Stem cell and extracellular vesicle therapies for wound healing: An umbrella review of predominantly diabetic and preclinical evidence.

Abstract

Chronic and complex skin wounds, including diabetic ulcers and burns, represent a major clinical challenge with substantial morbidity and healthcare costs. Regenerative approaches have evolved from stem cell-based therapies toward stem cell-free strategies, particularly mesenchymal stroma/stem cell-derived extracellular vesicles (MSC-EVs). However, the relative strength, consistency, and translational readiness of these approaches remain unclear. The aim of this study is to synthesize and critically appraise evidence from systematic reviews and meta-analyses on cell-based and cell-free regenerative therapies for wound healing, with emphasis on clinical relevance, methodological quality, and recent developments. An umbrella review was conducted in accordance with PRISMA 2020 guidance. PubMed/MEDLINE, Scopus, and Web of Science were searched for systematic reviews and meta-analyses published in English within the last 5 years. Eligible reviews evaluated cell-based therapies and/or extracellular vesicle-based interventions for skin wound healing in clinical and/or animal models. Methodological quality was assessed using AMSTAR-2, and overlap of primary studies was evaluated using the corrected covered area (CCA). Seven systematic reviews and meta-analyses were included, encompassing both clinical and preclinical evidence. Notably, the majority of included evidence was derived from diabetic wound models, particularly in preclinical animal studies. Cell-based therapies demonstrated clinically relevant benefits in specific settings, such as autologous skin cell suspensions for burns and biologic skin substitutes for diabetic foot ulcers, although certainty of evidence was low to moderate. In contrast, MSC-EVs showed large and consistent effects on wound closure, angiogenesis, collagen deposition, and inflammatory modulation in preclinical models. No randomized human trials of EV-based wound therapies were identified. Current evidence suggests a paradigm shift toward stem cell-free regenerative strategies in wound healing. While cell therapies have limited but established clinical roles, MSC-EVs offer strong preclinical efficacy and translational potential. Standardization, regulatory alignment, and well-designed clinical trials are required to enable safe clinical implementation.