Harnessing the Therapeutic Potential of Cell Secretomes and Extracellular Vesicles for Craniofacial Regenerative Applications.

Although tissue engineering and cell therapy have been widely investigated as promising regenerative modalities, their clinical translation has partly been limited by a lack of standardization, high costs, and regulatory barriers. Recently, cell-free therapies (CFT) in the form of cell secretomes [conditioned media (CM)] and extracellular vesicles (EVs) have emerged as viable alternatives to cell therapies. However, much of the evidence is based on preclinical studies. This scoping review aimed to summarize the current evidence for using human-derived CFT, with a focus on EVs, for craniofacial regeneration. Based on predefined inclusion criteria and a systematic search covering three electronic databases (MEDLINE, EMBASE, Web of Science), 122 animal studies (n = 27 CM, n = 95 EVs), and 4 clinical studies (n = 2 CM, n = 2 EVs), mostly reporting on bone and periodontal regeneration, were included. The use of oral-derived CFT, particularly from the periodontal ligament, dental pulp, and gingiva, was frequently reported. A wide range of pre-conditioning strategies, dosages, and delivery methods were tested. The preclinical data revealed a clear adjunctive benefit of CFT with biomaterial scaffolds versus scaffolds alone for bone and periodontal regeneration. Limited clinical data based on small patient groups confirmed the safety and feasibility of CFT, although robust evidence for efficacy is lacking. Finally, several issues related to the clinical translation of CFT have been highlighted for future consideration.