6-Bromoindirubin-3′-oxime Promotes Osteogenic Differentiation of Periodontal Ligament Stem Cells and Facilitates Bone Regeneration in a Mouse Periodontitis Model

Effective bone tissue engineering is important to overcome the unmet clinical challenges of periodontal tissue regeneration. Successful bone tissue engineering comprises three key factors: stem cells, growth factors, and scaffolds. 6-Bromoindirubin-3'-oxime (BIO) is an inhibitor of glycogen synthase kinase-3 (GSK-3) that can activate the Wnt signaling pathway by enhancing β-catenin activity. In this study, the effects of BIO on the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs) were investigated. Poly(lactic-co-glycolic acid) (PLGA) and hyaluronic acid (HA) emerged as promising biomaterials; thus, we developed a novel HA hydrogel embedded with BIO-encapsulated PLGA microspheres and injected the formulation into the gingival sulcus of mice with experimental periodontitis. The release speed of this system was fast in the first week and followed a sustained release phase until week 4. In vivo experiments showed that this PLGA-BIO-HA hydrogel system can inhibit periodontal inflammation, promote bone regeneration, and induce the expression of bone-forming markers alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteocalcin (OCN) in a mouse periodontitis model. Therefore, this PLGA-BIO-HA hydrogel system provides a promising therapeutic strategy for periodontal bone regeneration.