Regenerative medicine strategies for the treatment of radiation-induced ulcers: Mechanisms, challenges, and future directions.

BACKGROUND: Radiation-induced ulcers are serious chronic complications of radiation therapy and are characterized by a pathological microenvironment involving persistent inflammation, oxidative stress, vascular damage, and fibroblast dysfunction. Conventional therapies often yield poor outcomes because they fail to reverse the abnormal microenvironment of irradiated wounds. OBJECTIVE: This review provides an updated synthesis of regenerative medicine strategies for radiation-induced ulcers, with a particular emphasis on mechanistic insights, translational challenges, and clinically relevant therapeutic approaches. METHODS: Evidence from stem cell-based regeneration, cell-free and platelet-based bioactive preparations, growth factor-based therapies, gene and RNA-based therapies, and functional biomaterials was reviewed, with an emphasis on cellular senescence, oxidative stress regulation, immunomodulation, angiogenesis, and tissue remodeling. RESULTS: Radiation-induced ulcers arise from coupled cascades of DNA damage, cellular senescence and SASP signaling, oxidative stress, vascular injury, fibroblast epigenetic dysfunction, and immune dysregulation. Across these therapeutic modalities, regenerative interventions primarily target a common set of pathological processes, including senescence-associated inflammation, redox imbalance, vascular loss, and defective extracellular-matrix remodeling. Stem cells and their derivatives act chiefly through paracrine signaling; cell-free and platelet-based products deliver bioactive cargo without live-cell transplantation; growth factor and gene/RNA strategies provide more defined molecular control; and functional biomaterials afford local protection and controlled release. However, radiation-specific evidence remains largely preclinical, with translation limited by product heterogeneity, manufacturing and potency standardization, long-term safety, cost-effectiveness, and reimbursement. CONCLUSION: Regenerative medicine represents a promising multidimensional strategy for treating radiation-induced ulcers; however, broader clinical application requires rigorous randomized controlled trials, standardized production protocols, and long-term safety monitoring. Future breakthroughs are likely to depend on omics-guided precision therapy, organ-on-a-chip platforms, and AI-optimized biomaterial design.