Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Review Article

Advances in Dermoepidermal Skin Substitutes for Diabetic Foot Ulcers

Author(s): Francisco Javier Álvaro-Afonso, Yolanda García-Álvarez, Jose Luis Lázaro-Martínez, Despoina Kakagia and Nikolaos Papanas*

Volume 18, Issue 2, 2020

Page: [182 - 192] Pages: 11

DOI: 10.2174/1570161117666190408170144

Price: $65

Abstract

Diabetic foot ulcers (DFUs) are one of the major complications of diabetes, representing a leading cause of hospitalisation and non-traumatic lower limb amputations. Multidisciplinary management, patient education, glucose control, debridement, off-loading, infection control, and adequate perfusion are the mainstays of standard care. Despite all these, at least 30% of DFUs fail to heal within 20 weeks. Therefore, dermoepidermal skin substitutes (DSS) have been used as a new therapeutic adjunct for DFUs. This brief review outlines the recent advances in DSS for the treatment of DFUs. PubMed and Cochrane databases were systematically searched in May to July 2018 for systematic reviews published after 2013 and for randomised controlled trials (RCTs). A retrospective evaluation of 28 RCTs was performed. Rates of complete wound closure and time to healing were examined for 17 commonly available DSS. Healing rates after 12 weeks and time to complete closure in DFUs are heterogeneous among the 28 RCT. The best healing rates at 12 weeks were accomplished with dermal cellular substitutes (Epifix®, 100% and Amnioband®, 85%) and with dermal acellular substitutes (Allopatch®, 80% and Hyalograft®, 78.8%). Based on these studies, DSS used in conjunction with standard care appear to improve the healing rates of DFUs, as compared with standard care alone. Nonetheless, new studies with more homogeneous samples are needed to ascertain the role of ulcer size, duration, depth and/or type in the efficacy of DSS. Moreover, future RCTs should include patients with severe comorbidities, in order to be more representative of clinical reality.

Keywords: Dermoepidermical skin substitutes, diabetic foot ulcers, PAD, diabetes, glucose control.

