Login Register Cart 0
Generic placeholder image

Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Physiological and Pathophysiological Aspects of Diabetic Foot Ulcer and its Treatment Strategies

Author(s): Vadivelan Ramachandran*, Tharani Mohanasundaram, Darshan Karunakaran, Monika Gunasekaran and Ruchi Tiwari

Volume 19, Issue 8, 2023

Published on: 05 December, 2022

Article ID: e031122210617 Pages: 13

DOI: 10.2174/1573399819666221103141715

Price: $65

conference banner
Abstract

Background: Diabetes foot ulcers (DFU) are among the most common complications in diabetic patients, leading to amputation and psychological distress. This mini-review covers the general physiology of ulcer healing as well as the pathophysiology of DFU and its therapies. Only a few treatments have been sanctioned and numerous compounds from various pharmacological groups are now being tested at various stages for the prevention and treatment of DFUs.

Objective: The main objective of this mini-review is to give concise information on how diabetes mellitus impairs the healing of chronic ulcers by disrupting numerous biological systems of the normal healing process, resulting in diabetic foot ulceration, and the current therapeutic approaches.

Methods: A review of accessible material from systemic searches in the PubMed/Medline, Scopus, Cochrane Database of Systematic Reviews, published review articles, and Clinical Trials databases (US National Library of Medicine) with no period of limitation was conducted.

Results: The treatment of DFUs comprises wound dressings, use of matrix metalloproteinase inhibitors in wound dressing, antibiotics, skin substitutes, pressure off-loading growth factors and stem cells, gene therapy, topical oxygen therapy, etc.

Conclusion: The majority of these treatments are aimed at treating diabetic foot ulcers and preventing diabetic wounds from becoming infected. Yet, there is no single therapy that can be advised for diabetic foot ulcer patients. Future treatment strategies should be considered an appropriate treatment option for persistent wounds.

Keywords: Diabetic foot ulcer, amputation, diabetes mellitus, matrix metalloproteinase, pressure off-loading growth factors, stem cells, gene therapy.

