THE ROLE OF ULTRASOUND CONTRAST AGENTS IN PRODUCING SONOPORATION

Sonoporation uses ultrasound (US) and ultrasound contrast agents (UCAs) to enhance cell permeabilization, thereby allowing delivery therapeutic compounds noninvasively into specific target cells. The objective of this dissertation was to elucidate the biophysical mechanism of sonoporation, specifically the role of the UCA. Monolayer cells were exposed in a solution of UCA, permeability agent, and saline. Exposure-effect studies varied the peak rarefactional pressure from 4 kPa to 4.14 MPa. Two UCAs (OptisonTM and Definity®), three US frequencies (1, 3, and 5 MHz), three cells lines (Chinese hamster ovary cells, mouse fibroblasts, and mouse bone marrow stromal precursor), and three transfection agents (FITC-Dextran, Calcein, and FluoSpheres carboxylate-modified microspheres) were examined. Exposure duration, pulse repetition frequency, number of pulses, and UCA concentration were also varied. The experimental observations demonstrated that inertial cavitation was not the physical mechanism for sonoporation. Microstreaming due to linear or nonlinear oscillations of the UCA was principally responsible. This microstreaming, when produced near a cell, resulted in shear stress on the cell membranes, causing th