Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania.
Sci Adv. 2019 Aug 28;5(8):eaax2476. doi: 10.1126/sciadv.aax2476. eCollection 2019 Aug.
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.
在长骨发育和自然骨折愈合过程中，软骨内骨化起始于间充质细胞的凝聚，由局部形态发生素信号和机械线索引导。在这里，我们旨在模拟发育过程以实现大骨缺损的再生。我们假设，封装微球中呈现的工程化人骨髓间充质凝聚物中的转化生长因子-β1（TGF-β1）和/或骨形态发生蛋白-2（BMP-2），可根据体内机械线索促进软骨内缺陷的再生。间充质凝聚物诱导骨形成依赖于形态发生素的呈现，BMP-2+TGF-β1 完全恢复了机械功能。延迟的体内可动性负荷显著提高了双形态发生素组的骨形成速率。在体外，BMP-2 或 BMP-2+TGF-β1 引发了强大的软骨内谱系承诺。然而，体内实验中，BMP-2+TGF-β1 组中明显存在大量软骨形成，机械负荷增强了这种形成。总之，这项研究展示了一种仿生模板，可在体内重现组织工程中的发育形态发生和机械线索。
