Therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicles combined with injectable hydrogels in bone defect repair: a systematic review and meta-analysis of preclinical studies

BACKGROUND: Critical-sized bone defects represent a major clinical challenge due to their limited intrinsic regenerative potential and the considerable limitations of existing surgical interventions. In recent years, the integration of mesenchymal stem cell-derived extracellular vesicles (MSCEVs) with injectable hydrogels (IHs) has gained attention as a promising, cell-free regenerative approach. Although each component independently confers therapeutic benefits, their combined efficacy has not yet been thoroughly evaluated. METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidelines. Relevant studies were identified through comprehensive searches in PubMed, Embase, Scopus, Web of Science, and ProQuest. Standardized mean differences (SMD) were calculated using a random-effects model. Risk of bias was assessed using the SYRCLE tool, and sensitivity analysis, publication bias assessment, and subgroup analyses were conducted. RESULTS: A quantitative analysis of the included literature revealed that MSCEV-IHs constructs significantly enhanced bone regeneration compared with the control groups, with improved BV/TV at 4 weeks (SMD = 3.52) and 8 weeks (SMD = 6.30), BMD (SMD = 5.45), trabecular number (SMD = 7.52), and thickness (SMD = 6.46). Angiogenesis (SMD = 3.53) and osteogenic markers RUNX2 (SMD = 5.86), BMP2 (SMD = 2.57), OPN (SMD = 7.22), and OCN (SMD = 7.66) were significantly upregulated. CONCLUSION: The use of MSCEVs in combination with IHs has demonstrated substantial potential to enhance both angiogenesis and osteogenic activity in bone defects. However, the considerable heterogeneity across existing studies presents a major barrier to clinical translation. To advance this strategy toward clinical application, harmonized protocols and standardized methodologies are critically needed for consistent validation and optimization.