The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index; none of the 10 sources its claims cite is checked for support yet.
Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials
Open accessAbstract
Chronic diabetic foot ulcers and venous leg ulcers remain difficult to treat due to delayed healing and high complication rates. Biologic skin allografts derived from living or amniotic tissue provide extracellular matrix components, cytokines, growth factors and viable cells that facilitate tissue repair. This investigation systematically reviewed randomised controlled trials comparing Apligraf, Theraskin, Amnioband, Amnioexcel, EpiCord and Epifix for chronic lower extremity wounds. Searches were conducted in PubMed, Embase and Cochrane databases. Primary outcomes included complete wound closure at 12 weeks, time to healing and percent area reduction. Secondary outcomes included infection, amputation and recurrence rates. Nineteen trials with a total of 1303 participants met inclusion criteria. Analysis demonstrated statistical significance in 12‐week wound closure ( p = 0.0394), with Theraskin achieving the highest mean closure (84.7%) and Amnioexcel the lowest (37.5%). Epifix and Amnioband showed faster healing trends and greater closure advantages compared with standard care. Reported complications were uncommon and inconsistently defined. While no single graft demonstrated statistically superior outcomes, descriptive trends suggest Theraskin, Epifix and Amnioband may offer greater clinical benefit. These findings provide comparative insight to guide clinical selection of skin substitutes and highlight the need for large‐scale head‐to‐head trials to establish relative efficacy.
Overview
CoChat Summary
TL;DR
This systematic review and meta-analysis of RCTs compared six skin allografts for diabetic foot and venous leg ulcers and found a statistically significant overall difference in 12-week wound closure, but no significant pairwise differences between grafts. Descriptive trends favored Theraskin, Epifix, and Amnioband, while complications were uncommon but inconsistently defined.
Key findings
- Across included trials, 12-week wound closure differed significantly by graft type (p = 0.0394; the Discussion also reports p = 0.0256), but Tukey–Kramer post hoc testing found no statistically significant pairwise comparisons. Theraskin had the highest mean closure (84.7%) and Amnioexcel the lowest (37.5%).
- Percent area reduction was not significantly different across Amnioband, Theraskin, and Epifix (χ²(2) = 3.20, p = 0.2019); Amnioband had the highest mean PAR (88.9%), followed by Theraskin (77.8%) and Epifix (66%).
- Wound closure difference versus standard of care was not statistically significant (χ²(3) = 7.40, p = 0.0601); Epifix (mean = 48%) and Amnioband (mean = 46.5%) showed higher differences, followed by Theraskin (40%) and Apligraf (20.5%).
- Time-to-healing was summarized descriptively only: Epifix had the shortest median (13 days), followed by Amnioband (37 days), Theraskin (47 days), and Apligraf (range 49–181 days). Complications were generally lower in graft-treated ulcers but inconsistently reported.
Methods
- Systematic review and meta-analysis conducted per PRISMA; searches of PubMed, Embase, and Cochrane from inception to April 30, 2025, for English-language RCTs in adults ≥18 years with DFUs and/or VLUs comparing Apligraf, Theraskin, Amnioband, Amnioexcel, EpiCord, or Epifix against SOC or another allograft.
- Two independent reviewers screened and extracted data; quality/bias assessed with RoB2 and the Downs and Black Checklist. The abstract reports 19 trials with 1303 participants, while the Results section reports 20 RCTs involving 1303 patients.
- Statistical analysis used JMP Pro 18; Levene’s test assessed homogeneity, with one-way ANOVA plus Tukey’s HSD for homogeneous outcomes and Kruskal–Wallis plus Bonferroni-adjusted pairwise comparisons for heterogeneous outcomes; α = 0.05.
Limitations
- The paper states heterogeneity among included studies, small sample sizes, variable RCT quality, and challenges comparing specific allografts; DFU and VLU pathophysiologies differ, limiting comparability, and each RCT had unique inclusion/exclusion criteria and intervention protocols.
- The paper also states limited statistical power and risk of type II error, few studies for some allografts weakening subgroup analysis, and inconsistent complication reporting/definitions that prevented quantitative meta-analysis.
- Evident in the text: trial count differs between the abstract (19 trials) and Results (20 RCTs), and the 12-week closure p-value differs between the abstract/Results (p = 0.0394) and Discussion (p = 0.0256); time-to-healing had fewer than three data points per graft, so no inferential analysis was performed.
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Integrity signals
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Claims the paper makes
0 Valid · 0 Not valid · 9 Not checked · 91 Own results and interpretations
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Amnioband and EpiCord also performed favourably, with a wound closure rate of 83% and 81% respectively.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Amnioexcel reported the lowest wound closure rate (37.5%) and second longest time‐to‐healing (57.6 days), but only had data available from one RCT.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Apligraf reported the longest time‐to‐healing (85.4 days) and second lowest wound closure rate (54%).”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Theraskin showed the highest average wound closure at 12 weeks (84.7%) and a moderate wound closure difference to SOC (40%) and time to healing (46.9 days).”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper states — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some of the adverse events were more serious and not necessarily graft‐related, such as bleeding and infections in other parts of the body.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Complications
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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- It may state two separate claims as one. 31
- Probably not a substantial claim. 33
- The quote only partly states this claim. 1
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Time to Healing
“Epifix demonstrated the shortest time‐to‐healing with a median of 13 days, followed by Amnioband (37 days), and Theraskin (47 days).”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
“Epifix showed a similarly high wound closure rate (80%) and the shortest time to healing (18.3 days)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Search Results
“Wound closure at 12 weeks and time to healing met the assumption of homogeneity of variance (Levene's p > 0.05), and were analysed using one‐way ANOVA followed by Tukey's HSD post hoc test.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Time to Healing
“formal inferential analysis using a one‐way ANOVA or Kruskal–Wallis could not be performed due to the restricted sample size.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
“Amnioexcel reported the lowest wound closure rate (37.5%) and second longest time‐to‐healing (57.6 days), but only had data available from one RCT.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Time to Healing
“Across the available data, only one outcome was reported for Amnioband, Epifix and Theraskin, with three outcomes reported for Apligraf.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Abstract
“Nineteen trials with a total of 1303 participants met inclusion criteria.”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Search Results
“A total of 20 RCTs involving 1303 patients, both graft treated and SOC, were included”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Results > Wound Closure at 12 Weeks
“Theraskin vs. Amnioexcel showed a mean difference of 47% (p = 0.122), Epifix versus Amnioexcel showed a mean difference of 45% (p = 0.1008), and Amnioband versus Amnioexcel showed a mean difference of 44% (p = 0.1156).”
