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Background: Limited information on the normal range of urination frequencies in women is available to guide bladder health promotion efforts. Objectives: This study used data from the Boston Area Community Health (BACH) Survey to (a) estimate normative reference ranges in daytime and nighttime urination frequencies in healthy women based on two operational definitions of "healthy" and (b) compare urination frequencies by age, race/ethnicity, and fluid intake. Methods: A secondary analysis of cross-sectional interview data collected from female participants was performed using less restrictive ("healthy") and strict ("elite healthy") inclusion criteria. All analyses were weighted to account for the BACH sampling design. Normative reference values corresponding to the middle 95% of the distribution of daytime and nighttime urination frequencies were calculated overall and stratified by age, race/ethnicity, and fluid intake. Generalized linear regression with a log-link was used to estimate rate ratios of daytime and nighttime urination frequencies by age, race/ethnicity, and fluid intake. Results: Of the 2,534 women who completed the BACH follow-up interviews, 1,505 women met healthy eligibility criteria, and 300 met elite healthy criteria. Overall, reference ranges for urination frequencies were 2–10 times/day and 0–4 times/night in healthy women and 2–9 times/day and 0–2 times/night in elite healthy women. Women ages 45–64 years, but not 65+ years, reported a greater number of daytime urination than those aged 31–44 years, whereas women 65+ years reported a greater number of nighttime urination. Black women reported fewer daytime urination and more nighttime urinations than White women. Women who consumed less than 49 oz daily reported fewer daytime and nighttime urinations than those who drank 50–74 oz; drinking 75+ oz had only a small effect on urination frequencies. Discussion: Normative reference values for daytime and nighttime urination frequencies were similar in women using strict and relaxed definitions of health. These results indicate a wide range of "normal" urination frequencies, with some differences by age, race/ethnicity, and fluid intake. Future research is needed to examine urination frequencies in minority women and whether fluid intake amount and type influence the development of lower urinary tract symptoms. [ABSTRACT FROM AUTHOR]

Background: Little research to date has investigated the spectrum of bladder health in women, including both bladder function and well-being. Therefore, we expanded our previous baseline analysis of bladder health in the Boston Area Community Health (BACH) Survey to incorporate several additional measures of bladder-related well-being collected at the 5-year follow-up interview, including one developed specifically for women. Methods: At follow-up, participants reported their frequency of 15 lower urinary tract symptoms (LUTS), degree of life impact from and thought related to urinary symptoms or pelvic/bladder pain/discomfort, and perception of their bladder condition. Prevalence ratios were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. The BACH Survey was approved by the New England Research Institutes Institutional Review Board and all participants provided written informed consent. Results: Generally similar findings were observed in the 5-year cross-sectional analysis as at baseline, irrespective of how we categorized LUTS or measured bladder-related well-being. Approximately one in five women (16.2%–18.0% of 2527 eligible women) reported no LUTS and no diminished bladder-related well-being, the majority (55.8%–65.7%) reported some LUTS and/or diminished well-being, and a further one in five (16.9%–26.6%) reported the maximum frequency, number, or degree of LUTS and/or diminished well-being. Measures of storage function (urinating again after <2 hours, perceived frequency, nocturia, incontinence, and urgency) and pain were independently associated with bladder-related well-being. Conclusions: Our similar distribution of bladder health and consistent associations between LUTS and bladder-related well-being across multiple measures of well-being, including a female-specific measure, lend confidence to the concept of a bladder health spectrum and reinforce the bothersome nature of storage dysfunction and pain. [ABSTRACT FROM AUTHOR]

An individualized treatment rule (ITR) formalizes personalized medicine by assigning treatment as a function of patients' clinical information, which contrasts with a static treatment rule that assigns everyone the same treatment. ITR identification has become a common aim in randomized clinical trials but sample size considerations for this aim are lacking. One approach is to select a sample size that will reliably identify an ITR with a performance close to the theoretical optimal rule. However, this approach could still lead to identifying ITRs that perform worse than the optimal static rule, particularly in the absence of substantial effect heterogeneity. This limitation motivates sample size considerations aimed at reliable identification of a beneficial ITR, which outperforms the optimal static rule, and analysis methods that identify the estimated optimal static rule when there is substantial uncertainty about whether an ITR will improve outcomes. To address these limitations, we propose a sample size approach based on the probability of identifying a beneficial ITR and introduce an approach for selecting the LASSO penalty parameter such that in the absence of treatment effect heterogeneity the estimated optimal static rule is identified with high probability. We apply these approaches to the PLUTO trial aimed at developing methods to assist with smoking cessation. [ABSTRACT FROM AUTHOR]

Remanent bubble nuclei generated by primary cavitation collapse can limit the efficiency of histotripsy softtissue fractionation. When these residual bubbles persist from one histotripsy pulse to the next, they can seed the repetitive nucleation of cavitation bubbles at a discrete set of sites within the focal volume. This effect?referred to as cavitation memory? manifests in inefficient lesion formation, because certain sites within the focal volume are overtreated whereas others remain undertreated. Although the cavitation memory effect can be passively mitigated by using a low pulse repetition frequency (PRF) that affords remanent nuclei sufficient time for dissolution between successive pulses, this low PRF also results in slow lesion production. As such, it would be highly desirable to maintain the high per-pulse efficiency associated with low pulse rates when much higher PRFs are utilized. In this vein, we have developed a strategy for the active removal of the remanent bubble nuclei following primary cavitation collapse, using low-amplitude ultrasound sequences (termed bubble-removal sequences) to stimulate the aggregation and subsequent coalescence of these bubbles. In this study, bubbleremoval sequences were incorporated in high-PRF histotripsy treatment (100 Hz) of a red blood cell tissue-mimicking phantom that allows for the visualization of lesion development in real time. A series of reference treatments were also conducted at the low PRF of 1 Hz to provide a point of comparison for which cavitation memory effects are minimal. It was found that bubble-removal sequences as short as 1 ms are capable of maintaining the efficacious lesion development characteristics associated with the low PRF of 1 Hz when the much higher pulse rate of 100 Hz is used. These results were then extended to the treatment of a large volume within the tissue phantom, and optimal bubble-removal sequences identified for the singlefocal- spot case were utilized to homogenize a 10 ? 10 mm region at high rate. [ABSTRACT FROM AUTHOR]

