Precise Lesion Formation in Histotripsy Therapy Using Strategic Pulsing Methods..

Abstract

Histotripsy is a noninvasive, cavitation-based ultrasound therapy that can create mechanical tissue ablation through dense energetic clouds of microbubbles generated by high-pressure and short ultrasound pulses. Histotripsy therapy has been shown capable of 1) creating intracardiac flow channels for congenital heart disease treatment, 2) fractionating blood clots for treating deep vein thrombosis, 3) fractionating prostatic tissue for benign prostatic hyperplasia (BPH) treatments, and 4) fragmenting model renal calculi for treating kidney stone. The overall objective of this dissertation is to develop ultrasound pulsing techniques that can lead to more precise and controlled bubble cloud generation in histotripsy therapy. Three strategic pulsing methods have been developed and characterized in this dissertation. 1) Bubble cloud formation using the intrinsic threshold mechanism: when ultrasound pulses shorter than 3 cycles are applied, the generation of bubble clouds only depends on one or two negative half cycles exceeding an intrinsic threshold of the medium. This intrinsic threshold is highly repeatable and has a very sharp transition zone. 2) Dual-beam histotripsy: a low-frequency pump pulse is applied to enable a high-frequency probe pulse to exceed the intrinsic threshold. The high-frequency probe pulse provides precision in lesion formation, while the low-frequency pump pulse, which is more resistant to attenuation and aberration, raises the pressure level of the targeted treatment region. 3) Frequency compounding: a near half-cycle (monopolar) pulse is synthesized using an array transducer composed of elements with various resonant frequencies. Histotripsy using a negative-polarity half-cycle pulse can limit the influence of positive phases on bubble cloud generation, leading to a more precise and controlled lesion formation. These three techniques were realized using custom design ultrasound array transducers and examined in red-blood-cell tissue-mimicking phantoms, and the first two techniques were further validated in ex vivo tissues. Additionally, an application in metastatic lymph node ablation is studied in vivo using supra-intrinsic-threshold pulses. In conclusion, this dissertation demonstrates three strategic ultrasound pulsing methods that can lead to precise lesion formation in histotripsy therapy. Future work involves examining the applicability of these pulsing methods in in vivo experiments and studying potential applications for monopolar pulses in ultrasound diagnostic imaging.