Breaking the Self-Reinforcing Cycle of Aging: Biomaterial Strategies for Aged Bone Regeneration.

With accelerating population aging, age-related bone loss, osteoporosis, and delayed bone defect repair have become major challenges in regenerative medicine. Bone aging is not caused by the decline of a single cell type, but is a multilevel pathological process driven by the continuous coupling and mutual reinforcement of intracellular damage accumulation, senescence signal propagation, and microenvironmental deterioration. Based on established aging theories, this review integrates regenerative impairment in aged bone into three interconnected pathological cycles from the perspectives of dynamic feedback and regenerative intervention. Intracellular damage and homeostatic imbalance promote cellular senescence; senescent cells spread senescence signals through SASP and immune dysregulation, inducing abnormalities in metabolism, extracellular matrix (ECM) structure, and intercellular communication; the deteriorated microenvironment then further aggravates intracellular damage and homeostatic disruption, forming a self-reinforcing pathological loop. Within this framework, we summarize biomaterial strategies targeting intracellular damage, senescent cells and SASP-mediated propagation, and the aged microenvironment, and discuss multifunctional and responsive materials for staged or multi-level intervention. This framework organizes dispersed aging mechanisms into a dynamic network of feedback relationships and actionable nodes, providing guidance for mechanism-oriented biomaterial design and strategy selection in aged bone regeneration.