[1]
Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017; 376(24): 2367-75.
[http://dx.doi.org/10.1056/NEJMra1615439] [PMID: 28614678]
[2]
Abdissa D, Adugna T, Gerema U, Dereje D. Prevalence of diabetic foot ulcer and associated factors among adult diabetic patients on follow-up clinic at Jimma Medical Center, Southwest Ethiopia, 2019: An institutional-based cross-sectional study. J Diabetes Res 2020; 2020: 1-6.
[http://dx.doi.org/10.1155/2020/4106383] [PMID: 32258165]
[3]
Diabetes now affects one in 10 adults worldwide. 2021. Available from: https://www.idf.org/news/240:diabetes-now-affects-one-in-10-adults-worldwide.html
[4]
Reardon R, Simring D, Kim B, Mortensen J, Williams D, Leslie A. The diabetic foot ulcer. Aust J Gen Pract 2020; 49(5): 250-5.
[http://dx.doi.org/10.31128/AJGP-11-19-5161] [PMID: 32416652]
[5]
Tan JL, Lash B, Karami R, et al. Restoration of the healing microenvironment in diabetic wounds with matrix-binding IL-1 receptor antagonist. Commun Biol 2021; 4(1): 422.
[http://dx.doi.org/10.1038/s42003-021-01913-9] [PMID: 33772102]
[6]
Jia G, Lockette W, Sowers JR. Mineralocorticoid receptors in the pathogenesis of insulin resistance and related disorders: From basic studies to clinical disease. Am J Physiol Regul Integr Comp Physiol 2021; 320(3): R276-86.
[http://dx.doi.org/10.1152/ajpregu.00280.2020] [PMID: 33438511]
[7]
Tiwari R, Wal P, Singh P, Tiwari G, Rai A. A review on mechanistic and pharmacological findings of diabetic peripheral neuropathy including pharmacotherapy. Curr Diabetes Rev 2021; 17(3): 247-58.
[http://dx.doi.org/10.2174/1573399816666200914141558] [PMID: 32928092]
[8]
Ayavoo T, Murugesan K, Gnanasekaran A. Roles and mechanisms of stem cell in wound healing. Stem Cell Investig 2021; 8: 4.
[http://dx.doi.org/10.21037/sci-2020-027] [PMID: 33829056]
[9]
Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother 2019; 112: 108615.
[http://dx.doi.org/10.1016/j.biopha.2019.108615] [PMID: 30784919]
[10]
Deng L, Du C, Song P, et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev 2021; 2021: 1-11.
[http://dx.doi.org/10.1155/2021/8852759] [PMID: 33628388]
[11]
Shi C, Wang C, Liu H, et al. Selection of appropriate wound dressing for various wounds. Front Bioeng Biotechnol 2020; 8: 182.
[12]
Komi DEA, Khomtchouk K, Santa Maria PL. A review of the contribution of mast cells in wound healing: Involved molecular and cellular mechanisms. Clin Rev Allergy Immunol 2020; 58(3): 298-312.
[PMID: 30729428]
[13]
Smigiel KS, Parks WC. Macrophages, wound healing, and fibrosis: Recent insights. Curr Rheumatol Rep 2018; 20(4): 17.
[http://dx.doi.org/10.1007/s11926-018-0725-5] [PMID: 29550962]
[14]
Kulwas A, Drela E, Jundziłł W, Góralczyk B, Ruszkowska-Ciastek B, Rość D. Circulating endothelial progenitor cells and angiogenic factors in diabetes complicated diabetic foot and without foot complications. J Diabetes Complications 2015; 29(5): 686-90.
[15]
Okonkwo UA, DiPietro LA. Diabetes and wound angiogenesis. Int J Mol Sci 2017; 18(7): 1419.
[16]
Brudno Y, Ennett-Shepard AB, Chen RR, Aizenberg M, Mooney DJ. Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and promaturation factors. Biomaterials 2013; 34(36): 9201-9.
[http://dx.doi.org/10.1016/j.biomaterials.2013.08.007] [PMID: 23972477]
[17]
Alipour H, Shahriari-Namadi M, Ebrahimi S, Moemenbellah-Fard MD. Wound healing potential: Evaluation of molecular profiling and amplification of Lucilia sericata angiopoietin-1 mRNA midpart. BMC Res Notes 2020; 13(1): 308.
