Hedieh A. Tamaddoni

Acoustic Bubble Removal to Enhance SWL Efficacy at High Shock Rate: An In Vitro Study

Rate-dependent efficacy has been extensively documented in shock wave lithotripsy (SWL) stone comminution, with shock waves (SWs) delivered at a low rate producing more efficient fragmentation in comparison to those delivered at high rates. Cavitation is postulated to be the primary source underlying this rate phenomenon. Residual bubble nuclei that persist along the axis of SW propagation can drastically attenuate the waveforms negative phase, decreasing the energy which is ultimately delivered to the stone and compromising comminution. The effect is more pronounced at high rates, as residual nuclei have less time to passively dissolve between successive shocks. In this study, we investigate a means of actively removing such nuclei from the field using a low-amplitude acoustic pulse designed to stimulate their aggregation and subsequent coalescence. To test the efficacy of this bubble removal scheme, model kidney stones were treated in vitro using a research electrohydraulic lithotripter. SWL was applied at rates of 120, 60, or 30 SW/min with or without the incorporation of bubble removal pulses. Optical images displaying the extent of cavitation in the vicinity of the stone were also collected for each treatment. Results show that bubble removal pulses drastically enhance the efficacy of stone comminution at the higher rates tested (120 and 60 SW/min), while optical images show a corresponding reduction in bubble excitation along the SW axis when bubble removal pulses are incorporated. At the lower rate of 30 SW/min, no difference in stone comminution or bubble excitation was detected with the addition of bubble removal pulses, suggesting that remnant nuclei had sufficient time for more complete dissolution. These results corroborate previous work regarding the role of cavitation in rate-dependent SWL efficacy, and suggest that the effect can be mitigated via appropriate control of the cavitation environment surrounding the stone.

Removal of residual nuclei following a cavitation event using low-amplitude ultrasound

Microscopic residual bubble nuclei can persist on the order of 1 s following a cavitation event. These bubbles can limit the efficacy of ultrasound therapies such as shock wave lithotripsy and histotripsy, because they attenuate pulses that arrive subsequent to their formation and seed repetitive cavitation activity at a discrete set of sites (cavitation memory). Here, we explore a strategy for the removal of these residual bubbles following a cavitation event, using low-amplitude ultrasound pulses to stimulate bubble coalescence. All experiments were conducted in degassed water and monitored using high-speed photography. In each case, a 2-MHz histotripsy transducer was used to initiate cavitation activity (a cavitational bubble cloud), the collapse of which generated a population of residual bubble nuclei. This residual nuclei population was then sonicated using a 1 ms pulse from a separate 500-kHz transducer, which we term the bubble removal pulse. Bubble removal pulse amplitudes ranging from 0 to 1.7 MPa were tested, and the backlit area of shadow from bubbles remaining in the field following bubble removal was calculated to quantify efficacy. It was found that an ideal amplitude range exists (roughly 180 to 570 kPa) in which bubble removal pulses stimulate the aggregation and subsequent coalescence of residual bubble nuclei, effectively removing them from the field. Further optimization of bubble removal pulse sequences stands to provide an adjunct to cavitation-based ultrasound therapies such as shock wave lithotripsy and histotripsy, mitigating the effects of residual bubble nuclei that currently limit their efficacy.

Removal of residual nuclei following a cavitation event: a parametric study

The efficacy of ultrasound therapies such as shock-wave lithotripsy and histotripsy can be compromised by residual cavitation bubble nuclei that persist following the collapse of primary cavitation. In our previous work, we have developed a unique strategy for mitigating the effects of these residual bubbles using low-amplitude ultrasound pulses to stimulate their aggregation and subsequent coalescence-effectively removing them from the field. Here, we further develop this bubble removal strategy through an investigation of the effect of frequency on the consolidation process. Bubble removal pulses ranging from 0.5 to 2 MHz were used to sonicate the population of residual nuclei produced upon collapse of a histotripsy bubble cloud. For each frequency, mechanical index (MI) values ranging from 0 to approximately 1.5 were tested. Results indicated that, when evaluated as a function of bubble removal pulse MI, the efficacy of bubble removal shows markedly similar trends for all frequencies tested. This behavior divides into three distinct regimes (with provided cutoffs being approximate): 1) MI <; 0.2: Minimal effect on the population of remanent cavitation nuclei; 2) 0.2 <; MI <; 1: Aggregation and subsequent coalescence of residual bubbles, the extent of which trends toward a maximum; and 3) MI > 1: Bubble coalescence is compromised as bubble removal pulses induce high-magnitude inertial cavitation of residual bubbles. The major distinction in these trends came for bubble removal pulses applied at 2 MHz, which were observed to generate the most effective bubble coalescence of all frequencies tested. We hypothesize that this is a consequence of the secondary Bjerknes force being the major facilitator of the consolidation process, the magnitude of which increases when the bubble size distribution is far from resonance such that the phase difference of oscillation of individual bubbles is minimal.

