Shear Stress Modulates Intrafibrillar Mineralization Via Collagen–Amorphous Precursors Interface

Autologous bone remains the gold standard for bone repair, but its clinical use is limited. Current bone substitutes often mimic only the inorganic composition of bone, overlooking its hierarchical organic-inorganic structure. To address this, we propose a shear-assisted Synchronous Self-assembly and Mineralization (Shear-SSM) strategy. We hypothesize that moderate fluid shear stress (FSS) weakens the hydration layer between collagen and polyaspartic acid-stabilized amorphous calcium phosphate (PAsp-ACP), enhancing interfacial interactions, promoting ACP infiltration into collagen fibrils, and enabling coordinated intra- and extrafibrillar mineralization, ultimately yielding a bone repair material with a structure and composition that closely mimics natural bone. We examined the effects of FSS on collagen self-assembly, PAsp-ACP stability, and mineralization behavior using microscopy, thermogravimetric analysis, and molecular dynamics simulations. A shear-dialysis system enabled real-time monitoring and control of mineralization conditions. FSS enhanced PAsp-ion binding, peeling away the hydration layer, and delayed ACP-to-HA transformation, while accelerating collagen fibril formation . Under the Shear-SSM model, ordered ACP infiltration and parallel alignment of hydroxyapatite crystals achieved a Ca/P ratio and inorganic content closely resembling natural bone. In vitro, mineralized scaffolds enhanced BMSC adhesion, proliferation, and osteogenic differentiation. In vivo, they promoted bone regeneration and angiogenesis in a rat mandibular defect model. This study presents Shear-SSM as a novel biomimetic strategy to reconstruct both the composition and structure of native bone. The resulting scaffold exhibits excellent biocompatibility, osteoinductivity, and regenerative potential, offering a promising approach for advanced bone repair.