Microenvironmental barriers to healing in osteoradionecrosis and opportunities for regenerative intervention

Osteoradionecrosis (ORN) is a debilitating sequela of radiotherapy (RT) for head and neck cancer (HNC), characterized by persistent bone exposure or radiographic non-viability and profound tissue repair failure. Despite advances in radiation delivery and clinical management, ORN remains challenging to treat, with therapeutic strategies largely focused on symptom control, infection mitigation, or surgical reconstruction rather than restoration of regenerative capacity. Emerging evidence suggests that radiation-induced cellular senescence represents a central and underrecognized driver of ORN pathophysiology. Ionizing radiation disrupts the bone microenvironment through sustained vascular injury, impaired osteogenic-angiogenic coupling, chronic inflammation, and the accumulation of senescent bone-resident and stromal cells that secrete a pro-inflammatory senescence-associated secretory phenotype (SASP). Together, these changes create a hostile niche that suppresses bone remodeling and wound healing long after radiation exposure. This review synthesizes current understanding of radiation-induced injury to the bone microenvironment, critically evaluates existing classification systems and treatment strategies for ORN, and examines emerging regenerative approaches. We further propose senotherapeutic strategies targeting radiation-induced cellular senescence as a complementary and potentially transformative avenue to restore tissue repair capacity. By integrating regenerative biomaterials with targeted modulation of senescence, future therapies may move beyond palliation toward true biological resolution of ORN. Biomaterial delivery systems (e.g., injectable hydrogels, mineral composite scaffolds, and cryogel platforms) are emerging as promising vehicles for spatiotemporally controlled senotherapeutic delivery within the irradiated bone niche.