranCell] in the treatment of diabetic ulcers. http://www.who.int/trialsearch/Trial2 aspx?TrialID=ISRCTN14871374. 2005.

  84. Moustafa M, Bullock AJ, Creagh FM, et al. Randomized, controlled, single-blind study on use of autologous keratinocytes on a transfer dressing to treat nonhealing diabetic ulcers. Regen Med. 2007;2(6):887–902.

    PubMed  Google Scholar 

  85. Martin BR, Sangalang M, Wu S, Armstrong DG. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. Int Wound J. 2005;2(2):161–5.

    PubMed  PubMed Central  Google Scholar 

  86. Mulder G, Tenenhaus M, D’Souza GF. Reduction of diabetic foot ulcer healing times through use of advanced treatment modalities. Int J Low Extrem Wounds. 2014;13(4):335–46.

    PubMed  Google Scholar 

  87. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009;6(3):196–208.

    PubMed  PubMed Central  Google Scholar 

  88. 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.

    PubMed  Google Scholar 

  89. Bijan Najafi, Comparative Effectiveness of Two Acellular Matrices [Dermacell vs. Integra] for Management of Deep Diabetic Foot Ulcers. https://clinicaltrialsgov/show/NCT03476876. 2018.

  90. Shin D. The use of acellular dermal matrix paste for treatment of diabetic foot ulcer. Wound Repair Regen. 2019;27(3):A17.

  91. Tchanque-Fossuo CN, Dahle SE, Lev-Tov H, et al. Cellular versus acellular matrix devices in the treatment of diabetic foot ulcers: interim results of a comparative efficacy randomized controlled trial. J Tissue Eng Regen Med. 2019;13(8):1430–7.

    CAS  PubMed  Google Scholar 

  92. 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.

    PubMed  Google Scholar 

  93. Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2(2):CD011255.

  94. Frykberg RG, Franks PJ, Edmonds M, et al. A multinational, multicenter, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO2) therapy in the treatment of chronic diabetic foot ulcers: the TWO2 study. Diabetes Care. 2020;43(3):616–24.

    CAS  PubMed  Google Scholar 

  95. Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care. 2018;27(Sup9):S30–45.

    PubMed  Google Scholar 

  96. Driver VR, Reyzelman A, Kawalec J, French M. A prospective, randomized, blinded, controlled trial comparing transdermal continuous oxygen delivery to moist wound therapy for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2017;63(4):12–28.

    PubMed  Google Scholar 

  97. Kaufman H, Gurevich M, Tamir E, Keren E, Alexander L, Hayes P. Topical oxygen therapy stimulates healing in difficult, chronic wounds: a tertiary centre experience. J Wound Care. 2018;27(7):426–33.

    PubMed  Google Scholar 

  98. Londahl M. Number eight in the service of diabetic foot ulcer healing. Diabetes Care. 2020;43(3):515–7.

    PubMed  Google Scholar 

  99. Hunt SD, Elg F. Clinical effectiveness of hemoglobin spray (Granulox®) as adjunctive therapy in the treatment of chronic diabetic foot ulcers. Diabet Foot Ankle. 2016;7:33101 (published 2016 Nov 7).

  100. Tiaka EK, Papanas N, Manolakis AC, Maltezos E. The role of hyperbaric oxygen in the treatment of diabetic foot ulcers. Angiology. 2012;63(4):302–14.

    PubMed  Google Scholar 

  101. de Smet GHJ, Kroese LF, Menon AG, et al. Oxygen therapies and their effects on wound healing. Wound Repair Regen. 2017;25(4):591–608.

    PubMed  Google Scholar 

  102. Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2015;2015(6):CD004123 (published 2015 Jun 24).

  103. 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.

    CAS  PubMed  Google Scholar 

  104. O’Reilly D, Linden R, Fedorko L, et al. A prospective, double-blind, randomized, controlled clinical trial comparing standard wound care with adjunctive hyperbaric oxygen therapy (HBOT) to standard wound care only for the treatment of chronic, non-healing ulcers of the lower limb in patients with diabetes mellitus: a study protocol. Trials. 2011;12:69 (published 2011 Mar 7).

