Tendon to bone (enthesis) rupture, which may cause disability and persistent pain, shows high rate of re‐rupture after surgical repair. Tendon or enthesis scaffolds have been widely studied, but few of these materials can recapitulate the tissue continuity. Thus, this study is conducted to prepare a triphasic decellularized bone‐fibrocartilage‐tendon (D‐BFT) composite scaffold. The D‐BFT scaffold is developed using a combination of physical, chemical, and enzymatic treatments using liquid nitrogen, Triton‐X 100, sodium‐dodecyl sulfate, and DNase I, which effectively removes the cell components while preserving the biological composite and microstructure. Moreover, the mechanical properties of D‐BFT are highly preserved and similar to those of the human Achilles tendon. Additionally, in vitro, mesenchymal stem cells (MSCs) adhered, proliferated, and infiltrated into the D‐BFT scaffold, and MSC differentiation is confirmed by up‐regulation of osteogenic‐related and tenogenic‐related genes. The repair outcomes are explored by applying the D‐BFT scaffold in the model of femur‐tibia defects in vivo, which shows good repair results. Thus, the D‐BFT scaffold developed in this study is a promising graft for enthesis regeneration.

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Bone defects associated with soft tissue injuries are an important cause of deformity that threatens people’s health and quality of life. Although bone substitutes have been extensively explored, effective biomaterials that can coordinate early inflammation regulation and subsequent repair events are still lacking. We prepared a spatial form periosteal bone extracellular matrix (ECM) scaffold, which has advantages in terms of low immunogenicity, good retention of bioactive ingredients, and a natural spatial structure. The periosteal bone ECM scaffold with the relatively low-stiffness periosteum (41.6 ± 3.7 kPa) could inhibit iNOS and IL-1β expression, which might be related to actin-mediated YAP translocation. It also helped to promote CD206 expression with the potential influence of proteins related to immune regulation. Moreover, the scaffold combined the excellent properties of decalcified bone and periosteum, promoted the formation of blood vessels, and good osteogenic differentiation (RUNX2, Col 1α1, ALP, OPN, and OCN), and achieved good repair of a cranial defect in rats. This scaffold, with its natural structural and biological advantages, provides a new idea for bone healing treatment that is aligned with bone physiology.