Commentary on ‘A Multi‐Centre, Randomised, Controlled Clinical Trial Assessing Cryopreserved Ultra‐Thick Human Amniotic Membrane in the Treatment of Complex Diabetic Foot Ulcers’

Dear Editor,

We have conducted a careful appraisal of Caporusso et al.'s [1] article titled ‘A Multi‐Centre, Randomised, Controlled Clinical Trial Assessing Cryopreserved Ultra‐Thick Human Amniotic Membrane in the Treatment of Complex Diabetic Foot Ulcers’, recently published in your esteemed journal. We intend to offer a constructive scholarly critique of the methodological framework employed and to propose potential avenues for refinement in consequent research endeavours. The main goal of this study was to examine the safety and efficacy of cryopreserved ultra‐thick human amniotic membrane products derived from umbilical cord (cUC) versus standard of care (SOC) for diabetic foot ulcers (DFUs) with exposed bone, tendon, muscle and/or joint capsule and controlled osteomyelitis. The reported findings indicate that adjunctive cUC is safe and achieves a high 50‐week healing rate with fewer than four applications in complex DFUs that are often excluded from clinical trials. While this addresses a clinically vital problem, some reporting and interpretive issues warrant clarification before findings inform practice.

First, the demographic profiling described in this research is somewhat limited. The socioeconomic status, rural versus urban residence, educational levels, alcohol use and opioid exposure are not fully specified. Incorporating these factors might enrich the analysis by accounting for additional patient‐specific variables that influence outcomes. Additional patient factors potentially influencing prognosis, such as diabetic retinopathy, psychiatric and autoimmune conditions, insulin resistance, physical activity, types of antidiabetic medications, diabetes duration, waist circumference, types of microorganisms, types of antibiotics and nutritional status, warrant explicit consideration owing to their plausible associations with outcomes [2, 3]. Furthermore, a subset of patients was enrolled during the COVID‐19 era; the study does not address potential effects of SARS‐CoV‐2 infection and long COVID on outcomes. Second, the present study would benefit from more complete reporting of several laboratory parameters and biomarkers. Micronutrients and inflammatory indices (Vitamin A, B12, D, C, E, zinc, magnesium, selenium, high‐sensitivity CRP (hs‐CRP), ferritin, monocyte‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, neutrophil‐to‐lymphocyte ratio, systemic inflammation response index, systemic immune‐inflammation index) and other relevant markers may clarify associations with outcomes [4, 5, 6]. Third, the current study would benefit from a transparent tabulation of all adverse events by severity, association with study product and timing relative to cUC applications. Furthermore, the use of adjunctive therapies was permitted when wounds did not decrease by ≥ 50% at 8 weeks; the criteria for these adjuncts and their allocation between arms should be reported in more detail to evaluate potential confounding.

In conclusion, while the current investigation contributes valuable knowledge regarding the safety and efficacy of cUC versus SOC for DFUs, addressing the above weaknesses would support external validity and facilitate translation into clinical practice. We encourage the respected authors and the editorial board to consider these enhancements and to provide further explanations to aid interpretation.

Author Contributions

Mohammad Barary: investigation, writing – original draft, writing – review and editing. Neda Meftah: investigation, writing – original draft. Majid Khalilizad: investigation, writing – original draft. Mostafa Javanian: investigation, writing – original draft. Mehdi Tavassoli: investigation, writing – original draft. Soheil Ebrahimpour: investigation, supervision, writing – original draft. All authors read and approved the final manuscript.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.