Career Development Benefit: This award will allow me to forge the relationships required for continued mentorship and training in this area of research and to grow a nascent research effort focused on selected problems in orthopedic regeneration that can be addressed through biomaterials design. The objectives of this proposal are fully integrated with a comprehensive career development plan. My early career development aims focus on (1) learning to lead research teams and to sustain a growing research enterprise, (2) developing collaborations with clinicians working on combat-relevant problems in regeneration, (3) developing and using relevant models of bone marrow stem cell (MSC) survival in wound environments, and (4) developing expertise in stem cell biology, protein engineering, and orthopedics.

Applicability of Research: Regenerating bone tissue following traumatic injury is one of the most challenging medical problems facing wounded Warriors. Combat wounds are especially difficult to treat because injuries are so severe. The most promising approaches to address these challenges rely on the body's own source of MSCs to regenerate tissue and restore function.

However, MSCs are very rare, thus making regeneration of large wounds nearly impossible. The ideal source of MSCs is from the same patient (these are known as autologous MSCs). Use of autologous MSCs gets around the problem of having to use cells from another donor and a lifelong dependence on immune suppression, which vastly reduces quality of life. This work strives to develop methods to use the body's own MSCs by addressing two key limitations:

(1) Scarcity of autologous progenitor cells (MSCs). Overcoming this limitation is an essential first step in realizing the full regenerative potential of MSCs following catastrophic injury. This work describes methods to increase the number of autologous stem cells at sites of injury by using innovative methods from protein engineering and materials science to induce these cells to reproduce and contribute to tissue regeneration.

(2) Inability of existing implant materials to actively promote regeneration. Current implant materials are unable support the formation of new tissue with sufficient efficacy to fill large voids. We propose to increase the efficacy of a widely used orthopedic material in order to give it biologically active properties that will promote MSC growth and survival. The use of an existing material used in the clinic will greatly accelerate the testing and validation of this approach for actual clinical use.

If successful, this work could transform the way large bone injuries are treated and could give surgeons many more options to save limbs that would otherwise be amputated. The primary beneficiaries of this work will be Warfighters who suffer from traumatic injury to their limbs and other bone-related injuries. The clinical application of this work will be to transform an inert material used to fill bone voids into a biologically active material that can guide tissue regeneration. Benefits include the ability to treat much larger wounds and ultimately to salvage limbs.

The selection of an already clinically approved implant material to modify with growth factors will speed the development of this technology and accelerate its use in a clinical setting. Collaboration with Armed Forces Institute of Regenerative Medicine (AFRIM) researchers at MIT (Massachusetts Institute of Technology) and the Cleveland Clinic will take advantage of expertise in clinical development and greatly increase the likelihood of success. Evaluation of this approach in large animal models is planned for mid-2011. Successful results could put this technology in clinical trials by late 2012.