Post Hoc Analysis of Passive Cavitation Imaging for Classification of Histotripsy-Induced Liquefaction in Vitro.
ABSTRACT: Histotripsy utilizes focused ultrasound to generate bubble clouds for transcutaneous tissue liquefaction. Bubble activity maps are under development to provide image guidance and monitor treatment progress. The aim of this paper was to investigate the feasibility of using plane wave B-mode and passive cavitation images to be used as binary classifiers of histotripsy-induced liquefaction. Prostate tissue phantoms were exposed to histotripsy pulses over a range of pulse durations (5- ) and peak negative pressures (12-23 MPa). Acoustic emissions were recorded during the insonation and beamformed to form passive cavitation images. Plane wave B-mode images were acquired following the insonation to detect the hyperechoic bubble cloud. Phantom samples were sectioned and stained to delineate the liquefaction zone. Correlation between passive cavitation and plane wave B-mode images and the liquefaction zone was assessed using receiver operating characteristic (ROC) curve analysis. Liquefaction of the phantom was observed for all the insonation conditions. The area under the ROC (0.94 versus 0.82), accuracy (0.90 versus 0.83), and sensitivity (0.81 versus 0.49) was greater for passive cavitation images relative to B-mode images ( ) along the azimuth of the liquefaction zone. The specificity was greater than 0.9 for both imaging modalities. These results demonstrate a stronger correlation between histotripsy-induced liquefaction and passive cavitation imaging compared with the plane wave B-mode imaging, albeit with limited passive cavitation image range resolution.
Project description:Histotripsy is a therapeutic ultrasound modality under development to liquefy tissue mechanically via bubble clouds. Image guidance of histotripsy requires both quantification of the bubble cloud activity and accurate delineation of the treatment zone. In this study, magnetic resonance (MR) and diagnostic ultrasound imaging were combined to assess histotripsy treatment in vitro and ex vivo. Mechanically ablative histotripsy pulses were applied to agarose phantoms or porcine livers. Bubble cloud emissions were monitored with passive cavitation imaging (PCI), and hyperechogenicity via plane wave imaging. Changes in the medium structure due to bubble activity were assessed with diagnostic ultrasound using conventional B-mode imaging and T 1-, T 2-, and diffusion-weighted MR images acquired at 3 Tesla. Liquefaction zones were correlated with diagnostic ultrasound and MR imaging via receiver operating characteristic (ROC) analysis and Dice similarity coefficient (DSC) analysis. Diagnostic ultrasound indicated strong bubble activity for all samples. Histotripsy-induced changes in sample structure were evident on conventional B-mode and T 2-weighted images for all samples, and were dependent on the sample type for T 1- and diffusion-weighted imaging. The greatest changes observed on conventional B-mode or MR imaging relative to baseline in the samples did not necessarily indicate the regions of strongest bubble activity. Areas under the ROC curve for predicting phantom or liver liquefaction were significantly greater than 0.5 for PCI power, plane wave and conventional B-mode grayscale, T 1, T 2, and ADC. The acoustic power mapped via PCI provided a better prediction of liquefaction than assessment of the liquefaction zone via conventional B-mode or MR imaging for all samples. The DSC values for T 2-weighted images were greater than those derived from conventional B-mode images. These results indicate diagnostic ultrasound and MR imaging provide complimentary sets of information, demonstrating that multimodal imaging is useful for assessment of histotripsy liquefaction.
