Beyond bioactivity: Chitosan macromolecular coatings on titanium surfaces drive osseointegration and immune suppression through targeted epigenetic regulation.

OBJECTIVES: To address titanium (Ti) implant failures caused by inadequate osseointegration and persistent inflammation by developing a novel dual-action coating. This coating utilizes a chitosan (CH) matrix to deliver epigenetic pharmaceuticals, 5-azacytidine (AZ) and trichostatin A (TR), onto Ti surfaces (AZ/TR-CH@TI). MATERIALS AND METHODS: Coating morphology and successful drug integration were validated via FTIR and SEM. Drug release kinetics were evaluated in physiological (pH 7.4) and inflammatory (pH 5.5) conditions over 48 hr. In vitro assessments utilizing MG63 osteoblast-like cells evaluated biocompatibility, anti-inflammatory responses, and osteogenic differentiation using real-time gene expression analysis, functional assays (alkaline phosphatase, Alizarin red), and immunofluorescence. RESULTS: The composite exhibited an intelligent, pH-responsive controlled drug release. AZ/TR-CH@TI significantly enhanced biocompatibility, achieving 124.6% cell proliferation and 89.3% wound closure compared to uncoated controls. Gene expression analysis demonstrated potent anti-inflammatory effects, with TNF-α and IL-6 reduced to 0.31- and 0.35-fold, respectively. Concurrently, it augmented osteogenesis, up-regulating RUNX2 (2.60-fold), BMP2 (4.87-fold), and type-1 collagen (4.15-fold). Assays unequivocally validated comprehensive osteogenic differentiation and significant mineralization. CONCLUSION: This macromolecular epigenetic drug-loaded CH coating effectively mitigates inflammation while simultaneously stimulating bone formation. The AZ/TR-CH@TI system presents a highly promising therapeutic approach to improve Ti osseointegration for clinical orthopaedic and dental applications.