Scaffold-Mediated Microenvironmental Modulation Targeting Osteoclasts for ONFH Niche Reprogramming

Abstract

Osteonecrosis of the femoral head (ONFH) is a progressive and disabling condition characterized by bone microenvironmental dysregulation, including imbalanced bone remodeling, impaired angiogenesis, and dysregulated osteoimmunity. In hip-preserving surgeries for early-stage ONFH, the most common approach is core decompression with grafting. Although widely used synthetic scaffolds, such as ceramics and metals, provide structural support or partially improve blood supply, they cannot counteract the complex pathological microenvironment of ONFH, resulting in poor long-term efficacy. To address these limitations, bioactive scaffolds incorporating functional agents have been developed to modulate pathological abnormalities and improve regenerative outcomes. This review summarizes recent advances in bioactive scaffolds for ONFH, focusing on systems functionalized with small molecules, growth factors, stem cells, exosomes, and metal ions that regulate cellular behaviors and signaling pathways in ONFH microenvironment. Emerging evidence indicates that osteoclasts exhibit heterogeneity, influencing resorptive, angiogenic, osteogenic, and immunoregulatory processes. Building on these insights, we discuss osteoclast heterogeneity and its potential relevance to ONFH, proposing that future scaffold strategies may harness osteoclast-mediated regulation to restore the osteonecrotic niche. By integrating mechanistic insights with material design, bioactive scaffolds provide a framework for targeted microenvironmental modulation and functional bone regeneration in ONFH.