[http://dx.doi.org/10.1186/s13104-020-05141-y] [PMID: 32611449]
[18]
Albiero M, Bonora BM, Fadini GP. Diabetes pharmacotherapy and circulating stem/progenitor cells. State of the art and evidence gaps. Curr Opin Pharmacol 2020; 55: 151-6.
[http://dx.doi.org/10.1016/j.coph.2020.10.019] [PMID: 33271409]
[19]
Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999; 341(10): 738-46.
[http://dx.doi.org/10.1056/NEJM199909023411006] [PMID: 10471461]
[20]
Ramasastry SS. Acute wounds. Clin Plast Surg 2005; 32(2): 195-208.
[http://dx.doi.org/10.1016/j.cps.2004.12.001] [PMID: 15814117]
[21]
Pichu S, Sathiyamoorthy J, Krishnamoorthy E, Umapathy D, Viswanathan V. Impact of the hypoxia inducible factor-1α (HIF-1α) pro582ser polymorphism and its gene expression on diabetic foot ulcers. Diabetes Res Clin Pract 2015; 109(3): 533-40.
[http://dx.doi.org/10.1016/j.diabres.2015.05.014] [PMID: 26113285]
[22]
Amin N, Doupis J. Diabetic foot disease: From the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World J Diabetes 2016; 7(7): 153-64.
[http://dx.doi.org/10.4239/wjd.v7.i7.153] [PMID: 27076876]
[23]
Gary Sibbald R, Woo KY. The biology of chronic foot ulcers in persons with diabetes. Diabetes Metab Res Rev 2008; 24(S1): S25-30.
[http://dx.doi.org/10.1002/dmrr.847] [PMID: 18442179]
[24]
Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest 2007; 117(5): 1219-22.
[http://dx.doi.org/10.1172/JCI32169] [PMID: 17476353]
[25]
Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D’Amore PA. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007; 170(4): 1178-91.
[http://dx.doi.org/10.2353/ajpath.2007.060018] [PMID: 17392158]
[26]
Caley MP, Martins VLC, O’Toole EA. Metalloproteinases and Wound Healing. Adv Wound Care 2015; 4(4): 225-34.
[http://dx.doi.org/10.1089/wound.2014.0581] [PMID: 25945285]
[27]
Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005; 54(6): 1615-25.
[http://dx.doi.org/10.2337/diabetes.54.6.1615] [PMID: 15919781]
[28]
Niture SK, Jaiswal AK. Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis. J Biol Chem 2011; 286(52): 44542-56.
[http://dx.doi.org/10.1074/jbc.M111.275073] [PMID: 22072718]
[29]
Gilbey SG. Neuropathy and foot problems in diabetes. Clin Med 2004; 4(4): 318-23.
[http://dx.doi.org/10.7861/clinmedicine.4-4-318] [PMID: 15372890]
[30]
Tavee J, Zhou L. Small fiber neuropathy: A burning problem. Cleve Clin J Med 2009; 76(5): 297-305.
[http://dx.doi.org/10.3949/ccjm.76a.08070] [PMID: 19414545]
[31]
Boulton AJM, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med 2004; 351(1): 48-55.
[http://dx.doi.org/10.1056/NEJMcp032966] [PMID: 15229307]
[32]
Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ 2014; 348(5): g1799.
[http://dx.doi.org/10.1136/bmj.g1799] [PMID: 24803311]
[33]
Krishnan STM, Quattrini C, Jeziorska M, Malik RA, Rayman G. Neurovascular factors in wound healing in the foot skin of type 2 diabetic subjects. Diabetes Care 2007; 30(12): 3058-62.
[http://dx.doi.org/10.2337/dc07-1421] [PMID: 17898089]
[34]
Graiani G, Emanueli C, Desortes E, et al. Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice. Diabetologia 2004; 47(6): 1047-54.
[http://dx.doi.org/10.1007/s00125-004-1414-7] [PMID: 15164170]
[35]
Russell JW, Zilliox LA. Diabetic neuropathies. Continuum 2014; 20(5): 1226-40.
[http://dx.doi.org/10.1212/01.CON.0000455884.29545.d2]
[36]
Dinh T, Veves A. Microcirculation of the diabetic foot. Curr Pharm Des 2005; 11(18): 2301-9.
[http://dx.doi.org/10.2174/1381612054367328] [PMID: 16022669]