The breakup, penetration, droplet size, and size distribution of a Jet A-l fuel in air crossflow has been investigated with focus given to the impact of surrounding air pressure. Data have been collected by particle Doppler phased analyzer (PDPA), Mie-scattering with high speed photography augmented by laser sheet, and Mie-scattering with intensified chargecoupled device (ICCD) camera augmented by nanopulse lamp. Nozzle orifice diameter, do was 0.508 mm and nozzle orifice length to diameter ratio, lo/do, was 5.5. Air crossflow velocities ranged from 29.57 to 137.15 mis, air pressures from 2.07 to 9.65 bar, and temperature held constant at 294.26 K. Fuel flow provides a range offuellair momentum flux ratio (q) from 5 to 25 and Weber number from 250 to 1000. From the results, adjusted correlation of the mean drop size has been proposed using drop size data measured by PDPA as follows: (D0/D32) = 0.267Wea0.44q0.08 (ρl/ρa)0.30 (μl/μa)-0.16. This correlation agrees well and shows roles of aerodynamic Weber number, Wea, momentum flux ratio, q, and density ratio, μl/μa. Change of the breakup regime map with respect to surrounding air pressure has been obsen ed and revealed that the boundary betw een each breakup modes can be predicted by a transformed correlation obtained from above correlation. In addition, the spray trajectory for the maximum Mie-scattering intensity at each axial location downstream of injector is extracted from averaged Mie-scattering images. From these results, correlations with the relevant parameters including q, x/do density ratio, viscosity ratio, and Weber number are made over a range of conditions. According to spray trajectory at the maximum Mie-scattering intensity, the effect of surrounding air pressure becomes more important in the farfield. On the other hand, effect of aerodynamic Weber number is more important in the neaifield. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: In this study, the negative pressure values at which inertial cavitation consistently occurs in response to a single, two-cycle, focused ultrasound pulse were measured in several media relevant to cavitation-based ultrasound therapy. The pulse was focused into a chamber containing one of the media, which included liquids, tissue-mimicking materials, and ex vivo canine tissue. Focal waveforms were measured by two separate techniques using a fiber-optic hydrophone. Inertial cavitation was identified by high-speed photography in optically transparent media and an acoustic passive cavitation detector. The probability of cavitation (Pcav) for a single pulse as a function of peak negative pressure (p −) followed a sigmoid curve, with the probability approaching one when the pressure amplitude was sufficient. The statistical threshold (defined as Pcav = 0.5) was between p − = 26 and 30 MPa in all samples with high water content but varied between p − = 13.7 and >36 MPa in other media. A model for radial cavitation bubble dynamics was employed to evaluate the behavior of cavitation nuclei at these pressure levels. A single bubble nucleus with an inertial cavitation threshold of p − = 28.2 megapascals was estimated to have a 2.5 nm radius in distilled water. These data may be valuable for cavitation-based ultrasound therapy to predict the likelihood of cavitation at various pressure levels and dimensions of cavitation-induced lesions in tissue. [Copyright &y& Elsevier]

Abstract: Clinically available thrombolysis techniques are limited by either slow reperfusion (drugs) or invasiveness (catheters) and carry significant risks of bleeding. In this study, the feasibility of using histotripsy as an efficient and noninvasive thrombolysis technique was investigated. Histotripsy fractionates soft tissue through controlled cavitation using focused, short, high-intensity ultrasound pulses. In vitro blood clots formed from fresh canine blood were treated by histotripsy. The treatment was applied using a focused 1-MHz transducer, with five-cycle pulses at a pulse repetition rate of 1kHz. Acoustic pressures varying from 2 to 12MPa peak negative pressure were tested. Our results show that histotripsy can perform effective thrombolysis with ultrasound energy alone. Histotripsy thrombolysis only occurred at peak negative pressure ≥6MPa when initiation of a cavitating bubble cloud was detected using acoustic backscatter monitoring. Blood clots weighing 330mg were completely broken down by histotripsy in 1.5 to 5min. The clot was fractionated to debris with >96% weight smaller than 5μm diameter. Histotripsy thrombolysis treatment remained effective under a fast, pulsating flow (a circulatory model) as well as in static saline. Additionally, we observed that fluid flow generated by a cavitation cloud can attract, trap and further break down clot fragments. This phenomenon may provide a noninvasive method to filter and eliminate hazardous emboli during thrombolysis. (E-mail: adamdm@umich.edu) [Copyright &y& Elsevier]

Spatial variability in acoustic backscatter is investigated as a potential feedback metric for assessment of lesion morphology during cavitation-mediated mechanical tissue disruption ("histotripsy"). A 750-kHz annular array was aligned confocally with a 4.5 MHz passive backscatter receiver during ex vivo insonation of porcine myocardium. Various exposure conditions were used to elicit a range of damage morphologies and backscatter characteristics [pulse duration = 14 /Ls, pulse repetition frequency (PRF) = 0.07-3.1 kHz, average ISPPA = 22-44 kW/cm²]. Variability in backscatter spatial localization was quantified by tracking the lag required to achieve peak correlation between sequential RF A-lines received. Mean spatial variability was observed to be significantly higher when damage morphology consisted of mechanically disrupted tissue homogenate versus mechanically intact coagulation necrosis (2.35 ± 1.59 mm versus 0.067 ± 0.054 mm, p < 0.025). Statistics from these variability distributions were used as the basis for selecting a threshold variability level to identify the onset of homogenate formation via an abrupt, sustained increase in spatially dynamic backscatter activity. Specific indices indicative of the state of the homogenization process were quantified as a function of acoustic input conditions. The prevalence of backscatter spatial variability was observed to scale with the amount of homogenate produced for various PRFs and acoustic intensities. [ABSTRACT FROM AUTHOR]

