Inertial cavitation behaviors and bioeffects in pulsed focused ultrasound

Pulsed HIFU-induced inertial cavitation can be used to permeabilize tissue for promoting drug extravasation and penetration. In addition to HIFU frequency, peak rarefactional pressure (p-), and pulse duration, the threshold for inducing inertial cavitation has recently been correlated with nonlinear distortion of the focal waveform. Here, the effect of nonlinear distortion and HIFU frequency within the range of 0.28–1.9 MHz were investigated in transparent gel phantoms with simultaneous high-speed photography and passive cavitation detection (PCD). Transducers with different F-numbers (0.77–1.5) delivered 1 ms-long pulses with varying p- (1–15 MPa) at 1 Hz pulse rate. For all frequencies, increasing acoustic power and nonlinear distortion led to bubble behaviors changing both quantitatively and qualitatively from isolated, stationary bubbles to sparse bubble clouds that proliferated slowly towards the transducer. Different behaviors corresponded to specific spectral characteristics of the PCD signals. Exposures corresponding to particular behaviors at 1 MHz and 0.3 MHz frequencies were then applied to surgically exposed porcine liver, kidney, and pancreas in vivo with concurrent administration of Evans Blue Dye (EBD). Exposures with spectral signatures of proliferating bubbles on PCD corresponded to enhanced EBD extravasation and hemorrhagic injury to all tissues. [Work supported by NIH R01EB023910 and R01CA154451.]