|Bioengineered skin in diabetic foot ulcers
|Teng YJ, Li YP, Wang JW, Yang KH, Zhang YC, Wang YJ, Tian JH, Ma B, Wang JM, Yan X
This review concluded that patients with diabetic foot ulcers might benefit from bioengineered skin due to its effectiveness, safety, and reduced risk of infections, compared with control treatment. The authors highlighted the various limitations of the studies included in the review and acknowledged that these prevented them from drawing firm conclusions. The conclusions reflect the evidence presented.
To evaluate the effectiveness and safety of bioengineered skin in the treatment of patients with diabetic foot ulcers.
MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Science Citation Index, Science Direct, Chinese Biomedical Database, CNKI, and Chinese Journals Full-text Database were searched. Search dates spanned 1912 to 2008. Search terms were reported. Bibliographies were examined for further relevant studies.
Randomised controlled trials (RCTs) of patients with diabetic foot ulcers that compared bioengineered skin treatment with a control group and reported effectiveness or safety were eligible for inclusion. The primary outcome of interest was complete wound closure (defined as full epithelialisation); secondary outcomes of interest were complications (including ulcer infection, osteomyelitis and cellulitis), severe adverse events and ulcer (wound) recurrence.
The included studies were of patients with full thickness plantar, forefoot, medial and/or lateral foot ulcers of at least two weeks duration. The area of ulcers ranged between 1cm2 and 20cm2. Both insulin dependent and non insulin dependent patients were included. Bioengineered skin treatments used were Dermagraft, Graftskin and Hyalograft 3D. Treatment regimens varied between studies. Follow-up ranged from four weeks to 14 months.
Two reviewers selected studies for inclusion. Disagreements were resolved by consensus after referral to a third reviewer.
Assessment of study quality
Two reviewers independently assessed methodological quality in terms of randomisation, allocation concealment, blinding, comparability at baseline and analysis (intention-to-treat analysis, interventions and outcomes). Withdrawals/loss to follow-up was assessed.
Odds ratios and the corresponding 95% confidence intervals were extracted for outcomes.
The number of reviewers engaged in data extraction was not reported.
Methods of synthesis
Pooled odds ratios and 95% confidence intervals were calculated using a fixed-effects model (in the absence of significant heterogeneity) or a random-effects model (where there was significant heterogeneity). Heterogeneity was examined using I2 and Χ2 tests. Publication bias was assessed using a funnel plot. Subgroup analyses were performed for type of bioengineered skin and type of complication.
Results of the review
Seven RCTs were included in the review (n=880, range 17 to 245). Randomisation was adequate in six studies. Five studies were single blinded. Five studies reported adequate allocation concealment. Withdrawal/loss to follow-up was reported in six studies. All studies were comparable at baseline and reported intention-to-treat analysis. Follow-up ranged from four weeks to 14 months.
Bioengineered skin was associated with significantly better complete wound healing than with conventional treatment (OR 1.88, 95% CI 1.41 to 2.51; seven RCTs). This was not associated with significant statistical heterogeneity.
Subgroup analyses found that Dermagraft (OR 1.76, 95% CI 1.22 to 2.56; four RCTs) and Graftskin (OR 2.05, 95% CI 1.20 to 3.50; two RCTs) but not Hyalograft 3D were associated with better wound healing than control. The Dermagraft analysis was associated with low heterogeneity (I2=36%); the other subgroup analyses showed no significant statistical heterogeneity.
There was no significant difference in ulcer recurrence between bioengineered skin and control groups (five RCTs; I2=0%).
Incidence of complications was significantly greater in the control group than with the bioengineered skin group (OR 0.69, 95% CI 0.53 to 0.91; seven RCTs). Wound infection (six RCTs), osteomyelitis (three RCTs) and cellulitis (four RCTs) were reported. The difference was significant between groups for wound infection only, in favour of bioengineered skin (OR 0.68, 95% CI 0.48 to 0.98). There was statistically significant heterogeneity for osteomyelitis (I2=55%). There was no evidence of publication bias.
Patients with diabetic foot ulcers might benefit from bioengineered skin because of its effectiveness, safety, and reduced risk of infections, compared with control treatment. The limitations of the primary studies limited the authors' ability to draw firm conclusions.
The research question was supported by well-defined inclusion criteria. A number of relevant databases were searched, including sources of unpublished studies, which reduced the risk of publication bias (publication bias was not indicated by the funnel plot). It was unclear whether the searches were restricted by language. Study selection and validity assessment was performed by two reviewers; it was unclear whether similar steps to reduce error and bias were taken for data extraction.
Study quality was assessed using appropriate criteria. Meta-analysis appeared appropriate, but confidence intervals were wide for some findings and this limited the reliability of the results. Statistical heterogeneity was assessed. The authors acknowledged the limitations of small sample sizes and lack of long-term follow-up. They highlighted that the limitations of the primary studies limited their ability to draw firm conclusions.
The conclusions reflect the evidence presented.
Implications of the review for practice and research
Practice: The authors stated that Hyalograft-3D had not been approved by the national drug regulatory authority in China.
Research: The authors stated that further RCTs were needed to assess the safety and effectiveness of Hyalograft-3D.
Teng YJ, Li YP, Wang JW, Yang KH, Zhang YC, Wang YJ, Tian JH, Ma B, Wang JM, Yan X. Bioengineered skin in diabetic foot ulcers. Diabetes Obesity and Metabolism 2010; 12(4): 307-315
Other publications of related interest
Teng YJ, Wang JW, Wang YJ, Yang KH, Yan X, Tian JH, Ma B, Wang JM, Li YP. A meta-analysis of tissue engineered skin improved wound closure in diabetic foot ulcers. Chinese Journal of Evidence-Based Medicine 2009; 9(5): 584-592.
Subject indexing assigned by NLM
Diabetes Mellitus, Type 1 /complications; Diabetic Foot /physiopathology /therapy; Female; Humans; Male; Randomized Controlled Trials as Topic; Skin; Tissue Engineering /methods; Treatment Outcome; Wound Healing /physiology
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.