Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing.
Journal
Drugs
ISSN: 1179-1950
Titre abrégé: Drugs
Pays: New Zealand
ID NLM: 7600076
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
pubmed:
1
1
2021
medline:
26
10
2021
entrez:
31
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33382445
doi: 10.1007/s40265-020-01415-8
pii: 10.1007/s40265-020-01415-8
doi:
Substances chimiques
Anti-Ulcer Agents
0
Hypoglycemic Agents
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
29-56Commentaires et corrections
Type : CommentIn
Type : CommentIn
Références
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.
Petrova N, Edmonds M. Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006;11(4):709–24.
pubmed: 17064227
Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ. 2017;359:j5064.
pubmed: 29146579
pmcid: 5688746
Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.
pubmed: 10471461
Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43.
pubmed: 16291068
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.
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.
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.
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: 19638800
Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018;1411(1):153–65.
pubmed: 29377202
pmcid: 5793889
Atkin L, Rippon M. Autolysis: mechanisms of action in the removal of devitalised tissue. Br J Nurs. 2016;25(20 Suppl):S40–7.
pubmed: 27834531
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.
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).
Smith RG. Enzymatic debriding agents: an evaluation of the medical literature. Ostomy Wound Manage. 2008;54(8):16–34.
pubmed: 18716339
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: 20529148
pmcid: 7951583
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: 28862974
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: 24145042
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: 28267678
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.
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: 17965032
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: 19575178
pmcid: 2723663
Abela G. Benefits of maggot debridement therapy on leg ulcers: a literature review. Br J Community Nurs. 2017;22(Sup6):S14–9.
pubmed: 28570137
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 .
doi: 10.1186/s12896-016-0263-z
pubmed: 27006073
pmcid: 4804476
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.
pubmed: 26691053
Majtan J. Honey: an immunomodulator in wound healing. Wound Repair Regen. 2014;22(2):187–92.
pubmed: 24612472
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.
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.
Greener B, Hughes AA, Bannister NP, Douglass J. Proteases and pH in chronic wounds. J Wound Care. 2005;14(2):59–61.
pubmed: 15739652
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).
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: 29617058
Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002;183(4):406–12.
pubmed: 11975928
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.
pubmed: 18457680
Schwentker A, Vodovotz Y, Weller R, Billiar TR. Nitric oxide and wound repair: role of cytokines? Nitric Oxide. 2002;7(1):1–10.
pubmed: 12175813
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.
pubmed: 10564562
Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell. 1986;46(2):155–69.
pubmed: 3013421
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.
pubmed: 1969656
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.
pubmed: 3908487
pmcid: 424359
Mehendale F, Martin P. The cellular and molecular events of wound healing. Cutaneous wound healing. London: Martin Dunitz; 2001. p. 15–38.
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).
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.
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.
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.
pubmed: 25060693
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).
Papanas N, Maltezos E. Benefit-risk assessment of becaplermin in the treatment of diabetic foot ulcers. Drug Saf. 2010;33(6):455–61.
pubmed: 20486728
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.
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: 21173589
Okabe K, Hayashi R, Aramaki-Hattori N, Sakamoto Y, Kishi K. Wound treatment using growth factors. Mod Plast Surg. 2013;3(3):108–12.
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.
pubmed: 9576942
pmcid: 20437
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.
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: 19638336
Martí-Carvajal AJ, Gluud C, Nicola S, et al. Growth factors for treating diabetic foot ulcers. Cochrane Database Syst Rev. 2015;10:CD008548.
ClinicalTrials.gov Identifier: NCT01217476 The TRAfermin in neuropathic diabetic foot ulcer study—Northern Europe the TRANS-North Study [NCT01217476]. Last update 2014.
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.
pubmed: 29148070
pmcid: 5809344
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.
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.
pubmed: 28682675
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: 31394225
Robson MC, Payne WG. Growth factor therapy to aid wound healing. Wound healing. Boca Raton: CRC Press; 2005. p. 521–32.
