Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically-responsive bioartificial tissue that responds to mechanical loading to produce a pre-programmed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically-sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug, interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not direct cellular deformation, suggesting tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically-relevant loading.

中文翻译：

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用于在工程组织中自主递送药物的合成机械遗传基因电路

机械生物学信号调节生理和病理条件下的细胞反应。利用合成生物学和组织工程学，我们开发了一种机械响应性生物人工组织，该组织可响应机械负荷以产生预编程的治疗性生物药物。通过解构由激活机械敏感离子通道瞬态受体电位香草酸4（TRPV4）诱导的信号网络，我们在软骨细胞中创建了合成的TRPV4反应性遗传电路。我们将这些细胞工程化为通过产生抗炎性生物药物白介素1受体拮抗剂对机械负荷作出反应的活组织。软骨细胞TRPV4是通过渗透负荷激活的，而不是直接引起细胞变形的，这表明组织负荷被转换为激活TRPV4的渗透信号。用TRPV4应答回路转导的组织的渗透压或机械负载可保护构建体免受白介素1引起的炎症降解。这种合成的机械生物学方法被用于开发一种机械生成系统，以实现由生理相关负荷驱动的长期，自主调节的药物递送。