Design considerations, assembly details, and operating procedures of one version of a cost-effective basic fiber-optic probe hydrophone (FOPH) are described in order to convey practical information to groups interested in constructing a similar device. The use of fiber optic hydrophones can overcome some of the limitations associated with traditional polyvinylidene difluoride (PVDF) hydrophones for calibration of acoustic fields. Compared to standard PVDF hydrophones, FOPH systems generally have larger bandwidths, enhanced spatial resolution, reduced directionality, and greater immunity to electromagnetic interference, though they can be limited by significantly lower sensitivities. The FOPH system presently described employs a 100-μm multimode optical fiber as the sensing element and incorporates a 1-W laser diode module, 2×2 optical coupler, and general-purpose 50-MHz silicon p-i-n photodetector. Wave forms generated using the FOPH system and a reference PVDF hydrophone are compared, and intrinsic and substitution methods for calibrating the FOPH system are discussed. The voltage-to-pressure transfer factor is approximately 0.8 mV/MPa (-302 dB re 1 V/μPa), though straightforward modifications to the optical components in the FOPH system are discussed that can significantly increase this value. Recommendations are presented to guide the choice of optical components and to provide practical insight into the routine usage of the FOPH device. [ABSTRACT FROM AUTHOR]

Abstract: Methods were investigated to acoustically control the extent to which cavitation-mediated tissue homogenization is responsible for lesion formation in vitro. These results may guide potential therapeutic procedures that induce damage predominantly via mechanical disruption and, thereby, avoid limitations associated with thermal ablative modalities. Porcine myocardium was insonified at 750 kHz using pulse sequences consisting of high-amplitude pulses (22 MPa Pr) interleaved with variable-amplitude “sustaining” pulses (e.g., 6.9 MPa Pr), which were intended to provide sufficient acoustic input to maintain cavitation activity between primary pulses, but to increase the spatial peak temporal average intensity (ISPTA) only marginally. Using modest temporal-average intensities (e.g., ISPTA ≈ 200 W/cm2), ≈ 0.5 cm3 lesions were produced consisting of homogenate that could be irrigated away to reveal smooth cavities. The prevalence of homogenate in a given lesion was sensitive to both pulse-repetition frequency and sustaining pulse amplitude, suggesting the existence of optimum acoustic parameters for producing homogenized lesions largely via mechanical perturbation. (E-mail: jeparson@umich.edu) [Copyright &y& Elsevier]

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after <2 hours (PRs = 1.2–1.5, all p < 0.05). Conclusions: Our findings suggest that bladder health exists on a continuum, with approximately one in five women considered to have optimal bladder health (no LUTS/interference), the majority to have intermediate health (LUTS/interference rarely to usually), and a further one in five to have worse or poor health (LUTS/interference almost always). These findings underscore the need for LUTS prevention and bladder health promotion. [ABSTRACT FROM AUTHOR]

Retracted blood clots have been previously recognized to be more resistant to drug-based thrombolysis methods, even with ultrasound and microbubble enhancements. Microtripsy, a new histotripsy approach, has been investigated as a non-invasive, drug-free and image-guided method that uses ultrasound to break up clots with improved treatment accuracy and a lower risk of vessel damage compared with the traditional histotripsy thrombolysis approach. Unlike drug-mediated thrombolysis, which is dependent on the permeation of the thrombolytic agents into the clot, microtripsy controls acoustic cavitation to fractionate clots. We hypothesize that microtripsy thrombolysis is effective on retracted clots and that the treatment efficacy can be enhanced using strategies incorporating electronic focal steering. To test our hypothesis, retracted clots were prepared in vitro and the mechanical properties were quantitatively characterized. Microtripsy thrombolysis was applied on the retracted clots in an in vitro flow model using three different strategies: single-focus, electronically-steered multi-focus and dual-pass multi-focus. Results show that microtripsy was used to successfully generate a flow channel through the retracted clot and the flow was restored. The multi-focus and the dual-pass treatments incorporating the electronic focal steering significantly increased the recanalized flow channel size compared to the single-focus treatments. The dual-pass treatments achieved a restored flow rate up to 324 mL/min without cavitation contacting the vessel wall. The clot debris particles generated from microtripsy thrombolysis remained within the safe range. The results of this study show the potential of microtripsy thrombolysis for retracted clot recanalization with the enhancement of electronic focal steering. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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 waveform's 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. [ABSTRACT FROM AUTHOR]

