Why Hard-to-Heal Diabetic Foot Ulcers Demand New Biologic Approaches
Diabetic foot ulcers (DFUs) remain one of the most consequential complications of diabetes mellitus, with a lifetime incidence estimated between 19% and 34% in people living with the disease. Despite optimal standard care — offloading, debridement, infection control, and vascular optimization — a substantial proportion of ulcers fail to close within 12 weeks and are classified as hard-to-heal. These chronic wounds are characterized by sustained inflammation, impaired angiogenesis, blunted growth-factor signaling, and a senescent cellular environment that ordinary dressings cannot easily reverse. Against this backdrop, cell-based therapies — and in particular mesenchymal stem cells (MSCs) — have emerged as a focus of intensive translational research over the past decade.
What Are Mesenchymal Stem Cells, and Why Are They Relevant to Wound Healing?
MSCs are multipotent stromal cells that can be isolated from bone marrow, adipose tissue, umbilical cord (including Wharton’s jelly), and other adult tissues. They are non-immunogenic in their allogeneic form and exhibit a distinctive ability to home to sites of tissue injury. Crucially, the current mechanistic understanding has shifted away from the idea that MSCs heal wounds by transdifferentiating into skin cells. Instead, the dominant effect appears to be paracrine: MSCs secrete a complex cocktail of cytokines, growth factors, and extracellular vesicles that modulate the wound microenvironment.
Mechanisms of Action
A 2023 review in Frontiers in Endocrinology summarized the principal effects observed across preclinical and early clinical studies: induction of angiogenesis through vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) release; polarization of wound macrophages from a pro-inflammatory M1 phenotype toward a reparative M2 phenotype; stimulation of fibroblast and keratinocyte proliferation; and acceleration of re-epithelialization. These effects directly target the pathophysiological deficits that define hard-to-heal diabetic wounds.
What the Clinical Evidence Now Shows
Over the past several years, multiple randomized controlled trials and meta-analyses have examined MSC therapy in DFU, allowing more meaningful conclusions than were possible from earlier case series.
Meta-Analytic Findings on Healing
A 2025 meta-analysis by Mei and colleagues, published in the International Journal of Lower Extremity Wounds, pooled randomized controlled trial data and reported a significant improvement in complete ulcer healing with MSC therapy compared with standard care (relative risk 1.63; 95% CI 1.23–2.16; P = 0.0007). The effect was most pronounced in smaller ulcers — under 5 cm² — where the relative risk reached 1.71. For larger ulcers, the pooled benefit was not statistically significant, suggesting wound size may modulate response.
An earlier 2022 meta-analysis update by Cao and colleagues, including cell-based therapies more broadly, found that treated patients had markedly higher healing rates (OR 4.64; 95% CI 3.11–6.90) and a shorter time to closure by approximately 17 days compared with controls. That analysis also reported reduced amputation rates (OR 0.29; 95% CI 0.18–0.49), although more recent restricted analyses of MSC-only trials have not consistently replicated the amputation effect.
Cell Source Matters
Hetta and colleagues, in a 2024 comprehensive review in Health Science Reports, noted that outcomes vary with cell source. Autologous bone marrow–derived MSCs (BMMSCs) have shown the strongest signals for complete healing, while umbilical cord–derived and adipose-derived MSCs (ADSCs) are gaining attention because they avoid the morbidity of marrow harvest and can be prepared from allogeneic donors with consistent potency. A 2024 review in the World Journal of Diabetes highlighted that ADSCs are particularly attractive due to their abundance, ease of harvest, and a secretome with strong pro-angiogenic activity.
Safety Profile
Across randomized data summarized in the 2022 review by Nalisa and colleagues in the Journal of Diabetes Research, and confirmed in subsequent pooled analyses, MSC therapy has shown a favorable safety profile in DFU patients, with no consistent signal of serious adverse events attributable to the cell product itself. Most adverse events reported have been local and self-limited.
Important Limitations and Open Questions
Despite encouraging effect sizes, the evidence base has limitations that warrant clinical caution. Trials remain relatively small, with significant heterogeneity in cell source, dose, delivery route (topical, intralesional, intramuscular, or combinations), and adjunctive standard care. Long-term outcomes such as recurrence and durable limb preservation are inadequately reported. Manufacturing standardization, regulatory status, and cost-effectiveness vary substantially across jurisdictions. The mixed findings on amputation reduction in the most rigorous recent analyses underline that MSC therapy should currently be regarded as an adjunct to — not a replacement for — established components of DFU care, including offloading, infection control, revascularization where indicated, and metabolic optimization.
Clinical Takeaways
Mesenchymal stem cell therapy represents one of the more biologically plausible and clinically supported emerging strategies for diabetic foot ulcers that have failed to progress under best standard care. Current evidence suggests improved complete-healing rates and shorter time to closure, particularly for smaller, well-perfused wounds, with bone marrow– and adipose-derived MSCs showing the strongest signals. The therapy works largely through paracrine effects that restore angiogenesis, reduce chronic inflammation, and stimulate epithelial and connective tissue repair. Larger, standardized trials with longer follow-up are needed before MSC therapy can be considered routine, but the trajectory of the literature supports its growing role in the limb-salvage armamentarium for hard-to-heal DFUs.
References
- Mei XH, Zhang T, Yang Y, et al. Efficacy of Mesenchymal Stem Cells in the Treatment of Diabetic Foot Ulcers: A Meta-Analysis of Randomized Controlled Trials. International Journal of Lower Extremity Wounds. 2025.
- Hetta HF, et al. Mesenchymal stem cell therapy in diabetic foot ulcer: An updated comprehensive review. Health Science Reports. 2024;7(8):e2036.
- Nalisa DL, et al. Stem Cell Therapy for Diabetic Foot Ulcers: Theory and Practice. Journal of Diabetes Research. 2022;2022:6028743.
- Lopes L, et al. Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds. Frontiers in Endocrinology. 2023;14:1099310.
- Cao Y, et al. Effectiveness and safety of stem cell therapy for diabetic foot: a meta-analysis update. Stem Cell Research & Therapy. 2022;13:391.
- Carstens MH, et al. Adipose-derived stem cells in diabetic foot care: Bridging clinical trials and practical application. World Journal of Diabetes. 2024;15(6):1162–1175.
- Senneville É, Albalawi Z, van Asten SA, et al. IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections. Clinical Infectious Diseases. 2023.
Comments
