Recapitulating Endochondral Ossification for Bone Repair: From Development to Engineering Strategy

Endochondral ossification (ECO) is the fundamental mechanism underlying long bone development and fracture healing, driven by a cartilage template that orchestrates highly ordered cellular differentiation, vascular invasion, and matrix remodeling. In recent years, ECO has emerged as a key strategy in bone tissue engineering (BTE) due to its remarkable potential in constructing vascularized bone and repairing large bone defects. This review centers on the strategies to recapitulate ECO, beginning with an overview of the essential biological events and molecular regulatory networks that define this process. We then highlight state-of-the-art strategies for inducing or mimicking ECO in vitro from a tissue engineering perspective, including seed cell selection and programming, biomaterial scaffold design and fabrication, and the delivery and dynamic regulation of bioactive factors, and propose potential improvement strategies based on the limitations of current engineering approaches. In addition, bibliometric analysis is employed to delineate research hotspots and development trends. Looking ahead, the refinement of in vitro engineering strategies may enable precise control of key events in the ECO process, providing more efficient, controllable, and physiologically relevant solutions for large bone defect repair.