ThinkIR: The University of Louisville\u27s Institutional Repository
Abstract
T-cell transformation is an ever-expanding treatment for several types of cancer, with a potential to be adapted to other disorders in which the immune system plays a key role in the pathophysiology. Currently, all FDA approved chimeric antigen receptor (CAR) T-cell cancer therapies rely on transformation via viral transduction. However, viral transduction is plagued by poor consistency and the potential to create adverse immune reactions when T-cells are reintroduced into a patient. Other transformation methods are being explored, with an alternative called acoustofluidic sonoporation showing promise. In these procedures, cells are passed through a channel, of the millimeter scale, while ultrasound (US) is applied. The US causes unstable cavitation of perfluorocarbon microbubbles (MBs) resulting in rupture that reversibly permeabilizes cells, allowing entry of almost any water-soluble biologic (e.g. DNA/RNA, small molecules, etc.). While current research demonstrates that acoustofluidic sonoporation may be better than other transfection methods, there is a limited understanding of the fluid dynamics within the acoustofluidic devices and the physical mechanisms of the alteration in cell permeability. In this thesis, computational fluid dynamic (CFD) modeling was utilized to simulate fluid and particle flow through various acoustofluidic channel geometries and the results were compared with biological delivery experiments to cells. It was found a 1-mm diameter Concentric Spiral channel is an optimal design as it maximizes wall shear stress (WSS) and US exposure, as compared to 1-mm and 2-mm diameter Rectilinear channels. With further refinement of the CFD simulations, optimization of channel geometry, flow rate, and US parameters could be enhanced. This optimization could enable acoustofluidic sonoporation to be translated into manufacturing of CAR T-cell therapies for clinical treatments of cancer and other disorders in the future
