Histotripsy Methods for Pancreatic Cancer

Abstract

Histotripsy is a focused ultrasound ablation modality that uses nanometer-sized endogenous gas nuclei to form a cloud of microbubbles to mechanically disintegrate tissue. The key features of histotripsy are that it is non-invasive, non-thermal, and non-ionizing. By applying microsecond-length, high pressure (> 15 MPa) pulses, these nuclei can rapidly expand and collapse, inducing high stress and strain on the surrounding tissue leading to cell rupture. The cavitation "bubble cloud" has millimeter precision to achieve clear boundaries between treated and untreated tissue. Histotripsy treatments can be monitored in real-time with B-mode ultrasound (US) imaging, where the bubble cloud appears as a bright hyperechoic region due to the strong scattering of acoustic energy by the bubbles. Previous work has shown that histotripsy can be tissue-selective with stiffer tissues being more resistant to the therapy due to their mechanical properties leading to preservation of critical structures like vessels and ducts. The feasibility and safety of histotripsy has been well-established for the treatment of liver cancer, both pre-clinically and clinically, but has yet to be developed for pancreatic cancer. The majority of pancreatic cancer patients are diagnosed late-stage, presenting with locally advanced or metastatic disease, leading to a select few that are candidates for surgery. Chemotherapy, radiation therapy, or a combination of the two have been used as front-line treatment options for patients albeit limited. While current ablative strategies have improved mortality rates, the overall survival for patients is still dismal. The main limitations of these ablative strategies are a lack of targeting precision and real-time treatment feedback as well as risk of damage to critical structures and inducing pancreatitis, along with other adverse events, given the sensitive nature of the pancreas. This dissertation investigates the safety and feasibility of using ultrasound-guided histotripsy to ablate pancreatic tissue with non-invasive and endo-surgical approaches. The research described herein 1) explores the feasibility of applying histotripsy trans-abdominally to healthy porcine pancreas, 2) evaluates histotripsy's safety profile in the pancreas of a large porcine model in vivo, and 3) establishes the feasibility of endoscopic histotripsy transducers for surgical and trans-gastric pancreas ablation. Future work will build on these studies to optimize histotripsy treatments for pancreatic tumors and further develop alternative endo-surgical histotripsy devices for improved targeting of these and other tumor types in anatomically challenging locations.