Localized injectable Scl-Ab/VEGF hydrogel enhances dual osteogenic and angiogenic signaling to promote osteoporotic fracture healing

Impairment of localized angiogenic and osteogenic signaling networks significantly delays the healing of osteoporotic fractures. Systemic administration of sclerostin monoclonal antibody (Scl-Ab) encounters clinical restrictions due to potential cardiovascular risks highlighted by FDA black box warnings, and fails to ensure adequate local drug concentrations. This study aimed to develop an injectable localized drug delivery system for the sustained co-delivery of Scl-Ab and vascular endothelial growth factor (VEGF), evaluating its potential translational applicability in treating osteoporotic fractures. An injectable non-covalent hydrogel matrix (A-ND) capable of loading Scl-Ab and VEGF was synthesized through physical crosslinking of acrylamide, sodium p-styrene sulfonate, and acryloyloxyethyltrimethylammonium chloride.In vitro experiments evaluated the effects of the system on bone marrow mesenchymal stem cell (BMSC) migration and osteogenic differentiation. In vivo, randomized cohorts of ovariectomized (OVX) rats with stabilized femoral fractures were treated locally with the hydrogel formulations (n = 6 rats per group). Local bone repair and systemic biosafety were evaluated at 12 weeks using radiography, micro-CT analysis, biomechanical testing, localized tissue molecular biological assays, and histological examination. The A-ND hydrogel exhibited a highly porous microstructure (~3 μm) and enabled stable sustained release of Scl-Ab and VEGF over 28 days. In vitro, the combined dual-drug group (D1) significantly enhanced BMSC migration and mineralized matrix deposition (OD: 1.639 ± 0.016), associated with the upregulation of downstream markers linked to Wnt and AKT signaling. In vivo, compared with single-agent and control cohorts, the D1 group achieved advanced fracture bridging and remodeling, demonstrating the highest radiographic scores (4.00 ± 0.000) and maximum biomechanical load-bearing capacity (187.80 ± 17.29 N). Histological and hematological examinations confirmed that major organs maintained intact architecture and systemic parameters remained within normal ranges. Localized injection of the Scl-Ab/VEGF@A-ND delivery system effectively accelerates osteoporotic fracture repair by concurrently supporting local osteogenic and angiogenic pathways. This platform proposes a safe, minimally invasive, and precision-targeted translational strategy for the treatment of fragile fractures.