  Histotripsy is a non-thermal focused ultrasound ablation method that destroys
tissue through the generation and activity of acoustic cavitation. Intrinsic
threshold histotripsy generates bubble clouds when the dominant negative
pressure phase of a single-cycle pulse exceeds an intrinsic threshold of ~25-30
MPa. The ablation efficiency is dependent upon the size and density of bubbles
within the bubble cloud. This work investigates the effects of dual-frequency
pulsing schemes on the bubble cloud behavior and ablation efficiency in
intrinsic threshold histotripsy. A modular histotripsy transducer applied
dual-frequency histotripsy pulses to tissue phantoms with a 1:1 pressure ratio
from 500 kHz and 3 MHz frequency elements and varying the 3 MHz pulse arrival
relative to the arrival of the 500 kHz pulse (-100 ns, 0 ns, and +100 ns).
High-speed optical imaging captured cavitation effects to characterize bubble
cloud and individual bubble dynamics. Lesion formation and ablation efficiency
were also investigated in red blood cell (RBC) phantoms. Results showed that
the single bubble and bubble cloud size for dual-frequency cases were
intermediate to published results for the component single frequencies of 500
kHz and 3 MHz. Bubble cloud size and dynamics were also shown to be altered by
the arrival time of the 3 MHz pulse relative to the 500 kHz pulse, with more
uniform cloud expansion and collapse observed for early (-100 ns) arrival.
Finally, RBC phantom experiments showed that dual-frequency exposures were
capable of generating precise lesions with smaller areas and higher ablation
efficiencies than previously published results for 500 kHz or 3 MHz. Overall,
results demonstrate dual-frequency histotripsy's ability to modulate bubble
cloud size and dynamics can be leveraged to produce precise lesions at higher
ablation efficiencies than previously observed for single-frequency pulsing.