Graphical Abstract
[1]
Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, et al. The global burden of diabetic foot disease. Lancet 2005; 366: 1719-24.
[2]
Garcia-Morales E, Lazaro-Martinez JL, Martinez-Hernandez D, et al. Impact of diabetic foot related complications on the Health Related Quality of Life (HRQol) of patients: A regional study in Spain. Int J Low Extrem Wounds 2011; 10: 6-11.
[3]
Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017; 376: 2367-75.
[4]
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: 217-28.
[5]
Fortington LV, Geertzen JH, van Netten JJ, et al. Short and long term mortality rates after a lower limb amputation. Eur J Vasc Endovasc Surg 2013; 46: 124-31.
[6]
Sandnes DK, Sobel M, Flum DR. Survival after lower-extremity amputation. J Am Coll Surg 2004; 199: 394-402.
[7]
Armstrong DG, Wrobel J, Robbins JM. Guest Editorial: Are diabetes-related wounds and amputations worse than cancer? Int Wound J 2007; 4: 286-7.
[8]
Lopez-Valverde ME, Aragon-Sanchez J, Lopez-de-Andres A, et al. Perioperative and long-term all-cause mortality in patients with diabetes who underwent a lower extremity amputation. Diabetes Res Clin Pract 2018; 141: 175-80.
[9]
Fernando ME, Seneviratne RM, Tan YM, et al. Intensive versus conventional glycaemic control for treating diabetic foot ulcers. Cochrane Database Syst Rev 2016; 1: CD010764
[10]
Bus SA, Valk GD, van Deursen RW, et al. Specific guidelines on footwear and offloading. Diabetes Metab Res Rev 2008; 24(Suppl. 1): S192-3.
[11]
Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers. Cochrane Database Syst Rev 2013; 1: CD002302
[12]
Edwards J, Stapley S. Debridement of diabetic foot ulcers. Cochrane Database Syst Rev 2010; 1: CD003556
[13]
Game FL, Jeffcoate WJ. Dressing and diabetic foot ulcers: A current review of the evidence. Plast Reconstr Surg 2016; 138(3)(Suppl.): 158S-64S.
[14]
Dumville JC, Soares MO, O’Meara S, et al. Systematic review and mixed treatment comparison: Dressings to heal diabetic foot ulcers. Diabetologia 2012; 55: 1902-10.
[15]
Liu S, He CZ, Cai YT, et al. Evaluation of negative-pressure wound therapy for patients with diabetic foot ulcers: Systematic review and meta-analysis. Ther Clin Risk Manag 2017; 13: 533-44.
[16]
Zhao D, Luo S, Xu W, et al. Efficacy and safety of hyperbaric oxygen therapy used in patients with diabetic foot: A meta-analysis of randomized clinical trials. Clin Ther 2017; 39: 2088-94 e2.
[17]
Lazaro-Martinez JL, Alvaro-Afonso FJ, Garcia-Alvarez Y, et al. Ultrasound-assisted debridement of neuroischaemic diabetic foot ulcers, clinical and microbiological effects: A case series. J Wound Care 2018; 27: 278-86.
[18]
Cruciani M, Lipsky BA, Mengoli C, et al. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database Syst Rev 2013; 8: CD006810
[19]
Santema TB, Poyck PP, Ubbink DT. Systematic review and meta-analysis of skin substitutes in the treatment of diabetic foot ulcers: Highlights of a cochrane systematic review. Wound Repair Regen 2016; 24: 737-44.
[20]
Margolis DJ, Allen-Taylor L, Hoffstad O, et al. Healing diabetic neuropathic foot ulcers: Are we getting better? Diabet Med 2005; 22: 172-6.
[21]
Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen 2006; 14: 680-92.
[22]
Nicholas MN, Yeung J. Current status and future of skin substitutes for chronic wound healing. J Cutan Med Surg 2017; 21: 23-30.
[23]
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. J Clin Epidemiol 2009; 62: e1-e34.
[24]
Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996; 276: 637-9.
[25]
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: CD011255
[26]
Teng YJ, Li YP, Wang JW, et al. Bioengineered skin in diabetic foot ulcers. Diabetes Obes Metab 2010; 12: 307-15.
[27]
Cook EA, Cook JJ, Badri H, et al. Bioengineered alternative tissues. Clin Podiatr Med Surg 2014; 31: 89-101.
[28]
Oyibo SO, Jude EB, Tarawneh I, et al. A comparison of two diabetic foot ulcer classification systems: The Wagner and the University of Texas wound classification systems. Diabetes Care 2001; 24: 84-8.
[29]
Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J 2014; 11: 122-8.
[30]
Sanders L, Landsman AS, Landsman A, et al. A prospective, multicenter, randomized, controlled clinical trial comparing a bioengineered skin substitute to a human skin allograft. Ostomy Wound Manage 2014; 60: 26-38.
[31]
Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996; 19: 350-4.
[32]
Edmonds M. European, Australian Apligraf Diabetic Foot Ulcer Study G. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds 2009; 8: 11-8.
[33]
Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: A prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J 2016; 13: 272-82.
[34]
Walters J, Cazzell S, Pham H, et al. Healing rates in a multicenter assessment of a sterile, room temperature, acellular dermal matrix versus conventional care wound management and an active comparator in the treatment of full-thickness diabetic foot ulcers. Eplasty 2016; 16: e10
[35]
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: 196-208.
[36]
DiDomenico LA, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective, randomised, multi-centre clinical trial in 80 patients. Int Wound J 2018; 15: 950-7.
[37]
Zelen CM, Orgill DP, Serena T, et al. A prospective, randomised, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allogenic human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J 2017; 14: 307-15.
[38]
You HJ, Han SK, Rhie JW. Randomised controlled clinical trial for autologous fibroblast-hyaluronic acid complex in treating diabetic foot ulcers. J Wound Care 2014; 23: 521-2.
[39]
