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

ABSTRACT: 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.

SUBMITTER: Duryea AP

PROVIDER: S-EPMC4181596 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Duryea Alexander P AP Cain Charles A CA Tamaddoni Hedieh A HA Roberts William W WW Hall Timothy L TL

IEEE transactions on ultrasonics, ferroelectrics, and frequency control 20141001 10

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 pul ...[more]

PMID: 25265172

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Project description:Histotripsy has been shown to be an effective treatment for model kidney stones, eroding their surface to tiny particulate debris via a cavitational bubble cloud. However, similar to shock wave lithotripsy, histotripsy stone treatments display a rate-dependent efficacy, with pulses applied at a low rate generating more efficient stone erosion in comparison with those applied at a high rate. This is hypothesized to be the result of residual cavitation bubble nuclei generated by bubble cloud collapse. Although the histotripsy bubble cloud only lasts on the order of 100 ?s, these microscopic remnant bubbles can persist on the order of 1 s, inducing direct attenuation of subsequent histotripsy pulses and influencing bubble cloud dynamics. In an effort to mitigate these effects, we have developed a novel strategy to actively remove residual cavitation nuclei from the field using low-amplitude ultrasound pulses. Previous work has demonstrated that with selection of the appropriate acoustic parameters these bubble removal pulses can stimulate the aggregation and subsequent coalescence of microscopic bubble nuclei, effectively deleting them from the target volume. Here, we incorporate bubble removal pulses in histotripsy treatment of model kidney stones. It was found that when histotripsy is applied at low rate (1 Hz), bubble removal does not produce a statistically significant change in erosion. At higher pulse rates of 10, 100, and 500 Hz, incorporating bubble removal results in 3.7-, 7.5-, and 2.7-fold increases in stone erosion, respectively. High-speed imaging indicates that the introduction of bubble removal pulses allows bubble cloud dynamics resulting from high pulse rates to more closely approximate those generated at the low rate of 1 Hz. These results corroborate previous work in the field of shock wave lithotripsy regarding the ill effects of residual bubble nuclei, and suggest that high treatment efficiency can be recovered at high pulse rates through appropriate manipulation of the cavitation environment surrounding the stone.

Project description:Following collapse of a histotripsy cloud, residual microbubbles may persist for seconds, distributed throughout the focus. Their presence can attenuate and scatter subsequent pulses, hindering treatment speed and homogeneity. Previous studies have demonstrated use of separate low-amplitude (~1?MPa) pulses interleaved with histotripsy pulses to drive bubble coalescence (BC), significantly improving treatment speed without sacrificing homogeneity. We propose that by using electronic focal steering (EFS) to direct the therapy focus throughout specially-designed EFS sequences, it is possible to use low-gain regions of the therapy beam to accomplish BC during EFS without any additional acoustic sequence. First, to establish proof of principle for an isolated focus, a 50-foci EFS sequence was constructed with the first position isolated near the geometric focus and remaining positions distributed post-focally. EFS sequences were evaluated in tissue-mimicking phantoms with gas concentrations of 20% and 100% with respect to saturation. Results using an isolated focus demonstrated that at 20% gas concentration, 49 EFS pulses were sufficient to achieve BC in all samples for pulse repetition frequency (PRF)?????800 Hz and 84.1%??±??3.0% of samples at 5?kHz PRF. For phantoms prepared with 100% gas concentration, BC was achieved by 49 EFS pulses in 39.2%??±??4.7% of samples at 50 Hz PRF and 63.4%??±??15.3% of samples at 5?kHz. To show feasibility of using the EFS-BC method to ablate a large volume quickly, a 1000-foci EFS sequence covering a volume of approximately 27?ml was tested. Results indicate that the BC effect was similarly present. A treatment rate of 27??±??6?ml min-1 was achieved, which is signficantly faster than standard histotripsy and ultrasound thermal ablation. This study demonstrates that histotripsy with EFS can achieve BC without employing a separate acoustic sequence which has the potential to accelerate large-volume ablation while minimizing energy deposition.

Project description:Focused ultrasound (FUS) in combination with systemically injected microbubbles can be used to non-invasively open the blood-brain barrier (BBB) in targeted regions for a variety of therapeutic applications. Over the past two decades, preclinical research into the safety and efficacy of FUS-induced BBB opening has proven this technique to be transient and efficacious, propelling FUS-induced BBB opening into several clinical trials in recent years. However, as clinical trials further progress, the neuroinflammatory response to FUS-induced BBB opening needs to be better understood. In this study, we provide further insight into the relationship of microbubble cavitation and the resulting innate immune response to FUS-induced BBB opening. By keeping ultrasound parameters fixed (i.e. frequency, pressure, pulse length, etc.), three groups of mice were sonicated using a real-time cavitation controller until a target cavitation dose was reached (1 x 107 V2•s, 5 x 107 V2•s, 1 x 108 V2•s). The change in relative gene expression of the mouse inflammatory cytokines and receptors were evaluated at three different time-points (6 h, 24 h, and 72 h) after FUS. At both 6 and 24 h time-points, significant changes in relative gene expression of inflammatory cytokines and receptors were observed across all cavitation groups. However, the degree of changes in relative expression levels and the number of genes with significant changes in expression varied across the cavitation groups. Groups with a higher cavitation dose exhibited both greater changes in relative expression levels and greater number of significant changes. By 72 h post-opening, the gene expression levels returned to baseline in all cavitation dose groups, signifying a transient inflammatory response to FUS-induced BBB opening at the targeted cavitation dose levels. Furthermore, the real-time cavitation controller was able to produce consistent and significantly different BBB permeability enhancement volumes across the three different cavitation dose groups. These results indicate that cavitation monitoring and controlling during FUS-induced BBB opening can be used to potentially modulate or limit the degree of neuroinflammation, further emphasizing the importance of implementing cavitation controllers as FUS-induced BBB opening is translated into the clinic.

Dataset Information

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

Publications

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

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