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Dynamics of Coated Microbubbles for Contrast Enhanced Ultrasound Imaging and Drug Delivery: Subharmonic Response, Cavitation and Microstreaming Open Access

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In this research, we are studying the dynamics of contrast microbubbles in the presence of ultrasound waves for different applications from sonoporation to estimation of local blood pressure. Ultrasound waves are pressure waves capable of transporting energy into the body at precise locations as they are absorbed relatively little by tissues. Their non-invasive, safe and painless transmission through the skin makes them suitable for diagnostic imaging, drug delivery, and gene therapy applications. Contrast microbubbles are gas core micron size bubbles encapsulated with a layer of protein, lipid, and phospholipid to prevent them against early dissolution in the bloodstream. These microbubbles have been initially developed for increasing the contrast of the image in ultrasound imaging. It has been shown that in the presence of ultrasound, contrast microbubbles can facilitate the transportation of drugs through a process called sonoporation. Sonoporation is the acoustically induced temporary perforation of membranes. By the exposure of ultrasound, contrast microbubbles may show two types of motion; stable cavitation and inertial cavitation. Stable cavitation occurs at low excitation pressures making the microbubbles pulsate repeatedly over many cycles. Stable cavitation can create fluid flow around the microbubble (microstreaming) capable of rupturing cells and vesicles due to enhanced shear rates. Inertial cavitation occurs at high amplitude ultrasound excitation pressures causing the bubble to collapse and implode. Collapsing microbubbles in the vicinity of a wall may generate a high velocity liquid microjet penetrating towards the wall. The impingement of microjet along with its high velocity creates high shear stresses in the cell membrane resulting in sonoporation. In the first part of this research, we simulate the formation of microjet of contrast microbubbles near a wall. We have assumed the cell membrane as a rigid wall for simplification. A boundary element method has been developed for the numerical study of the microjet. Zero thickness interfacial rheology models have been used to simulate the encapsulation of the contrast microbubbles. In the second and third parts of this research, we study phenomena where contrast microbubbles are excited with low ultrasound pressure causing them to pulsate repeatedly instead of collapsing and forming a jet. When the bubble is pulsating, it generates fluctuations in the flow. The time average of these fluctuations usually is not zero creating a non-linear second order effect called microstreaming. Microstreaming can increase the permeability of cell membranes (sonoporation) in biological tissues for better passage of therapeutic agents across the vascular barrier and cell membranes. In the second part, we conduct an analytical study to show microstreaming flow near a plane rigid wall generated by spherical pulsation of microbubbles, and in the third part, we use boundary element method to simulate microstreaming flow near the plane rigid wall without restricting the contrast microbubble to pulsate spherically. In the fourth part of the dissertation, we study the subharmonic response from pulsating contrast microbubbles. Contrast microbubbles are strongly nonlinear. Under a strong enough excitation, they generate second harmonic (response at frequency 2f when excited at f) and subharmonic (response at frequency f/2) signals giving rise to harmonic and subharmonic imaging modalities. Recently, it has been proposed that subharmonic response of contrast microbubbles can be used for noninvasively estimating the local organ level blood pressure. Local organ-level pressure estimation can provide critical information for accurate diagnosis of cardiovascular diseases such as portal hypertension or heart valve defects. Here, we aim to find a correlation between the subharmonic response from contrast microbubble and the ambient pressure for local blood pressure estimation.

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