Targeting the redox and mitochondrial barrier with a naringin-releasing bioactive composite film patch for osteoporotic bone defect repair.

BACKGROUND: Osteoporotic bone defect (OPBD) repair is impaired by persistent oxidative stress and mitochondrial dysfunction, which compromise the osteogenic capacity of bone marrow-derived mesenchymal stem cells. Naringin (NG) has antioxidant, mitochondria-protective, and osteogenic activities; however, direct local administration may provide insufficient retention and temporal control at the defect site. A conformal poly(ε-caprolactone)/nano-hydroxyapatite film may therefore serve as a local depot for sustained naringin delivery while providing a bone-mimetic interface. PURPOSE: This study aimed to determine whether a naringin-releasing PCL/nHA bioactive composite film patch could target the redox-mitochondrial barrier and enhance osteoporotic bone defect repair. METHODS: The composite films were evaluated for morphology, wettability, mechanical properties, NG loading/release, degradation-related behavior, cytocompatibility, mitochondrial protection, and in vivo bone regeneration in an ovariectomy-induced osteoporotic tibial defect model. RESULTS: The films showed improved wettability, mechanically handleable properties, and sustained NG release for up to 24 days. NG-loaded films promoted BMSCs osteogenic differentiation and mineralization and attenuated TBHP-induced oxidative injury by reducing ROS accumulation and preserving mitochondrial membrane potential. Transcriptomic and targeted validation analyses supported the involvement of redox- and mitochondrial-associated pathways, particularly Keap1/Nrf2-related antioxidant signaling. In vivo, NG-loaded PCL/nHA films accelerated defect repair and improved trabecular microarchitecture, with increased BV/TV and improved Tb.Th, Tb.N, and Tb.Sp at 3 and 6 weeks. CONCLUSION: NG-loaded PCL/nHA bioactive composite films provide sustained local NG delivery and improve osteoporotic bone defect repair by modulating oxidative stress, protecting mitochondrial function, and supporting osteogenic activity.