Objective To evaluate the potential efficacy of mesenchymal stem cells (MSCs) in periodontal regeneration in humans on the following main outcomes: clinical attachment level (CAL), probing depth (PD), and gingival recession (GR). Background The clinical application of stem cells in periodontal regeneration has begun in recent years, but clinical practices are not yet standardized and no recommendations are available at this time. Methods Electronic database searches and hand searches were conducted. All types of studies, case series, and case reports were qualitatively described. Double‐blind randomized controlled trials (RCTs) evaluating MSCs in periodontal regeneration were included in a meta‐analysis if they compared administration of MSCs vs application of stem cell‐free therapy in the control group, in healthy patients with periodontal defects, with a minimum of three mo of follow‐up. Results Fifteen reports were included in qualitative analysis, involving 123 patients and 158 periodontal defects. Only two small RCTs at high risk of bias, with a total of 59 patients and 70 periodontal defects, were included in the meta‐analysis. A small but significant difference between test and control groups was found for CAL at three mo (−0.90 mm, 95% CI [−1.51; −0.29]), but not for PD and GR. Conclusion Low‐quality evidence suggests that MSC‐based therapy may have a small impact on periodontal regeneration. However, due to the monocentric character, the small sample size, and potential heterogeneity across the two included RCTs, these results must not be considered as definitive. High‐quality RCTs are needed before any clinical use of MSCs in periodontal regeneration.

Mesenchymal stem cells (MSC) are involved in the regeneration of the different missing or compromised periodontal tissues. MSC‐derived small extracellular vesicles (sEV) have recently been explored as a favorable substitution for stem cell therapy, as they are capable of producing therapeutic effects comparable to those of their parent cells, with advantages over cell therapy. The aim of this review is to evaluate the use of mesenchymal stem cells (MSC)‐derived sEV as cell‐free therapy in periodontal regeneration. A review of the scientific literature on sEV and their use in periodontal regeneration was performed. The main characteristics of sEV are described, and their mechanisms of action and potential biological effects in periodontal regeneration are studied. A summary of existing preclinical studies conducted in animals is performed. The results indicate that sEV derived from MSC are emerging as a promising new therapeutic tool in the field of periodontal regeneration and may become an ideal therapeutic option. In this review, we have summarized recent advances in this regard in order to better understand this newly emerging treatment. First results in vivo are promising and show a favorable potential for cell‐free therapy in periodontal regeneration.