Enhancing cell membrane porosity using microbubbles in ultrasound

Development of a numerical tool to model sonoporation of endothelial cell membrane Sonoporation is an acoustical method to increase the permeability of membranesin particular endothelial cell membranes that line the inner walls of blood vesselsin order to extravasate large drug moleculesEnhanced permeabilization can be obtained due to the mechanical stress generated when microbubbles in the form of ultrasound contrast agents are excited inside a micro vessel using ultrasoundThe underlying fluid dynamics forces responsible for this stress can come from various sources vizshock waves emitted upon bubble collapseacoustic transients emitted from the bubbleshearing forces due to acoustic streamingor micro jets from aspherical bubble collapseA major impediment in rapid development of this technology is the lack of complete understanding of the underlying mechanismsi ethe details of the bubble and cells interaction as well as the sonoporation mechanismNumerical modeling coupled with fundamental experiments can help bridge this gapIn this SBIR workwe propose to develop a computational tool to model sonoporation of endothelial cell membrane using acoustically activated ultrasound contrast agentsThe numerical model will address non spherical bubble dynamics in a confined environment like a micro vesselIt will also model the vessel responsedeformationand potential mechanical micro failure and sonoporationWe will model the acoustic propagation through the inhomogeneous biological medium using a compressible Navier Stokes solver augmented with a Lagrangian mixed cell approach to track the interface between phases and to capture the deformations of the microbubblesA structural solver that treats the blood vessel as a viscoelastic material along with a contact surface model to simulate a realistic endothelial cell membrane will be used to capture the deformation of the membrane and a fluid structure coupling will be used to couple the bubble and membrane dynamicsIn Phase Iwe will concentrate on single non spherical bubble dynamics interaction with the vessel and validate the numerical model using experimental data available in the literatureIn Phase II we will collaborate with University of Washington to further validate the developed model with controlled sonoporation experiments in an environment closer to clinical applicationsWe will further develop the model in Phase II to include bubble clouds containing thousands of microbubbles by tracking individual bubbles in a Lagrangian frameworkThe resulting computational tool developed under this SBIR program will be integrated within our current software packageDYNAFSas an addon modulecommercialized and offered to researchers and sonoporator manufacturers The product resulting from this project will be a design tool that can be used by sonoporator device developersclinical practitionersand researchersThe tool will enable one to perform parametric studies that can shed light on the fluid dynamic forces responsible for sonoporationIt will allow to explore a wide range of parameters to identify promising experimental and practical configurations and setupsand to help optimize sonoporators for achieving increased drug uptake with minimum cell damage