Extracellular Matrix-Based and Extracellular Matrix-Bioinspired Scaffolds for Extracellular Vesicle Delivery in Dental Pulp Regeneration: A Narrative Review
Current findings support the feasibility of scaffold-assisted EV delivery for regenerative endodontics, but important challenges remain, including standardization of EV production and characterization, scalable manufacturing, regulatory approval, and demonstration of long-term safety and functional pulp–dentin complex regeneration.
Abstract
Vital pulp therapy aims to preserve pulp vitality by stimulating reparative processes. However, conventional approaches often result in incomplete tissue regeneration. Extracellular vesicles (EVs) have emerged as promising cell-free therapeutic agents because of their ability to regulate angiogenesis, odontogenesis, and immune responses through the transfer of bioactive molecules. Despite their significant regenerative potential, the clinical application of EVs remains limited by rapid clearance, insufficient local retention, and uncontrolled release following administration. To address these challenges, various extracellular matrix (ECM)-based and ECM-bioinspired scaffolds have been developed as delivery platforms. These scaffolds can provide structural support and enable controlled, localized release of EVs. This narrative review critically evaluates the current evidence regarding scaffold systems as EV delivery platforms for dental pulp regeneration, comparing their biological performance, methodological quality, and translational potential. Across the available studies, scaffold-assisted EV delivery consistently enhanced angiogenesis, odontogenic differentiation, mineralization, and immunomodulation; however, the evidence remains preclinical and is characterized by substantial heterogeneity regarding EV source, isolation and characterization methods, scaffold composition, experimental models, and outcome assessment. Current findings support the feasibility of scaffold-assisted EV delivery for regenerative endodontics, but important challenges remain, including standardization of EV production and characterization, scalable manufacturing, regulatory approval, and demonstration of long-term safety and functional pulp–dentin complex regeneration. Further well-designed translational and clinical studies will be essential before routine clinical implementation can be considered.
Extracellular vesicles (EVs) are nanoscale, membrane-bound particles released by most cell types and play essential roles in intercellular communication. By transporting proteins, lipids, and nucleic acids, they regulate inflammation, angiogenesis, immune responses, and tissue regeneration. Their biocompatibility and ability to deliver targeted molecular cargo make them promising diagnostic and therapeutic tools. In dentistry, EVs support periodontal repair, dentin–pulp regeneration, bone healing, and implant integration. They are also valuable as salivary biomarkers for oral and systemic diseases. Beyond dentistry, EVs are being explored in oncology, cardiovascular repair, neurology, and regenerative medicine as versatile cell-free therapeutic platforms. This review provides a comprehensive overview of the biology, biogenesis, physiological functions, and mechanisms of action of extracellular vesicles, with a particular focus on their emerging applications in tissue regeneration. A literature search was conducted using PubMed and Google Scholar databases for studies published between 2010 and 2025. Original research articles, review papers, and relevant book chapters published in English were included. EVs have emerged as powerful cell-free mediators of regeneration, capable of orchestrating osteogenesis, angiogenesis, immunomodulation, and tissue repair across maxillofacial structures. Their diverse cargo of miRNAs, proteins, and growth factors enables precise modulation of cellular signaling pathways essential for healing. Current evidence highlights their promising applications in periodontal, pulp–dentin, and craniofacial bone regeneration, as well as their diagnostic value through salivary biomarkers. Continued advancements in EVs standardization, large-scale production, and clinical translation will be critical for integrating EVs-based therapies into future regenerative dentistry and maxillofacial medicine.
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