Uncontrolled bleeding is a significant clinical problem in both civilian and military traumatic injuries; inboth cases, exsanguination prior to hospitalization is the primary cause of death for both men and women.Furthermore, healing following trauma can be complicated by infection, keloid formation, insufficient blood flow,or conditions such as diabetes and obesity. Clot formation is critical to the cessation of bleeding after traumaand involves the activation of circulating platelets that hone to the site of injury and aggregate to form a plateletplug, stemming bleeding. Activated platelets also bind fibrin fibers forming at a site of injury to form a platelet-fibrin mesh. Platelets then utilize actin-myosin machinery to apply forces to the clot network, contracting andstabilizing the clot and facilitating its role as a provisional matrix to support subsequent cellular infiltration of thewound environment. In cases of traumatic injury, exsanguination can cause platelets to become depleted,impairing their ability to stop bleeding and promote healing. Platelet transfusion is the current standard of care;however, isolated platelets have a short shelf-life, contributing to major supply chain issues. Additionally,potential immunologic concerns associated with transfusion of blood products highlights the critical unmet needto develop platelet alternatives to treat bleeding after trauma. We have recently developed synthetic platelet-likeparticles (PLPs) created from highly deformable microparticles coupled to fibrin-targeting motifs that are capableof honing to injuries through high affinity binding to fibrin forming at the sites of injury. Our initial studiesdemonstrate that PLPs are able to recapitulate several functions of native platelets, including clot augmentationin vitro, decreasing bleeding times and overall blood loss in in vivo rodent models of trauma, and improvedhealing responses in vivo following injury. The long-term goal of this project is to develop hemostatic PLPs foremergency medicine applications to augment clotting and decrease blood loss and associated deaths due toexsanguination. The objective of this application is to evaluate the long-term stability and safety of PLPs. Ourcentral hypothesis is that PLPs will have significantly superior shelf-life compared to native platelets whilemaintaining a maximum tolerated dose well above their therapeutic dosage, thereby supporting moving thistechnology forward into further preclinical development. The specific aims of this project are: 1) Determine PLPstability and 2) Determine maximum tolerated dose. RELEVANCE TO PUBLIC HEALTH
This project is relevant to NIH's mission as it focuses on developing a novel platelet-like-particle therapeutic for
treatment of bleeding after trauma. Actins ; Bleeding time procedure ; Bleeding Time ; Blood ; Blood Reticuloendothelial System ; Blood Coagulation Disorders ; Coagulation Disorder ; Coagulopathy ; bleeding disorder ; clotting disorder ; Blood Platelets ; Marrow platelet ; Platelets ; Thrombocytes ; Blood Transfusion ; Cause of Death ; Cessation of life ; Death ; Diabetes Mellitus ; diabetes ; Elements ; Emergency Medicine ; Female ; Fibrin ; Goals ; Hemorrhage ; Bleeding ; blood loss ; Hemostatic Agents ; Hemostatics ; Hospitalization ; Hospital Admission ; In Vitro ; Infection ; intravenous injection ; Keloid ; keloid skin disorder ; male ; men ; men's ; Military Personnel ; Armed Forces Personnel ; Military ; military population ; Mission ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Myosin ATPase ; Actin-Activated ATPase ; Myosin Adenosine Triphosphatase ; Myosin Adenosinetriphosphatase ; Myosins ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Obesity ; adiposity ; corpulence ; Particle Size ; Public Health ; Cell Surface Receptors ; Role ; social role ; Safety ; Technology ; Temperature ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Time ; Weight ; Woman ; fibrin receptor ; Platelet Transfusion ; Blood Platelet Transfusion ; Plts ; Injury ; injuries ; dosage ; Organ ; improved ; Site ; Area ; Clinical ; Evaluation ; Fiber ; Blood flow ; Therapeutic ; Morphology ; Shapes ; Contracting Opportunities ; Contracts ; Life ; blood product ; particle ; tech development ; technology development ; aqueous ; novel ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; response ; Molecular Interaction ; Binding ; Clotting ; Coagulation ; Coagulation Process ; Dose ; Affinity ; in vivo ; Cellular Infiltration ; Rodent Model ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Monitor ; healing ; response to injury ; injury response ; Trauma ; Coupled ; innovation ; innovate ; innovative ; Impairment ; stem ; standard of care ; Traumatic injury ; preclinical development ; pre-clinical development ; wound environment ;
