Honeycomb-inspired porous biomimetic scaffold with specific adaptability to host cells behavior for bone repair.

In the field of bone defect repair, the three-dimensional architecture and bioactivity of tissue-engineered bone scaffolds play a pivotal role. However, two major challenges remain: the cell type–specific response of host cells to scaffold pore architecture and the sustained promotion of angiogenesis and osteogenesis essential for large-segment bone regeneration. Inspired by the structural characteristics of natural honeycombs, this study integrates 3D printing with hydrogel engineering to construct a novel composite scaffold. Its macro-level innovation lies in a multilevel pore structure, while its functional core stems from a meticulously designed “nano-bio interface”: layered double hydroxides (LDHs) loaded with deferoxamine (DFO) are assembled into nanosheets (DFO@LDHs) as key functional units, and are simultaneously integrated into both a polycaprolactone (PCL) framework (D@LP) and a glycidyl methacrylate-modified hyaluronic acid (HA-GMA) hydrogel (D@LG) to form the final composite scaffold (D@LG/D@LP). This nano-bio interface not only enables sustained, controlled release of bioactive factors but also actively regulates cellular spatiotemporal behavior. The unique pore distribution and degradation characteristics of the hydrogel and 3D-printed scaffold preferentially guide endothelial cell adhesion and microvascular network formation, subsequently initiating stem cell differentiation and bone matrix deposition. Both in vitro and in vivo experiments confirm the scaffold’s excellent biocompatibility. Through a nanomaterial-driven cascade regulation mechanism, it coordinates the activation of angiogenesis and osteogenesis, significantly accelerating vascularized bone regeneration. This work demonstrates an effective strategy for empowering three-dimensional scaffolds through nano-bio interface construction, achieving spatiotemporal programming for complex tissue regeneration.