Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration

作者：Anna M. McDermott, Samuel Herberg, Devon E. Mason, Joseph M. Collins, Hope B. Pearson, James H. Dawahare, Rui Tang, Amit Patwa, Mark W. Grinstaff, Daniel J. Kelly, Eben Alsberg, Joel D. Boerckel · 发表于：Science Translational Medicine · 年份：2019 · DOI：10.1126/scitranslmed.aav7756 · 被引用次数：211 · 研究领域：Bone fractures and treatments、Bone Tissue Engineering Materials、Knee injuries and reconstruction techniques

Large bone defects cannot form a callus and exhibit high complication rates even with the best treatment strategies available. Tissue engineering approaches often use scaffolds designed to match the properties of mature bone. However, natural fracture healing is most efficient when it recapitulates development, forming bone via a cartilage intermediate (endochondral ossification). Because mechanical forces are critical for proper endochondral bone development and fracture repair, we hypothesized that recapitulating developmental mechanical forces would be essential for large bone defect regeneration in rats. Here, we engineered mesenchymal condensations that mimic the cellular organization and lineage progression of the early limb bud in response to local transforming growth factor-β1 presentation from incorporated gelatin microspheres. We then controlled mechanical loading in vivo by dynamically tuning fixator compliance. Mechanical loading enhanced mesenchymal condensation-induced endochondral bone formation in vivo, restoring functional bone properties when load initiation was delayed to week 4 after defect formation. Live cell transplantation produced zonal human cartilage and primary spongiosa mimetic of the native growth plate, whereas condensation devitalization before transplantation abrogated bone formation. Mechanical loading induced regeneration comparable to high-dose bone morphogenetic protein-2 delivery, but without heterotopic bone formation and with order-of-m...