Summary: In patients with complex diabetic foot ulcers (DFUs) involving exposed bone, tendon, muscle, and/or joint capsule with controlled osteomyelitis (N=118), adjunctive cryopreserved ultra-thick human amniotic membrane derived from umbilical cord (cUC) applied at baseline and reapplied every ≥4 weeks if healing stalled for up to 4 applications demonstrated comparable healing rates at 26 weeks (66.1% vs 59.8%, p=0.40) and 50 weeks (77.1% vs 71.6%, p=0.29) with trend toward higher long-term healing compared to standard of care alone including surgical debridement, bone resection, wound dressings, offloading, and 6-week systemic antibiotics, with comparable adverse event rates (89.8% vs 87.3%).
| PICO | Description |
|---|---|
| Population | 118 adults with complex diabetic foot ulcers exhibiting exposed bone, tendon, muscle, and/or joint capsule, with controlled osteomyelitis across multiple US centers. |
| Intervention | Adjunctive treatment with cryopreserved ultra-thick human amniotic membrane derived from umbilical cord (cUC), applied at baseline and reapplied every ≥4 weeks if healing stalled, for up to 4 applications plus standard of care. |
| Comparison | Standard of care (SOC) alone: surgical debridement, bone resection as needed, appropriate wound dressings, offloading strategies, and a 6-week course of systemic antibiotics. |
| Outcome | Complete healing at 26 weeks: 66.1% (cUC + SOC) vs 59.8% (SOC alone), p=0.40. At 50 weeks: 77.1% vs 71.6%, p=0.29. Adverse events comparable (89.8% vs 87.3%). Non-significant trend toward higher long-term healing with fewer applications in cUC group. |
Clinical Context
Complex diabetic foot ulcers involving exposed deep structures represent among the most challenging wounds in clinical practice. These wounds carry amputation rates of 15-25% and are associated with significant morbidity, mortality, and healthcare costs. Standard treatment involves aggressive surgical debridement, prolonged antibiotic courses, and meticulous wound care, yet healing rates remain suboptimal.
Amniotic membrane products have gained attention as adjunctive wound therapies due to their rich content of growth factors, cytokines, and extracellular matrix components that promote tissue regeneration. Cryopreserved preparations maintain biological activity while offering practical advantages in storage and handling. The ultra-thick umbilical cord-derived product tested here provides a robust scaffold intended to persist longer in challenging wound environments.
This multi-center RCT addressed a critical gap: whether amniotic membrane technology adds value in the most severe DFU cases where standard approaches frequently fail. Previous studies focused on less complex wounds; this trial specifically enrolled patients with exposed bone, tendon, or joint—wounds traditionally considered high-risk for amputation.
Clinical Pearls
1. No Significant Benefit Over Aggressive Standard Care: The 6% absolute difference in healing at 26 weeks (66.1% vs 59.8%) was not statistically significant. This suggests that when standard of care is optimized with proper debridement, offloading, and antibiotics, the additional benefit of cUC may be modest.
2. Long-Term Trend Warrants Attention: The 50-week data showed 77.1% vs 71.6% healing, suggesting potential late benefits. Some complex wounds may require extended observation periods to demonstrate treatment effects.
3. Safety Profile Is Reassuring: Comparable adverse event rates (89.8% vs 87.3%) indicate that cUC application doesn’t add safety concerns to an already high-risk population. The high overall AE rates reflect the underlying disease severity, not treatment toxicity.
4. Fewer Applications May Suffice: The trend toward healing with fewer cUC applications suggests the membrane may accelerate early healing phases even if final outcomes are similar.
Practical Application
For clinicians managing complex DFUs with exposed deep structures, this trial suggests that optimized standard of care remains the foundation of treatment. Cryopreserved amniotic membrane may be considered as adjunctive therapy, particularly for wounds showing inadequate progress despite optimal standard management.
Key implementation considerations include ensuring adequate surgical debridement before membrane application, maintaining appropriate offloading throughout treatment, completing full antibiotic courses for osteomyelitis, and allowing 4+ weeks between applications to assess response. Cost-benefit analysis should factor in the modest efficacy difference against product costs.
Broader Evidence Context
This trial joins a growing body of evidence on biological wound products for diabetic ulcers. Previous studies of amniotic membrane in less severe DFUs showed more pronounced benefits, suggesting the treatment effect may diminish as wound complexity increases. The FDAAA-registered trial design and multi-center execution add credibility to findings.
Compared to other advanced therapies (hyperbaric oxygen, negative pressure wound therapy, growth factors), cUC showed similar patterns: incremental rather than transformative benefits when added to optimized standard care. This reinforces that no single adjunctive therapy substitutes for fundamental wound care principles.
Study Limitations
The study was powered for a larger effect size than observed, potentially missing smaller but clinically relevant differences. The 50-week follow-up, while longer than many wound trials, may still underestimate late healing. Patient and investigator blinding was not possible given the visible nature of the intervention. Cost-effectiveness analysis was not included. The specific cUC product tested may not generalize to other amniotic membrane preparations.
Bottom Line
Cryopreserved ultra-thick amniotic membrane from umbilical cord shows a non-significant trend toward improved healing in complex diabetic foot ulcers with exposed deep structures. Optimized standard of care remains essential; cUC may be considered as adjunctive therapy for wounds failing conventional management, with realistic expectations of modest incremental benefit.
Source: Caporusso J, et al. “A Multi-Centre, Randomised, Controlled Clinical Trial Assessing Cryopreserved Ultra-Thick Human Amniotic Membrane in the Treatment of Complex Diabetic Foot Ulcers.” Read article here.
