| Summary: | Bone bionics and structural engineering have sparked a broad interest in optimizing artificial scaffolds for better bone regeneration. However, the mechanism behind scaffold pore morphology-regulated bone regeneration remains unclear, making the structure design of scaffolds for bone repair challenging. To address this issue, we have carefully assessed diverse cell behaviors of bone mesenchymal stem cells (BMSCs) on the β-tricalcium phosphate (β-TCP) scaffolds with three representative pore morphologies (i.e., cross column, diamond, and gyroid pore unit, respectively). Among the scaffolds, BMSCs on the β-TCP scaffold with diamond pore unit (designated as D-scaffold) demonstrated enhanced cytoskeletal forces, elongated nucleus, faster cell mobility, and better osteogenic differentiation potential (for example, the alkaline phosphatase expression level in D-scaffold were 1.5–2 times higher than other groups). RNA-sequencing analysis and signaling pathway intervention revealed that Ras homolog gene family A (RhoA)/Rho-associated kinase-2 (ROCK2) has in-depth participated in the pore morphology-mediated BMSCs behaviors, indicating an important role of mechanical signaling transduction in scaffold-cell interactions. Finally, femoral condyle defect repair results showed that D-scaffold could effectively promote endogenous bone regeneration, of which the osteogenesis rate was 1.2–1.8 times higher than the other groups. Overall, this work provides insights into pore morphology-mediated bone regeneration mechanisms for developing novel bioadaptive scaffold designs.
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