Regenerative Applications and Performance of Periodontal Ligament Stem Cells: A Comprehensive Review of In Vivo Studies

Periodontal ligament stem cells (PDLSCs) represent a promising cell source for true periodontal regeneration due to their ability to form bone, cementum, and functional ligament. This review critically synthesised twelve in vivo studies (rats = 5, pigs = 2, dogs = 2, sheep = 2, one human trial) evaluating PDLSC transplantation for periodontal defects. A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library (to May 2025) identified 358 records, of which 12 met predefined inclusion criteria. Data extraction encompassed cell source, scaffold, dose, follow-up, and quantitative regenerative outcomes. Nine studies reported cell doses (5 × 105–2 × 107 cells) and six PDLSC regeneration rates (33–100%). After normalisation for host mass, effective delivery ranged from 105 to 106 cells·kg−1, with optimal outcomes typically above 105 cells·kg−1. PDLSC transplantation consistently enhanced alveolar bone, cementum, and periodontal-ligament regeneration compared with scaffold-alone or untreated controls, with the highest outcomes obtained using biocompatible scaffolds such as Hydroxyapatite/Tricalcium Phosphate (HA/TCP), Gelfoam, or amniotic membrane. Both autologous and allogeneic PDLSC achieved equivalent performance and excellent safety, while xenogeneic models confirmed immune tolerance. Despite encouraging results, the evidence remains preliminary—most studies were short-term and small-scale, and only one randomised human trial has been published. Standardisation of cell preparation, scaffold selection, dosing (absolute and mass-normalised), and follow-up is urgently needed. Future research should include Good Manufacturing Practice (GMP)-compliant clinical trials and mechanistic studies on PDLSC differentiation, paracrine signalling, and exosome-mediated effects to consolidate their translational potential for predictable periodontal regeneration.