Polyphenol Hyaluronic Acid Mediates Cascade Regulation of Collagen Assembly/Mineralization for Bone Regeneration

Abstract Current collagen‐based bone repair materials struggle to emulate the multiscale regulatory functions of natural extracellular matrix, particularly lacking the critical ability of proteoglycans to synergistically regulate collagen assembly and hydration microenvironment. This study constructs a biomimetic molecular bridge through dopamine‐modified hyaluronic acid (HAD), achieving ordered collagen fiber assembly and optimized mineralization kinetics via polysaccharide‐polyphenol coupling. Molecular dynamics simulations revealed that HAD regulates fiber spacing via entropy‐driven mechanisms through covalent anchoring of lysine residues on collagen surfaces and hydrogen bond network formation. The optimized MHAD‐r‐Col scaffold established a dynamic hydration network, enhancing Ca²⁺/PO₄³⁻ ion enrichment and amorphous calcium phosphate (ACP) in situ nucleation, achieving 54.12% calcium phosphate deposition (5.3‐fold improvement over pure collagen) and a 13‐fold increase in elastic modulus to 120 kPa. In vitro experiments demonstrate significant promotion of bone marrow mesenchymal stem cell proliferation and guided cell migration. In a rabbit cranial defect model, the scaffold achieved a 40.3% new bone volume fraction at 4 weeks, with repair site fracture strength reaching 39.1 ± 0.8 N (2.1‐fold of controls), along with significant upregulation of osteogenic markers (RUNX2, OCN). This study establishes a novel paradigm for polysaccharide‐mediated “structure‐function” integrated bone repair material design.