§ Assessing the Outcomes and Complications of Skin Allografts in Healing Diabetic Foot and Venous Leg Ulcers: A Systematic Review of Randomised Controlled Trials > Discussion
“While comparisons of skin substitutes against Amnioexcel approached significance (p values ranging from 0.077 to 0.094), these findings should be carefully interpreted as potential trends”
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Citations
Cites
Challenges in the Treatment of Chronic Wounds
Frykberg, R. G., & Banks, J. (2015) · Advances in Wound Care · doi:10.1089/wound.2015.0635 · Cited by 2,437
Veves, A., Falanga, V., Armstrong, D. G., Sabolinski, M. L., & Study, T. A. D. F. U. (2001) · Diabetes Care · doi:10.2337/diacare.24.2.290 · Cited by 643
Management of Diabetic Foot Ulcers
Αλεξιάδου, Κ., & Doupis, J. (2012) · Diabetes Therapy · doi:10.1007/s13300-012-0004-9 · Cited by 566
Human Wound and Its Burden: Updated 2022 Compendium of Estimates
Sen, C. K. (2023) · Advances in Wound Care · doi:10.1089/wound.2023.0150 · Cited by 360
Falanga, V., & Sabolinski, M. (1999) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1999.00201.x · Cited by 326
Health-related quality of life of diabetic foot ulcer patients and their caregivers
Nabuurs-Franssen, M. H., Huijberts, M. S. P., Nieuwenhuijzen Kruseman, A. C., Willems, J., & Schaper, N. C. (2005) · Diabetologia · doi:10.1007/s00125-005-1856-6 · Cited by 310
Diagnosis and Management of Diabetic Foot Complications
Boulton, A. J. M., Armstrong, D. G., Krisner, R., Attinger, C. E., Lavery, L. A., Lipsky, B. A., Mills, J. L., & Steinberg, J. S. (2018) · ADA Clinical Compendia · doi:10.2337/db20182-1 · Cited by 301
Zelen, C. M., Serena, T. E., Denozière, G., & Fetterolf, D. E. (2013) · International Wound Journal · doi:10.1111/iwj.12097 · Cited by 268
Diabetic Foot Ulcers: Pathophysiology, Immune Dysregulation, and Emerging Therapeutic Strategies
Dawi, J., Tumanyan, K., Tomas, K., Misakyan, Y., Gargaloyan, A., Gonzalez, E., Hammi, M., Tomas, S., & Venketaraman, V. (2025) · Biomedicines · doi:10.3390/biomedicines13051076 · Cited by 241
Biological Background of Dermal Substitutes
van der Veen, V. C., van der Wal, M. B. A., van Leeuwen, M. C. E., Ulrich, M. M. W., & Middelkoop, E. (2010) · Burns · doi:10.1016/j.burns.2009.07.012 · Cited by 222
Research works printed but not linked: 3
- Browse N. L., 2005, Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists
- Baranoski S. A. E., 2020, Wound Care Essentials, 199
- Schmid P., 2000, Immunohistologic Characterization of Graftskin (Apligraf), Wounds, 12, 4A
Cited by
Still being checked.
Metadata
- Authors
- Mathe, C., Reddi, S., Nahm, W., Trikala, A., & Schwartz, S.
- Affiliations
- California University of Science and Medicine (US)
- California University of Science and Medicine Colton California USA
- New York University (US)
- Corresponding author
- Mathe, Christopher
- Venue
- International Wound Journal
- Publisher
- Wiley
- Published
- 2026-06
- Volume
- 23
- Issue
- 6
- Pages
- e70892-e70892
- ISSN
- 1742-4801 (ISSN-L)
- 1742-481X
- PMC
- PMC13581071
- OpenAlex
- W7163575583
- Semantic Scholar
- 243630078e19b5ad0647ac99b3d9a7af1ca60eb3
- Cited by
- 0
- References
- 39
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- creativecommons.org/licenses/by-nc/4.0/ (vor, 3 d)
- doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
- Locations
- International Wound Journal (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- skin allografts, diabetic foot ulcer, venous leg ulcers, wound healing, Apligraf, wound closure, amputation, wound infection, chronic wounds
- MeSH terms
- Aged, Female, Humans, Male, Middle Aged, Varicose Ulcer, Wound Healing, Randomized Controlled Trials as Topic, Skin Transplantation, Treatment Outcome, Diabetic Foot, Skin, Artificial, Allografts
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
