Mechanically tuned dual-network scaffolds orchestrate neuro-angio-osteo coupling for enhanced bone regeneration

Current bone grafts often lack the complex regenerative cues required for complete healing. This study introduced a dual-network scaffold composed of amorphous magnesium calcium pyrophosphate (AMCP), cassava starch (CS), and polyvinyl alcohol (PVA), engineered to overcome these limitations. PVA integration reinforced hydrogen bonding within the scaffold, enhancing mechanical properties and orchestrating a controlled three-stage degradation process. This included mitigating initial swelling, promoting cell adhesion via improved surface roughness, and stabilizing the structure during bone ingrowth. The resulting construct promoted neurovascular bone repair by enhancing cell adhesion/proliferation while retaining ion release capacity. Mechanistically, the scaffold activated the PI3K-AKT pathway in osteoblasts (ROCK upregulation, ATP boost via Ppa1/ATP synthase), stimulated angiogenesis (VEGFA, Serpine1, VEGFR1, Cdkn1a), and promoted neurogenesis (Wasf1, Limk2). VEGFA-mediated endothelial cell activation appeared central to coordinating the process, leading to enhanced neuro-angio-osteo interactions. Thus, the AMCP/CS/PVA scaffold provided a promising biomimetic platform for spatiotemporally coordinated bone regeneration by integrating multifaceted mechanical cues and regenerative signals.