Smiell JM, Treadwell T, Hahn HD, et al. Real-world experience with a decellularized dehydrated human amniotic membrane Allograft. Wounds 2015; 27: 158-69.
[40]
Margolis DJ, Kantor J, Santanna J, et al. Risk factors for delayed healing of neuropathic diabetic foot ulcers: A pooled analysis. Arch Dermatol 2000; 136: 1531-5.
[41]
Pacaccio DJ, Cazzell SM, Halperin GJ, et al. Human placental membrane as a wound cover for chronic diabetic foot ulcers: A prospective, postmarket, CLOSURE study. J Wound Care 2018; 27(Sup7): S28-37.
[42]
Knighton DR, Ciresi KF, Fiegel VD, et al. Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF). Ann Surg 1986; 204: 322-30.
[43]
Lobmann R, Ambrosch A, Schultz G, et al. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 2002; 45: 1011-6.
[44]
Shakespeare W. The merry wives of Windsor. In: Wells STG, Ed. The Complete Works of William Shakespeare. 1st ed. Oxford, England: Oxford University Press 1988; pp. 483-508.
[45]
Papanas N, Mani R. How to cope with the increasing burden of the diabetic foot: “Better three hours too soon than a minute too late. Int J Low Extrem Wounds 2014; 13: 171-2.
[46]
Vas P, Panagopoulos P, Papanas N. Editorial: “Ah, wherefore with infection should he live?”: Microbial virulence factors in diabetic foot ulceration. Curr Vasc Pharmacol 2016; 14: 498-501.
[47]
Vas PRJ, Edmonds M, Kavarthapu V, et al. The Diabetic Foot Attack: “Tis Too Late to Retreat! Int J Low Extrem Wounds 2018; 17: 7-13.
[48]
Carsin H, Ainaud P, Le Bever H, et al. Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five year single-center experience with 30 patients. Burns 2000; 26: 379-87.
[49]
Ortega-Zilic N, Hunziker T, Lauchli S, et al. EpiDex(R) Swiss field trial 2004-2008. Dermatology 2010; 221: 365-72.
[50]
Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: A prospective 16-week pilot study. Int Wound J 2006; 3: 181-7.
[51]
Caravaggi C, Grigoletto F, Scuderi N. Wound bed preparation with a dermal substitute (Hyalomatrix(R) PA) facilitates re-epithelialization and healing: Results of a multicenter, prospective, observational study on complex chronic ulcers (The FAST Study). Wounds 2011; 23: 228-35.
[52]
Haslik W, Kamolz LP, Nathschlager G, et al. First experiences with the collagen-elastin matrix Matriderm as a dermal substitute in severe burn injuries of the hand. Burns 2007; 33: 364-8.
[53]
Lecheminant J, Field C. Porcine urinary bladder matrix: A retrospective study and establishment of protocol. J Wound Care 2012; 21: 476.
[54]
Niezgoda JA, Van Gils CC, Frykberg RG, et al. Randomized clinical trial comparing OASIS wound matrix to regranex gel for diabetic ulcers. Adv Skin Wound Care 2005; 18: 258-66.
[55]
Marston WA, Hanft J, Norwood P, et al. 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: 1701-5.
[56]
Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs 1997; 21: 1203-10.
[57]
Zelen CM, Serena TE, Denoziere G, et al. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J 2013; 10: 502-7.
[58]
Zelen CM, Gould L, Serena TE, et al. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J 2015; 12: 724-32.
[59]
Snyder RJ, Shimozaki K, Tallis A, et al. A prospective, randomized, multicenter, controlled evaluation of the use of dehydrated amniotic membrane allograft compared to standard of care for the closure of chronic diabetic foot ulcer. Wounds 2016; 28: 70-7.
[60]
Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix ((R)) for the treatment of chronic diabetic foot ulcers: Results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J 2014; 11: 554-60.
[61]
Frykberg RG, Gibbons GW, Walters JL, et al. A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane. Int Wound J 2017; 14: 569-77.
[62]
Burke JF, Yannas IV, Quinby WC Jr, et al. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 1981; 194: 413-28.
[63]
Driver VR, Lavery LA, Reyzelman AM, et al. A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Repair Regen 2015; 23: 891-900.
[64]
Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 1999; 7: 201-7.
[65]
Cassidy C, St Peter SD, Lacey S, et al. Biobrane versus duoderm for the treatment of intermediate thickness burns in children: A prospective, randomized trial. Burns 2005; 31: 890-3.
[66]
Caravaggi C, De Giglio R, Pritelli C, et al. HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: A prospective, multicenter, controlled, randomized clinical trial. Diabetes Care 2003; 26: 2853-9.
[67]
Veves A, Falanga V, Armstrong DG, et al. 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: 290-5.
[68]
Lipkin S, Chaikof E, Isseroff Z, et al. Effectiveness of bilayered cellular matrix in healing of neuropathic diabetic foot ulcers: Results of a multicenter pilot trial. Wounds 2003; 15: 230-6.
[69]
Landsman A, Roukis TS, DeFronzo DJ, et al. Living cells or collagen matrix: Which is more beneficial in the treatment of diabetic foot ulcers? Wounds 2008; 20: 111-6.
[70]
Uccioli L, Giurato L, Ruotolo V, et al. Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: Results of a multicenter, randomized controlled clinical trial with long-term follow-up. Int J Low Extrem Wounds 2011; 10: 80-5.
[71]
DiDomenico L, Landsman AR, Emch KJ, et al. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds 2011; 23: 184-9.
[72]
You HJ, Han SK, Lee JW, et al. Treatment of diabetic foot ulcers using cultured allogeneic keratinocytes: A pilot study. Wound Repair Regen 2012; 20: 491-9.
[73]
DiDomenico LA, Orgill DP, Galiano RD, et al. Aseptically processed placental membrane improves healing of diabetic foot ulcerations: Prospective, randomized clinical trial. Plast Reconstr Surg Glob Open 2016; 4: e1095

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy