Natural fracture healing recapitulates bone development through endochondral ossification, resulting in clinical success rates of 90-95%. However, large bone defects of critical size cannot form a callus and exhibit high rates of complication and non-union even after intervention. Bone tissue engineering holds promise, but traditional approaches have focused on direct, intramembranous bone formation. We propose that mimicking the endochondral process that is naturally selected for bone development and fracture repair may improve regenerative outcome. Since physical stimuli are critical for proper endochondral ossification during bone morphogenesis and fracture healing, mechanical loading may be essential to enable reliable endochondral defect regeneration as in callus-mediated fracture repair. Here we report that in vivo mechanical loading, via dynamically tuned fixator compliance, restored bone function through endochondral ossification of engineered human mesenchymal condensations. The condensations mimic limb bud morphogenesis in response to local morphogen presentation by incorporated gelatin microspheres. Endochondral regeneration in large defects exhibited zonal cartilage and woven bone mimetic of the native growth plate, with active YAP signaling in human hypertrophic chondrocytes in vivo. Mechanical loading regulated vascular invasion and enhanced endochondral regeneration, with an order-of-magnitude greater response to loading than that observed for intramembranous repair, restoring intact bone properties. This study represents the first demonstration of the effects of mechanical loading on transplanted cell-mediated bone defect regeneration and establishes the importance of in vivo mechanical cues, cellular self-organization, and inductive signal presentation for recapitulation of development for tissue engineering.
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