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BIO-INSPIRED ENZYME RESPONSIVE NANOTECHNOLOGIES FOR THE TREATMENT OF BLEEDING DYSFUNCTIONS

Sekhon, Ujjal Didar Singh
http://rave.ohiolink.edu/etdc/view?acc_num=case162179711461253

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Transfusion of donor-derived platelets is a clinical standard-of-care to treat bleeding risks and hemorrhagic complications in hematology/oncology, surgery, trauma and congenital platelet disorders. However, these platelet products face severe logistical challenges due to their limited availability and portability, high risk of bacterial contamination and extremely short (5-7 days) shelf-life. This can be potentially addressed by designing `synthetic platelet surrogates’ that functionally and modularly mimic platelet-mediated hemostatic mechanisms and allow in vitro manufacture and scale-up for on-demand use. To this end, a novel liposome-templated procoagulant synthetic platelet (P-SP) nanoparticle system was engineered that: (i) Achieves platelet-mimetic ability of injury selective adhesion and aggregation via specific activity of vWF-binding, collagen-binding and active platelet integrin αIIbβ3-binding peptides decorated on the nanoparticle, and (ii) Mimics platelets’ procoagulant mechanism of phosphatidylserine (PS) exposure for thrombin amplification in a unique plasmin-responsive manner using a plasmin-cleavable cholesterol-tethered polyethylene glycol (PEG) mask on the nanoparticle surface. This design exploits the local plasmin upregulation at a vascular injury site to expose the procoagulant PS, amplify thrombin, and augment fibrin generation site-specifically for augmenting clot quality and stability. In vitro evaluation in human plasma confirmed that P-SP enables plasmin-responsive PS exposure, coagulation factor assembly and enhanced thrombin generation even when native platelets were depleted. In vitro analysis in human plasma and whole blood showed that P-SP significantly improves clot robustness and stability against lysis by in situ fibrin generation. Additional in vitro studies revealed P-SP’s ability to rescue hemostatic function in antiplatelet drug induced platelet dysfunction scenarios. In vivo in a mouse thrombocytopenia (TCP) model, the P-SP vesicles significantly reduced tail-bleeding time and blood loss, comparable to syngeneic platelet dose. Furthermore, in a rat liver hemorrhage model, the P-SP vesicles significantly reduced bleeding and improved survival. No sign of systemic thrombotic risks was found in either animal model. These studies demonstrate the potential of a bioinspired enzyme responsive nanotechnology platform as a viable platelet surrogate for transfusion management of bleeding when natural platelets are of limited availability or have diminished function.
Anirban Sen Gupta, PhD (Advisor)
422 p.
Biomedical Engineering; Biomedical Research

Recommended Citations

Citations

  • Sekhon, U. D. S. (2021). BIO-INSPIRED ENZYME RESPONSIVE NANOTECHNOLOGIES FOR THE TREATMENT OF BLEEDING DYSFUNCTIONS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case162179711461253

    APA Style (7th edition)

  • Sekhon, Ujjal Didar Singh. BIO-INSPIRED ENZYME RESPONSIVE NANOTECHNOLOGIES FOR THE TREATMENT OF BLEEDING DYSFUNCTIONS. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case162179711461253.

    MLA Style (8th edition)

  • Sekhon, Ujjal Didar Singh. "BIO-INSPIRED ENZYME RESPONSIVE NANOTECHNOLOGIES FOR THE TREATMENT OF BLEEDING DYSFUNCTIONS." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case162179711461253

    Chicago Manual of Style (17th edition)

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