Active removal of residual bubble nuclei following a cavitation event

Residual microscopic bubble nuclei can persist on the order of 1 second following a cavitation event. These bubbles may limit the efficiency of ultrasound therapies such as shock wave lithotripsy and histotripsy, as they attenuate pulses that arrive subsequent to their formation and seed cavitation memory. Here, we explore a strategy for the removal of residual bubble nuclei following a cavitation event, using a low amplitude ultrasound burst to stimulate bubble coalescence. All experiments were conducted in degassed water and monitored using high speed photography. The following general pulse scheme was used: (A) Cavitation Initiation Pulse: A cavitational bubble cloud was initiated by a 1 MHz therapy transducer using a very short intense pulse (P- > 30 MPa); (B) Nuclei Removal Pulse: Residual bubble nuclei were sonicated using a 2 ms pulse from a separate 350 kHz unfocused transducer to stimulate coalescence. Nuclei removal pulses with amplitudes ranging from 0 to 750 kPa were tested; (C) Interrogation Pulse: The presence of residual nuclei following the removal pulse was probed using a second lower amplitude pulse from the therapy transducer sufficient to cause residual microscopic nuclei to expand and be more easily detected via high speed imaging. The backlit area of shadow from expanded bubbles was calculated to quantify the efficacy of nuclei removal. It was found that the control case (nuclei removal pulse amplitude = 0) generated a bubble shadow area of 0.64 ± 0.08 mm2. For nuclei removal pulse amplitudes of 50 to 150 kPa, minimal coalescence was observed in high speed video, and the area of bubbles excited by the interrogation pulse did not differ significantly from control (p> 0.08). Pronounced bubble coalescence was observable for nuclei removal pulses ≥250 kPa, with the extent of coalescence increasing with pulse amplitude. Bubble shadow area was significantly reduced relative to control in these cases (p≤ 0.02). We hypothesize that the primary and secondary Bjerknes forces act in concert to produce the bubble coalescence observed in this study.

Acoustic methods for cavitation threshold modulation

One of the main objectives of this study is to develop active tissue protection techniques for histotripsy treatment by modulating the pressure threshold of bubble cloud initiation and focal sharpening using bubble suppressing pulses. Histotripsy is a cavitation based ultrasound therapy that can achieve tissue fractionation through a mechanical process using controlled cavitation bubble clouds. In this study, we investigate the effect of applying bubble suppressing pulses before and during shock scattering histotripsy on the cavitation initiation pressure threshold. This threshold is expected to increase by reducing the probability of having an appropriate initial nuclei presence at the focus. Bubble suppressing pulses are utilized to sharpen the focus and produce a dense bubble cloud at the focus with minimized cavitation events in the peripheral zones.

Acoustic removal of cavitation nuclei to enhance stone comminution in shockwave lithotripsy

Cavitation bubbles are formed by shockwaves as part of the normal SWL procedure and can assist in fragmentation when they collapse against a stone. However, following collapse, the bubble cloud leaves behind a large population of residual micron sized bubble “nuclei” that can interfere with subsequent shockwaves. This often manifests as more efficient fragmentation at lower shockwave repetition rates where there is sufficient time for nuclei to dissolve. This study will show how the application of low amplitude, unfocused ultrasound bursts can be used to stimulate bubbles to coalescence or dispersion from the shockwave path by the primary and secondary Bjerknes forces. Applying these bursts in between shockwaves reduces the bubble nuclei shielding effect allowing more energy to reach the stone and increasing efficacy. Our results will show this technique is effective at reducing the number of shocks required for stone comminution on a clinical electromagnetic lithotripter with a simple supplemental transd...

