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Cochrane skin substitutes review

Skin substitutes can achieve complete ulcer closure

A Cochrane Review paper has reported that skin substitutes can increase the likelihood of achieving complete ulcer closure compared with standard care alone in the treatment of diabetic foot ulcers.

A Cochrane Review paper has reported that skin substitutes can increase the likelihood of achieving complete ulcer closure compared with standard care alone in the treatment of diabetic foot ulcers. However, the paper found that the “effectiveness on the long term, including lower limb salvage and recurrence, is currently lacking and cost-effectiveness is unclear.” The paper, ‘Systematic review and meta-analysis of skin substitutes in the treatment of diabetic foot ulcers: Highlights of a Cochrane systematic review’, was published in Wound Repair and Regeneration, The International Journal and Tissue Repair and Regeneration.

The paper evaluated the effectiveness of skin substitutes on ulcer healing and limb salvage in the treatment of diabetic foot ulcers, and included skin substitute for all kinds of skin grafts and (bioengineered) skin substitutes, both cellular and acellular.


The researchers conducted a literature search and identified 17 from the 283 unique articles that met the inclusion criteria which were included in this review. In 13 of the 17 included trials, a skin substitute was compared with standard care. In the remaining four trials, two types of skin substitutes were compared. Sixteen of the included trials assessed the effectiveness of a bioengineered skin substitute. In only one trial, the effectiveness of a non-bioengineered skin graft was assessed. Most trials assessed the effect of a cellular, bioengineered product. The acellular bioengineered skin substitutes OASIS and Graftjacket were the only ones that were assessed.

Study size of the included trials ranged from 23 to 314 randomised participants and included 1,655 randomised participants with diabetic foot ulceration. Fourteen of the trials included chronic or hard to heal ulcers, which were present for at least two, four or six weeks. None of the trials included patients with ischemic ulceration since inadequate arterial foot perfusion was an exclusion criterion for trial participation. Furthermore, 15 trials excluded participants with infected ulceration.


When including all randomised participants, the proportion of completely healed ulcers ranged between 7.7% and 56.3% in the standard care group and 21.1% and 92.3% in the intervention group. The pooled risk ratio (RR) for complete ulcer healing was 1.55 in favour of the intervention group (95% CI 1.30–1.85; RD 0.25, 95% CI 0.14–0.37; NNT 4, 95% CI 3–8).

Graftjacket was the only subgroup containing an acellular product (RR 1.9, 95% CI 0.97–3.71). Compared to standard care, the only individual products that showed a statistically significant beneficial effect on complete ulcer closure were Apligraf/Graftskin, Epifix and Hyalograft 3D.

Four trials compared two different types of skin substitutes, but the review found that none of these trials showed statistically significant differences as to the proportion of ulcers healed between the treatment strategies.

The review also found that:

  • The time of complete ulcer healing was very heterogeneous and so it was not possible to make clinical relevant comparisons for this outcome, the review notes.
  • The pooled results of all lower limb amputations (including toe amputations and excluding secondary bone resections) found a statistically significant lower amputation rate for the skin substitute group at 12 weeks (RR 0.42; 95% CI 0.23–0.81; RD −0.06; 95% CI −0.10–0.01; NNT 17; 95% CI 10–100).

“It is clear that skin substitutes cannot be seen as a single treatment option but should always be part of a multidisciplinary approach,” the authors state. “As such, conventional therapy remains the mainstay in the treatment of diabetic foot ulcers at present day. Skin substitutes may be used in the near future as an addition to standard care in selected patients with chronic foot ulceration, in particular, when evidence for the (costs)-effectiveness on the long term is more established.”

However, the authors acknowledge that the majority of trials mainly focused on the reduction in wound size or the healing speed. Therefore, whether complete ulcer healing was achieved is unknown and the “clinical relevance of these surrogate endpoints remains unclear.”

The article was edited from the original article, under the Creative Commons license. To access this paper, please click here

A more detailed review of skin substitutes for treating foot ulcers in people with diabetes was recently published in the Cochrane Database of Systematic Reviews – Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. For more information on this paper, please click here