Design and Fabrication of Biomimetic Gradient Bone Tissue Engineering Scaffolds: Evolution from Single-Gradient to Multi-Gradient.

The regeneration of bone and the repair of large segmental bone defects represent critical challenges in regenerative medicine. Natural bone tissue is an anisotropic material characterized by an intricate gradient distribution in structure, mechanical properties, and biochemical composition; this multi-dimensional heterogeneity is crucial for maintaining its physiological functions and guiding regeneration. Although tissue engineering scaffolds have demonstrated significant potential in the treatment of bone defects, homogeneous or single-gradient scaffolds often struggle to precisely recapitulate the high degree of heterogeneity and anisotropy of natural bone from the macroscopic to the microscopic level, thereby limiting their capability in repairing complex bone defects. In recent years, biomimetic gradient scaffolds-particularly those employing multi-gradient synergistic designs that integrate physical structure, biochemical composition, and mechanical properties-have emerged as a research frontier in this field due to their ability to accurately mimic the natural bone microenvironment and regulate cellular behavior. This research aims to systematically review the latest research progress in gradient scaffolds for bone tissue engineering. First, gradient characteristics of biomimetic gradient bone scaffolds are summarized; second, the design strategies for gradient scaffolds are discussed in depth, with a focus on the applications and advantages of advanced fabrication techniques, such as additive manufacturing, in constructing multi-dimensional gradient structures; finally, based on current research findings, the emerging development trends and future research directions of biomimetic gradient bone scaffolds are outlined to provide a reference for innovative breakthroughs in the field of bone tissue engineering.