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Michael T. Griffin
BioE PhD Dissertation Defense
2:00 PM, Wednesday, December 11, 2019
IBB 1128 (Suddath Seminar Room)
Advisor: David N. Ku, MD PhD (Georgia Institute of Technology)
Committee:
Cyrus K. Aidun, PhD (Georgia Institute of Technology)
C. Ross Ethier, PhD (Georgia Institute of Technology)
Shannon L. Meeks, MD (Emory University)
Susan N. Thomas, PhD (Georgia Institute of Technology)
High Shear Arterial Thrombosis: Microfluidic Diagnostics and Nanotherapeutics
Atherothrombosis is the causal event in acute myocardial infarction and stroke. These occlusive arterial thrombi require the confluence of high shear rates from a stenosis, exposure of mural collagen from a ruptured plaque cap, and the aggregation of platelets on elongated vWF. A functional assay of thrombotic occlusion would be able to diagnose the propensity of individual patients to occlude and determine patient-specific drug regimens. Current platelet function tests do not have the relevant fluid mechanics, collagen surface, or proper anticoagulant to mimic arterial thrombotic occlusion. I have created an improved microfluidic assay that includes all the above factors, uses a small amount of whole blood, and is validated against clinical thrombosis over two orders of magnitude in size.
Antiplatelet therapies, such as aspirin and clopidogrel, have been developed to irreversibly inhibit platelet activation or binding. However, they do not work as intended for a large percentage of the population, as up to 60% of patients exhibit resistance to therapy per current non-specific platelet assays. Resistance persists even with dual antiplatelet therapy (DAPT). The poor therapeutic efficacy of current anti-platelet agents with their associated major bleeding risks indicate the need for both a functional thrombosis assay and improved antithrombotic agents.
The overall goal of this thesis is to develop a low variability device for clinical diagnostics and arterial thrombosis research. I hypothesize that the main sources of variability observed in previous microfluidic assays of thrombosis are due to three fundamental design factors of high relevance to arterial thrombosis. Secondly, I hypothesize that the endpoint of occlusion time in the improved assay will be sensitive to antiplatelet responsiveness. Finally, I hypothesize that such a device can be utilized to develop and evaluate new antithrombotic nanoparticle therapies. Both in vitro and in vivo models of thrombosis will be utilized to investigate the hypotheses in this thesis.
