Zn-dihydromyricetin/Cu-dual-network hydrogel antimicrobial coating for cascade repair of bone defects

To address clinical challenges such as infection, inflammation, oxidative stress, and poor osseointegration during bone repair with titanium implants, this study developed a multifunctional hydrogel coating designated TN/GS-Cu/Zn@D. The coating utilized a gelatin methacryloyl (GelMA) / sodium alginate (SA)-Cu-dual-network hydrogel as the carrier, loaded with Zn-dihydromyricetin nanoparticles (Zn-DHM NPs), which enabled the responsive release of Cu²⁺, Zn²⁺, and dihydromyricetin (DHM) within an infected acidic microenvironment. In vitro studies demonstrated that the coating exhibited broad-spectrum antibacterial activity (based on Cu²⁺ and Zn²⁺), effectively scavenged ROS and alleviated oxidative stress (based on DHM); it also induced macrophage polarization toward the M2 phenotype (via DHM and Zn²⁺) to mediate immune regulation and promote bone formation. Concurrently, the coating directly stimulated osteogenic differentiation and angiogenesis by upregulating osteogenic and vascular-related genes and proteins (via Cu²⁺ and Zn²⁺). Transcriptomic analysis revealed that the coating synergistically regulated bone repair processes by activating signaling pathways such as PI3K-Akt. In rat subcutaneous infection and femoral defect models, the TN/GS-Cu/Zn@D coating demonstrated significant multifaceted biological effects including anti-infection, antioxidant, anti-inflammatory, pro-angiogenic, and pro-osteogenic activities, thereby effectively promoting osseointegration. This study provided a novel strategy for developing smart coatings for titanium implants with multi-microenvironment synergistic regulation capabilities.