[37]
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.
[PMID: 22928161]
[38]
Volmer-Thole M, Lobmann R. Neuropathy and diabetic foot syndrome. Int J Mol Sci 2016; 17(6): 917.
[http://dx.doi.org/10.3390/ijms17060917] [PMID: 27294922]
[39]
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008; 453(7193): 314-21.
[http://dx.doi.org/10.1038/nature07039] [PMID: 18480812]
[40]
Dong J, Chen L, Zhang Y, et al. Mast cells in diabetes and diabetic wound healing. Adv Ther 2020; 37(11): 4519-37.
[http://dx.doi.org/10.1007/s12325-020-01499-4] [PMID: 32935286]
[41]
Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabetic wound healing. Transl Res 2021; 236: 109-16.
[http://dx.doi.org/10.1016/j.trsl.2021.05.006] [PMID: 34089902]
[42]
Basu Mallik S, Jayashree BS, Shenoy RR. Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds. J Diabetes Complications 2018; 32(5): 524-30.
[http://dx.doi.org/10.1016/j.jdiacomp.2018.01.015] [PMID: 29530315]
[43]
Dunnill C, Patton T, Brennan J, et al. Reactive oxygen species (ROS) and wound healing: The functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J 2017; 14(1): 89-96.
[http://dx.doi.org/10.1111/iwj.12557] [PMID: 26688157]
[44]
Lucas T, Waisman A, Ranjan R, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol 2010; 184(7): 3964-77.
[http://dx.doi.org/10.4049/jimmunol.0903356] [PMID: 20176743]
[45]
Ferrante CJ, Leibovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care 2012; 1(1): 10-6.
[http://dx.doi.org/10.1089/wound.2011.0307] [PMID: 24527272]
[46]
Miao M, Niu Y, Xie T, Yuan B, Qing C, Lu S. Diabetes-impaired wound healing and altered macrophage activation: A possible pathophysiologic correlation. Wound Repair Regen 2012; 20(2): 203-13.
[http://dx.doi.org/10.1111/j.1524-475X.2012.00772.x] [PMID: 22380690]
[47]
Muire PJ, Schwacha MG, Wenke JC, Systemic T. Systemic t cell exhaustion dynamics is linked to early high mobility group box protein 1 (HMGB1) driven hyper-inflammation in a polytrauma rat model. Cells 2021; 10(7): 1646.
[http://dx.doi.org/10.3390/cells10071646] [PMID: 34209240]
[48]
Morey M, O’Gaora P, Pandit A, Hélary C. Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages. PLoS One 2019; 14(8): e0220577.
[http://dx.doi.org/10.1371/journal.pone.0220577] [PMID: 31415598]
[49]
Hu J, Zhang L, Liechty C, et al. Long noncoding RNA GAS5 regulates macrophage polarization and diabetic wound healing. J Invest Dermatol 2020; 140(8): 1629-38.
[http://dx.doi.org/10.1016/j.jid.2019.12.030] [PMID: 32004569]
[50]
Zgheib C, Hodges MM, Hu J, Liechty KW, Xu J. Long non-coding RNA Lethe regulates hyperglycemia-induced reactive oxygen species production in macrophages. PLoS One 2017; 12(5): e0177453.
[http://dx.doi.org/10.1371/journal.pone.0177453] [PMID: 28494015]
[51]
Lee J, Rodero MP, Patel J, Moi D, Mazzieri R, Khosrotehrani K. Interleukin‐23 regulates interleukin‐17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization. FASEB J 2018; 32(4): 2086-94.
[http://dx.doi.org/10.1096/fj.201700773R] [PMID: 29208701]
[52]
Zhang X, Dai J, Li L, Chen H, Chai Y. NLRP3 inflammasome expression and signaling in human diabetic wounds and in high glucose induced macrophages. J Diabetes Res 2017; 2017: 1-7.
[http://dx.doi.org/10.1155/2017/5281358] [PMID: 28164132]
[53]
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.
[http://dx.doi.org/10.1177/0022034510362960] [PMID: 20354230]
[54]
