# Synergistic potentials of small extracellular vesicles, biomaterials, and 3D bioprinting in periodontal regeneration: a scoping review

## TL;DR

This review explores how small extracellular vesicles, when combined with biomaterials and 3D bioprinting, can help regenerate periodontal tissues affected by periodontitis.

## Contribution

The paper provides a scoping review on the translational potential of sEVs in periodontal regeneration, integrating clinical and preclinical findings with 3D bioprinting.

## Key findings

- sEVs from MSCs and immune cells show promise in promoting osteogenesis, angiogenesis, and immunomodulation in periodontal regeneration.
- 3D bioprinted sEV constructs improve localized regenerative outcomes in preclinical models.
- Current research highlights the need to address technical and biological challenges for clinical translation of sEV-based therapies.

## Abstract

Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of both soft (gingiva and periodontal ligament) and hard (cementum and alveolar bone) supporting tissues. The complex periodontal microenvironment often limits the effectiveness of current clinical treatments in achieving functional tissue regeneration. Although mesenchymal and immune cell-based therapies hold promise, concerns related to cell viability and immune compatibility limit their clinical translation. As a natural secretome, small extracellular vesicles (sEVs) are cell-secreted nanoparticles that deliver bioactive molecules for cell-to-cell communication to modulate immune response and promote tissue regeneration. To assess the translational readiness of sEVs therapy, this scoping review first outlines the current clinical trials of mesenchymal stem cells (MSCs)-sEVs in periodontitis, followed by a transition to preclinical application of integrating sEVs with biomaterial scaffolds to enhance localized regenerative outcomes. We then analyzed eight preclinical studies utilizing 3D bioprinted MSCs-sEVs/human umbilical vein endothelial cells-sEVs (or immune cell-derived sEVs) constructs in bone and vasculature regeneration models, and one study related to in vitro periodontal regeneration. These constructs exhibited improved outcomes in osteogenesis, angiogenesis, and immunomodulation, supporting their potential for future translational applications in periodontal therapy. Given the early stage of bioprinted sEVs constructs in periodontitis, we outline critical research gaps and potential future directions to overcome current technical and biological challenges. Together, this review demonstrated the translational trajectory of sEV-based strategies for periodontal regeneration. It offers a potential roadmap for utilizing sEV-based periodontal regeneration across clinical, preclinical, and biofabrication applications, highlighting their potential as next-generation, cell-free therapeutics in regenerative periodontics.