Functionalized hydrogel–microsphere composites stimulating neurite outgrowth for vascularized bone regeneration

Neurovascularized bone regeneration remains an enormous challenge in the clinic. Biomaterials mimicking the developmental microenvironment might be promising tools to enhance tissue regeneration. In this study, functionalized hydrogel-microsphere composites are developed to enhance bone regeneration via a recapitulating neurovascularized microenvironment. RGD peptide and the porous structure generated by the degradation of gelatin microspheres (GMs) are beneficial for the proliferation and migration of human mesenchymal stem cells (hMSCs); mesoporous silica nanoparticles (MSNs) promote osteogenic differentiation of hMSCs through the delivery of BFP-1 peptide; the QK peptide from the GMs is sustained-released to recruit endogenous endothelial cells (ECs), and IK19 peptide grafted on the hydrogel guides the neurite outgrowth. The in vivo results show that the hydrogel-microsphere composites not only promote new bone formation, but also facilitate nerve infiltration and angiogenesis. Furthermore, the neurovascularized niche created by this composite stimulated neurite growth through MAPK, PI3K, IL17 and TNF signaling pathways, enabling vascularized bone regeneration. The findings suggest a novel bioengineering approach to guide the construction of neurovascularized bone repair materials, which is beneficial for achieving functional bone regeneration and repair.