Hamid, Rayan2026-07-012026-07-012026https://hdl.handle.net/10566/24787Background: Periodontal ligament stem cells (PDLSCs) are a promising cell source for periodontal regeneration due to their capacity to differentiate into cementoblastic, osteoblastic, and ligament-forming lineages. Various biological, pharmacological, and scaffold-based enhancement strategies have been proposed to augment their regenerative potential in preclinical models; however, the available animal evidence has not been systematically synthesised. Objective: To evaluate the effectiveness of enhancement strategies designed to improve PDLSC-mediated periodontal regeneration in preclinical animal studies. Methods: A systematic review was conducted in accordance with PRISMA guidelines and prospectively registered in Prospero CRD42022321772. Electronic searches of PubMed, Web of Science, ScienceDirect, EBSCOhost, Scopus, Cochrane Central Register of Controlled Trials, WHO International Clinical Trials Registry Platform (ICTRP), and Scispace were performed up to August 2025. Preclinical animal studies investigating enhancement strategies applied to PDLSCs for periodontal regeneration were eligible. In vitro studies, human clinical trials, studies without enhancement interventions, and non-English publications were excluded. Two reviewers independently screened studies using Covidence and extracted data using a predefined form. Risk of bias was assessed using the SYRCLE tool. Due to methodological heterogeneity, a qualitative synthesis was undertaken. Results: Six out of 513 met the inclusion criteria. Enhancement approaches included platelet-rich plasma, methylsulfonylmethane, harmine, metformin, and metformin-integrated scaffolds. Enhanced PDLSC constructs demonstrated significantly greater bone, cementum, and periodontal ligament formation compared with unenhanced PDLSCs. Interventions were not directly compared; therefore, relative superiority could not be determined. Limitations included small sample sizes, heterogeneous defect models, short follow-up periods, and inconsistent reporting of allocation concealment and blinding Conclusion: Enhancement strategies appear to improve PDLSC-mediated periodontal regeneration in preclinical models. However, the current evidence base remains limited and methodologically heterogeneous. Further well-designed animal studies are required before translational implications can be reliably assessed.enPeriodontal RegenerationPeriodontal Ligament Stem CellsBiomaterialsAnimal ModelsEnhancement MaterialsThesis