  105. Stoekenbroek RM, Santema TB, Legemate DA, Ubbink DT, van den Brink A, Koelemay MJ. Hyperbaric oxygen for the treatment of diabetic foot ulcers: a systematic review. Eur J Vasc Endovasc Surg. 2014;47(6):647–55.

    CAS  PubMed  Google Scholar 

  106. Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998–1003.

    PubMed  PubMed Central  Google Scholar 

  107. Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial. Diabetes Care. 2016;39(3):392–9.

    CAS  PubMed  Google Scholar 

  108. Santema KTB, Stoekenbroek RM, Koelemay MJW, et al. Hyperbaric oxygen therapy in the treatment of ischemic lower-extremity ulcers in patients with diabetes: results of the DAMO2CLES multicenter randomized clinical trial. Diabetes Care. 2018;41(1):112–9.

    CAS  PubMed  Google Scholar 

  109. Margolis DJ, Gupta J, Hoffstad O, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Chuang SY, Yang SH, Chen TY, Pang JH. Cilostazol inhibits matrix invasion and modulates the gene expressions of MMP-9 and TIMP-1 in PMA-differentiated THP-1 cells. Eur J Pharmacol. 2011;670(2-3):419–26.

    CAS  PubMed  Google Scholar 

  111. de Franciscis S, Gallelli L, Battaglia L, et al. Cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease. Int Wound J. 2015;12(3):250–3.

    PubMed  Google Scholar 

  112. Elraiyah T, Tsapas A, Prutsky G, et al. A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers. J Vasc Surg. 2016;63(2 Suppl):46S–58S.e2.

  113. Cosentino F, Lüscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol. 1998;32(Suppl 3):S54–61.

    CAS  PubMed  Google Scholar 

  114. Murat S, Baris S, Aikimbaev K, Tetiker T. Effect of Iloprost on endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease. Int J Diabetes Metabol. 2008;16:7–11.

    Google Scholar 

  115. Rullan M, Cerdà L, Frontera G, Masmiquel L, Llobera J. Treatment of chronic diabetic foot ulcers with bemiparin: a randomized, triple-blind, placebo-controlled, clinical trial [published correction appears in Diabet Med. 2008 Oct;25(10):1257]. Diabet Med. 2008;25(9):1090–1095.

  116. Apelqvist J, Castenfors J, Larsson J, Stenström A, Persson G. Ketanserin in the treatment of diabetic foot ulcer with severe peripheral vascular disease. Int Angiol. 1990;9(2):120–4.

    CAS  PubMed  Google Scholar 

  117. Martínez-de Jesús FR, Morales-Guzmán M, Castañeda M, Pérez-Morales A, García-Alonso J, Mendiola-Segura I. Randomized single-blind trial of topical ketanserin for healing acceleration of diabetic foot ulcers. Arch Med Res. 1997;28(1):95–9.

    PubMed  Google Scholar 

  118. Pirfenidone Drug Action.Available from: https://bnf.nice.org.uk/drug/pirfenidone.html.

  119. Armendariz-Borunda Juan. Efficacy of Pirfenidone Plus MODD in Diabetic Foot Ulcers ClinicalTrials.gov Identifier: NCT02632877:2015.

  120. Gasca-Lozano LE, Lucano-Landeros S, Ruiz-Mercado H, et al. Pirfenidone accelerates wound healing in chronic diabetic foot ulcers: a randomized, double-blind controlled trial. J Diabetes Res. 2017;2017:3159798.

    PubMed  PubMed Central  Google Scholar 

  121. Janka-Zires M, Almeda-Valdes P,Uribe-Wiechers AC et al. Topical Administration of Pirfenidone Increases healing of chronic diabetic foot ulcers: a randomized crossover study. J Diabetes Res. 2016; 2016:7340641. https://doi.org/10.1155/2016/7340641.

