A Universal Metal-Flavonoid Coating Strategy: Engineering Biomaterials for Diabetic Bone Regeneration

Under metabolic disorders such as diabetes, the regenerative capacity of bone tissue is compromised, characterized by hyperglycemia-induced oxidative stress, impaired osteogenesis, and dysregulated angiogenesis. These complications undermine the efficacy of conventional bone repair materials, limiting their capacity to promote effective healing. Herein, we developed a metal-flavonoid functionalized coating strategy that integrates osteogenic and angiogenic metal ions with natural antioxidant flavonoids. Leveraging their chelation ability and strong surface affinity, a one-pot approach is established to endow conventional bone repair materials with tailored biofunctions that modulate the diabetic bone microenvironment and facilitate regeneration. Among the tested candidates, copper-quercetin (CQ) coating is screened as the optimal formulation owing to its potent antioxidative, osteoinductive, and pro-angiogenic properties under high-glucose (HG) conditions. Conventional bone repair materials (e.g., β-tricalcium phosphate, β-TCP) modified with this coating significantly ameliorated oxidative stress, restored osteogenesis, and rescued angiogenesis impaired by persistent hyperglycemia. In diabetic rats, CQ-coated β-TCP (β-TCP@CQ) accelerated bone healing by 1.68-fold compared to unmodified controls. Mechanistically, the CQ coating activated the ATP7A/SOD3/FLT1 axis to restore copper homeostasis in bone marrow mesenchymal stem cells while stimulating the PI3K-Akt pathway to enhance osteogenic differentiation. Moreover, the coating exhibited broad versatility across multiple biomaterial compositions (metals, ceramics, polymers, and composites) and structures (2D discs, 3D scaffolds). This metal-flavonoid coating strategy demonstrated feasibility and scalability, while also providing a mechanistic foundation and technical platform for the effective use of conventional bone repair materials in complex pathological contexts.