Stone comminution in shock wave lithotripsy (SWL) has been documented to result from mechanical stresses conferred directly to the stone, as well as the activity of cavitational microbubbles. Studies have demonstrated that the presence of this cavitation activity is crucial for stone subdivision; however, its exact role in the comminution process remains somewhat weakly defined, in part because it is difficult to isolate the cavitational component from the shock waves themselves. In this study, we further explored the importance of cavitation in SWL stone comminution through the use of histotripsy ultrasound therapy. Histotripsy was used to target model stones designed to mimic the mid-range tensile fracture strength of naturally occurring cystine calculi with controlled cavitation at strategic time points in the SWL comminution process. All SWL was applied at a peak positive pressure (p+) of 34 MPa and a peak negative pressure (p–) of 8 MPa; a shock rate of 1 Hz was used. Histotripsy pulses had a p– of 33 MPa and were applied at a pulse repetition frequency (PRF) of 100 Hz. Ten model stones were sonicated in vitro with each of five different treatment schemes: A) 10 min of SWL (600 shocks) with 0.7 s of histotripsy interleaved between successive shocks (totaling to 42 000 pulses); B) 10 min of SWL (600 shocks) followed by 10 min of histotripsy applied in 0.7-s bursts (1 burst per second, totaling to 42 000 pulses); C) 10 min of histotripsy applied in 0.7-s bursts (42 000 pulses) followed by 10 min of SWL (600 shocks); D) 10 min of SWL only (600 shocks); E) 10 min of histotripsy only, applied in 0.7-s bursts (42 000 pulses). Following sonication, debris was collected and sieved through 8-, 6-, 4-, and 2-mm filters. It was found that scheme D, SWL only, generated a broad range of fragment sizes, with an average of 14.9 ± 24.1% of the original stone mass remaining > 8 mm. Scheme E, histotripsy only, eroded the surface of stones to tiny particulate debris that was small enough to pass through the finest filter used in this study (<2 mm), leaving behind a single primary stone piece (>8 mm) with mass 85.1 ± 1.6% of the original following truncated sonication. The combination of SWL and histotripsy (schemes A, B, and C) resulted in a shift in the size distribution toward smaller fragments and complete elimination of debris > 8 mm. When histotripsy-controlled cavitation was applied following SWL (B), the increase in exposed stone surface area afforded by shock wave stone subdivision led to enhanced cavitation erosion. When histotripsy-controlled cavitation was applied before SWL (C), it is likely that stone surface defects induced by cavitation erosion provided sites for crack nucleation and accelerated shock wave stone subdivision. Both of these effects are likely at play in the interleaved therapy (A), although shielding of shock waves by remnant histotripsy microbubble nuclei may have limited the efficacy of this scheme. Nevertheless, these results demonstrate the important role played by cavitation in the stone comminution process, and suggest that the application of controlled cavitation at strategic time points can provide an adjunct to traditional SWL therapy. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

A feedback method for obtaining real-time information on the mechanical disruption of tissue through ultrasound cavitation is presented. This method is based on a substantial reduction in ultrasound imaging backscatter from the target volume as the tissue structure is broken down. Ex-vivo samples of porcine liver were exposed to successive high-intensity ultrasound pulses at a low duty cycle to induce mechanical disruption of tissue parenchyma through cavitation (referred to as histotripsy). At the conclusion of treatment, B-scan imaging backscatter was observed to have decreased by 22.4 ± 2.3 dB in the target location. Treated samples of tissue were found to contain disrupted tissue corresponding to the imaged hypoechoic volume with no remaining discernable structure and a sharp boundary. The observed, substantial backscatter reduction may be an effective feedback mechanism for assessing treatment efficacy in ultrasound surgery using pulsed ultrasound to create cavitation. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that pulsed ultrasound can physically remove soft tissue through cavitation. A new strategy to enhance the cavitation-induced erosion is proposed wherein tissue erosion is initiated by a short, high-intensity sequence of pulses and sustained by lower intensity pulses. We investigated effects of the initiating sequence on erosion and cavitation sustained by lower intensity pulses. Multiple three-cycle pulses at a pulse repetition frequency of 20 kHz delivered by a 788-kHz focused transducer were used for tissue erosion. Fixing the initiating sequence at ISPPA of 9000 W/cm², 16 combinations of different numbers of pulses within the initiating sequence and different sustaining pulse intensities were tested. Results showed: the initiating sequence increases the probability of erosion occurrence and the erosion rate with only slight overall increases in propagated energy; the initiating sequence containing more pulses does not increase the sustained cavitation period; and if extinguished and reinitiated, the sustained cavitation period becomes shorter after each initiation, although the waiting time between adjacent cavitation periods is random. The high-intensity, initiating sequence enhances cavitational tissue erosion and enables erosion at intensities significantly lower than what is required to initiate erosion. [ABSTRACT FROM AUTHOR]

Shock scattering histotripsy involves a complex interaction between positive and negative phases of an acoustic burst to initiate a robust cavitation bubble cloud. To more precisely study these effects and optimize shock scattering histotripsy therapy, we constructed a frequency compounding transducer to generate pseudomonopolar ultrasound pulses. The transducer consisted of 113 individual piezoelectric elements with various resonant frequencies (250 kHz, 500 kHz, 750 kHz, 1 MHz, 1.5 MHz, 2 MHz, and 3 MHz). For each resonant frequency, an extremely short pulse could be generated. Pseudomonopolar peak positive pulses were generated by aligning the principal peak positive pressures of individual frequency components temporally, so that they added constructively, and destructive interference occurred outside the peak-positive-overlapped temporal window. After inverting the polarity of the excitation signals, pseudomonopolar peak negative pulses were generated similarly by aligning principal peak negative pressures. Decoupling the positive and negative acoustic phases could have significant advantages for therapeutic applications enhancing precision and avoiding cavitation at tissue interfaces by using mostly positive pressure pulses. For example, we show that 16 shock scattering bubble clouds can be generated using only peak positive pulses following a single peak negative pulse that initiates a pressure release “seed cloud” from which the first shock front is “scattered.” Subsequent positive only pulses result in a precise elongated lesion within red blood cell phantoms. [ABSTRACT FROM AUTHOR]

Acoustic aberrations caused by natural heterogeneities of biological soft tissue are a substantial problem for histotripsy, a therapeutic ultrasound technique that uses acoustic cavitation to mechanically fractionate and destroy unwanted target tissue without damaging surrounding tissue. These aberrations, primarily caused by sound speed variations, result in severe defocusing of histotripsy pulses, thereby decreasing treatment efficacy. The gold standard for aberration correction (AC) is to place a hydrophone at the desired focal location to directly measure phase aberrations, which is a method that is infeasiblein vivo. We hypothesized that the acoustic cavitation emission (ACE) shockwaves from the initial expansion of inertially cavitating microbubbles generated by histotripsy can be used as a point source for AC. In this study, a 500-kHz, 112-element histotripsy phased array capable of transmitting and receiving ultrasound on all channels was used to acquire ACE shockwaves. These shockwaves were first characterized optically and acoustically. It was found that the shockwave pressure increases significantly as the source changes from a single bubble to a dense cavitation cloud. The first arrival of the shockwave received by the histotripsy array was from the outer-most cavitation bubbles located closest to the histotripsy array. Hydrophone and ACE AC methods were then tested onex vivoporcine abdominal tissue samples. Without AC, the focal pressure is reduced by 49.7% through the abdominal tissue. The hydrophone AC approach recovered 55.5% of the lost pressure. Using the ACE AC method, over 20% of the lost pressure was recovered, and the array power required to induce cavitation was reduced by approximately 31.5% compared to without AC. These results supported our hypothesis that the ACE shockwaves coupled with a histotripsy array with transmit and receive capability can be used for AC for histotripsy through soft tissue. [ABSTRACT FROM AUTHOR]

