Calcium ion-mediated silk bulk materials with adaptive mechanics and intrinsic osteogenic activity for bone regeneration

The development of protein-based orthopedic biomaterials that integrate high performance with robust bioactivity for bone regeneration remains challenging. Here, inspired by ion-mediated natural silk spinning and calcium-mediated bone regeneration, we develop a calcium ion-mediated silk (CaIMS) bulk material via a scalable thermal moulding strategy. By engineering ion-associated protein-water interactions, the molecular structures and mechanical properties of bulk silk materials can be tailored. Mechanistic investigations reveal that Ca²⁺ exhibits a strong interaction with the silk fibroin backbone, increasing the glass transition temperature (T_g) and suppressing β-sheet crystallization during thermal processing. Meanwhile, water molecules preferentially coordinated by Ca²⁺ act as dynamic plasticizers, enabling effective thermoplastic processability while preserving structural integrity. Through coordinated regulation of calcium chloride content and environmental humidity, CaIMS bulk materials exhibit adaptable mechanical properties. The incorporated Ca²⁺ acts as an intrinsic mineralization reservoir, enabling in situ apatite formation and creating a pro-osteogenic microenvironment that significantly enhances osteogenic differentiation in vitro and bone regeneration in vivo. This work demonstrates CaIMS bulk materials as a promising platform for bone repair and highlights the critical role of ion-associated protein-water interactions in the development of functional regenerative biomaterials. STATEMENT OF SIGNIFICANCE: Inspired by ion-mediated natural silk spinning and calcium-mediated bone regeneration, we develop calcium ion-mediated silk (CaIMS) bulk materials for bone repair. Using a thermal moulding process, calcium ions simultaneously control the material's stiffness, toughness, and ability to form bone‑like mineral. Unlike conventional implants that trade strength for bioactivity, our silk retains adaptable mechanics while actively promoting new bone growth. The embedded calcium acts as a built‑in reservoir for mineralization, creating a pro‑healing environment that enhances cell differentiation and accelerates bone regeneration in rats. This work introduces ion‑protein interactions as a powerful design strategy for next‑generation, load‑bearing biomaterials that are both mechanically robust and biologically active.