Borys S, Hohendorff J, Frankfurter C, Kiec-Wilk B, Malecki MT. Negative pressure wound therapy use in diabetic foot syndromefrom mechanisms of action to clinical practice. Eur J Clin Invest 2019; 49(4): e13067.
[http://dx.doi.org/10.1111/eci.13067] [PMID: 30600541]
[55]
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.
[http://dx.doi.org/10.1369/jhc.2008.951194] [PMID: 18413645]
[56]
Menghini R, Uccioli L, Vainieri E, 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.
[http://dx.doi.org/10.1007/s00592-013-0478-6] [PMID: 23636268]
[57]
Martins VL, Caley M, O’Toole EA. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res 2013; 351(2): 255-68.
[http://dx.doi.org/10.1007/s00441-012-1410-z] [PMID: 22526628]
[58]
Nguyen VT, Farman N, Palacios-Ramirez R, et al. Cutaneous wound healing in diabetic mice is improved by topical mineralocorticoid receptor blockade. J Invest Dermatol 2020; 140(1): 223-34.
[http://dx.doi.org/10.1016/j.jid.2019.04.030] [PMID: 31278904]
[59]
Balaji S, King A, Crombleholme TM, Keswani SG. The role of endothelial progenitor cells in postnatal vasculogenesis: Implications for therapeutic neovascularization and wound healing. Adv Wound Care 2013; 2(6): 283-95.
[http://dx.doi.org/10.1089/wound.2012.0398] [PMID: 24527350]
[60]
Li M, Yu H, Pan H, et al. Nrf2 suppression delays diabetic wound healing through sustained oxidative stress and inflammation. Front Pharmacol 2019; 10: 1099.
[http://dx.doi.org/10.3389/fphar.2019.01099] [PMID: 31616304]
[61]
Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin wound healing: An update on the current knowledge and concepts. Eur Surg Res 2017; 58(1-2): 81-94.
[http://dx.doi.org/10.1159/000454919] [PMID: 27974711]
[62]
Alavi A, Sibbald RG, Mayer D, et al. Diabetic foot ulcers. J Am Acad Dermatol 2014; 70(1): 1.e1-1.e18.
[http://dx.doi.org/10.1016/j.jaad.2013.06.055] [PMID: 24355275]
[63]
Smith K, Collier A, Townsend EM, et al. One step closer to understanding the role of bacteria in diabetic foot ulcers: Characterising the microbiome of ulcers. BMC Microbiol 2016; 16(1): 54.
[http://dx.doi.org/10.1186/s12866-016-0665-z] [PMID: 27005417]
[64]
LuTheryn G, Glynne-Jones P, Webb JS, Carugo D. Ultrasound‐mediated therapies for the treatment of biofilms in chronic wounds: A review of present knowledge. Microb Biotechnol 2020; 13(3): 613-28.
[http://dx.doi.org/10.1111/1751-7915.13471] [PMID: 32237219]
[65]
Pitocco D, Spanu T, Di Leo M, et al. Diabetic foot infections: A comprehensive overview. Eur Rev Med Pharmacol Sci 2019; 23(2): 26-37.
[PMID: 30977868]
[66]
Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: A critical review. Diabetes Metab Res Rev 2020; 36(S1): e3272.
[http://dx.doi.org/10.1002/dmrr.3272] [PMID: 32176449]
[67]
Camilleri A, Gatt A, Formosa C. Inter-rater reliability of four validated diabetic foot ulcer classification systems. J Tissue Viability 2020; 29(4): 284-90.
[http://dx.doi.org/10.1016/j.jtv.2020.09.002] [PMID: 32921550]
[68]
Obagi Z, Damiani G, Grada A, Falanga V. Principles of wound dressings: A review. Surg Technol Int 2019; 35: 50-7.
[PMID: 31480092]
[69]
Davies P, McCarty S, Hamberg K. Silver-containing foam dressings with Safetac: A review of the scientific and clinical data. J Wound Care 2017; 26(S6): S1-S32.
[70]
Okur ME, Bülbül EÖ, Mutlu G, et al. An updated review for the diabetic wound healing systems. Curr Drug Targets 2022; 23(4): 393-419.
[http://dx.doi.org/10.2174/1389450122666210914104428] [PMID: 34521324]
[71]
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.
[http://dx.doi.org/10.1111/wrr.12630] [PMID: 29617058]