Bubble-induced color Doppler (BCD) is a histotripsy-therapy monitoring technique that uses Doppler ultrasound to track the motion of residual cavitation nuclei that persist after the collapse of the histotripsy bubble cloud. In this study, BCD is used to monitor tissue fractionation during histotripsy tissue therapy, and the BCD signal is correlated with the destruction of structural and non-structural components identified histologically to further understand how BCD monitors the extent of treatment. A 500-kHz, 112-element phased histotripsy array is used to generate approximately 6- × 6- × 7-mm lesions within ex vivo bovine liver tissue by scanning more than 219 locations with 30-1000 pulses per location. A 128-element L7-4 imaging probe is used to acquire BCD signals during all treatments. The BCD signal is then quantitatively analyzed using the time-to-peak rebound velocity (tprv) metric. Using the Pearson correlation coefficient, the tprv is compared with histologic analytics of lesions generated by various numbers of pulses using a significance level of 0.001. Histologic analytics in this study include viable cell count, reticulin-stained type III collagen area and trichrome-stained type I collagen area. It is found that the tprv metric has a statistically significant correlation with the change in reticulin-stained type III collagen area with a Pearson correlation coefficient of -0.94 (p <0.001), indicating that changes in BCD are more likely because of destruction of the structural components of tissue. [ABSTRACT FROM AUTHOR]

Histotripsy is a non-invasive, non-thermal ablation technique that uses high-amplitude, focused ultrasound pulses to fractionate tissue via acoustic cavitation. The goal of this study was to illustrate the potential of histotripsy with electronic focal steering to achieve rapid ablation of a tissue volume at a rate matching or exceeding those of current clinical techniques (∼1-2 mL/min). Treatment parameters were established in tissue-mimicking phantoms and applied to ex vivo tissue. Six-microsecond pulses were delivered by a 250-kHz array. The focus was electrically steered to 1000 locations at a pulse repetition frequency of 200 Hz (0.12% duty cycle). Magnetic resonance imaging and histology of the treated tissue revealed a distinct region of necrosis in all samples. Mean lesion volume was 35.6 ± 4.3 mL, generated at 0.9-3.3 mL/min, a speed faster than that of any current ablation method for a large volume. These results suggest that histotripsy has the potential to achieve non-invasive, rapid, homogeneous ablation of a tissue volume. [ABSTRACT FROM AUTHOR]

Histotripsy is a minimally invasive ultrasound therapy that has shown rapid liquefaction of blood clots through human skullcaps in an in vitro intracerebral hemorrhage model. However, the efficiency of these treatments can be compromised if the skull-induced aberrations are uncorrected. We have developed a catheter hydrophone which can perform aberration correction (AC) and drain the liquefied clot following histotripsy treatment. Histotripsy pulses were delivered through an excised human skullcap using a 256-element, 500-kHz hemisphere array transducer with a 15-cm focal distance. A custom hydrophone was fabricated using a $0.5\times 0.5\times0.3$ mm PZT-5h crystal interfaced to a coaxial cable and integrated into a drainage catheter. An AC algorithm was developed to correct the aberrations introduced between histotripsy pulses from each array element. An increase in focal pressure of up to 60% was achieved at the geometric focus and 27%–62% across a range of electronic steering locations. The sagittal and axial −6-dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 and 3 mm in the absence of aberration. After performing AC, lesions with diameters ranging from 0.24 to 1.35 mm were generated using electronic steering over a $10 \times 10$ mm grid in a tissue-mimicking phantom. An average volume of 4.07 ± 0.91 mL was liquefied and drained after using electronic steering to treat a 4.2-mL spherical volume in in vitro bovine clots through the skullcap. [ABSTRACT FROM AUTHOR]

This in vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. A 4-cm diameter spherical volume of in vitro blood clot was treated through 3 excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: λ/2, 2 λ/3 and λ with 50 pulses per location. The pulse repetition frequency across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in the range of 6-59 mL in 0.9-42.4 min. The fastest rate was 16.6 mL/min. The best parameter combination was λ spacing at 500 kHz, which produced large liquefaction through 3 skullcaps (23.1 ± 4.0, 37.1 ± 16.9 and 25.4 ± 16.9 mL) with the fast rates (3.2 ± 0.6, 5.1 ± 2.3 and 3.5 ± 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4°C. [ABSTRACT FROM AUTHOR]

