Engineering Intravenous Therapies for Trauma

Abstract

Trauma leading to severe hemorrhage and shock on average kills patients within 3 to 6 hours after injury. With average prehospital transport times reaching 1-6 hours in low- to middle-income countries, stopping the bleeding and reversing hemorrhagic shock is vital. This thesis aims to develop a “Bridge to Blood” that combines PolySTAT, an intravenous hemostat that crosslinks fibrin at the wound site, with a Low Volume Resuscitant (LVR) designed to refill the vascular space after severe hemorrhage. For PolySTAT, the main goals of this work have been to continue its translation through the optimization of its water solubility and synthesis method (Chapter 2), to determine its safety and efficacy in large animal models (Chapter 3), and to understand mechanistically how PolySTAT affects coagulation (Chapter 4). All of these chapters support the clinical translation of PolySTAT and gather the data necessary for an Investigational New Drug Application with the FDA. For the LVR, the goal of this work was to show proof of concept of how to engineer polymer chemistry, structure, and architecture to provide the desired oncotic effect in vivo and to avoid disruption of coagulation in in vitro assays (Chapter 5). This chapter has set the foundation for the lab to engineer new LVRs and complete the “Bridge to Blood”. Chapter 6 demonstrates how to leverage the flexible nature of the PolySTAT platform, and its ability to target fibrin networks in vivo, to target to and activate CAR T Cells in solid tumors as a potential treatment for cancer. The final chapter, Chapter 7, outlines future work to build on the PolySTAT and LVR platforms in hopes of overcoming challenges identified from the work completed in the previous chapters.