DEVELOPING IN-VITRO SYNTHETIC BLOOD CLOT MODELS FOR TESTING THROMBOLYTIC DRUGS

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DEVELOPING IN-VITRO SYNTHETIC BLOOD CLOT MODELS FOR TESTING THROMBOLYTIC DRUGS

thesis
posted on 21.04.2022, 16:34 authored by Ziqian ZengZiqian Zeng

  

Thrombosis is the pathological formation of a blood clot in the body that blocks blood circulation, leading to high morbidity and mortality rates. Thrombolytic drugs that offer rapid clot dissolution are promising treatments yet current drugs are often associated with limited efficacy and high bleeding risks. While numerous animal thrombosis models have been developed for drug screening, the translation of therapeutic agents into and through clinical trials remains limited. This is largely due to animal models’ poor reproducibility and distinctive physiology to that of humans. In-vitro flow models that utilize both human blood components and physiologically relevant flow conditions can provide for a more representative testing environment to screen thrombolytic drugs. Developing better in-vitro models may not eliminate the need for preclinical animal testing but can help exclude inefficient agents earlier in the drug development pipeline to expedite the drug evaluation process. Existing in-vitro thrombolysis flow models are not ideal as they either adopt over-simplified clot substrates or utilize small-length-scale geometries that insufficiently mimic native hemodynamics. Thus, we propose to first develop a static fluorescently labeled clot lysis assay for an initial high throughput screening of thrombolytic drugs, and ultimately engineer a highly reproducible, physiological scale, flowing clot lysis model for more human relevant drug efficacy evaluation. Developing the static clot lysis assay not only helps to understand the mechanism of how diversified clotting conditions affect clot properties but also offer a chance to well-characterize fluorescence conjugations to fibrins. The ultimate flow model combines an in-vivo-like fluorescence incorporated synthetic clot (FISC) and a human-relevant flow system. Guided by results from static clotting experiments diversified FISCs are fluorescently optimized and fabricated dynamically using a Chandler loop setup at various conditions. The flow system is a tubing-based structure that comprises of a peristaltic pump, and a well-controlled flow chamber to provide for physiological shear and pulsatile levels. Therefore, the proposed synthetic clot model is a versatile platform that can mimic a variety of thrombosis conditions and offer representative drug testing and dosing results across numerous thrombolytic agents.

History

Degree Type

Doctor of Philosophy

Department

Biomedical Engineering

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

NATHAN J. ALVES

Advisor/Supervisor/Committee co-chair

SHERRY L. VOYTIK-HARBIN

Additional Committee Member 2

JULIE C. LIU

Additional Committee Member 3

VITALIY L. RAYZ