Abstract
Many useful therapeutic bio-effects can be generated using ultrasound-induced cavitation. However, cavitation is also capable of causing unwanted cellular and vascular damage, which should be monitored to ensure treatment safety. In this work, the unique opportunity provided by passive acoustic mapping (PAM) to quantify cavitation dose across an entire volume of interest during therapy is utilised to provide setup-independent measures of spatially localised cavitation dose. This spatiotemporally quantifiable cavitation dose is then related to the level of cellular damage generated. The cavitation-mediated destruction of equine red blood cells mixed with one of two types of cavitation nuclei at a variety of concentrations is investigated. The blood is placed within a 0.5-MHz ultrasound field and exposed to a range of peak rarefactional pressures up to 2 MPa, with 50 to 50,000 cycle pulses maintaining a 5% duty cycle. Two co-planar linear arrays at 90° to each other are used to generate 400-µm-resolution frequency domain robust capon beamforming PAM maps, which are then used to generate estimates of cavitation dose. A relationship between this cavitation dose and the levels of haemolysis generated was found which was comparable regardless of the applied acoustic pressure, pulse length, cavitation agent type or concentration used. PAM was then used to monitor cellular damage in multiple locations within a tissue phantom simultaneously, with the damage–cavitation dose relationship being similar for the two experimental models tested. These results lay the groundwork for this method to be applied to other measures of safety, allowing for improved ultrasound monitoring of cavitation-based therapies.
Highlights
These emissions allow for ultrasound-based monitoring of cavitation therapies, and the intensity of the emissions has been found to correlate with the levels of cellular damage generated (Chen et al 2003; Hwang et al 2006) and bloodÀbrain barrier opening (Tung et al 2010; Tsai et al 2016) where it has proved useful for feedback control (Arvanitis et al 2012; O’Reilly and Hynynen 2012; Sun et al 2017; Kamimura et al 2018)
Arrays of transducers can be used in combination with beamforming algorithms such as passive acoustic mapping (PAM), which uses the relative time of arrival between different elements of the array to allow for the localisation and spatial segregation between the sources of acoustic emissions in both the time
These measurements closely correspond to the free-field pressures caused by the absence of attenuating structures at 0.5 MHz in the majority of the acoustic propagation path from the transducer to the 1-cm sample contained within the thin-walled tube
Summary
Cavitation is capable of significantly enhancing drug delivery for brain, cardiovascular, oncological, transdermal and intracellular applications (Hynynen et al 2001; Fan et al 2012; Bazan-Peregrino et al 2013; Sutton et al 2013; Bhatnagar et al 2016; Bian et al 2017; Mannaris et al 2018; Stride and Coussios 2019), but can generate potentially adverse bio-effects that need to be monitored to ensure treatment safety. These emissions allow for ultrasound-based monitoring of cavitation therapies, and the intensity of the emissions has been found to correlate with the levels of cellular damage generated (Chen et al 2003; Hwang et al 2006) and bloodÀbrain barrier opening (Tung et al 2010; Tsai et al 2016) where it has proved useful for feedback control (Arvanitis et al 2012; O’Reilly and Hynynen 2012; Sun et al 2017; Kamimura et al 2018) This monitoring is limited to the confocal region between the single-element passive cavitation detector and the therapeutic ultrasound field and is incapable of monitoring several locations simultaneously. Arrays of transducers can be used in combination with beamforming algorithms such as passive acoustic mapping (PAM), which uses the relative time of arrival between different elements of the array to allow for the localisation and spatial segregation between the sources of acoustic emissions in both the time
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