Immune-modulating copper-doped bioactive glass-based injectable hydrogel for periodontitis therapy

Periodontitis, a chronic inflammatory disorder driven by microbial dysbiosis and aberrant host immune responses, poses a significant challenge to periodontal tissue regeneration owing to persistent infection and impaired osteogenesis.

Herein, we engineered an injectable hydrogel (denoted Cu@BG-HA) via borate ester crosslinking of copper-doped mesoporous bioactive glass nanoparticles (Cu@BG, 480 nm) with hyaluronic acid, aiming to concurrently address antibacterial, immunomodulatory, and osteogenic deficits in the periodontal microenvironment.

The Cu@BG-HA hydrogel was synthesized through dynamic borate ester bond formation between Cu@BG nanoparticles and HA polymer networks. The physicochemical properties, ion release kinetics, and therapeutic efficacy were systematically characterized using in vitro models of bacterial infection, macrophage polarization, and osteoblast differentiation.

The Cu@BG-HA hydrogel demonstrated sustained Cu²⁺ release over 24 days, achieving eradication rates of 99.8% ± 3.2% against Staphylococcus aureus and 98.6% ± 1.7% against Porphyromonas gingivalis. Under lipopolysaccharide/interferon-γ (LPS/IFN-γ) stimulation, the hydrogel effectively orchestrated macrophage phenotype switching from pro-inflammatory M1 toward anti-inflammatory M2 states in RAW264.7 cells. Furthermore, Cu@BG-HA markedly potentiated osteogenic differentiation of MC3T3-E1 pre-osteoblasts, evidenced by 1.8- and 1.7-fold enhancements in alkaline phosphatase activity and mineralized nodule formation, respectively, relative to control conditions.

Collectively, these findings establish Cu@BG-HA as a multifunctional, minimally invasive therapeutic platform that integrates potent antibacterial, immunomodulatory, and pro-osteogenic functionalities. This strategy offers substantial translational potential for periodontitis management and may be extendable to other inflammatory osteolytic pathologies.