Characterization of Bubble Cloud Formation and Tissue Ablation using a High Frequency Endoscopic Histotripsy System

Abstract

Objective: Histotripsy is a non-thermal focused ultrasound ablation strategy to non-invasively destroy tissue by generating a cavitation bubble cloud. Prior work has established the potential of histotripsy for many applications including the non-invasive treatment of liver tumors. In order to expand histotripsy beyond the currently available clinical systems for targeting deep abdominal tumors, recent work has developed miniaturized high frequency devices capable of higher precision using devices within an endoscopic form factor. This work investigates the use of one of these high-frequency histotripsy devices to evaluate cavitation generation and ablation capacity in a variety of ex vivo porcine tissues (brain, liver, kidney, pancreas, lymph node) and in vivo murine liver. Methods: A 6.3 MHz histotripsy transducer with an aperture of 10 mm and focal length of 7 mm was co-registered with a 30 MHz ultrasound imaging array. Optical imaging was used to identify cloud formation for different pulsing cycles while ultrasound imaging was used to monitor ex vivo and in vivo histotripsy ablations in tissue. Histological sections were examined, and statistical analyses were performed on imaging data. Results: Well-defined bubble clouds ranging from 0.54 ± 0.12 mm to 0.82 ± 0.12 mm (axial) were maintained over the course of 10,000 pulses for 3, 5, 8, and 12 cycles for peak negative pressures (p-) of 33–42 MPa. Larger bubble clouds were generated at higher p- for all cycles. Pearson Correlation Coefficients above 0.8 for all cases indicated strong correlation between US and optical imaging. Histotripsy bubble clouds were identified and maintained on US imaging with hypoechoic zones seen immediately post-treatment for all tissue types in both ex vivo and in vivo treatments. Histological results showed complete ablation of the targeted regions in excised porcine brain, kidney, pancreas, and lymph node. Ex vivo porcine liver exhibited extensive loss of hepatocytes but did retain subtle lobular architecture due to remnants of portal connective tissue. In vivo murine liver showed partial ablation, suggesting higher treatment doses are required. Conclusions: Results demonstrate the potential of miniaturized high-frequency histotripsy devices for precise and effective histotripsy ablation of a wide range of potential applications and establish the potential of this device for use in preclinical murine histotripsy studies.