Stem Cell-Based and Stem Cell-Related Regenerative Therapies for Pure Venous Ulcers: A Systematic Review

Previous systematic reviews of stem cell-based therapies for lower limb ulcers have largely focused on arterial, diabetic or mixed-aetiology ulcers, while evidence in strictly defined pure venous ulcers remains scarce. This systematic review evaluated the efficacy and safety of stem cell-based and stem cell-related regenerative therapies for pure venous ulcers. PubMed, Embase, Web of Science and the Cochrane Library were searched up to February 2026 for comparative clinical studies. Studies involving arterial, diabetic, mixed or non-venous ulcers, non-comparative designs or insufficiently extractable data were excluded. Three studies involving 43 patients were included, comprising two randomised controlled trials and one non-randomised comparative study. Interventions included autologous bone marrow-derived mesenchymal stem cells in fibrin spray, hair follicle-containing punch grafts and antlerogenic stem cell extract. In one randomised double-blind pilot trial, mesenchymal stem cells in fibrin spray accelerated linear healing by approximately 10-fold compared with saline spray and fibrin spray alone (p < 0.01). Another randomised trial found greater ulcer area reduction at 18 weeks in hair follicle-treated areas than in control areas (75.15% [SD 23.03] vs. 33.07% [SD 46.17], p = 0.002). The non-randomised study reported significant improvements in wound area, circumference and healing-related indices, although Ki-67 expression did not differ significantly. No major treatment-related safety concerns were reported, although adverse-event data were limited. Current evidence suggests potential benefit, but findings remain preliminary because of small samples, heterogeneous interventions and variable outcome definitions. Larger standardised studies are needed. Trial Registration: CRD420261304878.