US-Ireland R&D Partnership: Design of Genetically Engineered Tensile Load-Bearing Soft Tissues Inspired by Embryonic Tendon Development

该奖项将支持最终目的是在实验室制造肌腱和韧带的研究。目前，许多肌腱和韧带损伤的治疗需要用患者身体另一部分或死者的肌腱替换撕裂的组织。由于这两种选择都会导致并发症，理想的解决方案是使用人造肌腱来取代撕裂的组织。不幸的是，没有任何材料或生物组织能够复制人体肌腱的功能，也没有成功地用于治疗患者。该项目将提供在实验室中生产能够替代肌腱和韧带的强大组织所需的基本知识。这将通过研究肌腱如何在动物胚胎中自然形成来实现。此外，通过鼓励实验室培养的组织遵循更类似于正常肌腱发育的发育途径，现有的制造人造肌腱的技术将得到加强。这些结果最终将改善人类健康，并通过降低因治疗结果不佳而产生的医疗成本来改善美国经济。此外，由美国-爱尔兰研发伙伴关系基金支持的国际合作将加强对来自代表性不足人群的学生的培训，并使公众能够广泛参与。通过使用多尺度力学测试、超微结构成像和计算建模，这项研究将建立组织工程构建复制肌腱功能所必须达到的基本结构和力学基准。对鸡胚胎肌腱的基因操作将识别在肌腱发育后期观察到的触发结构变化的机械转导机制。此外，该项目还将开发一种新型的纳米颗粒-水凝胶基因传递系统，用于操控肌腱结构在体外培养和体内植入过程中的成熟。最后，这些技术将在一项研究中达到顶峰，研究驱动胚胎肌腱发育的机械转导机制的外源性启动是否会产生能够满足既定结构和力学基准的组织工程生物材料。总而言之，这项工作将通过将肌腱发育生物学的知识应用于组织工程，在生产坚固的拉伸承载软组织方面取得突破。此外，在发育中的鸡胚胎的特定组织中时间操纵基因活性的新方法将广泛地推动发育生物学领域的发展。在肌腱构造中操纵分子信号通路的能力也将提供一个模型系统来研究驱动肌腱发育的关键因素。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award will support research with the ultimate aim of creating tendons and ligaments in a laboratory. Currently, the treatment of many tendon and ligament injuries requires replacing the torn tissue with a tendon from another part of the patient’s body or from a deceased person. Since both of these options cause complications, the ideal solution would be to use an artificial tendon to replace the torn tissue. Unfortunately, no material or biological tissue has been able to reproduce the function of human tendons or has been successfully used to treat patients. This project will provide the fundamental knowledge necessary to produce strong tissues in a laboratory that are capable of replacing tendons and ligaments. This will be accomplished by studying how tendons form naturally in animal embryos. Additionally, the existing techniques for creating artificial tendons will be enhanced by encouraging lab-grown tissues to follow a developmental pathway that is more similar to normal tendon development. These results will eventually improve human health and improve the US economy by reducing healthcare costs resulting from poor treatment outcomes. Additionally, the international collaboration supported by this US-Ireland R&D Partnership grant will enhance training for students from underrepresented populations and enable broad public outreach.Through the use of multiscale mechanical testing, ultrastructural imaging, and computational modeling, this study will establish the essential structural and mechanical benchmarks that must be met for tissue engineered constructs to replicate tendon function. Genetic manipulation of embryonic chicken tendons will identify the mechanotransduction mechanisms that trigger the structural changes observed in late tendon development. Furthermore, this project will develop a novel nanoparticle-hydrogel gene delivery system for manipulating tendon construct maturation during in vitro culture and in vivo implantation. Finally, these techniques will culminate in an investigation of whether exogenous initiation of the mechanotransduction mechanisms that drive embryonic tendon development will produce a tissue-engineered biomaterial that can meet the established structural and mechanical benchmarks. Together, this work will provide a breakthrough in the production of robust tensile load-bearing soft tissues by applying knowledge of tendon developmental biology to tissue engineering. Additionally, the novel approach to temporally manipulate gene activity within specific tissues of developing chick embryos will broadly advance the field of developmental biology. The ability to manipulate molecular signaling pathways in tendon constructs will also provide a model system to study the key elements driving tendon development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.