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 .
doi: 10.1002/dmrr.3283
pubmed: 32176450
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 .
doi: 10.1002/dmrr.3284
pubmed: 32176446
Rohani MG, Parks WC. Matrix remodeling by MMPs during wound repair. Matrix Biol. 2015;44–46:113–21.
pubmed: 25770908
Opdenakker G, Van Damme J, Vranckx JJ. Immunomodulation as rescue for chronic atonic skin wounds. Trends Immunol. 2018;39(4):341–54.
pubmed: 29500031
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.
pubmed: 18387077
pmcid: 2326726
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.
pubmed: 18835949
pmcid: 2606842
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.
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.
pubmed: 7692970
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.
pubmed: 12093340
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: 11983003
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: 20437788
pmcid: 4680061
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).
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: 30364787
pmcid: 6198285
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.
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: 30243803
Game F, Jeffcoate W, Tarnow L, Day F, Fitzsimmons D, Jacobsen J. The LeucoPatch
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.
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.
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.
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.
pubmed: 9384327
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.
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).
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: 30136445
Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix(
pubmed: 25048468
pmcid: 7951030
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.
pubmed: 15209775
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.
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: 18034628
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: 16722865
pmcid: 7951241
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: 25384916
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: 19368581
pmcid: 7951349
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: 26297933
Bijan Najafi, Comparative Effectiveness of Two Acellular Matrices [Dermacell vs. Integra] for Management of Deep Diabetic Foot Ulcers. https://clinicaltrialsgov/show/NCT03476876. 2018.
Shin D. The use of acellular dermal matrix paste for treatment of diabetic foot ulcer. Wound Repair Regen. 2019;27(3):A17.
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.
pubmed: 31070860
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: 15942317
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.
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.
pubmed: 31619393
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: 30207844
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: 28448266
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: 30016136
Londahl M. Number eight in the service of diabetic foot ulcer healing. Diabetes Care. 2020;43(3):515–7.
pubmed: 32079686
Hunt SD, Elg F. Clinical effectiveness of hemoglobin spray (Granulox
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: 21873346
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: 28783878
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).
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.
pubmed: 23374620
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).
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.
pubmed: 24726143
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: 20427683
pmcid: 2858204
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.
pubmed: 26740639
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.
pubmed: 29074815
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.
pubmed: 23423696
pmcid: 3687310
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.
pubmed: 21925496
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: 23672237
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.
Cosentino F, Lüscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol. 1998;32(Suppl 3):S54–61.
pubmed: 9883749
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.
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.
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.
pubmed: 2254674
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: 9078595
Pirfenidone Drug Action.Available from: https://bnf.nice.org.uk/drug/pirfenidone.html .
Armendariz-Borunda Juan. Efficacy of Pirfenidone Plus MODD in Diabetic Foot Ulcers ClinicalTrials.gov Identifier: NCT02632877:2015.
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: 29675430
pmcid: 5840678
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 .
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: 31667978
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.
pubmed: 26505723
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.
pubmed: 24572860
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.
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.
pubmed: 16525273
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: 21216483
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.
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).
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.
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.
pubmed: 30679183
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: 19821960
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.
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.
pubmed: 22407991
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: 24527355
pmcid: 3763221
James GA, Swogger E, Wolcott R, et al. Biofilms in chronic wounds. Wound Repair Regen. 2008;16(1):37–44.
pubmed: 18086294
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: 20731798
pmcid: 2939909
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).
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.
pubmed: 25871534
pmcid: 4450333
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.
pubmed: 12764579
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.
Hetrick EM, Shin JH, Stasko NA, et al. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles. ACS Nano. 2008;2(2):235–46.
pubmed: 19206623
pmcid: 3571086
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.
pubmed: 21402405
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: 18078743
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.
pubmed: 11054889
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.
pubmed: 18758917
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: 30614086
pmcid: 6375388
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.
pubmed: 26695434
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.
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: 30822099
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.
pubmed: 11096195