Why Adjunctive Wound Therapies Matter
Even with the best standard of care — sharp debridement, offloading, infection control, and revascularization where indicated — a substantial proportion of diabetic foot ulcers (DFUs) fail to heal within 12 weeks. Wounds that remain open beyond this window are associated with markedly higher rates of infection, hospitalization, and lower-extremity amputation. To address this treatment gap, clinicians are increasingly turning to cellular, acellular, and matrix-like products (often grouped under the umbrella term CTPs, or skin substitutes), with placental-derived allografts and bioengineered skin equivalents now occupying a defined place in international guidelines (Chen et al., Diabetes/Metabolism Research and Reviews, 2024).
What Are Placental-Derived and Bioengineered Skin Products?
CTPs are a heterogeneous family of products designed to deliver structural extracellular matrix, growth factors, cytokines, and in some cases viable cells to a chronic wound bed. Broadly, they fall into three categories:
- Placental-derived allografts — including dehydrated human amnion/chorion membrane (e.g., dHACM/EpiFix), cryopreserved placental membrane (e.g., Grafix), and decellularised full-thickness placental membrane.
- Acellular dermal matrices — derived from human cadaveric or animal dermis (e.g., GraftJacket, DermACell), providing a collagen scaffold without living cells.
- Bioengineered cellular constructs — such as bilayered living skin equivalents (Apligraf) or fibroblast-seeded matrices (Dermagraft), which contribute viable keratinocytes and/or fibroblasts.
The biological rationale rests on supplying a chronic, inflammation-arrested wound with the matrix proteins, anti-inflammatory mediators, and growth factors normally provided by acute wound tissue, thereby helping shift the wound out of a stalled inflammatory phase (Niroomand et al., Advanced Therapeutics, 2025).
What the Randomized Evidence Shows
Placental Allografts
Randomized controlled trials of dHACM in non-healing DFUs have reported significantly higher 6- and 12-week complete closure rates compared with standard care alone, with relative healing improvements of roughly 2- to 3-fold in several pivotal trials. A prospective multicentre evaluation of weekly viable human amnion membrane allograft in 20 patients with chronic DFUs reported an 85% closure rate at 12 weeks, with no product-related adverse events (Tettelbach et al., Plastic and Reconstructive Surgery – Global Open, 2023).
More recently, a multicentre randomized trial of full-thickness decellularised placental membrane in 121 patients with persistent DFUs — enrolled between 2022 and 2024 — demonstrated significantly higher complete closure rates and faster wound area reduction compared with standard care (Journal of Wound Care, 2025). A complementary randomized trial of cryopreserved ultra-thick human amniotic membrane in 220 patients with complex DFUs (including wounds with exposed bone, tendon, or controlled osteomyelitis) similarly favored the allograft arm.
Bioengineered Skin Equivalents
Earlier RCTs of bilayered living skin equivalents (Apligraf) and fibroblast-derived dermal substitutes (Dermagraft) established that adjunctive use can increase 12-week closure rates by approximately 15–20 percentage points over standard care. These products remain referenced in current guidelines as evidence-supported options where the standard of care has plateaued.
Where CTPs Fit in International Guidelines
The 2023 IWGDF Guideline on Wound Healing Interventions issues a conditional, supportive recommendation for the adjunctive use of placental-derived products in non-infected, non-ischemic DFUs that have not progressed with best standard of care alone. The same guideline extends a similar conditional recommendation to sucrose octasulfate dressings, negative pressure wound therapy, hyperbaric oxygen, and topical oxygen therapy — all positioned as adjuncts to, not replacements for, foundational wound care (IWGDF 2023; Chen et al., Diabetes/Metabolism Research and Reviews, 2024).
Three principles run through the guideline:
- Best standard of care comes first. Adequate debridement, offloading, vascular assessment, and infection management must be optimized before considering an advanced product.
- Patient and wound selection matter. Most positive trials enrolled non-infected, adequately perfused, full-thickness ulcers persisting beyond 4–6 weeks of standard care.
- Resources must be available. CTPs are costly, and cost-effectiveness depends on appropriate selection and consistent application protocols.
Safety Considerations
Across pooled trial data, placental and bioengineered products have demonstrated a favorable safety profile, with no signal of increased infection, hypersensitivity, or disease transmission when sourced and processed under regulated tissue-banking standards.
Clinical Summary
For diabetic foot ulcers that fail to demonstrate meaningful progress despite optimized standard care, cellular and tissue-based products — particularly placental-derived allografts and bioengineered skin equivalents — have accumulated randomized evidence supporting improved healing rates and shorter time to closure. Current international guidelines position these therapies as conditional, evidence-supported adjuncts rather than first-line treatments. Appropriate patient selection, optimization of perfusion and offloading, and rigorous infection control remain the foundation on which any advanced therapy is built.
References
- Chen P, Vilorio NC, Dhatariya K, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes/Metabolism Research and Reviews. 2024;40(3):e3644.
- International Working Group on the Diabetic Foot. Guidelines on Interventions to Enhance Healing of Foot Ulcers in People with Diabetes. IWGDF, 2023.
- Niroomand A, et al. A Narrative Review on Efficacy of Cell- and Tissue-Based Therapies for Diabetic Foot Ulcer. Advanced Therapeutics. 2025.
- Tettelbach WH, et al. A Prospective Multicenter Study of a Weekly Application Regimen of Viable Human Amnion Membrane Allograft in the Management of Nonhealing Diabetic Foot Ulcers. Plastic and Reconstructive Surgery – Global Open. 2023;11(10):e5300.
- Multicentre randomised controlled trial of full-thickness decellularised placental membrane allograft versus standard of care in diabetic foot ulcers. Journal of Wound Care. 2025.
- Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. International Wound Journal. 2014;11(5):554-560.
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