Histotripsy is a non-invasive therapeutic technique that uses ultrasound generated from outside the body to create controlled cavitation in targeted tissue, and fractionates it into acellular debris. We have developed a new histotripsy approach, termed microtripsy, to improve targeting accuracy and to avoid collateral tissue damage. This in vivo study evaluates the safety and efficacy of microtripsy for non-invasive thrombolysis in a porcine deep vein thrombosis model. Acute thrombi were formed in left femoral veins of pigs (∼35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by real-time ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs; 10 pigs were euthanized on the same day (acute) and 4 at 2 wk (subacute). To evaluate vessel damage, 30-min free-flow treatment in the right femoral vein (no thrombus) was also conducted in 8 acute pigs. Blood flow was successfully restored or significantly increased after treatment in 13 of the 14 pigs. The flow channels re-opened by microtripsy had a diameter up to 64% of the vessel diameter (∼6 mm). The average treatment time was 16 min per centimeter-long thrombus. Only mild intravascular hemolysis was induced during microtripsy thrombolysis. No damage was observed on vessel walls after 2 wk of recovery, venous valves were preserved, and there was no sign of pulmonary embolism. The results of this study indicate that microtripsy has the potential to be a safe and effective treatment for deep vein thrombosis in a porcine model. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Histotripsy is a non-invasive ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. With a sufficient number of pulses, histotripsy can completely fractionate tissue into a liquid-appearing homogenate with no cellular structures. The location, shape and size of lesion formation closely match those of the cavitation cloud. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large stress and strain on the tissue structures immediately adjacent to the bubbles. In the work described here, the histotripsy bulk tissue fractionation process is visualized at the cellular level for the first time using a custom-built 2-MHz transducer incorporated into a microscope stage. A layer of breast cancer cells were cultured within an optically transparent fibrin-based gel phantom to mimic cells inside a 3-D extracellular matrix. To test the hypothesis, the cellular response to single and multiple histotripsy pulses was investigated using high-speed optical imaging. Bubbles were always generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubble during both bubble expansion and collapse. The largest displacements were observed during collapse for cells immediately adjacent to the bubble, with cells moving more than 150-300 μm in less than 100 μs. Cells often underwent multiple large deformations (>150% strain) over multiple pulses, resulting in the bisection of cells multiple times before complete removal. To provide theoretical support to the experimental observations, a numerical simulation was conducted using a single-bubble model, which indicated that histotripsy exerts the largest strains and cell displacements in the regions immediately adjacent to the bubble. The experimental and simulation results support our hypothesis, which helps to explain the formation of the sharp lesions formed in histotripsy therapy localized to the regions directly exposed to the bubbles. [ABSTRACT FROM AUTHOR]

Histotripsy is an ultrasound ablation method that depends on the initiation of a dense cavitation bubble cloud to fractionate soft tissue. Previous work has demonstrated that a cavitation cloud can be formed by a single acoustic pulse with one high-amplitude negative cycle, when the negative pressure amplitude exceeds a threshold intrinsic to the medium. The intrinsic thresholds in soft tissues and tissue phantoms that are water based are similar to the intrinsic threshold of water over an experimentally verified frequency range of 0.3–3 MHz. Previous work studying the histotripsy intrinsic threshold has been limited to experiments performed at room temperature (~20°C). In this study, we investigate the effects of temperature on the histotripsy intrinsic threshold in water, which is essential to accurately predict the intrinsic thresholds expected over the full range of in vivo therapeutic temperatures. Based on previous work studying the histotripsy intrinsic threshold and classical nucleation theory, we hypothesize that the intrinsic threshold will decrease with increasing temperature. To test this hypothesis, the intrinsic threshold in water was investigated both experimentally and theoretically. The probability of generating cavitation bubbles was measured by applying a single pulse with one high-amplitude negative cycle at 1 MHz to distilled degassed water at temperatures ranging from 10 °C to 90 °C. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured versus pressure amplitude. The results indicate that the intrinsic threshold (the negative pressure at which the cavitation probability $=\,0.5$ ) significantly decreases with increasing temperature, showing a nearly linear decreasing trend from 29.8 ± 0.4 MPa at 10 °C to 14.9±1.4 MPa at 90 °C. Overall, the results of this study support our hypothesis that the intrinsic threshold is highly dependent on the temperature of the medium, which may allow for better predictions of cavitation generation at body temperature in vivo and at the elevated temperatures commonly seen in high-intensity focused ultrasound regimes. [ABSTRACT FROM PUBLISHER]

This study demonstrates the ability of histotripsy to generate targeted lesions through the skullcap without using aberration correction. Histotripsy therapy was delivered using a 500-kHz 256-element hemispherical transducer with an aperture diameter of 30 cm, and a focal distance of 15 cm fabricated in our laboratory. This transducer is theoretically capable of producing peak rarefactional pressures, based on linear estimation, (p-)\text{LE}, in the free field in excess of 200 MPa with pulse durations \leq2 acoustic cycles. Three excised human skullcaps were used displaying attenuations of 73%–81% of the acoustic pressure without aberration correction. Through all three skullcaps, compact lesions with radii less than 1\,\text{mm} were generated in red blood cell agarose tissue phantoms without aberration correction, using estimated (p-)\text{LE} of 28\text{-}39\,\text{MPa}$, a pulse repetition frequency of 1\,\text{Hz}, and a total number of 300 pulses. Lesion generation was consistently observed at the geometric focus of the transducer as the position of the skullcap with respect to the transducer was varied, and multiple-patterned lesions were generated transcranially by mechanically adjusting the position of the skullcap with respect to the transducer to target different regions within. These results show that compact targeted lesions with sharp boundaries can be generated through intact skullcaps using histotripsy with very short pulses without using aberration correction. Such capability has the potential to greatly simplify transcranial ultrasound therapy for noninvasive transcranial applications, as current ultrasound transcranial therapy techniques all require sophisticated aberration correction. [ABSTRACT FROM AUTHOR]

Histotripsy therapy produces cavitating bubble clouds to increasingly fractionate and eventually liquefy tissue using high-intensity ultrasound pulses. Following cavitation generated by each pulse, coherent motion of the cavitation residual nuclei can be detected using metrics formed from ultrasound color Doppler acquisitions. In this paper, three experiments were performed to investigate the characteristics of this motion as real-time feedback on histotripsy tissue fractionation. In the first experiment, bubble-induced color Doppler (BCD) and particle image velocimetry (PIV) analysis monitored the residual cavitation nuclei in the treatment region in an agarose tissue phantom treated with two-cycle histotripsy pulses at >30\text MPa using a 500-kHz transducer. Both BCD and PIV results showed brief chaotic motion of the residual nuclei followed by coherent motion first moving away from the transducer and then rebounding back. Velocity measurements from both PIV and BCD agreed well, showing a monotonic increase in rebound time up to a saturation point for increased therapy dose. In a second experiment, a thin layer of red blood cells (RBC) was added to the phantom to allow quantification of the fractionation of the RBC layer to compare with BCD metrics. A strong linear correlation was observed between the fractionation level and the time to BCD peak rebound velocity over histotripsy treatment. Finally, the correlation between BCD feedback and histotripsy tissue fractionation was validated in ex vivo porcine liver evaluated histologically. BCD metrics showed strong linear correlation with fractionation progression, suggesting that BCD provides useful quantitative real-time feedback on histotripsy treatment progression. [ABSTRACT FROM PUBLISHER]

