Biomaterials targeting senescent cells for bone regeneration: State-of-the-art and future perspectives

Abstract

Bone defect treatment remains a significant clinical challenge, further exacerbated by the demographic transition toward an aging society. In elderly populations, the increased proportion of senescent cells emerges as a fundamental determinant that substantially compromises regenerative outcomes. In senescent bone tissues, the progressive accumulation of senescent cells compromises bone regenerative capacity through multifaceted mechanisms, encompassing both intrinsic functional impairment of senescent cells and the far-reaching impact of the senescence-associated secretory phenotype (SASP) on the surrounding cellular and tissue microenvironment. Advanced biomaterials provide a platform for targeted anti-senescence interventions. One strategy is the selective elimination of senescent cells, achieved by engineering materials as delivery systems for senolytics or as platforms that modulate immune clearance. A more nuanced approach seeks functional rejuvenation, using biomaterials to restore cellular homeostasis by mitigating inflammation, correcting metabolic dysfunction, and reprogramming gene expression. A holistic strategy remodels the senescent microenvironment itself, accomplished through materials designed to restore biochemical homeostasis, provide physical guidance, and reprogram biological communication. This review delineates these material-based strategies, from direct cellular targeting to comprehensive niche remodeling. We also evaluate the significant hurdles to clinical translation, including challenges in biological specificity, preclinical model fidelity, and regulatory pathways. Ultimately, this work provides a conceptual framework for designing next-generation biomaterials to regenerate aging bone tissues.