Abstract: We included seventeen studies with a total of 1655 randomised participants in this review. Risk of bias was variable among studies. Blinding of participants, personnel and outcome assessment was not possible in most trials because of obvious differences between the treatments. The lack of a blinded outcome assessor may have caused detection bias when ulcer healing was assessed. However, possible detection bias is hard to prevent due to the nature of the skin replacement products we assessed, and the fact that they are easily recognisable. Strikingly, nearly all studies (15/17) reported industry involvement; at least one of the authors was connected to a commercial organisation or the study was funded by a commercial organisation. In addition, the funnel plot for assessing risk of bias appeared to be asymmetrical; suggesting that small studies with 'negative' results are less likely to be published. Thirteen of the studies included in this review compared a skin graft or tissue replacement with standard care. Four studies compared two grafts or tissue replacements with each other. When we pooled the results of all the individual studies, the skin grafts and tissue replacement products that were used in the trials increased the healing rate of foot ulcers in patients with diabetes compared to standard care (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence). However, the strength of effect was variable depending on the specific product that was used (e.g. EpiFix® RR 11.08, 95% CI 1.69 to 72.82 and OrCel® RR 1.75, 95% CI 0.61 to 5.05). Based on the four included studies that directly compared two products, no specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement. Sixteen of the included studies reported on adverse events in various ways. No study reported a statistically significant difference in the occurrence of adverse events between the intervention and the control group. Only two of the included studies reported on total incidence of lower limb amputations. We found fewer amputations in the experimental group compared with the standard care group when we pooled the results of these two studies, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). Based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone. However, the data available to us was insufficient for us to draw conclusions on the effectiveness of different types of skin grafts or tissue replacement therapies. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.

Plain-language summary: We included thirteen randomised studies that compared two types of skin grafts or tissue replacements with standard care and four randomised studies that compared two grafts or tissue replacements with each other. In total 1655 patients were randomised in these seventeen trials. Risk of bias was variable among studies. The biggest drawbacks were the lack of blinding (i.e. patients and investigators were aware who was receiving the experimental therapy and who was receiving the standard therapy), industry involvement and the possibility that small studies were less likely to be published if they reported 'negative' results. Adverse advent rates (harm due to the treatment) varied widely. Based on the seventeen studies included in this review, skin grafts and tissue replacements, used in conjunction with standard care, increase the healing rate of foot ulcers and lead to slightly fewer amputations in people with diabetes compared with standard care alone. However, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain. There was not enough evidence for us to be able to recommend a specific type of skin graft or tissue replacement. This plain language summary is up-to-date as of 9 April 2015.