Removal of residual cavitation nuclei to enhance histotripsy fractionation of soft tissue.

Remanent bubble nuclei generated by primary cavitation collapse can limit the efficiency of histotripsy softtissue fractionation. When these residual bubbles persist from one histotripsy pulse to the next, they can seed the repetitive nucleation of cavitation bubbles at a discrete set of sites within the focal volume. This effect-referred to as cavitation memory- manifests in inefficient lesion formation, because certain sites within the focal volume are overtreated whereas others remain undertreated. Although the cavitation memory effect can be passively mitigated by using a low pulse repetition frequency (PRF) that affords remanent nuclei sufficient time for dissolution between successive pulses, this low PRF also results in slow lesion production. As such, it would be highly desirable to maintain the high per-pulse efficiency associated with low pulse rates when much higher PRFs are utilized. In this vein, we have developed a strategy for the active removal of the remanent bubble nuclei following primary cavitation collapse, using low-amplitude ultrasound sequences (termed bubble-removal sequences) to stimulate the aggregation and subsequent coalescence of these bubbles. In this study, bubbleremoval sequences were incorporated in high-PRF histotripsy treatment (100 Hz) of a red blood cell tissue-mimicking phantom that allows for the visualization of lesion development in real time. A series of reference treatments were also conducted at the low PRF of 1 Hz to provide a point of comparison for which cavitation memory effects are minimal. It was found that bubble-removal sequences as short as 1 ms are capable of maintaining the efficacious lesion development characteristics associated with the low PRF of 1 Hz when the much higher pulse rate of 100 Hz is used. These results were then extended to the treatment of a large volume within the tissue phantom, and optimal bubble-removal sequences identified for the singlefocal- spot case were utilized to homogenize a 10 × 10 mm region at high rate.