  122. Kim PJ, Attinger CE, Constantine T, Crist BD, Faust E, Hirche CR, et al. Negative pressure wound therapy with instillation: international consensus guidelines update. Int Wound J. 2020;17(1):174–86.

    PubMed  Google Scholar 

  123. Kim PJ, Attinger CE, Oliver N, Garwood C, Evans KK, Steinberg JS, et al. Comparison of outcomes for normal saline and an antiseptic solution for negative-pressure wound therapy with instillation. Plast Reconstr Surg. 2015;136(5):657e–64e.

    CAS  PubMed  Google Scholar 

  124. Kim PJ, Attinger CE, Steinberg JS, et al. The impact of negative-pressure wound therapy with instillation compared with standard negative-pressure wound therapy: a retrospective, historical, cohort, controlled study. Plast Reconstr Surg. 2014;133(3):709–16.

    CAS  PubMed  Google Scholar 

  125. Han S, Yoon T, Lee D, Lee M, Kim W. Potential of human bone marrow stromal cells to accelerate wound healing in vitro. Ann Plast Surg. 2005;55(4):414–419.

  126. Han SK, Chun KW, Gye MS, Kim WK. The effect of human bone marrow stromal cells and dermal fibroblasts on angiogenesis. Plast Reconstr Surg. 2006;117(3):829–35.

    CAS  PubMed  Google Scholar 

  127. Lu D, Chen B, Liang Z, 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.

    PubMed  Google Scholar 

  128. Lu D, Jiang Y, Deng W, Zhang Y, Liang Z, Wu Q, et al. Long-term outcomes of BMMSC compared with BMMNC for treatment of critical limb ischemia and foot ulcer in patients with diabetes. Cell Transpl. 2019;28(5):645–52.

    Google Scholar 

  129. Lonardi R, Leone N, Gennai S, Trevisi Borsari G, Covic T, Silingardi R. Autologous micro-fragmented adipose tissue for the treatment of diabetic foot minor amputations: a randomized controlled single-center clinical trial (MiFrAADiF). Stem Cell Res Ther. 2019;10(1):223 (published 2019 Jul 29).

  130. Albehairy A, Kyrillos F, Gawish H, State O, Abdelghaffar H, Elbaz O, et al. Autologous mononuclear versus mesenchymal stem cells in healing of recalcitrant neuropathic diabetic foot ulcers. Diabetologia. 2018;61:S7.

    Google Scholar 

  131. Moon KC, Suh HS, Kim KB, et al. Potential of allogeneic adipose-derived stem cell-hydrogel complex for treating diabetic foot ulcers. Diabetes. 2019;68(4):837–46.

    CAS  PubMed  Google Scholar 

  132. Mulder G, Tallis AJ, Marshall VT, 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.

    PubMed  Google Scholar 

  133. Human Stem Cell Institute Russia. Safety and efficacy of neovasculgen pl-VEGF165 gene therapy in patients with diabetic foot ClinicalTrials.gov Identifier: NCT02538705. 2017 April.

  134. Kwon MJ, An S, Choi S, Nam K, Jung HS, Yoon CS, et al. Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer. J Gene Med. 2012;14(4):272–8.

    CAS  PubMed  Google Scholar 

  135. Zhao G, Usui ML, Lippman SI, et al. Biofilms and inflammation in chronic wounds. Adv Wound Care (New Rochelle). 2013;2(7):389–99.

    PubMed  PubMed Central  Google Scholar 

  136. James GA, Swogger E, Wolcott R, et al. Biofilms in chronic wounds. Wound Repair Regen. 2008;16(1):37–44.

    PubMed  Google Scholar 

  137. Zhao G, Hochwalt PC, Usui ML, et al. Delayed wound healing in diabetic (db/db) mice with Pseudomonas aeruginosa biofilm challenge: a model for the study of chronic wounds. Wound Repair Regen. 2010;18(5):467–77.

