Molecular Pathogenesis of and Regenerative Strategies for Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a progressive, multifactorial bone disease characterized by ischemia-induced osteocyte death, microenvironmental imbalance, and failed tissue regeneration. According to recent advances in pathophysiological understanding, vascular injury, oxidative stress, and inflammatory storms form a pathogenic cascade leading to osteogenic dysfunction, adipogenic lineage drift of mesenchymal stem cells (MSCs), and epigenetic alterations that exacerbate bone degeneration. Despite improvements in early detection, traditional interventions-including bisphosphonates, hyperbaric oxygen therapy, and surgical decompression-have limited efficacy, particularly in the mid-to-late stages. This review systematically synthesizes emerging regenerative approaches across three domains: (1) Cellular and molecular therapies: Autologous MSC transplantation, exosomes, and apoptotic extracellular vesicles restore osteogenesis, modulate immunity, and promote angiogenesis, while gene-editing technologies such as CRISPR/Cas9 enhance MSC functionality. (2) Nanobiomaterial synergy: Enzyme-mimetic nanozymes and multifunctional polymeric scaffolds improve lesion targeting, reactive oxygen species clearance, and microenvironmental regulation. (3) Advanced bioengineering: Organoid models and 3D-bioprinted living joint prostheses enable the integration of vascularization, mechanical support, and precise drug delivery, representing transformative strategies in personalized repair. Together, these innovations highlight a future paradigm shift from passive support to active, mechanism-targeted regeneration, offering new hope for structural and functional reconstruction in ONFH. Multidisciplinary integration-bridging materials science, stem cell biology, and digital medicine-will be essential for successfully developing functional cures.