Parenchymal disease of the liver, known as diffuse liver disease, led to 1.4% of the total deaths in the United States in 2013. It causes impaired liver functioning and may lead to portal hypertension, encephalopathy, or hepatocellular carcinoma. Current methods of diagnosing diffuse liver disease are often invasive, subject to heterogeneous variation, and fail to distinguish between intermediate disease stages. Ultrasound imaging has long been used to monitor changes in tissue structure, and it is known that sound attenuation changes with disease progression. Tissue is acoustically nonlinear, meaning that propagating sound waves are distorted due to tissue properties and generate higher order harmonics. Since fatty deposits and fibrosis change with disease progression, we hypothesize that associated attenuation changes may be detected by changes in the nonlinear signal distortion and can be quantified as a marker of disease. We have designed a methodology based in Tissue Harmonic Imaging to use a quantified marker of attenuation to specifically detect diffuse liver disease. This project comprises of (1) a theoretical and experimental investigation of the influence of sound attenuation on harmonic content in tissue, (2) clinical patient data collection and development of MATLAB analysis tools utilizing the disease marker developed in Phase I, and (3) development of new imaging sequences capable of grading diffuse liver disease when coupled with the analysis tools. The noninvasive, easy to use, sensitive, and clinically usable methodology developed in this project has the potential for aiding in diagnosis of diffuse liver disease and enhancing quality of patient care.

Hepatocellular Carcinoma is the most common form of liver cancer accounting for a quarter of a million deaths annually across the globe. Microbubbles have been shown to be an effective vector for both gene and drug delivery. In combination with ultrasound, the microbubbles can be locally burst to deliver a drug payload via sonoporation – the temporary disturbance of the cell membrane. Ultrasound and microbubbles drug delivery is a strong candidate for the treatment of HCC because the liver that is easily accessible with ultrasound and the organ itself is highly perfused allowing for easy microbubble access. In microbubble gene and drug delivery, ultrasound parameters that induce cell death when used in combination with microbubbles are not well defined. While the literature agrees on general trends that greater exposure times and greater pressure lead to higher cell death, the specific combination of parameters that cause cell death are still disputed. We will design an enclosure such that cells can be cultured and exposed to ultrasound with microbubbles. We hypothesize that at greater exposure times, higher duty cycle, and greater pressures the cell viability will decrease. We hypothesize when multiple parameters are increased in combination, there will be a compounded decrease on cell viability. The rationale behind these hypotheses is that with greater power and force, greater stress and strain will be placed on the cell causing lowered cell viability. The goal of the project is to conclude specific values at which cell viability is compromised. From the study, it was found that while stronger acoustic parameters caused higher cell death, the variable that made the most difference was bubble concentration.