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Biomedical Imaging and Instrumentation

Contrast-Enhanced Ultrasound and Therapeutic Ultrasound

Development and Characterization of High Frequency Focused Ultrasound Transducer for High Precision Non-thermal Tissue Ablation

Thursday, October 12, 2023
1:00 PM – 1:15 PM PDT
Location: 339 (Center, Level 3)
Introduction:: Histotripsy is a non-invasive, non-thermal, non-ionizing, and image-guided focused ultrasound (FUS) ablation method1. In histotripsy, high pressure ( >25MPa) ultrasound pulses converge at the focus to generate a cavitation bubble cloud that mechanically ablates tissue into acellular debris. Histotripsy is currently being studied as a potential treatment for liver cancer in clinical trials and many other clinical applications preclinically.

Clinical histotripsy systems are cart-based devices with large transducer typically at frequencies ranging from 500kHz to 1MHz. Using these conventional systems, histotripsy can be applied to targeted organs non-invasively, guided by real-time ultrasound imaging. More recently, studies have developed miniaturized high frequency (2-6MHz) histotripsy devices for ultra-high precision histotripsy procedures. These devices have shown promise as improved tools for delivering interoperative and endoscopic histotripsy. In addition, these miniature high precision histotripsy devices would allow for improved preclinical studies of histotripsy in murine models, which have previously been limited due to the size of the histotripsy devices3. In this study, we investigate the histotripsy capabilities (bubble cloud characteristics and ablation) of two improved miniaturized histotripsy systems (2MHz and 6.3MHz devices) that enable high precision histotripsy treatments.


Materials and Methods:: Miniature 2MHz and 6.8MHz transducers were developed and tested for precise histotripsy ablations in ex vivo studies and in vivo experiments (Fig.1A/B). The 2MHz and 6.3MHz transducers had a focal distance of ~8mm and ~6mm respectively. Both transducers were co-registered with a 30MHz US imaging probe with high image resolution, allowing for real-time therapy guidance and monitoring. In vitro characterization of the histotripsy devices was conducted to measure the acoustic output of the transducers and characterize the bubble cloud dynamics using high speed cameras. Ex vivo tissue studies were then conducted to investigate the ability of these devices to ablate porcine kidney, brain, pancreas, lymph node, and canine oral melanomas, with ablation assessed post-treatment using US imaging and histological analysis (H&E). Volumetric ablations (~8mm3-27mm3) were performed using a motorized positioning system at a 1kHz pulse repetition frequency (PRF), 8-10 cycle pulses, and 2,000 – 10,000 pulses per point. Finally, in vivo murine studies were conducted to test the feasibility of using these devices for high precision liver and kidney ablation. Briefly, mice were first put under anesthesia, hair was removed, and a water coupling drape was adhered to the mice and filled with degassed water. The transducer was submerged and the liver and kidney were targeted using US imaging. Volumetric ablations of 27mm3 were performed using a motorized positioning system at a 1kHz PRF with 10 cycle pulses and 2,000 pulses per point. Bubble cloud formation was verified with US imaging and ablation was verified with histology (H&E).

Results, Conclusions, and Discussions::

In all ex vivo tissue studies, a bubble cloud was generated and imaged successfully throughout the treatment. Ablation zones could be seen as hypoechoic regions on US post-treatment for all tissue types studied (Fig.1C). H&E histology showed ablation for the canine oral melanoma.

2MHz in vivo murine studies showed successful bubble cloud generation in the liver, with the resulting ablation zone seen as a hypoechoic region on US post-treatment (Fig.1D). Histology (H&E) showed successful ablation of cells with similar dimensions as the treatment parameters (Fig.1E). Challenges imaging the liver were observed due to shadowing, potentially caused by the diaphragm or rib blockage. Locating and identifying the kidney proved troublesome with the 2MHz device.

The 6.3MHz in vivo murine studies showed successful bubble cloud generation and imaging in the liver and kidney (Fig.1F). The ablation zone in the liver can be seen as a hypoechoic region on US post-treatment. Bubble cloud visualization and ablation were more clearly observed through US in the lower regions of the liver when the transducer was positioned at an angle to avoid treating through the diaphragm. Locating and visualizing the kidney was challenging due to shadowing. H&E histology results are pending.

Overall, results showed that the 2MHz and 6.3MHz transducers appear to be promising alternatives for high precision histotripsy treatments. Comparisons with prior studies using conventional histotripsy systems at lower frequencies showed that the high frequency transducers produced smaller, well-confined bubble clouds that, along with improved US imaging, suggests these devices can be used for minimally invasive histotripsy procedures with significantly improved treatment precision. Results also highlight the ability of these devices to enable improved histotripsy studies in small animals, particularly for the 6.3MHz transducer. Future work is needed to develop these systems for specific clinical applications, such as the treatment of oral tumors in which high precision interoperative tissue ablations is desired.





Acknowledgements (Optional): :

References (Optional): : [1] Zhen Xu et al., Int. J. Hyperthermia, 2021

[2] Eli Vlaisavljevich et al., Ultrasound Med. Biol., 2016