    PubMed  PubMed Central  Google Scholar 

  138. Gomes A, Teixeira C, Ferraz R, Prudêncio C, Gomes P. Wound-healing peptides for treatment of chronic diabetic foot ulcers and other infected skin injuries. Molecules. 2017;22(10):1743 (published 2017 Oct 18).

  139. Leal EC, Carvalho E, Tellechea A, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol. 2015;185(6):1638–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Nakamura M, Kawahara M, Morishige N, Chikama T, Nakata K, Nishida T. Promotion of corneal epithelial wound healing in diabetic rats by the combination of a substance P-derived peptide [FGLM-NH2] and insulin-like growth factor-1. Diabetologia. 2003;46:839–42.

    CAS  PubMed  Google Scholar 

  141. Vellayappan M, Jaganathan SK, Manikandan A. Nanomaterials as a game changer in the management and treatment of diabetic foot ulcers. RSC Adv. 2016;6(115):114859–78.

    CAS  Google Scholar 

  142. Hetrick EM, Shin JH, Stasko NA, et al. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles. ACS Nano. 2008;2(2):235–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Yang Y, Xia T, Zhi W, et al. Promotion of skin regeneration in diabetic rats by electrospun core-sheath fibers loaded with basic fibroblast growth factor. Biomaterials. 2011;32(18):4243–54.

    CAS  PubMed  Google Scholar 

  144. Yang Y, Li X, Qi M, Zhou S, Weng J. Release pattern and structural integrity of lysozyme encapsulated in core–sheath structured poly [dl-lactide] ultrafine fibers prepared by emulsion electrospinning. Eur J Pharm Biopharm. 2007;69(1):106–16.

    PubMed  Google Scholar 

  145. Edmonds M, Bates M, Doxford M, Gough A, Foster A. New treatments in ulcer healing and wound infection. Diabetes Metab Res Rev. 2000;16(Suppl 1):S51–4.

    CAS  PubMed  Google Scholar 

  146. Zavan B, Vindigni V, Vezzù K, et al. Hyaluronan based porous nano-particles enriched with growth factors for the treatment of ulcers: a placebo-controlled study. J Mater Sci Mater Med. 2009;20(1):235–47.

    CAS  PubMed  Google Scholar 

  147. Stejskalová A, Oliva N, England FJ, Almquist BD. Biologically inspired, cell-selective release of aptamer-trapped growth factors by traction forces. Adv Mater. 2019;31(7):e1806380.

    PubMed  PubMed Central  Google Scholar 

  148. Castleberry SA, Almquist BD, Li W, et al. Self-assembled wound dressings silence MMP-9 and improve diabetic wound healing in vivo. Adv Mater. 2016;28(9):1809–17.

    CAS  PubMed  Google Scholar 

  149. Peppas N , Hilt J , Khademhosseini A, Langer R. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv Mater. 2006;18(11):1345–1360.

  150. da Silva LP, Reis RL, Correlo VM, Marques AP. Hydrogel-based strategies to advance therapies for chronic skin wounds. Annu Rev Biomed Eng. 2019;21(1):145–69.

    PubMed  Google Scholar 

  151. Reimer K, Vogt PM, Broegmann B, Hauser J, Rossbach O, Kramer A, et al. An innovative topical drug formulation for wound healing and infection treatment: in vitro and in vivo investigations of a povidone-iodine liposome hydrogel. Dermatology. 2000;201(3):235–41.

    CAS  PubMed  Google Scholar 

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  1. Diabetic Foot Clinic, King’s College NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK

    Danielle Dixon & Michael Edmonds

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Danielle Dixon—No conflicts of interest, nothing to declare. Michael Edmonds—Advisory board, Urgo Medical, Bayer AG, Biomonde, Molnlycke.

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Dixon, D., Edmonds, M. Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing. Drugs 81, 29–56 (2021). https://doi.org/10.1007/s40265-020-01415-8

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