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

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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.