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Sci Adv. 2019 Aug 28;5(8):eaax2476. doi: 10.1126/sciadv.aax2476. eCollection 2019 Aug.

Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair.

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Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania.
Philadelphia, PA, USA.
Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, USA.
School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH, USA.


Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-β1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-β1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-β1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

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