[72]
Gao J, Wang Y, Song J, Li Z, Ren J, Wang P. Negative pressure wound therapy for surgical site infections: A systematic review and meta‐analysis. J Adv Nurs 2021; 77(10): 3980-90.
[http://dx.doi.org/10.1111/jan.14876] [PMID: 33905552]
[73]
Jindatanmanusan P, Luanraksa S, Boonsiri T, Nimmanon T, Arnutti P. Wound fluid matrix metalloproteinase-9 as a potential predictive marker for the poor healing outcome in diabetic foot ulcers. Pathol Res Int 2018; 2018: 1-5.
[http://dx.doi.org/10.1155/2018/1631325] [PMID: 30410716]
[74]
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. Lancet Diabetes Endocrinol 2018; 6(3): 186-96.
[http://dx.doi.org/10.1016/S2213-8587(17)30438-2] [PMID: 29275068]
[75]
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.
[http://dx.doi.org/10.1002/adma.201503565] [PMID: 26695434]
[76]
Dixon D, Edmonds M. Managing diabetic foot ulcers: Pharmacotherapy for wound healing. Drugs 2021; 81(1): 29-56.
[http://dx.doi.org/10.1007/s40265-020-01415-8] [PMID: 33382445]
[77]
Zhang Z, Zhang W, Xu Y, Liu D. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. Asian J Surg 2022; 45(1): 68-78.
[http://dx.doi.org/10.1016/j.asjsur.2021.07.047] [PMID: 34376365]
[78]
Qi M, Zhou Q, Zeng W, et al. Growth factors in the pathogenesis of diabetic foot ulcers. Front Biosci 2018; 23(2): 310-7.
[PMID: 28930549]
[79]
Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord 2019; 20(2): 207-17.
[http://dx.doi.org/10.1007/s11154-019-09492-1] [PMID: 30937614]
[80]
Gökşen S, Balabanlı B, Coşkun-Cevher Ş. Application of platelet derived growth factor-BB and diabetic wound healing: The relationship with oxidative events. Free Radic Res 2017; 51(5): 498-505.
[http://dx.doi.org/10.1080/10715762.2017.1327715] [PMID: 28480814]
[81]
Kolumam G, Wu X, Lee WP, et al. IL-22R ligands IL-20, IL-22, and IL-24 promote wound healing in diabetic db/db mice. PLoS One 2017; 12(1): e0170639.
[http://dx.doi.org/10.1371/journal.pone.0170639] [PMID: 28125663]
[82]
Gardner JC, Wu H, Noel JG, et al. Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function. Am J Physiol Lung Cell Mol Physiol 2016; 310(9): L868-79.
[http://dx.doi.org/10.1152/ajplung.00363.2015] [PMID: 26919897]
[83]
Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care 2014; 3(10): 647-61.
[http://dx.doi.org/10.1089/wound.2013.0517] [PMID: 25302139]
[84]
El Gazaerly H, Elbardisey DM, Eltokhy HM, Teaama D. Effect of transforming growth factor Beta 1 on wound healing in induced diabetic rats. Int J Health Sci 2013; 7(2): 160-72.
[http://dx.doi.org/10.12816/0006040] [PMID: 24421745]
[85]
Garoufalia Z, Papadopetraki A, Karatza E, et al. Insulin-like growth factor-I and wound healing, a potential answer to nonhealing wounds: A systematic review of the literature and future perspectives. Biomed Rep 2021; 15(2): 66.
[http://dx.doi.org/10.3892/br.2021.1442] [PMID: 34155450]
[86]
Bus SA. The role of pressure offloading on diabetic foot ulcer healing and prevention of recurrence. Plast Reconstr Surg 2016; 138(3): 179S-87S.
[http://dx.doi.org/10.1097/PRS.0000000000002686] [PMID: 27556758]
[87]
Kim K, Mahajan A, Patel K, Syed S, Acevedo-Jake AM, Kumar VA. Materials and cytokines in the healing of diabetic foot ulcers. Adv Ther 2021; 4(9): 2100075.
[88]
Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers. Cochrane Libr 2013; (1): CD002302.
[http://dx.doi.org/10.1002/14651858.CD002302.pub2] [PMID: 23440787]
[89]
Cao Y, Gang X, Sun C, Wang G. Mesenchymal stem cells improve healing of diabetic foot ulcer. J Diabetes Res 2017; 2017: 1-10.
