Alendronate-Functionalized Polycaprolactone/Gelatin Electrospun Fibrous Membranes for Enhanced Osteogenesis and Antiosteoclastogenesis in Bone Regeneration

For alveolar bone defects associated with osteoclast-active periodontitis, polycaprolactone (PCL)-based electrospun guided bone regeneration (GBR) membranes exhibit limited bone repair ability due to insufficient osteogenic promotion and inadequate osteoclast-targeted inhibition. To address these challenges, gelatin (GEL) was incorporated into the membranes to enhance their osteogenic capacity, while alendronate (ALN)─a bisphosphonate with both osteoclast inhibitory activity and osteogenic potential─was loaded at varying concentrations (1, 5, 10 wt %) to fabricate PG-1ALN, PG-5ALN, and PG-10ALN membranes. The membranes were characterized based on their physicochemical properties, and drug release studies confirmed that the PG-ALN group exhibited sustained ALN release over 28 days. In vitro, PG-1ALN enhanced isolated osteogenesis, but it showed limited efficacy in coculture systems, exhibiting a correlation with unchanged BMP-2 and OSM levels in RAW264.7-conditioned medium. In contrast, PG-5ALN exhibited osteoclast suppression in both isolated and coculture models, supported by the lowest RANKL/OPG ratio of 0.025 (four times lower than that of the PCL group). Micro-CT and histological (H&E, Masson staining) of rat cranial defects demonstrated PG-5ALN's superior bone regeneration; the bone volume fraction (BV) in the PG-5ALN group increased to 5.4 mm³ (control PCL group: 1.3 mm³). The bone mineral density (BMD) in the PG-5ALN group rose to 0.30 g/cm² (control PCL group: 0.036 g/cm²), marked by dense OCN deposition and minimal TRAP-positive osteoclasts. Notably, PG-5ALN achieved optimal osteoimmunomodulation by balancing osteoblast activation and osteoclast inhibition, thereby advancing the design of dual-functional GBR membranes for osteoclast-active alveolar bone defects.