Project description:Boiling histotripsy is a High Intensity Focused Ultrasound (HIFU) technique which uses a number of short pulses with high acoustic pressures at the HIFU focus to induce mechanical tissue fractionation. In boiling histotripsy, two different types of acoustic cavitation contribute towards mechanical tissue destruction: a boiling vapour bubble and cavitation clouds. An understanding of the mechanisms underpinning these phenomena and their dynamics is therefore paramount to predicting and controlling the overall size of a lesion produced for a given boiling histotripsy exposure condition. A number of studies have shown the effects of shockwave heating in generating a boiling bubble at the HIFU focus and have studied its dynamics under boiling histotripsy insonation. However, not much is known about the subsequent production of cavitation clouds that form between the HIFU transducer and the boiling bubble. The main objective of the present study is to examine what causes this bubble cluster formation after the generation of a boiling vapour bubble. A numerical simulation of 2D nonlinear wave propagation with the presence of a bubble at the focus of a HIFU field was performed using the k-Wave MATLAB toolbox for time domain ultrasound simulations, which numerically solves the generalised Westervelt equation. The numerical results clearly demonstrate the appearance of the constructive interference of a backscattered shockwave by a bubble with incoming incident shockwaves. This interaction (i.e., the reflected and inverted peak positive phase from the bubble with the incoming incident rarefactional phase) can eventually induce a greater peak negative pressure field compared to that without the bubble at the HIFU focus. In addition, the backscattered peak negative pressure magnitude gradually increased from 17.4 MPa to 31.6 MPa when increasing the bubble size from 0.2 mm to 1.5 mm. The latter value is above the intrinsic cavitation threshold of -28 MPa in soft tissue. Our results suggest that the formation of a cavitation cloud in boiling histotripsy is a threshold effect which primarily depends (a) the size and location of a boiling bubble, and (b) the sum of the incident field and that scattered by a bubble.
Project description:Deep vein thrombosis (DVT) is a global health concern. The primary approach to achieve vessel recanalization for critical obstructions is catheter-directed thrombolytics (CDT). To mitigate caustic side effects and the long treatment time associated with CDT, adjuvant and alternative approaches are under development. One such approach is histotripsy, a focused ultrasound therapy to ablate tissue via bubble cloud nucleation. Pre-clinical studies have demonstrated strong synergy between histotripsy and thrombolytics for clot degradation. This report outlines a benchtop method to assess the efficacy of histotripsy-aided thrombolytic therapy, or lysotripsy. Clots manufactured from fresh human venous blood were introduced into a flow channel whose dimensions and acousto-mechanical properties mimic an iliofemoral vein. The channel was perfused with plasma and the lytic recombinant tissue-type plasminogen activator. Bubble clouds were generated in the clot with a focused ultrasound source designed for the treatment of femoral venous clots. Motorized positioners were used to translate the source focus along the clot length. At each insonation location, acoustic emissions from the bubble cloud were passively recorded, and beamformed to generate passive cavitation images. Metrics to gauge treatment efficacy included clot mass loss (overall treatment efficacy), and the concentrations of D-dimer (fibrinolysis) and hemoglobin (hemolysis) in the perfusate. There are limitations to this in vitro design, including lack of means to assess in vivo side effects or dynamic changes in flow rate as the clot lyses. Overall, the setup provides an effective method to assess the efficacy of histotripsy-based strategies to treat DVT.
Project description:Boiling histotripsy is a promising High-Intensity Focused Ultrasound (HIFU) technique that can be used to induce mechanical tissue fractionation at the HIFU focus via cavitation. Two different types of cavitation produced during boiling histotripsy exposure can contribute towards mechanical tissue destruction: (1) a boiling vapour bubble at the HIFU focus and (2) cavitation clouds in between the boiling bubble and the HIFU source. Control of the extent and degree of mechanical damage produced by boiling histotripsy is necessary when treating a solid tumour adjacent to normal tissue or major blood vessels. This is, however, difficult to achieve with boiling histotripsy due to the stochastic formation of the shock scattering-induced inertial cavitation clouds. In the present study, a new histotripsy method termed pressure-modulated shockwave histotripsy is proposed as an alternative to or in addition to boiling histotripsy without inducing the shock scattering effect. The proposed concept is (a) to generate a boiling vapour bubble via localised shockwave heating and (b) subsequently control its extent and lifetime through manipulating peak pressure magnitudes and a HIFU pulse length. To demonstrate the feasibility of the proposed method, bubble