# Safety Assessment of Extracellular Vesicle-Based Therapy in Regenerative Dentistry

## TL;DR

This review explores the safety and effectiveness of using extracellular vesicles from stem cells to regenerate dental tissues, highlighting their potential and remaining challenges.

## Contribution

The paper provides a comprehensive analysis of EV-based therapies in regenerative dentistry, emphasizing safety, efficacy, and standardization needs.

## Key findings

- EVs from dental pulp stem cells and mesenchymal stem cells promote tissue regeneration via key signaling pathways.
- Preclinical studies show EVs enhance odontogenic differentiation, angiogenesis, and bone repair with minimal adverse effects.
- Variations in EV isolation methods impact purity and functional reproducibility, highlighting standardization needs.

## Abstract

Extracellular vesicle (EV)-based therapies have emerged as promising, cell-free approaches for dental tissue regeneration. This narrative review integrates mechanistic insights, therapeutic efficacy data, and safety and delivery considerations from in vitro and in vivo studies to elucidate the molecular mechanisms by which EVs, particularly those from dental pulp stem cells (DPSCs) and mesenchymal stem cells (MSCs), drive regenerative processes via key signalling axes (PI3K/Akt, MAPK, BMP/Smad, and Hedgehog). Preclinical studies demonstrate that unmodified and engineered EVs enhance odontogenic differentiation, angiogenesis, bone repair, and immunomodulation in models of pulp regeneration, alveolar bone defects, osteonecrosis, and periodontitis. Isolation and purification methodologies were also evaluated, comparing ultracentrifugation, size-exclusion chromatography, and density-cushion approaches, and discussing how protocol variations affect EV purity, dosing metrics, and functional reproducibility. Early-phase clinical evaluations report only low-grade transient adverse events, underscoring a generally favourable safety profile. Despite these encouraging results, significant challenges remain: heterogeneity in EV cargo composition, lack of standardised potency assays, and incomplete long-term safety data. The review highlights the urgent need for rigorous, harmonised regulatory frameworks and robust quality control measures to ensure that EV-based modalities can be translated into safe, effective, and reproducible therapies in regenerative dentistry.