Dental Pulp Stem Cell-Derived Extracellular Vesicles for Dentin-Pulp Complex Regeneration: A Systematic Review and Meta-Analysis.

OBJECTIVES: To systematically examine and quantitatively synthesize preclinical studies assessing the impacts of dental pulp stem cell-derived extracellular vesicles (DPSC-EVs) on dentin-pulp complex (DPC) regeneration and related regenerative outcomes. DATA: Preclinical in-vitro and in-vivo studies assessing the effects of DPSC-EVs on regenerative outcomes associated with DPC regeneration, including odontogenic differentiation, immunoregulation, extracellular matrix (ECM) remodeling, angiogenesis, and neurovascular regeneration. SOURCES: Electronic searches were conducted in PubMed, Scopus, and Web of Science, without limitations on publication year or language. STUDY SELECTION: Preclinical studies assessing DPSC-EVs for DPC regeneration were selected via duplicate removal, title/abstract screening, and full-text evaluation following PRISMA guidelines. RESULTS: In-vitro, EV exposure upregulated BMP2 (5.2-fold), DSPP (4.9-fold), OCN (4.4-fold), DMP1 (2.7-fold), RUNX2 (2.0-fold), and ALP (2.3-fold) compared to controls. Angiogenic effect was significantly improved, with VEGF upregulated by nearly 2.5-fold and endothelial junction development by 2.9-fold. Additionally, EV treatment alleviated pro-inflammatory cytokine expression by 44% while elevating anti-inflammatory signaling almost 2.0-fold. In-vivo, EV treatment significantly enhanced odontogenic regeneration, angiogenesis, ECM formation, and neurovascular tissue development, with COL1A1 and DSPP exhibiting the highest reported regenerative outcomes. Odontogenically triggered, hypoxia-treated, and engineered EVs consistently showed superior biological functionality compared to traditional EVs. CONCLUSIONS: Existing preclinical evidence indicates that DPSC-EVs exhibit substantial capacity for DPC regeneration. Nonetheless, significant methodological heterogeneity and the lack of clinical evidence presently preclude conclusions concerning clinical effectiveness. Standardization of EV manufacturing, characterization, dosing, and translational assessment remains necessary before clinical implementation can be considered. CLINICAL SIGNIFICANCE: Existing preclinical evidence reflects that DPSC-EVs improve several biological pathways related to DPC regeneration, such as odontogenic differentiation, angiogenesis, ECM deposition, and immunoregulation. These outcomes support continued translational research of DPSC-EVs as a promising cell-free regenerative approach; nonetheless, clinical implementation awaits validation via large-animal and human clinical studies. REGISTRATION: Open Science Framework registration number: 10.17605/OSF.IO/MTP9.