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

Anna M. McDermott, Samuel Herberg, Devon E. Mason, Hope B. Pearson, James H. Dawahare, Joseph M. Collins, Rui Tang, Amit N. Patwa, Mark W. Grinstaff, Daniel J. Kelly, Eben Alsberg, View ORCID ProfileJoel D. Boerckel
doi: https://doi.org/10.1101/157362
Anna M. McDermott
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
3Department of Mechanical Engineering, Trinity Center for Bioengineering, Trinity College Dublin, Dublin, Ireland.
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Samuel Herberg
4Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
5Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
10Current address: Departments of Ophthalmology | Cell and Developmental Biology Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY.
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Devon E. Mason
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
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Hope B. Pearson
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
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James H. Dawahare
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
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Joseph M. Collins
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
6Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.
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Rui Tang
7Department of Biomedical Engineering, Boston University, Boston, MA.
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Amit N. Patwa
8Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH.
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Mark W. Grinstaff
8Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH.
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Daniel J. Kelly
3Department of Mechanical Engineering, Trinity Center for Bioengineering, Trinity College Dublin, Dublin, Ireland.
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Eben Alsberg
4Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
7Department of Biomedical Engineering, Boston University, Boston, MA.
9National Center for Regenerative Medicine, Division of General Medical Sciences, Case Western Reserve University, Cleveland, OH.
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Joel D. Boerckel
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN.
6Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.
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  • ORCID record for Joel D. Boerckel
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ABSTRACT

Large bone defects cannot heal without intervention and have high complication rates even with the best treatments available. In contrast, bone fractures naturally healing with high success rates by recapitulating the process of bone development through endochondral ossification.1 Endochondral tissue engineering may represent a promising paradigm, but large bone defects are unable to naturally form a callus. We engineered mesenchymal condensations featuring local morphogen presentation (TGF-β1) to mimic the cellular organization and lineage progression of the early limb bud. As mechanical forces are 2,3 critical for proper endochondral ossification during bone morphogenesis2,3 and fracture healing, we hypothesized that mechanical cues would be important for endochondral regeneration.4,5 Here, using fixation plates that modulate ambulatory load transfer through dynamic tuning of axial compliance, we found that in vivo mechanical loading was necessary to restore bone function to large bone defects through endochondral ossification. Endochondral regeneration produced zonal cartilage and primary spongiosa mimetic of the native growth plate. Live human chondrocytes contributed to endochondral regeneration in vivo, while cell devitalization prior to condensation transplantation abrogated bone formation. Mechanical loading induced regeneration comparable to high-dose BMP-2 delivery, but without heterotopic bone formation and with order-of-magnitude greater mechanosensitivity.6–8 In vitro, mechanical loading promoted chondrogenesis, and upregulated pericellular collagen 6 deposition and angiogenic gene expression. Consistently, in vivo mechanical loading regulated cartilage formation and neovascular invasion dependent on load timing. Together, this study represents the first demonstration of the effects of mechanical loading on transplanted cell-mediated bone defect regeneration, and provides a new template for recapitulating developmental programs for tissue engineering.

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Posted August 15, 2018.
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Recapitulating bone development for tissue regeneration through engineered mesenchymal condensations and mechanical cues
Anna M. McDermott, Samuel Herberg, Devon E. Mason, Hope B. Pearson, James H. Dawahare, Joseph M. Collins, Rui Tang, Amit N. Patwa, Mark W. Grinstaff, Daniel J. Kelly, Eben Alsberg, Joel D. Boerckel
bioRxiv 157362; doi: https://doi.org/10.1101/157362
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Recapitulating bone development for tissue regeneration through engineered mesenchymal condensations and mechanical cues
Anna M. McDermott, Samuel Herberg, Devon E. Mason, Hope B. Pearson, James H. Dawahare, Joseph M. Collins, Rui Tang, Amit N. Patwa, Mark W. Grinstaff, Daniel J. Kelly, Eben Alsberg, Joel D. Boerckel
bioRxiv 157362; doi: https://doi.org/10.1101/157362

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