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

美国-爱尔兰 R

• 批准号: 2127527
• 负责人: Spencer Szczesny
• 金额: $ 47.32万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2127527&HistoricalAwards=false
• 关键词: US; Ireland; R& Partnership; Design

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.

该奖项将支持最终目标是在实验室中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其他部位或死者的肌腱替换撕裂的组织。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替代撕裂的组织，不幸的是，没有材料或生物组织能够复制人类肌腱的功能或已成功用于治疗患者。项目将提供在实验室中生产能够替代肌腱和韧带的坚固组织所需的基础知识，这将通过研究肌腱在动物胚胎中自然形成的方式来实现。此外，通过鼓励实验室来增强制造人工肌腱的现有技术。 -生长的组织遵循更类似于正常肌腱发育的发育途径，这些结果将最终改善人类健康，并通过减少因治疗结果不佳而导致的医疗成本来改善美国经济。此外，美国与爱尔兰支持的国际合作。研发合作伙伴赠款将加强培训通过使用多尺度机械测试、超微结构成像和计算模型，这项研究将建立组织工程结构复制肌腱遗传功能必须满足的基本结构和机械基准。对胚胎鸡肌腱的操纵将确定触发肌腱发育后期观察到的结构变化的机械传导机制。此外，该项目将开发一种新型纳米颗粒-水凝胶基因传递系统，用于操纵肌腱结构的成熟。最后，这些技术将最终研究驱动胚胎肌腱发育的外源性启动机械传导机制是否能够满足既定的结构和机械基准。这项工作将通过将肌腱发育生物学知识应用于组织工程，在生产坚固的拉伸承重软组织方面取得突破。此外，暂时操纵发育中雏鸡胚胎特定组织内基因活性的新方法将广泛推进。操纵肌腱结构中分子信号通路的能力也将反映研究驱动肌腱发育的关键要素的模型系统。该奖项是 NSF 的法定使命，并通过使用基金会的智力价值和评估进行评估，被认为值得支持。更广泛的影响审查标准。