Cell-Based Therapies for Periodontal Regeneration: A Systematic Review and Meta-Analysis with Future Implications for...

Background/Objectives: Periodontitis is a chronic inflammatory disease characterized by progressive destruction of the periodontal supporting tissues. Regenerative responses may vary according to patient-related biological characteristics, periodontal defect morphology, the local inflammatory microenvironment, cellular source, biomaterial selection, and delivery strategy. Cell-based regenerative therapies may therefore provide a biological foundation for the future development of personalized periodontal regenerative approaches. This systematic review and meta-analysis evaluated the effectiveness of cell-based therapies for periodontal regeneration and considered how the current evidence may inform future personalized regenerative strategies. Methods: A comprehensive electronic search was conducted in MEDLINE via PubMed, Web of Science, Embase, and the Cochrane Library, with additional searches performed in SciELO and Latindex, in accordance with PRISMA guidelines. Randomized and quasi-randomized controlled clinical trials evaluating cell-based regenerative therapies for periodontal defects were included. The primary outcomes were clinical attachment level (CAL) gain and probing depth (PD) reduction, while radiographic bone regeneration was considered a secondary outcome. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random-effects models. Leave-one-out sensitivity analyses were performed to assess the stability of the pooled estimates. Results: Six clinical trials were included in the qualitative synthesis, and five contributed to the quantitative analysis. Cell-based regenerative therapies showed a small, non-significant effect for CAL gain (SMD = 0.17; 95% CI: -0.12 to 0.45; I² = 0%) and PD reduction (SMD = 0.13; 95% CI: -0.22 to 0.48; I² = 33.0%). Radiographic bone regeneration showed a larger favorable effect, although statistical significance was not reached and substantial heterogeneity was present (SMD = 1.25; 95% CI: -0.08 to 2.58; I² = 88.2%). Leave-one-out analyses did not materially alter the non-significant interpretation for CAL or PD, although some variation in effect magnitude and direction was observed. Radiographic bone regeneration was more sensitive to the exclusion of individual studies. Overall, superiority of cell-based regenerative therapies over control interventions was not demonstrated. Risk-of-bias assessment indicated a low overall risk for most randomized trials, with some concerns in one trial and moderate risk in the quasi-randomized study. Conclusions: Cell-based regenerative therapies showed preliminary but inconclusive signals of benefit for periodontal regeneration. However, no statistically significant superiority over control interventions was demonstrated for CAL gain, PD reduction, or radiographic bone regeneration. Further well-designed clinical trials are required before these approaches can be considered for routine or personalized periodontal regenerative strategies.