Systemic and local immunomodulation of fracture healing in polytrauma - Project Summary The economic cost of traumatic injuries accounted for approximately 20% of the US economy in 2019, and were a top ten cause of death in the United States.1 More than one half of this cost ($2.4 trillion) was among working- aged adults (aged 25–64 years).1 Musculoskeletal injuries, including fractures, are by far the most commonly involved body system injured in multisystem trauma.2 This interaction of systemic trauma and fracture healing has profound effects on patient recovery, quality of life, and societal resource utilization. The field of bone regeneration has been primarily focused on healing fractures and treating bone loss in the context of isolated musculoskeletal injuries. Most closed, isolated fractures heal well in contrast to fractures in polytrauma patients which exhibit impaired healing in greater than 30% of cases.3,4 Clinical evidence suggests there may be distinct physiologic, cellular, and molecular mechanisms contributing to fracture repair in polytrauma. The underlying mechanisms contributing to fracture repair in polytrauma environments are poorly studied. This proposal is structured to interrogate the role of polytrauma on fracture repair. Leveraging my combined orthopaedic surgeon clinical experience and training in mechanistic research, I will investigate the role of inflammation and immunomodulation in a polytrauma model of fracture healing, focusing specifically on the response of mesenchymal stromal cells (MSCs). (1) I will first characterize the upregulation of inflammatory cytokines and innate immune cells both systemically and locally at the fracture site in the presence and absence of polytrauma. (2) I will then characterize the anti-inflammatory and therapeutic effects of MSCs on fracture healing when delivered systemically versus locally to the fracture site in a murine polytrauma model. My career goal is to conduct clinically relevant mechanistic research as an orthopaedic traumatologist. This K08 proposal will allow me to focus my efforts on acquiring the skills necessary to become a successful, independent clinician-scientist. My prior experience in the lab has afforded me the deep appreciation for the rigors of scientific inquiry, experimental design, and data analytics. I am already quite familiar with many techniques and through this career development grant, I will expand my mechanistic skillset. This award will provide a solid foundation for ongoing rigorous study design, execution, troubleshooting, and data management that will launch an independently funded, clinically relevant, research career. My advisory committee is comprised of highly accomplished and diverse group of mentors who will help catalyze my continued growth into a competitive researcher in the field of bone injury and healing. I am fortunate to be part of a world-class trauma unit with clinical partners who will support my clinical load and protect my time for the intensive demands of executing rigorous science. By harnessing my unique position, I will focus my research endeavors to combat the ubiquitous societal scourge of musculoskeletal trauma and advance fracture care with a goal of enabling patients to recover more effectively.
