Research ArticleTissue Engineering

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

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Science Translational Medicine  05 Jun 2019:
Vol. 11, Issue 495, eaav7756
DOI: 10.1126/scitranslmed.aav7756

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Taking cues from development

One way that bone forms during development is termed endochondral ossification, a process requiring a cartilage intermediate. McDermott et al. mimicked this process during bone defect repair in rats, implanting cylindrical constructs of human mesenchymal stem cells and transforming growth factor–β1 into critical-sized femur defects and using fixation plates to apply mechanical loading. Loading altered cartilage persistence, blood vessel formation, and bone regeneration. Applying mechanical forces 4 weeks after construct implantation resulted in better bone bridging than loading at the time of implantation. This study demonstrates how mechanical loading can be used with tissue engineering to augment bone regeneration.

Abstract

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-magnitude greater mechanosensitivity. In vitro, mechanical loading promoted chondrogenesis and up-regulated pericellular matrix deposition and angiogenic gene expression. In vivo, mechanical loading regulated cartilage formation and neovascular invasion, dependent on load timing. This study establishes mechanical cues as key regulators of endochondral bone defect regeneration and provides a paradigm for recapitulating developmental programs for tissue engineering.

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