Diabetic foot ulcers (DFUs) are among the most difficult chronic wounds to heal. Even with attentive standard care—pressure offloading, sharp debridement, infection control, and revascularization where indicated—a substantial proportion of ulcers fail to close in a timely, orderly fashion. These non-healing wounds carry a high risk of infection, hospitalization, and amputation, and they consume enormous healthcare resources. This reality has driven interest in advanced wound therapies, including bioengineered skin substitutes. One such option that has attracted growing clinical and research attention is the acellular fish skin graft (FSG), a xenogeneic matrix derived from North Atlantic cod.
What Are Acellular Fish Skin Grafts?
An acellular fish skin graft is a decellularized sheet of intact fish skin—most commonly from North Atlantic cod—processed to remove cellular material while preserving its natural three-dimensional extracellular matrix. Because the tissue undergoes only gentle processing, it retains a porous microstructure that supports cellular ingrowth and revascularization, along with naturally occurring omega-3 fatty acids. Unlike mammalian-derived grafts, fish skin carries no risk of transmitting mammalian viral or prion disease, and it is free of the cultural or religious restrictions sometimes associated with porcine products. In practice, the graft functions as a temporary scaffold that the body gradually incorporates as new tissue forms.
Evidence from Randomized Controlled Trials
The most rigorous evidence comes from a prospective, multicenter, randomized controlled trial comparing omega-3-rich acellular fish skin graft with standard-of-care dressings in chronic DFUs. In a penultimate analysis of 94 patients, Lullove and colleagues (2022) reported complete wound closure at 12 weeks in 63.0% of ulcers treated with fish skin graft versus 31.3% treated with a collagen alginate dressing (P = .0036), with a mean time to healing of roughly seven weeks and a median of six graft applications.
The final analysis of that trial, published by Lantis and colleagues (2023), reinforced these findings. Among 102 patients analyzed by intention to treat, 56.9% of fish-skin-treated ulcers achieved closure at 12 weeks compared with 31.4% of controls (P = .0163). The mean percentage wound-area reduction was 86.3% with fish skin graft versus 64.0% with standard care (P = .0282). Notably, the study also modeled an annualized cost savings of approximately $2,818 per patient, suggesting that a more expensive dressing can still reduce overall treatment costs when it shortens healing time.
Pooled Evidence and Safety
A 2024 systematic review and meta-analysis by Gao and colleagues synthesized eight clinical studies encompassing 390 patients—145 treated with standard care alone and 245 with standard care plus fish skin graft. The complete healing rate was significantly higher with the addition of fish skin graft (odds ratio 3.44; 95% confidence interval 2.03–5.82; P < .001). Reported mean percentage area reduction across studies ranged widely, from 71.6% to 97.3%. Importantly, the analysis found no significant difference in ulcer recurrence or in the risk of serious adverse events between groups, indicating that the healing benefit did not come at a measurable safety cost.
Early Application May Matter
Timing appears to influence results. In an early prospective evaluation of postoperative diabetic foot wounds, Woodrow and colleagues (2019) observed that ulcers of less than three months’ duration achieved a median wound-area reduction exceeding 84.9% at six weeks, whereas wounds present for longer than three months reduced by less than 42% over the same period. No patients developed infection or skin reactions. Although the sample was small, the pattern is consistent with a broader principle in wound care: advanced therapies tend to perform best when introduced before a wound becomes deeply entrenched in a chronic, non-healing state.
Clinical Context and Limitations
Fish skin grafts are best understood as an adjunct to—not a replacement for—the foundations of diabetic foot ulcer care. Offloading, debridement, infection management, glycemic control, and vascular assessment remain essential, and skin substitutes are generally reserved for wounds that fail to progress despite optimal standard treatment. As a 2025 editorial in the World Journal of Diabetes emphasized, meaningful challenges persist: availability can be limited, patient acceptance varies, and the overall evidence base—while encouraging—still rests on a relatively small number of trials. Larger, well-designed randomized studies and integration into multidisciplinary care pathways will be needed to define exactly which patients benefit most.
Key Takeaways
Current evidence indicates that omega-3-rich acellular fish skin grafts, used alongside standard care, can significantly increase the likelihood of complete healing in chronic diabetic foot ulcers compared with standard care alone, with roughly a threefold improvement in closure odds in pooled analysis and no signal of increased recurrence or serious harm. Early application and appropriate patient selection appear to enhance outcomes, and the shorter healing times observed may offset the higher per-unit cost. At the same time, fish skin grafts complement rather than substitute for core ulcer management, and further large-scale trials are warranted to confirm long-term benefit and clarify their optimal role.
References
Lullove EJ, Liden B, McEneaney P, et al. Evaluating the effect of omega-3-rich fish skin in the treatment of chronic, nonresponsive diabetic foot ulcers: penultimate analysis of a multicenter, prospective, randomized controlled trial. Wounds. 2022;34(4):E34–E36.
Lantis JC II, Lullove EJ, Liden B, et al. Final efficacy and cost analysis of a fish skin graft vs standard of care in the management of chronic diabetic foot ulcers: a prospective, multicenter, randomized controlled clinical trial. Wounds. 2023;35(4):71–79.
Gao J, Ge LX, Gao QY, Zhang AM, Hu LJ. Efficacy of acellular fish skin graft in the management of chronic ulcer: a systematic review and meta-analysis. Langenbeck’s Archives of Surgery. 2024;409(1):64.
Woodrow T, Chant T, Chant H. Treatment of diabetic foot wounds with acellular fish skin graft rich in omega-3: a prospective evaluation. Journal of Wound Care. 2019;28(2):76–80.
Zhao Y, Shen QQ. Acellular fish skin grafts in diabetic foot ulcer care: advances and clinical insights. World Journal of Diabetes. 2025;16(1):100597.
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