Bone Defect Reconstruction Via Endochondral Ossification: A Developmental Engineering Strategy

Bone tissue engineering (BTE) is a growing area of research in extensive bone defect reconstruction. Traditional BTE strategies induce direct bone-like matrix formation by mimicking the embryological process of intramembranous ossification. However, clinical translation of traditional tissue-engineered bone grafts is hampered by their limited in vivo vascularization and poor bone regeneration after implantation. To overcome this hurdle, an emerging engineering strategy advocates to fabricate cartilaginous constructs for reconstruction of large bone defects, which was inspired by recapitulating the developmental processes of endochondral ossification (ECO). Such developmentally engineered constructs can act as a transient biomimetic template to facilitate bone regeneration in a critical-size defect. Accordingly, various studies following the principles of developmental engineering, including ectopic bone formation and orthotopic bone regeneration studies, have recently shown their unique abilities to survive under hypoxic conditions as well as induce neovascularization and ossification. This review introduces the concept and mechanism of the developmental BTE, highlights the routes of endochondral graft engineering, discusses states of large bone defect reconstruction via the ECO-based strategies, and offers perspectives on the challenges and future directions of translating current knowledge from bench to bedside.