Histotripsy fractionates soft tissue by well-controlled acoustic cavitation using microsecond-long, high-intensity ultrasound pulses. The feasibility of using histotripsy as a noninvasive, drug-free, and image-guided thrombolysis method has been shown previously. A new histotripsy approach, termed microtripsy, has recently been investigated for the thrombolysis application to improve treatment accuracy and avoid potential vessel damage. In this study, we investigated the effects of pulse repetition frequency (PRF) on microtripsy thrombolysis. Microtripsy thrombolysis treatments using different PRFs (5, 50, and 100 Hz) and doses (20, 50, and 100 pulses) were performed on blood clots in an in vitro vessel flow model. To quantitatively evaluate the microtripsy thrombolysis effect, the location of focal cavitation, the incident rate of pre-focal cavitation on the vessel wall, the size and location of the resulting flow channel, and the generated clot debris particles were measured. The results demonstrated that focal cavitation was always well confined in the vessel lumen without contacting the vessel wall for all PRFs. Pre-focal cavitation on the front vessel wall was never observed at 5Hz PRF, but occasionally observed at PRFs of 50 Hz (1.2%) and 100 Hz (5.4%). However, the observed pre-focal cavitation was weak and did not significantly affect the focal cavitation. Results further demonstrated that, although the extent of clot fractionation per pulse was the highest at 5 Hz PRF at the beginning of treatment (<20 pulses), 100 Hz PRF generated the largest flow channels with a much shorter treatment time. Finally, results showed fewer large debris particles were generated at a higher PRF. Overall, the results of this study suggest that a higher PRF (50 or 100 Hz) may be a better choice for microtripsy thrombolysis to use clinically due to the larger resulting flow channel, shorter treatment time, and smaller debris particles. [ABSTRACT FROM AUTHOR]

Histotripsy is a non-invasive ablation method that mechanically fractionates tissue by controlling acoustic cavitation. Previous work has revealed that tissue mechanical properties play a significant role in the histotripsy process, with stiffer tissues being more resistant to histotripsy-induced tissue damage. In this study, we propose a thermal pretreatment strategy to precondition tissues before histotripsy. We hypothesize that a thermal pretreatment can be used to alter tissue stiffness by modulating collagen composition, thus changing tissue susceptibility to histotripsy. More specifically, we hypothesize that tissues will soften and become more susceptible to histotripsy when preheated at ∼60°C because of collagen denaturation, but that tissues will rapidly stiffen and become less susceptible to histotripsy when preheated at ∼90°C because of collagen contraction. To test this hypothesis, a controlled temperature water bath was used to heat various ex vivo bovine tissues (tongue, artery, liver, kidney medulla, tendon and urethra). After heating, the Young's modulus of each tissue sample was measured using a tissue elastometer, and changes in tissue composition (i.e., collagen structure/density) were analyzed histologically. The susceptibility of tissues to histotripsy was investigated by treating the samples using a 750-kHz histotripsy transducer. Results revealed a decrease in stiffness and an increase in susceptibility to histotripsy for tissues (except urethra) preheated to 58°C. In contrast, preheating to 90°C increased tissue stiffness and reduced susceptibility to histotripsy for all tissues except tendon, which was significantly softened due to collagen hydrolysis into gelatin. On the basis of these results, a final set of experiments were conducted to determine the feasibility of using high-intensity focused ultrasound to provide the thermal pretreatment. Overall, the results of this study indicate the initial feasibility of a thermal pretreatment strategy to precondition tissue mechanical properties and alter tissue susceptibility to histotripsy. Future work will aim to optimize this thermal pretreatment strategy to determine if this approach is practical for specific clinical applications in vivo without causing unwanted damage to surrounding or overlying tissue. [ABSTRACT FROM AUTHOR]

When histotripsy pulses shorter than 2 cycles are applied, the formation of a dense bubble cloud relies only on the applied peak negative pressure (p−) exceeding the “intrinsic threshold” of the medium (absolute value of 26–30 MPa in most soft tissues). It has been found that a sub-threshold high-frequency probe pulse (3 MHz) can be enabled by a sub-threshold low-frequency pump pulse (500 kHz) where the sum exceeds the intrinsic threshold, thus generating lesion-producing dense bubble clouds (“dual-beam histotripsy”). Here, the feasibility of using an imaging transducer to provide the high-frequency probe pulse in the dual-beam histotripsy approach is investigated. More specifically, an ATL L7-4 imaging transducer (Philips Healthcare, Andover, MA, USA), pulsed by a V-1 Data Acquisition System (Verasonics, Redmond, WA, USA), was used to generate the high-frequency probe pulses. The low-frequency pump pulses were generated by a 20-element 345-kHz array transducer, driven by a custom high-voltage pulser. These dual-beam histotripsy pulses were applied to red blood cell tissue-mimicking phantoms at a pulse repetition frequency of 1 Hz, and optical imaging was used to visualize bubble clouds and lesions generated in the red blood cell phantoms. The results indicated that dense bubble clouds (and resulting lesions) were generated when the p− of the sub-threshold pump and probe pulses combined constructively to exceed the intrinsic threshold. The average size of the smallest reproducible lesions using the imaging probe pulse enabled by the sub-threshold pump pulse was 0.7 × 1.7 mm, whereas that using the supra-threshold pump pulse alone was 1.4 × 3.7 mm. When the imaging transducer was steered laterally, bubble clouds and lesions were steered correspondingly until the combined p− no longer exceeded the intrinsic threshold. These results were also validated with ex vivo porcine liver experiments. Using an imaging transducer for dual-beam histotripsy can have two advantages: (i) lesion steering can be achieved using the steering of the imaging transducer (implemented with the beamformer of the accompanying programmable ultrasound system), and (ii) treatment can be simultaneously monitored when the imaging transducer is used in conjunction with an ultrasound imaging system. [ABSTRACT FROM AUTHOR]

