Developing a Strontium-Releasing Graphene Oxide-/Collagen-Based Organic Inorganic Nanobiocomposite for Large Bone Defect Regeneration via MAPK Signaling Pathway

摘要

Significant efforts have been dedicated to fabricating favorable biomaterial-based bone substitutes for the repair of large bone defects. However, the development of bone biomaterials with suitable physiochemical and osteoinductive properties remains a challenge. Here, novel strontium-graphene oxide (Sr-GO) nanocomposites that allow long-term release of Sr ions are fabricated, which are used to reinforce collagen (Col) scaffolds through covalent cross-linking. The prepared Sr-GO-Col scaffold demonstrates significantly high water retention rates and excellent mechanical properties compared with unmodified Col scaffolds. The Sr-GO-modified Col scaffolds display a strong effect on adipose-derived stem cells by facilitating cell adhesion and osteogenic differentiation and by promoting the secretion of angiogenic factors to stimulate the in vitro tube formation of endothelial cells. Additionally, the secretion of angiogenic VEGF and osteogenic BMP-2 proteins is increased, which may be attributed to the synergistic effects of GO and Sr on the activation of the MAPK signaling pathway. The Sr-GO-Col constructs were then transplanted into rat critical-size calvarial bone defects, which showed the best bone regeneration and angiogenesis outcome at 12 weeks. Moreover, histological staining results show that the Sr-GO-Col group achieved complete defect bridging with the newly formed bone tissue and the residual Sr-GO nanoparticles are phagocytosed and degraded by multinucleated giant cells. These findings reveal that the incorporation of inorganic Sr-GO nanocomposites into biocompatible Col scaffolds is a viable strategy for fabricating favorable substitutes that enhance the regeneration of large bone defects.