ABSTRACT Biomaterials lacking exogenous biomolecule functionalization often fail to achieve high‐quality bone regeneration. Inspired by the native biomineralization mechanisms of the bone matrix, we developed a growth factor‐free, nanoscale‐engineered silk fibroin (NESF) hydrogel to enhance in situ biomineralization and promote effective endogenous bone regeneration. By modulating SF nanofiber length to enrich acidic groups, the hydrogel acquired an increased negative surface charge, providing initial physical cues that effectively attracted inorganic ions and promoted Ca 2+ ‐PO 4 3− nucleation, resulting in a 6.09‐fold enhancement in biomineralization. These intrinsic chemical modifications further boosted the biological activity of the NESF hydrogel by promoting the adhesion and proliferation of BMSCs, and facilitated osteogenic differentiation by elevating intracellular Ca 2+ influx and activating the MAPK/ERK signaling pathway. In vivo, the NESF hydrogel exhibited superior biocompatibility, biodegradability, and in situ biomineralization in a rat subcutaneous implantation model. Furthermore, it significantly enhanced both structural and functional bone regeneration in a rat critical‐sized femoral defect model, achieving near‐complete neo‐bone formation and markedly improved motor function. This simple nanoscale engineering strategy enables SF hydrogels to deliver a cascade of intrinsic physical, chemical, and biological cues for bone regeneration without relying on exogenous biomolecules, offering a promising and translational strategy for clinical bone defect repair.
Li et al. (Sat,) studied this question.
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