Mesenchymal stem cells-derived small extracellular vesicles and apoptotic extracellular vesicles for wound healing and skin regeneration: a systematic review and meta-analysis of preclinical studies.

Summary

This preclinical systematic review and meta-analysis of 83 studies finds that MSC-derived EVs improve wound closure, collagen deposition, and revascularization, with ApoSEVs outperforming ApoBDs and sEVs for closure/collagen while sEVs favor revascularization. Subcutaneous administration and ADSC sources were associated with better outcomes, but substantial methodological heterogeneity highlights the need for standardization before clinical translation.

Key Findings

• Across 83 preclinical studies, MSC-EVs improved wound closure, collagen deposition, and revascularization in diabetic and non-diabetic models.
• ApoSEVs outperformed ApoBDs and sEVs for wound closure and collagen deposition; sEVs outperformed ApoEVs for revascularization.
• Subcutaneous injection achieved greater improvements in closure, collagen, and revascularization than dressing/covering.
• ADSC-derived EVs yielded the best wound closure and collagen deposition; BMMSC-derived EVs were superior for revascularization.
• Marked heterogeneity in EV collection, isolation, storage, modification, dosing, route, and frequency underscores urgent need for standardization.

Clinical Implications

While not yet ready for clinical use, findings support prioritizing subcutaneous delivery and ADSC-sourced EVs in early-phase trials, with attention to outcome domains (closure, collagen, revascularization) matched to EV subtype.

Limitations

• High methodological heterogeneity across EV preparation, dosing, and administration protocols.
• Preclinical animal data limit direct clinical generalizability and may be subject to publication bias.

Future Directions

Develop consensus standards for EV characterization and dosing, and design phase I/II trials prioritizing subcutaneous delivery and ADSC sources with stratification by wound type and comorbidities.