Uncontrolled hemorrhage is the leading cause of combat deaths, accounting for over 90% of preventable deaths. Trauma-induced coagulopathy, or shock, is a major driver of trauma mortality, causing increased bleeding, heightened resuscitation requirements, and a four-fold increase in mortality. It is responsible for nearly 50% of deaths in the first 24 hours after injury, and represents the leading cause of preventable deaths. This is true in both military and civilian settings of traumatic injury. Effective management of trauma-related hemorrhage and shock is urgently needed to reduce mortality in combat casualty care and, in particular, prolonged field care. The gold standard for mitigating hemorrhage and shock is transfusion of whole blood (WB) or ratio matched blood components (red blood cells [RBCs], platelets, and plasma) as early as possible. However, blood products are not readily available for pre-hospital use in hemostatic resuscitation. In this proposal, we seek to develop a novel nanotechnology-enabled solution to address non-compressible torso hemorrhage control and increase survival after traumatic injury, which is a Combat Readiness Medical Research Program Rapid Development and Translational Research Award focus area.

Widespread use of WB or blood component transfusion faces several logistical challenges. Firstly, there is a persistent issue of donor shortage. Furthermore, fresh WB needs to be used within 24 hours, cold-stored WB preferably within 10 days, isolated RBCs within 20-40 days, and isolated platelets have a shelf-life of only ~5 days at room temperature, all of which limit the adequate availability and timely transfusion of these products. Robust efforts are being directed at resolving many of these challenges, e.g., utilization of pathogen reduction technologies and reduced temperature storage (cold-stored, freeze-dried, etc.) to minimize contamination, extend shelf-life, and improve availability/portability. An alternative approach that can complement these efforts is the engineering of “blood surrogates,” e.g., synthetic RBC and platelet surrogates, that can be manufactured in vitro at large scale, sterilized to minimize contamination, and have very long (months-to-years) shelf-life, portable as small volume suspension or freeze-dried powder, and can be administered intravenously on-demand at point of injury, en route, and in prolonged field care settings for hemostatic resuscitation of injured/hemorrhaging patient when natural blood products are of limited supply. Breakthroughs in synthetic chemistry and nanofabrication now permit design of novel bio-inspired blood component surrogates to optimize oxygenation and hemostasis. With this vision, Haima Therapeutics has developed SynthoPlate (SP), a hemostatic peptide-decorated lipid nanoparticle (platelet surrogate) and Kalocyte has developed a hemoglobin (Hb)-incorporating lipid-polymer hybrid nanoparticle (RBC surrogate), ErythroMer (EM). Both have shown tremendous promise individually, in improving tissue oxygenation (EM) and hemostasis (SP). Furthermore, Haima and Kalocyte will be working with Teleflex to co-formulate EM and SP with freeze-dried plasma (FDP) to create the world’s first biosynthetic whole blood surrogate (WBS) for remote damage control resuscitation applications.

Our central innovation is to compose a “dried whole blood surrogate” by combining EM, SP, and FDP in a fashion that can provide rapid rescue from hemorrhagic shock by driving tissue oxygenation and hemostasis and help realize the goal of zero preventable deaths after injury. Beyond the scope of this application, an Investigational New Drug application will be submitted to test the safety of the proposed combination product in Phase I clinical trials. Our initial primary indication for Food and Drug Administration approval for the WBS will be first-line treatment after traumatic injury during pre-hospital transportation. This vision aligns with the Combat Readiness Medical Research Program Rapid Development and Translational Research Award announcement listing the following focus area to improve readiness for delivering frontline care in combat situations and delivering lifesaving interventions during prolonged and en route care in austere and combat environments: Solutions that address hemorrhage control, including non-compressible torso hemorrhage.

Beyond mitigating trauma, the WBS co-formulation product has potential label expansion to mitigate bleeding for surgery, thrombocytopenia, and postpartum hemorrhage.