3D Bioprinted Tissue‐Engineered Bone with Enhanced Mechanical Strength and Bioactivities: Accelerating Bone Defect Repair through Sequential Immunomodulatory Properties

Abstract In this study, a new‐generation tissue‐engineered bone capable of temporally regulating the immune response, balancing proinflammatory and anti‐inflammatory activities, and facilitating bone regeneration and repair to address the challenges of delayed healing and nonunion in large‐sized bone defects, is innovatively developed. Using the innovative techniques including multiphysics‐assisted combined decellularization, side‐chain biochemical modification, and sterile freeze‐drying, a novel photocurable extracellular matrix hydrogel, methacrylated bone‐derived decellularized extracellular matrix (bdECM‐MA), is synthesized. After incorporating the bdECM‐MA with silicon‐substituted calcium phosphate and bone marrow mesenchymal stem cells, the tissue‐engineered bone is fabricated through digital light processing 3D bioprinting. This study provides in vitro confirmation that the engineered bone maintains high cellular viability while achieving MPa‐level mechanical strength. Moreover, this engineered bone exhibits excellent osteogenesis, angiogenesis, and immunomodulatory functions. One of the molecular mechanisms of the immunomodulatory function involves the inhibition of the p38‐MAPK pathway. A pioneering in vivo discovery is that the natural biomaterial‐based tissue‐engineered bone demonstrates sequential immunomodulatory properties that activate proinflammatory and anti‐inflammatory responses in succession, significantly accelerating the repair of bone defects. This study provides a new research basis and an effective method for developing autogenous bone substitute materials and treating large‐sized bone defects.