Regenerative Potential of Exosomes from 3D Spheroid-Cultured Stem Cells Compared with 2D Culture in Dentin-Pulp Regeneration: A Systematic Review.

Abstract

Purpose: This systematic review aimed to evaluate the current preclinical evidence on exosomes derived from three-dimensional stem cell culture systems and their direct or indirect relevance to dentin-pulp regeneration. Exosomes derived from stem cells have emerged as promising mediators of tissue regeneration because of their ability to transfer bioactive molecules that regulate cellular communication and tissue repair. Recent studies suggest that exosomes obtained from three-dimensional (3D) spheroid cultures may exhibit enhanced regenerative properties compared with those derived from conventional two-dimensional cultures.

Methods: A systematic review was conducted following the PRISMA 2020 guidelines. Electronic searches were performed in PubMed, Scopus, and ProQuest databases to identify relevant studies investigating exosomes derived from 3D cell culture systems with potential relevance to dentin-pulp regeneration. Studies were screened according to predefined inclusion and exclusion criteria. Data extraction focused on cell sources, exosome isolation methods, characterization techniques, and biological effects related to dental pulp regeneration.

Results: Ten studies met the inclusion criteria. The included studies demonstrated that exosomes derived from 3D spheroid cultures may enhance angiogenesis, support odontogenic differentiation, reduce inflammatory responses, and promote regenerative tissue repair. Several studies also reported increased expression of regenerative markers and improved cellular proliferation when compared with exosomes derived from conventional two-dimensional cultures. However, only a limited number of studies directly investigated dentin-pulp-related outcomes, while several provided indirect mechanistic evidence from non-dental preclinical models.

Conclusion: Exosomes derived from three-dimensional culture systems show promising potential as a cell-free therapeutic strategy for dentin-pulp regeneration. These vesicles may improve tissue repair through enhanced biological activity. However, the current evidence remains mainly preclinical, heterogeneous, and partly indirect. Further standardized experimental studies and clinical investigations are required to validate their translational application in regenerative endodontic therapy.