Multifunctional Scaffold Comprising Metal–Organic Framework, Hydrogel, and Demineralized Bone Matrix for the Treatment of Steroid‐Induced Femoral Head Necrosis

Abstract Overproduction of reactive oxygen species (ROS) results in oxidative stress, a critical factor in the pathogenesis of steroid‐induced osteonecrosis of the femoral head (SONFH). Excess ROS not only hinders the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells (BMSCs) but also impairs mitochondrial structure and function, resulting in irreversible cellular damage. Herein, a biomimetic multifunctional scaffold comprising Zn‐modified metal–organic framework 818 (Zn‐MOF‐818) loaded with deferoxamine (DFO), gelatin methacryloyl (GelMA) hydrogel, and demineralized bone matrix (DBM) is shown to scavenge excess ROS, promote angiogenesis, and regulate immunity. Introduced Zn significantly enhances the superoxide dismutase‐ and catalase‐like activities of MOF‐818, which increases ROS‐scavenging efficiency. Zn‐MOF‐818 disrupts the vicious intracellular cycle of mitochondrial dysfunction and ROS accumulation by enhancing mitophagy, stabilizing mitochondrial function, and upregulating antioxidant genes. Additionally, Zn‐MOF‐818 facilitates the polarization of macrophages toward the M2 phenotype and alleviates inflammation, creating an advantageous immune microenvironment for osteogenic differentiation of BMSCs. The release of DFO, an activator of the HIF‐1 α pathway, and Zn 2+ from Zn‐MOF‐818, along with the secretion of various cytokines from DBM (such as bone morphogenetic proteins and vascular endothelial growth factors), enhances angiogenesis and osteogenesis. This scaffold targets multiple factors concurrently, offering a promising new approach for treating SONFH.