ИСТИНА

Background: Boiling histotripsy (BH) uses sequences of millisecond-long ultrasound pulses with high amplitude shocks to mechanically liquefy target tissue with real-time monitoring of the treatment by ultrasound imaging. For pre-clinical BH treatment of abdominal organs, a high-power multi-element phased array system is needed to enable electronic focus steering for creating volumetric lesions and to introduce aberration corrections when focusing through inhomogeneous body wall. In addition, most BH studies have been performed under B-mode imaging of bubbles generated at the treatment site, which does not allow quantitative assessment of the degree of tissue liquefaction. Development of more comprehensive imaging modalities is therefore needed to enhance BH treatments. Materials and Methods: A prototype BH system was built comprising a custom 256-element 1.5 MHz phased array (Imasonic, Voray sur l’Ognon, France) for pre-clinical studies in porcine kidney and liver (Fig.1). The array has a focal distance of 120 mm, an outer diameter of 144 mm, and a 40 mm central opening for holding a coaxially aligned ultrasound imaging probe (ATL P6-3) to monitor the treatment. The BH array was electronically matched to the Verasonics V1 engine with a 1.2 kW external power source. Driving electronics were supplemented by an extra capacitor bank and software was custom-modified to deliver BH exposures, providing a pulse average acoustic power of up to 2.2 kW sustained for 10 ms with 1-2 Hz repetition rate. System performance was characterized by hydrophone measurements in water. Electronic steering capabilities of the array were evaluated for shock-producing conditions at the focus and power compensation was introduced to equalize BH exposures at multiple focal locations across the treatment regions. Volumetric mechanical lesions were generated in ex vivo liver tissue with 1 mm spacing between individual foci, 10 ms pulse length, 5 - 10 pulses/focus, and 1% duty cycle. Plane wave Doppler followed by B-mode imaging were implemented immediately after each BH pulse to visualize residual bubble motion during the treatments. The changes in the Doppler power and speed were used as metrics to assess the degree of tissue liquefaction. Results: Fully developed shocks of 100 MPa amplitude formed at the array focus in water at 275 W (12.5% of the maximum acoustic power of the system). Steering ranges of either 12 mm laterally or 24 mm axially corresponded to peak pressures of at least 90% of the maximum. Volumetric BH exposures in bovine liver with 10 pulses/per focus resulted in uniform tissue liquefaction with completely merged individual lesions while sparing connective tissue structures within the lesion (Fig. 2). Gross analysis showed a clear demarcation between the lesion and intact tissue with no apparent thermal damage. Additional exposures in porcine liver showed that maximum residual bubble velocities measured by Doppler were reached right after each BH pulse and increased from 18 to 30 cm/s as the treatment progressed with increased number of pulses per focus thus providing a quantitative metric for real-time control of tissue liquefaction. Conclusions: A pre-clinical BH prototype system was developed and successfully implemented to produce volumetric mechanical lesions in ex vivo tissue using electronic focus steering. Lesion formation was confirmed in real time by evaluating the degree of tissue liquefaction using color Doppler US imaging. This newly developed system should be capable, in terms of the power achievable, of delivering BH treatments transcutaneously in porcine liver and kidney in vivo. On-going work is aimed at using the array capabilities to introduce aberration correction for in vivo BH sonications through inhomogeneous body wall. Acknowledgements: Work supported by NIH R01EB7643, R01GM122859, R01EB25187, and RSF 20-12-00145.