[http://dx.doi.org/10.1155/2017/9328347] [PMID: 28386568]
[90]
Ebrahim N, Dessouky AA, Mostafa O, et al. Adipose mesenchymal stem cells combined with platelet-rich plasma accelerate diabetic wound healing by modulating the Notch pathway. Stem Cell Res Ther 2021; 12(1): 392.
[http://dx.doi.org/10.1186/s13287-021-02454-y] [PMID: 34256844]
[91]
Huang YZ, Gou M, Da LC, Zhang WQ, Xie HQ. Mesenchymal stem cells for chronic wound healing: Current status of preclinical and clinical studies. Tissue Eng Part B Rev 2020; 26(6): 555-70.
[http://dx.doi.org/10.1089/ten.teb.2019.0351] [PMID: 32242479]
[92]
Dhoke NR, Kaushik K, Das A. Cxcr6-based mesenchymal stem cell gene therapy potentiates skin regeneration in murine diabetic wounds. Mol Ther 2020; 28(5): 1314-26.
[http://dx.doi.org/10.1016/j.ymthe.2020.02.014] [PMID: 32112713]
[93]
Liu L, Chen JX, Zhang XW, et al. Retracted article: Chemokine receptor 7 overexpression promotes mesenchymal stem cell migration and proliferation via secreting Chemokine ligand 12. Sci Rep 2018; 8(1): 204.
[http://dx.doi.org/10.1038/s41598-017-18509-1] [PMID: 29317710]
[94]
Deev R, Plaksa I, Bozo I, Isaev A. Results of an international postmarketing surveillance study of pl-VEGF165 safety and efficacy in 210 patients with peripheral arterial disease. Am J Cardiovasc Drugs 2017; 17(3): 235-42.
[http://dx.doi.org/10.1007/s40256-016-0210-3] [PMID: 28050885]
[95]
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(1): 33101.
[http://dx.doi.org/10.3402/dfa.v7.33101] [PMID: 27829487]
[96]
Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci 2018; 1411(1): 153-65.
[http://dx.doi.org/10.1111/nyas.13569] [PMID: 29377202]
[97]
Haq A, Singh V, Sharma S. Medial plantar artery-based perforator and island flaps: A case series of applications in sole defects. J Wound Care 2022; 31(2): 130-8.
[http://dx.doi.org/10.12968/jowc.2022.31.2.130] [PMID: 35148628]
[98]
Angadi NB, Kagal U, Timshetti S. Effect of sitagliptin and vildagliptin on wound healing in male wistar rats - An experimental study. Asian J Pharm Clin Res 2018; 11(8): 392.
[http://dx.doi.org/10.22159/ajpcr.2018.v11i8.26061]
[99]
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: 1-7.
[http://dx.doi.org/10.1155/2016/7340641] [PMID: 27478849]
[100]
Tran MM, Haley MN. Does exercise improve healing of diabetic foot ulcers? A systematic review. J Foot Ankle Res 2021; 14(1): 19.
[101]
Wang J, Xu J. Effects of topical insulin on wound healing: A review of animal and human evidences. Diabetes Metab Syndr Obes Targets Ther 2020; 13: 719-27.
[102]
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.
[http://dx.doi.org/10.1146/annurev-bioeng-060418-052422] [PMID: 30822099]
[103]
Asadi MR, Torkaman G, Hedayati M, Mohajeri-Tehrani MR, Ahmadi M, Gohardani RF. Angiogenic effects of low-intensity cathodal direct current on ischemic diabetic foot ulcers: A randomized controlled trial. Diabetes Res Clin Pract 2017; 127: 147-55.
[http://dx.doi.org/10.1016/j.diabres.2017.03.012] [PMID: 28371685]
[104]
Jeppesen SM, Yderstraede KB, Rasmussen BSB, Hanna M, Lund L. Extracorporeal shockwave therapy in the treatment of chronic diabetic foot ulcers: A prospective randomised trial. J Wound Care 2016; 25(11): 641-9.
[http://dx.doi.org/10.12968/jowc.2016.25.11.641] [PMID: 27827284]
[105]
Kwan RLC, Wong WC, Yip SL, Chan KL, Zheng YP, Cheing GLY. Pulsed electromagnetic field therapy promotes healing and microcirculation of chronic diabetic foot ulcers: A pilot study. Adv Skin Wound Care 2015; 28(5): 212-9.