Histotripsy has been investigated as a noninvasive, drug-free, image-guided thrombolysis method that fractionates blood clots using acoustic cavitation alone. In previous histotripsy-mediated thrombolysis studies, cavitation clouds were generated using multi-cycle pulses and tended to form on vessel wall. To avoid potential cavitational damage to the vessel wall, a new histotripsy approach, termed microtripsy, has been recently discovered in which cavitation is generated via an intrinsic-threshold mechanism using single-cycle pulses. We hypothesize that microtripsy can generate and confine cavitation in vessel lumen without contacting the vessel wall, which results in recanalization within the clot and potentially eliminating vessel damage. To test our hypothesis, microtripsy was investigated for clot recanalization in an in vitro flow model. Clots were formed inside a vessel phantom (6.5 mm inner diameter) in line with a flow system. Microtripsy was applied by a 1-MHz transducer at a pulse repetition frequency of 50 Hz with a peak negative pressure (P?) of 30 MPa or 36 MPa. To create a flow channel through a clot, the cavitation focus was scanned through the clot at an interval of 0.3 or 0.7 mm. The treated clots were 3-D-scanned by a 20-MHz ultrasound probe to quantify the channels. Restored flow rates were measured and clot debris particles generated from the treatments were analyzed. In all treatments, the cavitation cloud was consistently generated in the center of the vessel lumen without contacting the vessel wall. After each treatment, a flow channel was successfully generated through and completely confined inside the clot. The channels had a diameter up to 60% of the vessel diameter, with restored flow up to 500 mL/min. The debris particles were small with more than 99.9% < 10 ?m and the largest at 153 um. Each clot (2 cm long) was recanalized within 7 min. The size of the flow channels increased by using higher P? and was significantly larger by using the 0.3 mm scan interval than those using 0.7 mm. The results in this study show the potential of this new microtripsy thrombolysis method for fast, precise, and effective clot recanalization, minimizing risks of vessel damage and embolism. [ABSTRACT FROM AUTHOR]

Histotripsy is an ultrasound ablation method that depends on the initiation of a cavitation bubble cloud to fractionate soft tissue. Previous work has indicated that a cavitation cloud can be formed by a single pulse with one high-amplitude negative cycle, when the negative pressure amplitude directly exceeds a pressure threshold intrinsic to the medium. We hypothesize that the intrinsic threshold in water-based tissues is determined by the properties of the water inside the tissue, and changes in tissue stiffness or ultrasound frequency will have a minimal impact on the histotripsy intrinsic threshold. To test this hypothesis, the histotripsy intrinsic threshold was investigated both experimentally and theoretically. The probability of cavitation was measured by subjecting tissue phantoms with adjustable mechanical properties and ex vivo tissues to a histotripsy pulse of 1–2 cycles produced by 345-kHz, 500-kHz, 1.5-MHz and 3-MHz histotripsy transducers. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured versus pressure amplitude. The results revealed that the intrinsic threshold (the negative pressure at which probability = 0.5) is independent of stiffness for Young's moduli ( E ) <1 MPa, with only a small increase (∼2–3 MPa) in the intrinsic threshold for tendon ( E = 380 MPa). Additionally, results for all samples revealed only a small increase of ∼2–3 MPa when the frequency was increased from 345 kHz to 3 MHz. The intrinsic threshold was measured to be between 24.7 and 30.6 MPa for all samples and frequencies tested in this study. Overall, the results of this study indicate that the intrinsic threshold to initiate a histotripsy bubble cloud is not significantly affected by tissue stiffness or ultrasound frequency in the hundreds of kilohertz to megahertz range. [ABSTRACT FROM AUTHOR]

Histotripsy thrombolysis is a non-invasive, drug-free, image-guided therapy that fractionates blood clots using well-controlled acoustic cavitation alone. Real-time quantitative feedback is highly desired during histotripsy thrombolysis treatment to monitor the progress of clot fractionation. Bubble-induced color Doppler (BCD) monitors the motion after cavitation generated by each histotripsy pulse, which has been found in gel and ex vivo liver tissue to be correlated with histotripsy fractionation. We investigated the potential of BCD to quantitatively monitor histotripsy thrombolysis in real time. To visualize clot fractionation, transparent three-layered fibrin clots were developed. Results indicated that a coherent motion follows the cavitation generated by each histotripsy pulse with a push and rebound pattern. The temporal profile of this motion expands and saturates as treatment progresses. A strong correlation exists between the degree of histotripsy clot fractionation and two metrics extracted from BCD: time of peak rebound velocity ( t PRV ) and focal mean velocity at a fixed delay ( V f,delay ). The saturation of clot fractionation ( i.e ., treatment completion) matches well the saturations detected using t PRV and V f,delay . The mean Pearson correlation coefficients between the progression of clot fractionation and the two BCD metrics were 93.1% and 92.6%, respectively. To validate BCD feedback in in vitro clots, debris volumes from histotripsy thrombolysis were obtained at different therapy doses and compared with V f,delay . There is also good agreement between the increasing and saturation trends of debris volume and V f,delay . Finally, a real-time BCD feedback algorithm to predict complete clot fractionation during histotripsy thrombolysis was developed and tested. This work illustrates the potential of BCD to monitor histotripsy thrombolysis treatment in real time. [ABSTRACT FROM AUTHOR]

In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery. [ABSTRACT FROM AUTHOR]