dynamics induced at the HIFU focus in an optically transparent liver tissue phantom were investigated using a high speed camera and a passive cavitation detection systems under a single 10, 50 or 100 ms-long 2, 3.5 or 5 MHz pressure-modulated HIFU pulse with varying peak positive and negative pressure amplitudes from 5 to 89 MPa and -3.7 to -14.6 MPa at the focus. Furthermore, a numerical simulation of 2D nonlinear wave propagation with the presence of a boiling bubble at the focus of a HIFU field was conducted by numerically solving the generalised Westervelt equation. The high speed camera experimental results showed that, with the proposed pressure-modulated shockwave histotripsy, boiling bubbles generated by shockwave heating merged together, forming a larger bubble (of the order of a few hundred micron) at the HIFU focus. This coalesced boiling bubble then persisted and maintained within the HIFU focal zone until the end of the exposure (10, 50, or 100 ms). Furthermore, and most importantly, no violent cavitation clouds which typically appear in boiling histotripsy occurred during the proposed histotripsy excitation (i.e. no shock scattering effect). This was likely because that the peak negative pressure magnitude of the backscattered acoustic field by the boiling bubble was below the cavitation cloud intrinsic threshold. The size of the coalesced boiling bubble gradually increased with the peak pressure magnitudes. In addition, with the proposed method, an oval shaped lesion with a length of 0.6 mm and a width of 0.1 mm appeared at the HIFU focus in the tissue phantom, whereas a larger lesion in the form of a tadpole (length: 2.7 mm, width: 0.3 mm) was produced by boiling histotripsy. Taken together, these results suggest that the proposed pressure-modulated shockwave histotripsy could potentially be used to induce a more spatially localised tissue destruction with a desired degree of mechanical damage through controlling the size and lifetime of a boiling bubble without the shock scattering effect.
Project description: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.
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:Histotripsy is a therapy that focuses short-duration, high-amplitude pulses of ultrasound to incite a localized cavitation cloud that mechanically breaks down tissue. To investigate the mechanism of cloud formation, high-speed photography was used to observe clouds generated during single histotripsy pulses. Pulses of 5-20 cycles duration were applied to a transparent tissue phantom by a 1-MHz spherically focused transducer. Clouds initiated from single cavitation bubbles that formed during the initial cycles of the pulse, and grew along the acoustic axis opposite the propagation direction. Based on these observations, we hypothesized that clouds form as a result of large negative pressure generated by the backscattering of shockwaves from a single bubble. The positive-pressure phase of the wave inverts upon scattering and superimposes on the incident negative-pressure phase to create this negative pressure and cavitation. The process repeats with each cycle of the incident wave, and the bubble cloud elongates toward the transducer. Finite-amplitude propagation distorts the incident wave such that the peak-positive pressure is much greater than the peak-negative pressure, which exaggerates the effect. The hypothesis was tested with two modified incident waves that maintained negative pressure but reduced the positive pressure amplitude. These waves suppressed cloud formation which supported the hypothesis.
Project description:Shock wave lithotripsy (SWL) suffers from the fact that it can produce residual stone fragments of significant size (>2 mm). Mechanistically, cavitation has been shown to play an important role in the reduction of such fragments to smaller debris. In this study, we assessed the feasibility of using cavitationally-based pulsed ultrasound therapy (histotripsy) to erode kidney stones. Previous work has shown that histotripsy is capable of mechanically fractionating soft tissue into fine, acellular debris. Here, we investigated the potential for translating this technology to renal calculi through the use of a commonly accepted stone model. Stone models were sonicated using a 1-MHz focused transducer, with 5-cycle pulses delivered at a rate of 1 kHz. Pulses having peak negative pressures ranging from 3 to 21 MPa were tested. Results indicate that histotripsy is capable of effectively eroding the stone model, achieving an average stone erosion rate of 26 mg/min at maximum treatment pressure; substantial stone erosion was only observed in the presence of a dense cavitational bubble cloud. Sequential sieving of residual stone fragments indicated that debris produced by histotripsy was smaller than 100 ?m in size, and treatment monitoring showed that both the cavitational bubble cloud and model stone appear as hyperechoic regions on B-mode imaging. These preliminary results indicate that histotripsy shows promise in its use for stone comminution, and an optimized erosion process may provide a potential adjunct to conventional SWL procedures.
Project description:The efficacy of ultrasound therapies such as hock-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.