| Summary: | Aim or Purpose: This study aims to provide a novel treatment to regenerate craniofacial bone defects with both physiological morphology and mastication-related function restoration. Materials and Methods: A nanoink was prepared by incorporating calcium phosphate oligomers (CPO) and bone morphogenetic protein-2 (BMP-2) into gelatin methacryloyl (GelMA), and the printability was evaluated. After photo-crosslinked, physiochemical characteristics of hydrogels were tested. A biomimetic scaffold, including upper cortical layer (with Haversian systems) and lower cancellous layer (with TPMS structure), was fabricated via projection-based 3D printing with gradient bioactive factors-loaded nanoinks. In vitro osteogenesis and angiogenesis ability of hydrogels were assessed, with mechanism explored by RNA-sequencing. A rabbit mandibular defect model was used to observe in vivo regeneration performance, with Bio-Oss granules treated as the control. Finite element analysis was used to visualize stress distribution of an implant placed in restored neo-bone. Results: A chemical interaction was observed between CPO and GelMA, resulting in homogeneous property, allowing ideal print precision. With CPO increased, mechanical property was enhanced. The hydrogels promoted osteogenic ability of BMSCs in bioactive factor-dose dependent manner, with higher VEGF protein detected in supernatant. Treated with conditional medium from BMSCs, the angiogenic activity of HUVECs was enhanced. RNA sequencing revealed this process involved ITGA10/PI3K/AKT pathway. In vivo results showed the biomimetic scaffold regenerated mandibular defects with natural microarchitecture, whereas Bio-Oss granules only induced homogeneous density of neo-bone. Finite element analysis confirmed this gradient-density structure contributed to a wider distribution of loading force and reduced stress concentration around the implant. Conclusions: The hierarchical 3D scaffold enables personalized bone regeneration with a functional distribution of occlusal loads.
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