Exosome Therapy for Stabilization of Extremity Injury

Objectives and Rationale: Extremity injuries, injuries to the upper and lower limbs, accounted for over two-thirds of the inpatient hospital costs and disability payments for Veterans of Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF). Extremity wounds frequently involve prolonged ischemic periods, which increase the risk for reperfusion injury. Therapeutic agents that can preserve and stabilize musculoskeletal tissues under these conditions will increase success with limb salvage and reduce the length of time required for recovery. Extracellular vesicles (EVs) secreted by stem cells have shown potential for stabilizing tissues during ischemic conditions. A key advantage of these vesicles in the prolonged field care (PFC) environment is that they are relatively stable through multiple freeze-thaw cycles and can be lyophilized into a dry powder that retains its bioactivity. Our application tests the hypothesis that these vesicles can be utilized effectively in the PFC setting to mitigate ischemia-reperfusion extremity injury.

Applicability: We envision stem cell-derived EVs as a novel approach to support tissue repair and tissue salvage during PFC. One immediate benefit of our study will be the preclinical assessment of EV therapy for limb ischemia-reperfusion injury. In addition our application will, for the first time, evaluate the comparative effectiveness of EV therapy relative to other proposed treatments for mitigating reperfusion injury such as hydrogen sulfide, Etanercept, erythropoietin, and C1 esterase inhibitors.

Relevance for Focus Areas: Our application is directed specifically to Focus Areas 2 and 3 of the Prolonged Field Care Research Award Program. The goal of Focus Area 2 is to develop next-generation resuscitation and stabilization methods for PFC and prolonged Damage Control Resuscitation (pDCR). The goal of Focus Area 3 is to develop enhanced treatment of injuries during PFC and pDCR. Technologies developed in Focus Area 3 will prevent infection, minimize further tissue loss, protect underlying tissues/organs, reduce ischemia and secondary injury, reduce pain and suffering, and provide safe transport in support of pDCR and/or remote operating environment scenarios. The in vivo studies proposed in our application will facilitate the development of stem cell-derived EVs as a new therapeutic approach for the treatment of extremity injury in the PFC environment.

Broader Impacts and Clinical Translation: Ultimately, our proposed therapeutic approach utilizing stem cell-derived EVs for tissue repair and tissue salvage could be applied to other types of combat-related injury. These may include traumatic brain injury, where stem cell-derived EVs have been shown to promote functional recovery, or burns where adipose-derived stem cells can improve wound healing after thermal injury . Ischemic injury is a complication that occurs in a number of different organs (e.g., myocardial ischemic injury, kidney ischemic injury, traumatic brain injury) and impacts broad segments of the civilian population. The proposed research, by advancing stem cell EV therapy as a novel approach for treating ischemic injury, will therefore serve the public purpose by addressing the healthcare needs of not only active duty military personnel, their families, and Veterans, but also civilians for whom ischemic injury is a major cause of morbidity and mortality.