(H-310) Investigation of Ultra High Rate Histotripsy Treatment Methods for Rapid Non-Invasive Tissue Ablation

Introduction:: Histotripsy is a non-invasive and non-thermal ablation modality that utilizes acoustic cavitation to mechanically disintegrate soft tissue. The expansion and collapse of cavitation bubbles create large strain at high strain rates that liquifies tissue. Precisely controlled by focused ultrasound (FUS), a millimeter sized region in which cavitation can occur, can be subjected to histotripsy-induced damage guided by real-time imaging. Using robotically assisted treatment methods, histotripsy can be used for the volumetric ablation of larger 3-dimensional tissue volumes. Histotripsy is being clinically investigated for liver tumor ablation as well as numerous pre-clinical applications. Current clinical histotripsy treatments, however, are limited in the size of the ablation volume (< 3cm in diameter), primarily due to limitations in treatment time for ablating larger volumes. Furthermore, decreasing overall treatment times would decrease the burden of such procedures for both doctors and patients. In this study, we investigate the use of ultra-high pulse repetition rate (PRF) histotripsy methods in order to achieve efficient and rapid tissue ablation, which would enable the advancement of histotripsy to the treatment of larger tumor volumes compared to current clinical devices.


Materials and Methods:: Histotripsy ablation using PRF’s ranging from 500-2500Hz were tested to determine if ultra-high rate histotripsy could be effectively used to generate volumetric tissue ablation in shorter treatment times than current clinical pulsing methods (~500Hz PRF). Volumetric ablations were performed in ex vivo porcine livers, which were harvested locally and treated within 48 hours, using an integrated cart-based histotripsy system that has been previously used in clinical trials. The cart system was modified to include a robotically controlled 700kHz histotripsy transducer with a coaxially aligned US imaging probe, recently developed by our team, capable of generating high-rate histotripsy treatments up to 2500Hz PRF. Histotripsy volumetric ablations of the liver were applied using single cycle pulses and PRF’s of 500, 1000, 1500, 2000, and 2500 Hz, where treatment doses varied from 400-800 pulses per point. Due to limitations in the speed of the robotically-assisted treatment arm, these dosages reflect the minimum possible dose that could be reliably delivered at the higher pulse repetition rates. For each PRF and dose level, porcine liver samples (n=4) were embedded in gelatin, aligned to the focus of the transducer, and an elliptical volume (3-4cm³) was targeted via US imaging. The cavitation threshold was recorded for each sample by a 7-point check distributed throughout the targeted volume. Treatments were subsequently performed at pressure levels 20% above the detected cavitation threshold. Post-treatment analysis for each sample group consisted of a gross morphological inspection of the resulting lesion (n=1) and a histological analysis (n=3) utilizing H&E and trichrome staining.


Results, Conclusions, and Discussions:: This investigation shows promising evidence for using ultra-high PRFs for non-invasive volumetric histotripsy tissue ablation. US monitorization of treatment showed successful generation of the bubble cloud in all cases that remained in the focus for the entirety of the treatment with no observable off target events. Histological analysis showed that a complete ablation with sharp demarcated boundaries was produced for all PRFs tested even at the lowest treatment doses that were feasible using the current clinical system (limited by speed of the robot). For example, complete ablation of the targeted region was consistently observed for 400 pulses per point at 1500Hz, 600 pulses per point at 2000Hz, and 800 pulses per point at 2500Hz (Fig. 1), where each dose levels represent the minimum dose that can delivered for their respective PRFs. The findings from this study suggest that ultra-high PRFs are capable of generating uniform and rapid volumetric tissue ablation. Furthermore, by overcoming the limitations on the speed of the robotic arm, results suggest that treatment times in future studies may be further decreased by allowing lower possible doses at the higher PRFs tested in this study. Overall, this work demonstrates the feasibility of a new ultra-high rate histotripsy treatment method that has the potential to advance histotripsy to the treatment of larger tissue volumes, which is essential to advancing the clinical utility of histotripsy as a method for non-invasive tumor ablation.


Acknowledgements (Optional): :

References (Optional): :