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Histotripsy is a focused ultrasound therapy for tissue ablation via the generation of bubble clouds. These effects can be achieved noninvasively, making sensitive and specific bubble imaging essential for histotripsy guidance. Plane-wave ultrasound imaging can track bubble clouds with an excellent temporal resolution, but there is a significant reduction in echoes when deep-seated organs are targeted. Chirp-coded excitation uses wideband, long-duration imaging pulses to increase signals at depth and promote nonlinear bubble oscillations. In this study, we evaluated histotripsy bubble contrast with chirp-coded excitation in scattering gel phantoms and a subcutaneous mouse tumor model. A range of imaging pulse durations were tested, and compared to a standard plane-wave pulse sequence. Received chirped signals were processed with matched filters to highlight components associated with either fundamental or subharmonic (bubble-specific) frequency bands. The contrast-to-tissue ratio (CTR) was improved in scattering media for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) with the longest-duration chirped-pulse tested (7.4 $\mu \text{s}$ pulse duration). The CTR was improved for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) by 4.25 dB ± 1.36 dB in phantoms and 3.84 dB ± 6.42 dB in vivo. No systematic changes were observed in the bubble cloud size or dissolution rate between sequences, indicating image resolution was maintained with the long-duration imaging pulses. Overall, this study demonstrates the feasibility of specific histotripsy bubble cloud visualization with chirp-coded excitation. [ABSTRACT FROM AUTHOR]

Deep vein thrombosis is a major source of morbidity worldwide. For critical obstructions, catheter-directed thrombolytics are the frontline therapy to achieve vessel recanalization. Techniques that aid lytic therapy are under development to improve treatment efficacy and reduce procedure-related complications. Histotripsy is one such adjuvant under development that relies on focused ultrasound for in situ nucleation of bubble clouds. Prior studies have demonstrated synergistic effects for clot dissolution when histotripsy is combined with lytic therapy. The success of this combination approach is hypothesized to promote thrombolytic efficacy via two mechanisms: erythrocyte fractionation (hemolysis) and increased lytic activity (fibrinolysis). In this study, the contributions of hemolysis and fibrinolysis to clot degradation under histotripsy and a lytic were quantified with measurements of hemoglobin and D-dimer, respectively. A linear regression analysis was used to determine the relationship between hemoglobin, D-dimer, and the overall treatment efficacy (clot mass loss). A similar analysis was conducted to gauge the role of bubble activity, which was assessed with passive cavitation imaging, on hemolysis and fibrinolysis. Tabulation of these data demonstrated hemolysis and fibrinolysis contributed equally to clot mass loss. Furthermore, bubble cloud activity promoted the generation of hemoglobin and D-dimer in equal proportion. These studies indicate a multifactorial process for clot degradation under the action of histotripsy and a lytic therapy. [ABSTRACT FROM AUTHOR]

Histotripsy is a focused ultrasound therapy for non-invasive tissue ablation. Unlike thermally ablative forms of therapeutic ultrasound, histotripsy relies on the mechanical action of bubble clouds for tissue destruction. Although acoustic bubble activity is often characterized as chaotic, the short-duration histotripsy pulses produce a unique and consistent type of cavitation for tissue destruction. In this review, the action of histotripsy-induced bubbles is discussed. Sources of bubble nuclei are reviewed, and bubble activity over the course of single and multiple pulses is outlined. Recent innovations in terms of novel acoustic excitations, exogenous nuclei for targeted ablation and histotripsy-enhanced drug delivery and image guidance metrics are discussed. Finally, gaps in knowledge of the histotripsy process are highlighted, along with suggested means to expedite widespread clinical utilization of histotripsy. [ABSTRACT FROM AUTHOR]

Bubble cloud persistence reduces the efficacy of mechanical liquefaction with shock-scattering histotripsy. In this study, the contribution of gas transfer to bubble longevity was investigated in silico by solving the equations for bubble oscillations and diffusion in parallel. The bubble gas content increased more than 5 orders of magnitude during the expansion phase, arresting the inertial collapse. The residual gas bubble required more than 15 ms for passive dissolution post excitation, consistent with experimental observation. These results demonstrate gas diffusion is an important factor in the persistence of histotripsy-induced cavitation. [ABSTRACT FROM AUTHOR]

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– 20~\mu \texts ) 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 ( p < 0.05 ) 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. [ABSTRACT FROM AUTHOR]

