Cavitation monitoring and spatial mapping for pulsed high-intensity focused ultrasound enhanced drug delivery

Thesis (Ph.D.)--University of Washington, 2014High intensity focused ultrasound (HIFU) is an emerging non-invasive ablation modality, in which high amplitude ultrasound waves are focused inside the human body to thermally ablate or mechanically disrupt the tissue at the focus. Ultrasound-enhanced drug delivery is an active and promising area of research. Enhanced drug diffusion and vascular permeability following HIFU is largely attributed to mechanical tissue disruption caused by ultrasound-induced bubble activity- cavitation. Although cavitation can be beneficial, the violent collapsing of bubbles may cause undesired tissue damage. Therefore, it is very important to monitor cavitation activity during pHIFU treatments and know the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue. Correlating the quantity and depth of drug penetration with the degree of cavitation is a significant challenge during in vivo treatment due to the highly complex dynamics of cavitation in different types of tissue. Furthermore, the current methods of cavitation detection are of either limited sensitivity or spatial mapping capability to monitor the site of occurrence and the extent of bubble activity in tissue. In this dissertation, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of broadband acoustic emissions. These metrics were used to characterize cavitation activity in gel phantoms, ex vivo tissue and in vivo transgenic pancreatic tumors at varying peak-rarefactional focal pressures. Cavitation thresholds were also determined in various media. In order to find the ideal HIFU parameters for drug delivery, cavitation metrics were measured and correlated with the degree of chemotherapeutic drug uptake in in vivo tumors immediately after HIFU exposures and systematic administration of chemotherapeutic drug. The study demonstrated that reliable and intense cavitation activity induced by pHIFU is a sufficient and necessary condition for enhanced drug delivery. To spatially detect cavitation, a new ultrasound imaging method termed "Bubble Doppler" was developed to detect microbubbles using a modification of Doppler processing. This method was shown to provide sensitivity superior to that of existing cavitation detection methods, and has high spatial resolution inherent to conventional Doppler imaging