Functionalized ZIF-8 modulates the oxidative stress microenvironment in osteoporosis to enhance osseointegration

The failure of titanium implants in osteoporotic patients is frequently attributed to a disrupted microenvironment characterized by excessive oxidative stress and an imbalance between bone formation and resorption. To address this, we engineered a functionalized composite scaffold (Ti/Gel/ZM) by incorporating melatonin-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles into a gelatin methacryloyl (GelMA) hydrogel on a 3D-printed titanium alloy scaffold. This scaffold was designed to provide a pH-responsive release of zinc ions and melatonin, triggered by the acidic osteoporotic microenvironment. In vitro assays demonstrated that the scaffold effectively scavenged reactive oxygen species (ROS), thereby restoring mitochondrial membrane potential and rescuing the osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) via the upregulation of Runx2, ALP, BMP2 and COL1. Simultaneously, the composite scaffold significantly inhibited RANKL-induced osteoclastogenesis in RAW264.7 cells. In vivo evaluation in an ovariectomized rat model confirmed that the Ti/Gel/ZM scaffold promoted rapid osseointegration and trabecular bone regeneration, as evidenced by enhanced bone volume fraction (BV/TV) and trabecular thickness. These results suggest that the Ti/Gel/ZM composite scaffold is a promising candidate for improving the osseointegration of titanium alloy implants in osteoporotic bone.