Multiphase Mineralized Collagen Scaffold for Infected Bone Regeneration Through Oxidative Metabolism Modulation

Abstract Bone defects, especially infected ones, present significant clinical challenges. Bone tissue engineering materials exhibiting remarkable osteogenic and antimicrobial properties have increasingly been focused upon to tackle such challenges. Herein, the preparation of a multiphase mineralized collagen scaffold with copper sulfide nanoparticles (mp‐MCS) is described, which promotes osteogenesis while providing excellent antibacterial properties. mp‐MCS exhibited a bone‐like hierarchical nanostructure and modulus, with rapid copper‐ion release in the first 24 h, followed by a slower sustained release. In vitro experiments, mp‐MCS supported cell viability and enhanced osteoblastic differentiation of bone marrow‐derived mesenchymal stem cells. Mechanistically, mp‐MCS boosted mitochondrial oxidative phosphorylation to facilitate energy production via controlled release of copper ions, which serve as a cofactor for enzymes in the electron transport chain, particularly cytochrome c oxidase. Additionally, the mimetic enzyme activities of the scaffold generated reactive oxygen species, disrupting cell membranes and metabolism in bacteria, leading to bacterial death and strong antibacterial effects. Genetic sequencing confirmed that mp‐MCS interfered with bacterial physiology and key metabolic pathways. In vivo, studies using rat calvarial bone‐defect models showed significant bone regeneration under both infected and non‐infected conditions. Overall, mp‐MCS shows great promise as a clinical solution for repairing bone defects, particularly in infection‐complicated cases.