[http://dx.doi.org/10.1097/01.ASW.0000462012.58911.53] [PMID: 25882659]
[106]
Sousa RG, Batista KNM. Laser therapy in wound healing associated with diabetes mellitus - review. An Bras Dermatol 2016; 91(4): 489-93.
[http://dx.doi.org/10.1590/abd1806-4841.20163778] [PMID: 27579745]
[107]
Wang HT, Yuan JQ, Zhang B, Dong ML, Mao C, Hu D. Phototherapy for treating foot ulcers in people with diabetes. Cochrane Libr 2017; 6: CD011979.
[http://dx.doi.org/10.1002/14651858.CD011979.pub2] [PMID: 28657134]
[108]
Uçkay I, Kressmann B, Malacarne S, et al. A randomized, controlled study to investigate the efficacy and safety of a topical gentamicin-collagen sponge in combination with systemic antibiotic therapy in diabetic patients with a moderate or severe foot ulcer infection. BMC Infect Dis 2018; 18(1): 361.
[http://dx.doi.org/10.1186/s12879-018-3253-z] [PMID: 30068306]
[109]
Uçkay I, Kressmann B, Di Tommaso S, et al. A randomized controlled trial of the safety and efficacy of a topical gentamicin–collagen sponge in diabetic patients with a mild foot ulcer infection. SAGE Open Med 2018; 6: 2050312118773950.
[http://dx.doi.org/10.1177/2050312118773950] [PMID: 29785265]
[110]
Huang YY, Lin CW, Cheng NC, et al. Effect of a novel macrophage-regulating drug on wound healing in patients with diabetic foot ulcers: A randomized clinical trial: A randomized clinical trial. JAMA Netw Open 2021; 4(9): e2122607.
[http://dx.doi.org/10.1001/jamanetworkopen.2021.22607] [PMID: 34477854]
[111]
Xu ZR, Ran XW, Xian Y, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections in China: A Phase 3, multicentre, randomized, double-blind, active-controlled, non-inferiority trial. J Antimicrob Chemother 2016; 71(6): 1688-96.
[http://dx.doi.org/10.1093/jac/dkw004] [PMID: 26888908]
[112]
Lauf L, Ozsvár Z, Mitha I, et al. Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis. Diagn Microbiol Infect Dis 2014; 78(4): 469-80.
[http://dx.doi.org/10.1016/j.diagmicrobio.2013.12.007] [PMID: 24439136]
[113]
Schaper NC, Dryden M, Kujath P, et al. Efficacy and safety of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of diabetic foot infections: Results of the RELIEF study. Infection 2013; 41(1): 175-86.
[http://dx.doi.org/10.1007/s15010-012-0367-x] [PMID: 23180507]
[114]
Walton DM, Minton SD, Cook AD. The potential of transdermal nitric oxide treatment for diabetic peripheral neuropathy and diabetic foot ulcers. Diabetes Metab Syndr 2019; 13(5): 3053-6.
[http://dx.doi.org/10.1016/j.dsx.2018.07.003] [PMID: 30030157]
[115]
Olson E, Mahar KM, Morgan L, Fillmore C, Holland C, Lavery L. Randomized phase I trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of topical daprodustat in healthy volunteers and in patients with diabetic foot ulcers. Clin Pharmacol Drug Dev 2019; 8(6): cpdd.654.
[http://dx.doi.org/10.1002/cpdd.654] [PMID: 30720931]
[116]
Rodgers KE, Bolton LL, Verco S, diZerega GS. NorLeu 3 -angiotensin (1-7) [DSC127] as a therapy for the healing of diabetic foot ulcers. Adv Wound Care 2015; 4(6): 339-45.
[http://dx.doi.org/10.1089/wound.2014.0609] [PMID: 26029484]
[117]
Barret JP, Podmelle F, Lipový B, et al. Accelerated reepithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns 2017; 43(6): 1284-94.
[http://dx.doi.org/10.1016/j.burns.2017.03.005] [PMID: 28400148]

Rights & Permissions Print Cite
Article Metrics
55
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy