Quantifying the Effect of Acoustic Parameters on Temporal and Spatial Cavitation Activity: Gauging Cavitation Dose

Abstract

Objective: Cavitation-enhanced delivery of therapeutic agents is under development for the treatment of cancer and neurodegenerative and cardiovascular diseases, including sonothrombolysis for deep vein thrombosis. The objective of this study was to quantify the spatial and temporal distribution of cavitation activity nucleated by Definity infused through the EKOS catheter over a range of acoustic parameters controlled by the EKOS endovascular system.

Methods: Three insonation protocols were compared in an in vitro phantom mimicking venous flow to measure the effect of peak rarefactional pressure, pulse duration and pulse repetition frequency on cavitation activity energy, location and duration. Inertial and stable cavitation activity was quantified using passive cavitation imaging, and a metric of cavitation dose based on energy density was defined.

Results: For all three insonation protocols, cavitation was sustained for the entire 30 min Definity infusion. The evolution of cavitation energy during each pulse duration was similar for all three protocols. For insonation protocols with higher peak rarefactional acoustic pressures, inertial and stable cavitation doses also increased. A complex relationship between the temporal behavior of cavitation energy within each pulse and the pulse repetition frequency affected the cavitation dose for the three insonation protocols. The relative predominance of stable or inertial cavitation dose varied according to insonation schemes. Passive cavitation images revealed the spatial distribution of cavitation activity.

Conclusion: Our cavitation dose metric based on energy density enabled the impact of different acoustic parameters on cavitation activity to be measured. Depending on the type of cavitation to be promoted or suppressed, particular pulsing schemes could be employed in future studies, for example, to correlate cavitation dose with sonothrombolytic efficacy.

Keywords: Cavitation behavior; Cavitation dose; Cavitation nucleation; Passive cavitation imaging; Sonothrombolysis.

Figure 1.

Schematic of flow phantom setup for passive cavitation acquisitions. Saline at 37°C was circulated from the reservoir, over the catheter, and back to the reservoir. The L11-5v array imaging plane included the first proximal active therapeutic ultrasound (TUS) transducer.

Figure 2.

Schematic of EKOS^™ catheter with 12 pairs of 2-mm long, 2.25 MHz therapeutic ultrasound (TUS) transducers. Along the 12 cm treatment zone of the catheter, the first six ultrasound transducer pairs were quiescent while the distal six transducer pairs were active and sonicated the DEFINITY^®. The first drug delivery hole was located 0.5 cm after the first of six quiescent transducer pairs (adapted from Lafond et al. ).

Figure 3.

Algorithm for the computation of spatially filtered passive cavitation images, total cavitation energy, and cavitation dose.

Figure 4.

Average inertial (red) and stable (green) total cavitation energy during the insonation pulse for protocol 1 (dashed lines) and protocol 2 (solid line), the error bars represent standard deviation, n = 4.

Figure 5.

Average a) inertial (red) and b) stable (green) total cavitation energy over the insonation pulse for protocol 3, scheme 1 (triangle), scheme 2 (dashed lines), scheme 3 (circle) and scheme 4 (solid line), n = 4. Only one error bar is represented for each scheme for visibility.

Figure 6.

a) Inertial and stable cavitation dose, $CRx$, for the three insonation protocols, n = 4. b) Inertial and stable cavitation dose over the pulse duration for the four schemes of the insonation protocol 3, *p<0.05, n = 4.

Figure 7.

Examples of composite passive cavitation and B-Mode images mapping stable (green) and inertial (red) cavitation activity averaged over 30 min for protocol 1 (left), protocol 2 (middle) and protocol 3 (right), without (upper row) and with (lower row) adaptive spatial filtering. Yellow represents a combination of stable (green) and inertial (red) cavitation activity at a location. To obtain the composite images, infused DEFINITY^® was sonicated by the most proximal active transducer of the EKOS^™ catheter. The entire pulse duration of acquired data was processed to form individual passive cavitation images. Individual images were averaged pixel-wise to obtain a 30 min average passive cavitation image that was overlaid on a B-mode image. The maximum energy level in the colormap was set to the maximum measured energy, with the dynamic range set to 20 dB re 1 μJ which spanned all the acquisitions. Note that the passive cavitation image of protocol 3 represents the average over the 30 min trial, which included 4 different schemes.

Figure 8.

Examples of composite passive cavitation and B-Mode images of 30 min averaged stable (green) and inertial (red) cavitation activity for each scheme in protocol 3. Infused DEFINITY^® was sonicated by the most proximal active transducer of the EKOS^™ catheter. The whole acquired pulse was processed and the resulting 30 min average passive cavitation image overlaid on a B-mode image according to the composite cavitation energy color map, where yellow represents both stable and inertial cavitation activity. The maximum energy level in the colormap was set to the maximum measured energy, with the dynamic range set to 20 dB re 1 μJ to cover all the acquisitions.