Passive Cavitation Detection during Pulsed HIFU Exposures of Ex Vivo Tissues and In Vivo Mouse Pancreatic Tumors

Abstract

Pulsed high-intensity focused ultrasound (pHIFU) has been demonstrated to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rarefactional focal pressures (1–12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms, pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KPC mice and closely recapitulate human disease in their morphology. The cavitation threshold, defined at 50 % cavitation probability, was found to vary broadly among the investigated tissues (within 2.5–10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but ex vivo it decreased rapidly and stopped over the first few pulses. Cavitation activity depended on the interplay between the destruction and circulation of cavitation nuclei, which are not only used up by HIFU treatment but also replenished or carried away by circulation in vivo. These findings are important for treatment planning and optimization in pHIFU-induced drug delivery, in particular for pancreatic tumors.

A new active cavitation mapping technique for pulsed HIFU applications-bubble doppler

“…During HIFU exposures, a series of 1 ms duration broadband signals were acquired by the PCD transducer and processed using a custom-made digital filter using MATLAB (MATLAB 2010b, The MathWorks, Natick, MA, USA) as described in our previous study [28]. Since the majority of focal HIFU waveforms used in this study were nonlinearly distorted (Fig.…”

“…We then calculated cavitation probability at each level as the ratio (expressed in percent) of the number of pHIFU focus locations, at which at least one cavitation event was observed throughout the exposure, to the total number of spots treated. Similar to our previous work, the cavitation threshold [28] was defined as the peak negative pressure level corresponding to a 50% probability of cavitation.…”

Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy

“…The animal was briefly reanesthetized for two subsequent blood draws (ie, at 3-hour and 24-hour time (18). To confirm consistent cavitation activity throughout exposure, broadband emissions that resulted from each focused ultrasound pulse were detected with a passive cavitation detector, and the signals were processed with a method similar to that in our previous studies to obtain the level of broadband noise emitted by cavitation bubbles (25). The details of passive cavitation detector signal acquisition, processing, and cavitation activity levels are given in Appendix E1 (online).…”

Towards a dosimetric framework for therapeutic ultrasound

“…Although there has already been significant work concerning both the probability and the quantification of cavitation [26][27][28][29][30] there is as yet no commonly agreed definition that is suitable for a wide range of sonication modalities (e.g. for bursts with low duty ratios as well as for continuous wave sonications).…”