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AdityaGirish_Dissertation Final .pdf (22.75 MB)

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Biomaterials Based Approaches for Treating Fibrin Defects in Bleeding Complications

Girish, Aditya
http://rave.ohiolink.edu/etdc/view?acc_num=case1639140703113543

Abstract Details

2022, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Non-compressible, uncontrolled hemorrhage resulting from traumatic injury or from hemostatic dysfunctions caused by congenital conditions, chronic disease or adverse drug reactions remains a major cause of mortality and injury worldwide. As a result, there is a substantial need for technologies and therapeutics that facilitate rapid stoppage of bleeding (hemostasis). Numerous clinical studies established that the gold standard of care is intravenous transfusions of whole blood (WB) or its components (plasma, platelets, red blood cells). However, availability of blood and blood products is limited outside of major hospitals. Use of blood products is also hampered by issues related to donor-dependence, portability, storage and contamination risks. In recent years, there has been substantial development of biomaterials-based technologies that can augment endogenous hemostatic mechanisms that are overwhelmed during massive hemorrhage. Many of these platforms focus on bolstering the initial phases of hemostasis, particularly the formation of platelet plugs at injury sites. However, hemostasis cannot be adequately maintained by platelets alone. The formation and stabilization of an insoluble, crosslinked fibrin mesh that rests on top of the platelet plug is critical to keeping it in place and preventing re-bleeding and further coagulopathic complications from occurring. To this end, I hypothesized that injury-site targeted enhancement of fibrin stabilization and de novo fibrin generation can augment hemostasis to treat coagulopathic bleeding. To test this hypothesis, I have developed three different platforms that improve different facets of fibrin stabilization and formation. The first technology delivers tranexamic acid (TXA) to injury sites, which can counteract excessive fibrin breakdown (hyperfibrinolysis) by plasmin, and thereby stabilizing fibrin. This platform significantly reduces bleeding and improves 72-hour survival odds in a rat liver hemorrhage model. The second technology I worked on, is a nanoparticle platform for injury-site targeted delivery of thrombin, which results in rapid formation of fibrin in vitro and reduction of blood loss in an in vivo mouse thrombocytopenia model. Lastly, I developed a fibrin-binding polymer that can crosslink fibrin and improve clot stability and resistance to lysis in vitro. Collectively, these technologies exemplify a novel, fibrin-focused biomaterials approach to hemostatic management that has heretofore been lacking.
Anirban Sen Gupta (Advisor)
Horst von Recum (Committee Chair)
Agata Exner (Committee Member)
Marvin Nieman (Committee Member)
218 p.
Biomedical Engineering; Biomedical Research; Engineering; Health; Health Care; Health Sciences; Materials Science; Pharmacology; Polymer Chemistry; Polymers
fibrin, fibrinogen, fibrinolysis, hyperfibrinolysis, injury, trauma, blood, bleeding dysfunction, platelet, hemorrhage, hemostasis, biomaterials, drug delivery, plasma, bleeding, clot, FXIIIa, thrombin, prothrombin, trauma-induced coagulopathy, coagulation, coagulation factors, tranexamic acid, tissue plasminogen activator, plasmin, plasminogen

Recommended Citations

Citations

  • Girish, A. (2022). Biomaterials Based Approaches for Treating Fibrin Defects in Bleeding Complications [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1639140703113543

    APA Style (7th edition)

  • Girish, Aditya. Biomaterials Based Approaches for Treating Fibrin Defects in Bleeding Complications. 2022. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1639140703113543.

    MLA Style (8th edition)

  • Girish, Aditya. "Biomaterials Based Approaches for Treating Fibrin Defects in Bleeding Complications." Doctoral dissertation, Case Western Reserve University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=case1639140703113543

    Chicago Manual of Style (17th edition)

case1639140703113543
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.