Advisor: Wilbur Lam, M.D. Ph.D. (Georgia Institute of Technology, Emory University)
Brandon Dixon, Ph.D. (Georgia Institute of Technology)
Todd Sulchek, Ph.D. (Georgia Institute of Technology)
Susan Thomas, Ph.D. (Georgia Institute of Technology)
Hua Wang, M.D., Ph.D. (Emory University)
DEVELOPING MICROFLUIDIC SYSTEMS TO RESOLVE LONGSTANDING QUESTIONS in hematology
Recent research has revealed that cells dynamically sense and respond to their physical microenvironments. In hematology, it has been shown that shear mediated red blood cell (RBC) deformation results in ATP release, and that platelets attenuate contraction force based on substrate stiffness. The objective of this thesis is to create microfluidic systems in which the biophysical and biochemical aspects of hematological processes are independently investigated toward the aim of discovering new solution spaces for diagnostics and therapeutics. To that end, this defense presents novel microfluidic systems: 1) an “endothelial”-ized, T-junction fluidic to elucidate the biophysical processes that define the mechanism of action of the ferric chloride thrombosis model and 2) microfluidic devices with single-micron features (pillars and canals) to examine the effects of physical interactions between blood cells—RBCs, platelets, and neutrophils—and geometrically relevant, non-biological matrices at the single cell level. Using this suite of devices, I resolve the mechanism of action of the FeCl3- thrombosis model, begin to characterize RBC fragmentation parameters, and give new insight into the pathological role of neutrophils in thrombosis. Microfluidic platforms allow for real-time, microscopic evaluation of cell response (via brightfield morphology and immunostaining) and precise spatiotemporal control of system inputs and flow characteristics, including shear stress. The mechanistic understandings gained by creating systems that successfully decouple the biophysical and biological aspects of blood cells, as is done in this work, can result in enhanced understanding of the etiology of pathologies, improved diagnostic assays for blood cell activity, and new targets for therapeutics.