The research presented in this proposal has been designed to develop a platform from which I can build a foundation for a career as an independent investigator. The objective of this proposal is to develop a composite bone and muscle injury model which we will then use to test engraftment of novel constructs and the resultant tissue regeneration and limb function. It is hypothesized that bone regeneration will be impaired in the presence of injury to the surrounding muscle and that this impairment will be overcome using novel tissue engineered muscle constructs to promote both muscle and bone regeneration.
The specific aims to address this hypothesis are:
Specific Aim I - To develop a composite injury model in the rat and quantitatively investigate the effect of muscle injury on bone regeneration and restoration of limb function.
Specific Aim II - To quantitatively analyze the functional contribution of novel muscle therapeutics and constructs to bone regeneration in a composite injury model. We will comprehensively and quantitatively characterize the functional deficit as a measure of gait and muscle strength along with revascularization and numerous bone regeneration metrics. This composite injury model will serve as a new model to test novel tissue engineered constructs and therapeutics for both muscle and bone to investigate bone regeneration in the presence of a muscle injury. Further understanding of the interaction between muscle and bone during the regenerative process will help lead to improved treatments. I have a successful record in developing novel animal models through collaborative projects and am therefore uniquely qualified to succeed in this project. In addition to the research component, this fellowship will give me the necessary skills to be a successful independent investigator. I will receive training in surgical techniques for new animal models, grant and manuscript writing, teaching and mentoring. The Guldberg laboratory is recognized internationally as a leader in the use of high resolution imaging techniques in the field of regenerative medicine and has produced numerous successful tenure track investigators. This will be an excellent training experience for me that will prepare me for the rest of my career.
The management of large bone defects caused by trauma, degenerative disease, or tumor resection remains one of the most challenging problems faced by orthopaedic surgeons. It is critical that we develop technologies that are practical and effective for repair of large multi-tissue defects. Current therapies are only effective when sufficient tissue is present and, even then, may lead to scar formation and limited restoration of function. The proposed research will thus benefit the general public by identifying effective treatment strategies for composite tissue injuries sustained via a broad range of traumatic incidences.
|Li, Mon Tzu A; Willett, Nick J; Uhrig, Brent A et al. (2014) Functional analysis of limb recovery following autograft treatment of volumetric muscle loss in the quadriceps femoris. J Biomech 47:2013-21|
|Willett, Nick J; Li, Mon-Tzu A; Uhrig, Brent A et al. (2013) Attenuated human bone morphogenetic protein-2-mediated bone regeneration in a rat model of composite bone and muscle injury. Tissue Eng Part C Methods 19:316-25|