Grants We Funded

Abstract
With over 100 million individuals affected annually, musculoskeletal trauma poses a unique challenge to clinicians and patients. Beyond the initial injury, patients with complex trauma are at high risk for pathologic healing and development of heterotopic ossification (HO). HO is the pathologic formation of extra-skeletal bone occurring in 20% of patients with severe musculoskeletal trauma, joint arthroplasty, pressure ulcers and burn injuries leading to substantial patient morbidity including chronic pain, open wounds, reduced joint mobility, and the need for surgical excision. We have previously established a mouse trauma model which has allowed us to study the phases of HO formation and to demonstrate that injury site immobilization reduces inflammation and HO. However, there are currently no clinical guidelines that direct immobilization protocols. Furthermore, the mechanism through which immobilization mitigates inflammation remains unknown. Recently, structural components released by neutrophils, known as neutrophil extracellular traps (NETs), have been implicated as critical elements in driving acute inflammation at the HO site and we have demonstrated that mechanical disruption of NETs during limb movement augments inflammation and promotes HO. Our central hypothesis is that early timed temporary immobilization of the affected injury site will mitigate inflammation through stabilization of NETs. Furthermore, pharmacologic inhibition of NET formation and propagation will reduce inflammation necessary for ectopic bone formation and therefore prophylax against HO. In specific aim 1, we will establish an optimal protocol for timed immobilization of the injury site using our validated Achilles tendon burn/tenotomy model. Furthermore, we will identify how mechanical disruption during limb movement alters NETs and validate a pharmacological inhibitor of primary NETosis (CI-Amidine) to reduce neutrophil and macrophage infiltration at the mobile tendon transection site during early phases after injury. In specific aim 2 we will target toll-like receptor 9 (TLR9), a known immune receptor contributing to NETs mediated inflammation, through pharmacologic inhibition (ODN-2088) or genetic loss (TLR-/-) in order to assess the effect of systemic inhibition of secondary NETosis. Our objective is to demonstrate that these novel interventions can mitigate NET formation and prevent HO thus providing the clinician with a powerful treatment armamentarium.

Biography
While I was born in St. Petersburg, Russia, my family relocated to Germany at a young age where I spend the formative years of my professional education. After developing a keen interest in plastic surgery I decided to pursue a career as an academic surgeon. I was intrigued by the excellence in education and teaching provided in the United States and, after graduation from medical school, was privileged to complete a postdoctoral fellowship under the mentorship of Drs. Gurtner and Longaker at Stanford University. In my research, I focused on projects in the fields of regenerative medicine, wound healing and tissue engineering and was fortunate to publish in prominent journals including Nature Medicine and Nature Communications. Learning from my mentors I was able to acquire a skill set to successfully accomplish complex scientific projects. Over the past three years as a plastic surgery resident at the University of Michigan I have been building the clinical foundation of my academic surgical career. I have remained strongly invested in research and have collaborated with Dr. Levi on multiple projects that were the basis for this application. I am confident that my research experience has uniquely prepared me to accomplish the goals of this proposal. The PSF National Endowment award will form the foundation for my academic career, my first NIH K award submission and will further allow me to transition to an independent plastic surgeon scientist.