Bioactive PCL/nSi-BMSCs composite scaffold regulates periosteal cell functions for neurovascularized bone regeneration

Proper innervation and vascularization are not only essential for maintaining bone homeostasis but also play a pivotal role in orchestrating efficient bone regeneration. Here, we investigate the regenerative potential of a polycaprolactone/Nanosilicates (PCL/nSi) scaffold loaded with bone marrow mesenchymal stem cells (BMSCs), with a particular emphasis on its modulatory effects on periosteal cells (PCs) during bone repair, especially in neurovascular regeneration. We systematically evaluated the effects of this composite on PCs migration, osteogenesis, neurogenesis, and angiogenesis, and further explored the underlying molecular mechanisms. The composite exhibited excellent biocompatibility and markedly enhanced PCs proliferation, migration, and osteogenic differentiation, primarily through activation of the PI3K-AKT signaling pathway. Beyond its osteogenic effects, the composite promoted angiogenic differentiation of endothelial cells (ECs) and upregulated neurogenic markers in PCs, thereby fostering a coordinated regenerative microenvironment. Collectively, these findings highlight the therapeutic promise of the PCL/nSi-BMSCs composite as a multifunctional and bioactive platform for bone tissue engineering capable of simultaneously supporting osteogenesis, angiogenesis, and neurogenesis.