Development of an MR-guided Histotripsy System for the Facilitation of Orthotopic Murine Tumor Model Ablations

Abstract

Histotripsy is an innovative non-invasive and non-ionizing mechanical ablation modality, significantly impacting the fields of locoregional antitumor modalities and immunotherapy. Histotripsy uses focused ultrasound pulses to generate cavitation bubble clouds within targeted tissues, resulting in the mechanical destruction of the tissue. Unlike other ablation methods, histotripsy relies on mechanical rather than thermal effects, achieving high-intensity focal pressure regions without significant heating of surrounding tissues. This precision allows for highly targeted tissue disruption while preserving essential structures. The efficacy and precision of histotripsy make it a promising technique for antitumor applications, with substantial potential demonstrated in both preclinical studies and recent clinical trials. Moreover, histotripsy is hypothesized to induce immunogenic cell death (ICD), which is crucial for triggering adaptive immune responses against cancer. ICD relies on the release of damage-associated molecular patterns (DAMPs) and tumor antigens, which activate immune cells and promote tumor-specific T cell responses. Despite these advantages, translating histotripsy to clinically relevant orthotopic tumor models poses significant challenges, particularly for non-immunogenic tumor microenvironments such as pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC). The implementation of murine models for these tumor types is crucial for effective translational research. The primary aim of this dissertation is to design, develop, and experimentally implement a miniature magnetic resonance (MR)-guided histotripsy system for conducting orthotopic murine histotripsy ablation experiments. This dissertation is organized into three main components: 1) the design and development of the first-generation orthotopic murine histotripsy system, 2) initial experimentation with this system, including the challenges and setbacks encountered, and 3) exploration of potential modifications and improvements to the first-generation system to facilitate future ablation experiments. This dissertation addresses several technical challenges, including imaging protocols for identifying and targeting tumors in the murine abdomen, the design and fabrication process of miniaturized transducer elements, configuring a histotripsy array capable of operating within the restricted acoustic window of the murine abdomen, and validation of post-treatment ablation efficacy. Initial in-vivo experiments demonstrated the feasibility of generating ablation zones in orthotopic murine liver and pancreatic tumor models. Gross pathology and histological analyses confirmed effective tissue disruption. However, post-treatment MR contrast was often subtle or nonexistent. Challenges included respiratory motion, reconciling MR image quality with system components, and side lobes causing off-target damage. Future work focuses on integrating acoustic emission data for cavitation detection and localizing of cavitation events during treatment. Additionally, modifications to the array's element packing distribution aim to mitigate grating lobes and improve targeting accuracy. This comprehensive approach aims to enhance the reliability and clinical relevance of MR-guided histotripsy for non-immunogenic tumor models in preclinical studies, subsequently paving the way for eventual clinical translation.