Hybrid fabrication of perfusable stiffness-flexible integrated scaffold mimicking hierarchical tubular bone

Reconstructing biomechanical hierarchy and vascularization in heterogeneous tissues is critical for effective repair. Achieving this requires integrating materials with distinct mechanical properties. To address this, we develop a hybrid fabrication strategy-Hybrid Fabrication of Stiffness-Flexible Integration (HFSF). This strategy enables the engineering bone scaffolds with both mechanical hierarchy and perfusable vasculature. The outer layer (ZP scaffold), mimicking cortical bone, is made using zeolitic imidazolate framework-8/polycaprolactone (ZIF-8/PCL) through fused deposition modeling (FDM). In vitro mineralization enhances its mechanical strength and osteogenic-angiogenic potential. A robust hydrogel (PH scaffold) mimicking cancellous bone is synthesized from o-nitrobenzyl alcohol-terminated tetra-armed polyethylene glycol/hyaluronic acid (PEGNB/HAMA) and fabricated via digital light processing (DLP) printing. The PH scaffold incorporates intricate vascular channels. In vitro culture with endothelial cell seeding upregulates endothelial gene expression and promotes angiogenesis. The ZPPH scaffold demonstrates excellent protection of internal structures, robust vascularization, and bone formation in both in vitro and in vivo models. This innovative “structure-mechanics-biology” strategy offers a promising approach for engineering vascularized, mechanically hierarchical scaffolds for heterogeneous tissue repair. • The HFSF-fabricated biomimetic bone scaffold can effectively distinguish the cancellous bone cortical structure and achieve mechanical hierarchical matching, while combined in vitro vascularization enables dual osteogenic-angiogenic regeneration. • Our approach enables the selective integration of multiple materials with distinct properties based on biomimetic structural designs, facilitating the fabrication of multi-scale bionic scaffolds that effectively combine stiff and flexible regions. • HFSF exhibits excellent potential for broader applications, enabling the fabrication of biomimetic scaffolds incorporating dual- or even tri-tissue systems, such as bone–periosteum and bone–ligament–muscle complexes.