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Cuttlebone inspired “S”-grooved topological structures facilitate osteogenic differentiation through the Rap1-ERK pathway

Ying Sun,Yining Cai,Shanshan Xu,Ningning Zhai,Zirui Wang,Zongpu Qiu,Shuying Han,Yuanqing Wei,Rui Liu,Hao Wu

While the regulatory roles of biomaterial topology in bone regeneration are recognized, the specific osteogenic mechanisms driven by distinct morphological features, particularly without biochemical cues, remain poorly understood. This study aimed to independently elucidate the osteogenic potential and underlying mechanisms solely attributable to the distinctive “S”-grooved topology derived from cuttlebone. Inspired by cuttlebone, we successfully fabricated a biomimetic polycaprolactone (PCL) membranes sheet with “S”-grooved topology using liquid silicone mold replication combined with PCL recasting techniques. Comprehensive characterization (SEM, CLSM) confirmed precise replication of the native “S”-grooved morphology (width: 100 ± 30 μm, depth: 20 ± 6 μm). In vitro studies revealed that these grooves promoted directional adhesion and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) via contact guidance, as evidenced by cytoskeleton alignment. Furthermore, the “S”-grooved topology significantly enhanced osteogenic differentiation of mouse pre-osteoblasts (MC3T3-E1), demonstrated by increased alkaline phosphatase (ALP) activity and mineralized nodule formation. Mechanistic investigations using RT-qPCR, Western blot, and dimethyl labeling-based quantitative proteomics on rBMSCs identified key involvement of the Rap1-ERK signaling pathway. Specifically, the “S”-grooved topology upregulated Rap1 expression and enhanced ERK phosphorylation, leading to increased expression of osteogenic markers (e.g., Runx2, OPN). These findings demonstrate that the biomimetic “S”-grooved topology alone, through contact guidance and activation of the Rap1-ERK mechanotransduction pathway, significantly enhances osteogenic differentiation, providing a foundation for designing topologically optimized biomaterials for bone regeneration biomimetic PCL membranes sheet with the “S”-grooved topology.