Design and performance of hemostatic biomaterials for managing hemorrhaging
Author(s)Avery, Reginald Keith
Massachusetts Institute of Technology. Department of Biological Engineering.
Bradley D. Olsen.
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The high mortality rates associated with uncontrolled bleeding motivate hemostatic material development for traumatic injuries. Uncontrolled, or hemorrhagic, internal bleeding requires hemostatic materials that can be directly delivered to or target the bleeding locations. To address these needs, injectable systems are being developed that: (1) generate artificial clots independent of the coagulation cascade or (2) interact with blood components to accelerate or otherwise improve coagulation processes. Hemostatic materials designed for internal bleeding can save lives in the battlefield, en route to emergency rooms, and in the operating room. This thesis first focuses on developing a shear-thinning hydrogel for injection onto bleeding surfaces and into ruptured vasculature. Based on in vitro assays of hydrogel performance, it was amenable to clinical delivery methods and reduced whole blood clotting times by 77%. In vivo bleeding models showed reduced blood loss and improved survival rates following a lethal liver injury. The hydrogel was also used as an embolic agent, where its occlusive potential in an anticoagulated model was demonstrated. Next, recombinant protein-based hemostatic materials were expressed to modulate clotting kinetics and performance. By incorporating clot interacting peptide sequences (CIPs) into a protein scaffold, a family of multifunctional fibrinogen like proteins (MFLPs) was developed and assayed. Clot turbidity, an indication of fibrin clot formation, was increased among enzyme-interacting CIPs. Mimicking the polymerization mechanism of fibrinogen, knob sequences were shown to be procoagulant at low concentrations by increasing clot turbidity, reducing clotting times, and inhibiting plasmin lysis. Finally, to understand the impact of hemostats on clot structure, imaging procedures were developed to systematically assess hemostatic materials and their influence on clot architecture. Static and dynamic approaches were developed to quantify the activity of hemostats based on the spatial distribution of fibrinogen, red blood cells, and platelets around hemostat surfaces. Quantification of these hemostat-blood component interactions resulted in a unique pattern of interactions for each hemostat studied. These techniques could serve as a screening technique for hemostats and improve characterization prior to in vivo assays. Taken together, the results highlight multiple approaches to address internal bleeding and opportunities to improve in vitro characterization of hemostats using microscopy.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2018.Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering.; Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology