Strontium Ranelate Incorporated Enzyme-Cross-Linked Gelatin Nanoparticle/Silk Fibroin Aerogel for Osteogenesis in OVX-Induced Osteoporosis

Osteoporosis is a wide-range disease with a negative impact on bone defect healing. Strontium ranelate (SR) has promising osteogenic potential for its dual function on stimulating osteoblasts and inhibiting osteoclast activity. However, it has limitations for its dose-dependent effect and side effects on systemic applications. Here, a sequentially cross-linking strategy including enzyme-cross-linking through tyrosinase from mushroom and physical folding is acquired to create SR loaded gelatin nanoparticle/silk fibroin aerogel (abbreviated as S/G-Sr-MT) with drug release controlling capacity. The results showed successful enzyme-cross-linking, excellent spatial structure, and enhanced mechanical properties of S/G-Sr-MT. Even Sr2+ loading and stable release with markedly inhibited initial burst release were detected. The biomineralization investigation showed rapid deposition of hydroxyapatite on the surface of S/G-Sr-MT. In vitro, spreading morphology and higher osteogenic gene expression of MC3T3-E1 seeded on S/G-Sr-MT were observed compared to other groups after 7 day culturing. In vivo, S/G-Sr-MT showed an obvious osteogenic capacity in calvaria defects of ovariectomized rats in which high Runx2 expression and inhibited TRAP activity were observed. Such results suggested the S/G-Sr-MT scaffold could stimulate osteogenic differentiation of osteoblasts while inhibiting osteoclast behaviors in vivo. These findings highlight the potential osteogenic ability and clinical application of SR incorporated enzyme-cross-linked scaffold in ovariectomized (OVX) bone healing.