Diabetic foot ulcers (DFUs) heal slowly even with good standard care, and a substantial proportion remain open for months. This has driven interest in topical biologic agents, including recombinant growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), which are intended to stimulate cell migration, proliferation, and new tissue formation in the wound bed. This article reviews what systematic reviews and meta-analyses from the past decade report about their effectiveness and safety.
What Growth Factors Are Meant to Do
Chronic diabetic wounds often show a disrupted signalling environment: reduced growth factor levels, increased protease activity, and impaired responses by fibroblasts and keratinocytes. Applying a purified or recombinant growth factor to the wound, or injecting it around the wound margin, aims to restore some of this missing signalling. These products are used as adjuncts. They do not replace the foundations of ulcer care, which remain offloading, debridement, infection control, and assessment of perfusion.
The Cochrane Evidence
The Cochrane review by Martí-Carvajal and colleagues (2015) pooled 28 randomised trials involving 2,365 participants and 11 types of growth factor. Complete wound closure was more frequent with growth factors than with placebo or no growth factor (52.5% versus 34.6%; relative risk 1.51, 95% CI 1.31 to 1.73, from 12 trials). There was no clear difference in lower-limb amputation (relative risk 0.74, 95% CI 0.39 to 1.39), and no trial reported quality of life. Adverse events were poorly reported. The authors rated the certainty of evidence as low for healing and very low for amputation, noting that the trials were small, at high risk of bias, and often industry-sponsored.
Epidermal Growth Factor Meta-Analyses
Recombinant human EGF has been examined more closely than most agents. Bui Thien and colleagues (2019) meta-analysed placebo-controlled trials (six studies, 530 patients) and found significantly higher complete healing with rhEGF, with similar benefit whether it was applied topically or injected into the lesion, and low heterogeneity between studies.
Rahim and colleagues (2023) analysed eight randomised trials with 620 patients (337 receiving EGF and 283 receiving placebo). The pooled complete-healing relative risk was about 1.5, and the effect was clearest at eight weeks (relative risk 2.59, 95% CI 1.42 to 4.72). Estimates at four and twelve weeks were imprecise, with confidence intervals that included no effect and considerable heterogeneity between trials. Taken together, these analyses suggest a possible benefit of EGF on healing, but the size and timing of that benefit remain uncertain.
Comparing Different Agents
Because few trials compare growth factors with one another directly, network meta-analysis has been used to rank them indirectly. Wong and colleagues (2024) analysed randomised trials of topical biologic and growth factor regimens against standard care, searching databases to December 2022. Human umbilical cord–derived products showed the highest cure rate, followed by recombinant human EGF. Human umbilical cord products, EGF, and FGF were each associated with a shorter time to healing, while platelet-rich plasma was associated with a lower risk of adverse events. The authors concluded that these options appear promising relative to standard care. Rankings from network meta-analyses depend on indirect comparisons across trials that differ in populations, ulcer severity, and dressing protocols, so they are best treated as hypothesis-generating.
Where Guidelines Stand
The 2023 International Working Group on the Diabetic Foot (IWGDF) guideline on interventions to enhance healing (Chen and colleagues, published in Diabetes/Metabolism Research and Reviews in 2024) restricts its adjunctive recommendations to people whose ulcers have not healed with optimal standard care and where resources allow. Its conditional recommendations cover sucrose octasulfate dressings, placental-derived products, autologous leucocyte, platelet and fibrin patches, topical and hyperbaric oxygen therapy, and negative pressure wound therapy for post-operative wounds. The guideline emphasises that the overall certainty of evidence for wound-healing interventions is low and that higher-quality trials are needed.
Key Takeaways
Pooled randomised data suggest that growth factors, and rhEGF in particular, may increase the proportion of diabetic foot ulcers that heal compared with placebo or standard care alone. The evidence is limited by small trials, risk of bias, industry sponsorship, heterogeneity, and incomplete safety reporting. No convincing effect on amputation or quality of life has been shown. Growth factors are therefore best understood as an adjunct to, not a substitute for, offloading, debridement, infection management, and vascular assessment.
References
- Martí-Carvajal AJ, Gluud C, Nicola S, et al. Growth factors for treating diabetic foot ulcers. Cochrane Database of Systematic Reviews. 2015;(10):CD008548.
- Bui Thien Q, Bui Quoc VP, Németh D, et al. Epidermal growth factor is effective in the treatment of diabetic foot ulcers: meta-analysis and systematic review. International Journal of Environmental Research and Public Health. 2019;16(14).
- Rahim F, Yan X, Shah JA, et al. Epidermal growth factor outperforms placebo in the treatment of diabetic foot ulcer: a meta-analysis. F1000Research. 2023;11:773.
- Wong AYW, Hooi NMF, Yeo BSY, et al. Improving diabetic wound healing outcomes with topical growth factor therapies: systematic review and network meta-analysis of randomised-controlled trials. Journal of Clinical Endocrinology & Metabolism. 2024. doi:10.1210/clinem/dgae128.
- Chen P, Vilorio NC, Dhatariya K, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes/Metabolism Research and Reviews. 2024;40(3):e3644.
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