Enhanced high rate shockwave lithotripsy stone comminution in an in-vivo porcine model using acoustic bubble coalescence

Cavitation plays a significant role in the efficacy of stone comminution during shockwave lithotripsy (SWL). Although cavitation on the surface of urinary stones helps to improve fragmentation, cavitation bubbles along the propagation path may shield or block subsequent shockwaves (SWs) and potentially induce collateral tissue damage. Previous in vitro work has shown that applying low-amplitude acoustic waves after each SW can force bubbles to consolidate and enhance SWL efficacy. In this study, the feasibility of applying acoustic bubble coalescence (ABC) in vivo was tested. Model stones were percutaneously implanted and treated with 2500 lithotripsy SWs at 120 SW/minute with or without ABC. Comparing the results of stone comminution, a significant improvement was observed in the stone fragmentation process when ABC was used. Without ABC, only 25% of the mass of the stone was fragmented to particles <2 mm in size. With ABC, 75% of the mass was fragmented to particles <2 mm in size. These results suggest that ABC can reduce the shielding effect of residual bubble nuclei, resulting in a more efficient SWL treatment.

Acoustic methods for modulating the cavitation initiation pressure threshold

The objective of this study is to develop tissue protection methods by modulating bubble cloud initiation pressure thresholds. Specifically, we investigated pressure thresholds to initiate cavitation bubble clouds by the shock scattering mechanism. Cavitation initiation displays a stochastic nature affected by existing nuclei populations in the medium. We hypothesized that by applying proper low pressure pulse sequences before and/or during histotripsy therapy, initiation pressure threshold and growth of cavitation bubble cloud could be modified. We applied histotripsy and cavitation suppressing pulses in both water and agarose gel for pulse repetition rates of 1, 10, and 100 Hz. Acoustic backscatter signals and optical imaging were used to detect and monitor initiation, maintenance, and growth of resulting cavitation bubble cloud. Results demonstrated that the use of cavitation suppressing pulses can increase the cavitation threshold by 20% in the targeted space. Furthermore, we showed these acoustic seq...

Control of cavitation through coalescence of cavitation nuclei

Therapeutic ultrasound in the form of SWL, HIFU, or histotripsy frequently generates cavitation nuclei (bubbles 1–10 um radius), which can persist up to about 1 s before dissolving. These nuclei can attenuate and reflect propagation of acoustic fields reducing SWL efficiency, enhancing HIFU heating, or shifting the location of a histotripsy focal zone making procedures less predictable. Depending on their location, nuclei can also directly cause tissue damage when a high amplitude sound field causes them to undergo inertial cavitation. These undesirable effects can be reduced by using a low amplitude sound field (MI <1) to stimulate coalescence of nuclei through primary and secondary Bjerknes forces. We will show nuclei coalescence significantly reduces sound field attenuation, improves SWL breakup of model kidney stones, and reduces collateral damage in soft tissues. We also show techniques for designing the non-focal acoustic fields for efficient coalescence with 3D printed acoustic lenses. Timothy Hall...

Non-focal acoustic lens designs for cavitation bubble consolidation

During shockwave lithotripsy, cavitation bubbles form on the surface of urinary stones aiding in the fragmentation process. However, shockwaves can also produce pre-focal bubbles, which may shield or block subsequent shockwaves and potentially induce collateral tissue damage. We have previously shown in-vitro that low amplitude acoustic waves can be applied to actively stimulate bubble coalescence and help alleviate this effect. A traditional elliptical transducer lens design produces the maximum focal gain possible for a given aperture. From experiments and simulation, we have found that this design is not optimal for bubble consolidation as the primary and secondary Bjerknes forces may act against each other and the effective field volume is too small. For this work, we designed and constructed non-focal transducer lenses with complex surface geometries using rapid prototyping stereolithography to produce more effective acoustic fields for bubble consolidation during lithotripsy or ultrasound therapy. W...