Abstract
Developmental engineering of living implants from different cell sources capable of stimulating bone regeneration by recapitulating endochondral ossification (ECO) is a promising strategy for large bone defect reconstruction. However, the clinical translation of these cell-based approaches is hampered by complex manufacturing procedures, poor cell differentiation potential, and limited predictive in vivo performance. We developed an adipose tissue-based developmental engineering approach to overcome these hurdles using hypertrophic cartilaginous (HyC) constructs engineered from lipoaspirate to repair large bone defects. The engineered HyC constructs were implanted into 4-mm calvarial defects in nude rats and compared with decellularized bone matrix (DBM) grafts. The DBM grafts induced neo-bone formation via the recruitment of host cells, while the HyC pellets supported bone regeneration via ECO, as evidenced by the presence of remaining cartilage analog and human NuMA-positive cells within the newly formed bone. However, the HyC pellets clearly showed superior regenerative capacity compared with that of the DBM grafts, yielding more new bone formation, higher blood vessel density, and better integration with adjacent native bone. We speculate that this effect arises from vascular endothelial growth factor and bone morphogenetic protein-2 secretion and mineral deposition in the HyC pellets before implantation, promoting increased vascularization and bone formation upon implantation. The results of this study demonstrate that adipose-derived HyC constructs can effectively heal large bone defects and present a translatable therapeutic option for bone defect repair.