A review article entitled "Scaffold-Mediated Microenvironmental Modulation Targeting Osteoclasts for ONFH Niche Reprogramming" has been published in Research. This article systematically summarizes the latest progress in functionalized bioactive scaffolds for regulating the intraosseous microenvironment in the treatment of early osteonecrosis of the femoral head (ONFH). Innovatively, from the perspective of osteoclast heterogeneity, it proposes a novel concept of "osteoclast-centric reprogramming of the osteonecrotic microenvironment," providing a new theoretical framework and design direction for the material-based treatment of ONFH.

01 Background
Osteonecrosis of the femoral head (ONFH) is a disease caused by vascular insufficiency, which progressively leads to trabecular bone structural destruction and femoral head collapse under long-term weight-bearing conditions, predominantly affecting young and middle-aged adults. Although hip-preserving treatments such as core decompression combined with bone grafting are attempted for early-stage ONFH, clinical follow-up results indicate significant uncertainty regarding their long-term efficacy. Accumulating evidence suggests that ONFH is not merely a structural defect but a disorder of the intraosseous microenvironment characterized by imbalanced bone remodeling, impaired angiogenesis, and abnormalities in inflammation and metabolism. Conventional biomaterials and inert scaffolds primarily provide physical filling and mechanical support, failing to effectively intervene in these pathological microenvironmental changes, which limits their long-term repair outcomes. This has prompted researchers to re-examine the material-based treatment strategies for ONFH from the perspective of "microenvironment modulation."

02 Key Findings and Comprehensive Review
Centered on the pathological characteristics of the ONFH intraosseous microenvironment, this review systematically collates the research progress of functionalized bioactive scaffolds in regulating bone remodeling, angiogenesis, and immunoinflammatory responses. It focuses on summarizing the mechanisms of action and application features of different types of functionalized scaffolds, including those loaded with small-molecule drugs, growth factors, bioactive peptides, cells and their derivatives, gene delivery systems, and metal ions. Building on this, the article further introduces the cutting-edge concept of osteoclast heterogeneity, emphasizing that osteoclasts not only participate in bone resorption but also play crucial regulatory roles in angiogenesis, osteogenic coupling, and osteoimmune modulation. Under the pathological microenvironment of ONFH, the imbalance between osteoclasts in different functional states may serve as a key cellular basis driving the progressive deterioration of the intraosseous microenvironment. Based on this insight, the article proposes that precise regulation of the quantity and functional status of osteoclasts through functionalized bioactive scaffolds holds promise for the overall remodeling of the intraosseous microenvironment, thereby providing a more stable and durable biological foundation for ONFH repair (Figure 1).

03 Future Outlook
The material-based treatment of ONFH is gradually shifting from the traditional model of structural filling to a pathological mechanism-oriented model of microenvironment modulation. Future design of functionalized bioactive scaffolds should, while meeting the requirements of mechanical support, place greater emphasis on the precise regulation of cellular behaviors and microenvironmental states—especially the modulation of osteoclast functional heterogeneity—to achieve dynamic balance among bone resorption, osteogenesis, and angiogenesis. With the continuous advancement of multifunctional delivery systems, hierarchical release strategies, and research on material-cell interactions, this strategy centered on microenvironment reprogramming is expected to further improve the efficacy of hip-preserving treatments for early ONFH and provide new insights for material-based intervention research in other ischemic or metabolic bone diseases.

The complete study is accessible via DOI:0.34133/research.1027