Multiscale 3D printing for hierarchical reconstruction and functional regeneration of bone tissue
Bone tissue engineering (BTE) has emerged as a promising approach for repairing critical bone defects that remain challenging to treat using conventional grafting strategies. Recent advances in three-dimensional (3D) printing have enabled the fabrication of patient-specific and biomimetic bone constructs with precise control over structural architecture, material composition, and biological functionality. However, native bone exhibits a highly hierarchical organization spanning multiple length scales, and current 3D printing approaches often remain limited by insufficient integration between macroscopic mechanical reconstruction, microscale cellular regulation, and nanoscale bioactive signaling. In this review, we provide a comprehensive overview of multiscale 3D printing strategies for bone tissue reconstruction, highlighting how additive manufacturing technologies facilitate the recapitulation of hierarchical bone structures. We first summarize the historical evolution of 3D printing in BTE and discuss advances in bioinks, biomaterials, and printing technologies. Subsequently, we analyze multiscale reconstruction strategies from three perspectives: macroscale fabrication for personalized anatomical restoration and mechanical support, microscale construction for cellular organization and vascular network formation, and nanoscale engineering for biomimetic extracellular matrix interfaces and molecular regulation. Furthermore, we discuss emerging strategies integrating smart responsive materials, bioactive cues, and computational design to enhance the regenerative capacity of 3D-printed bone constructs. Finally, current challenges and future perspectives are presented, focusing on vascularization, immune regulation, artificial intelligence-assisted scaffold optimization, four-dimensional bioprinting, and clinical translation. This review highlights the potential of multiscale 3D printing as a transformative platform for developing functional bone tissues and advancing personalized regenerative medicine.
