Cell-based therapies have moved from laboratory curiosity to the clinical literature on diabetes-related foot disease. Bone marrow concentrate, peripheral blood mononuclear cells, adipose-derived stem cells and umbilical cord mesenchymal cells have all been injected into chronic foot ulcers or ischaemic calf muscle in randomized trials over the past decade. The reported results are striking — and the quality of the evidence behind them is considerably weaker than the headline numbers suggest. Understanding both halves of that statement is what makes this literature useful clinically.
Why Regenerative Approaches Are Being Studied at All
A diabetes-related foot ulcer is not simply a wound that has been left open too long. Chronic ulcers in diabetes sit in a state of arrested healing characterised by impaired angiogenesis, senescent fibroblasts, persistent inflammation and reduced growth factor signalling. When neuropathy is compounded by peripheral arterial disease, a substantial minority of patients are also judged unsuitable for surgical or endovascular revascularisation. It is this “no-option” group — where standard care has been optimised and the wound still will not close — that has driven most regenerative research.
The theoretical rationale is that transplanted cells contribute to new vessel formation and secrete factors that shift the wound out of its stalled inflammatory phase. Whether that translates into limbs saved is an empirical question, not a mechanistic one.
What the Trial Data Show
A 2022 meta-analysis by Sun and colleagues in Stem Cell Research & Therapy pooled 14 studies and 683 participants, reporting higher healing rates, improved ankle-brachial index and transcutaneous oxygen pressure, longer pain-free walking distance, and a significantly lower amputation rate with cell therapy compared with conventional treatment. A larger 2024 GRADE-compliant review by Mudgal and colleagues, covering 20 studies and 1,304 participants, found a similar pattern: an absolute increase of roughly 36 percentage points in healing and a 19-percentage-point reduction in amputation. Critically, the authors rated the certainty of that evidence as ranging only from very low to moderate.
Source of cells appears to matter. A 2024 network meta-analysis by Tao and colleagues in the International Journal of Lower Extremity Wounds ranked umbilical cord mesenchymal stem cells highest for improving the ankle-brachial index. A separate 2023 review by Elsharkawi and colleagues, restricted to four randomized trials of adipose-derived stem cells, found complete healing in 83.5% of treated patients versus 52% of controls at 12 months, with no significant procedure-related complications reported.
Notably, cell therapy has not clearly outperformed other regenerative options. In a 2025 network meta-analysis in Annals of Plastic Surgery, Yang and colleagues compared platelet-rich plasma, epidermal growth factor and stem cell therapy across 23 randomized trials and 1,454 patients. Stem cells ranked first for the number of completely healed ulcers, but the differences between the three interventions were not statistically significant, and platelet-rich plasma actually achieved significantly faster healing times.
The Placebo Problem
The most instructive finding in this field comes from vascular medicine. Rigato, Monami and Fadini analysed 19 randomized controlled trials of autologous cell therapy for critical limb ischaemia in Circulation Research in 2017. Across all randomized trials, cell therapy reduced amputation risk by 37% and improved wound healing by 59%. However, when the analysis was restricted to placebo-controlled trials and to trials judged to be at low risk of bias, the benefit on every endpoint disappeared. Gao and colleagues reached a compatible conclusion in 2019: improvements in ulcer healing and overall amputation rate, but no significant improvement in major limb salvage, with all outcomes graded as low-quality evidence.
This is the signature of a literature dominated by small, unblinded, single-centre trials. Wound healing outcomes are particularly susceptible to assessment bias when neither patients nor evaluators are blinded, and publication bias favouring positive results has been raised repeatedly by reviewers in this area.
Where Guidelines Currently Stand
The 2023 International Working Group on the Diabetic Foot guideline on wound healing interventions, led by Chen and colleagues, issued 29 recommendations after a systematic GRADE review. It made conditional supportive recommendations for sucrose octasulfate dressings, negative pressure wound therapy for post-operative wounds, placental-derived products, the autologous leucocyte/platelet/fibrin patch, topical oxygen and hyperbaric oxygen — each only where best standard care alone had failed to heal the wound and resources permitted. Autologous stem cell transplantation did not attain a comparable supportive recommendation. The guideline group concluded plainly that the certainty of evidence in this field, while improving, remains poor overall, and called for better trials rather than more of them.
Clinical Summary
Cell-based therapy for the diabetic foot is biologically plausible, appears safe in reported series, and produces consistently positive results in pooled analyses of the trials conducted to date. Those same analyses show that the effect attenuates or vanishes under blinding and rigorous methodology, that no cell source has established superiority, and that regenerative therapy has not been shown to beat simpler options such as platelet-rich plasma. Current guidelines position adjunctive wound healing technologies as additions to — never substitutes for — the established fundamentals: offloading, debridement, infection control, revascularisation where indicated, and glycaemic management. Adequately powered, placebo-controlled, multicentre trials with health-economic analysis remain the missing piece.
References
- 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. 2023;40(3):e3644.
- Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circulation Research. 2017;120(8):1326–1340.
- Sun Y, Zhao J, Zhang L, Li Z, Lei S. Effectiveness and safety of stem cell therapy for diabetic foot: a meta-analysis update. Stem Cell Research & Therapy. 2022;13(1):416.
- Mudgal SK, Kumar S, Gaur R, et al. Effectiveness of Stem Cell Therapy for Diabetic Foot Ulcers: A Systematic Review and GRADE Compliant Bootstrapped Meta-Analysis of Randomized Clinical Trials. The International Journal of Lower Extremity Wounds. 2024;25(2):438–453.
- Yang HA, Hsu RJ, Jheng WL, Weng FJ, Lee JJ. Comparative Efficacy of Regenerative Therapies for Diabetic Foot Ulcers: A Network Meta-analysis. Annals of Plastic Surgery. 2025;94(3S Suppl 1):S24–S32.
- Elsharkawi M, Ghoneim B, O’Sullivan M, et al. Role of Adipose Derived Stem Cells in Patients with Diabetic Foot Ulcers: Systematic Review and Meta-Analysis of Randomised Controlled Trials. The International Journal of Lower Extremity Wounds. 2023;24(3):542–549.
- Tao Y, Yu Y, He C, Guo W. Therapeutic Effect of Stem Cells from Different Sources on Diabetic Foot Ulcers: Systematic Review and Network Meta-Analysis. The International Journal of Lower Extremity Wounds. 2024;25(2):389–400.
- Gao W, Chen D, Liu G, Ran X. Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Research & Therapy. 2019;10(1):140.
Comments