Passive cavitation detection has been an instrumental technique for measuring cavitation dynamics, elucidating concomitant bioeffects, and guiding ultrasound therapies. Recently, techniques have been developed to create images of cavitation activity to provide investigators with a more complete set of information. These techniques use arrays to record and subsequently beamform received cavitation emissions, rather than processing emissions received on a single-element transducer. In this paper, the methods for performing frequency-domain delay, sum, and integrate passive imaging are outlined. The method can be applied to any passively acquired acoustic scattering or emissions, including cavitation emissions. To compare data across different systems, techniques for normalizing Fourier transformed data and converting the data to the acoustic energy received by the array are described. A discussion of hardware requirements and alternative imaging approaches is additionally outlined. Examples are provided in MATLAB. [ABSTRACT FROM PUBLISHER]

Tissue-mimicking phantoms are employed for the assessment of shocked histotripsy pulses in vitro. These broadband shock waves are critical for tissue ablation and are influenced by the frequency-dependent attenuation of the medium. The density, sound speed and attenuation spectra (2-25 MHz) were measured for phantoms that mimic key histotripsy targets. The influence of non-linear propagation relative to the attenuation was described in terms of Gol'dberg number. An expression was derived to estimate the bandwidth of shocked histotripsy pulses for power law-dependent attenuation. The expression is independent of the fundamental frequency of the histotripsy pulse for linear frequency-dependent attenuation. [ABSTRACT FROM AUTHOR]

The use of ultrasound and microbubbles as an effective adjuvant to thrombolytics has been reported in vitro , ex vivo and in vivo . However, the specific mechanisms underlying ultrasound-enhanced thrombolysis have yet to be elucidated. We present visual observations illustrating two mechanisms of ultrasound-enhanced thrombolysis: acoustic cavitation and radiation force. An in vitro flow model was developed to observe human whole blood clots exposed to human fresh-frozen plasma, recombinant tissue-type plasminogen activator (0, 0.32, 1.58 or 3.15 μg/mL) and the ultrasound contrast agent Definity (2 μL/mL). Intermittent, continuous-wave ultrasound (120 kHz, 0.44 MPa peak-to-peak pressure) was used to insonify the perfusate. Ultraharmonic emissions indicative of stable cavitation were monitored with a passive cavitation detector. The clot was observed with an inverted microscope, and images were recorded with a charge-coupled device camera. The images were post-processed to determine the time-dependent clot diameter and root-mean-square velocity of the clot position. Clot lysis occurred preferentially surrounding large, resonant-sized bubbles undergoing stable oscillations. Ultraharmonic emissions from stable cavitation were found to correlate with the lytic rate. Clots were observed to translate synchronously with the initiation and cessation of the ultrasound exposure. The root-mean-square velocity of the clot correlated with the lytic rate. These data provide visual documentation of stable cavitation activity and radiation force during sub-megahertz sonothrombolysis. The observations of this study suggest that the process of clot lysis is complex, and both stable cavitation and radiation force are mechanistically responsible for this beneficial bio-effect in this in vitro model. [ABSTRACT FROM AUTHOR]

Ultrasound contrast agents (UCAs) can be employed to nucleate cavitation to achieve desired bioeffects, such as thrombolysis, in therapeutic ultrasound applications. Effective methods of enhancing thrombolysis with ultrasound have been examined at low frequencies (<1 MHz) and low amplitudes (<0.5 MPa). The objective of this study was to determine cavitation thresholds for two UCAs exposed to 120-kHz ultrasound. A commercial ultrasound contrast agent (Definity®) and echogenic liposomes were investigated to determine the acoustic pressure threshold for ultraharmonic (UH) and broadband (BB) generation using an in vitro flow model perfused with human plasma. Cavitation emissions were detected using two passive receivers over a narrow frequency bandwidth (540-900 kHz) and a broad frequency bandwidth (0.54-1.74 MHz). UH and BB cavitation thresholds occurred at the same acoustic pressure (0.3 ± 0.1 MPa, peak to peak) and were found to depend on the sensitivity of the cavitation detector but not on the nucleating contrast agent or ultrasound duty cycle. [ABSTRACT FROM AUTHOR]

The mechanical index (MI) was formulated to gauge the likelihood of adverse bioeffects from inertial cavitation. However, the MI formulation did not consider bubble activity from stable cavitation. This type of bubble activity can be readily nucleated from ultrasound contrast agents (UCAs) and has the potential to promote beneficial bioeffects. Here, the presence of stable cavitation is determined numerically by tracking the onset of subharmonic oscillations within a population of bubbles for frequencies up to 7 MHz and peak rarefactional pressures up to 3 MPa. In addition, the acoustic pressure rupture threshold of an UCA population was determined using the Marmottant model. The threshold for subharmonic emissions of optimally sized bubbles was found to be lower than the inertial cavitation threshold for all frequencies studied. The rupture thresholds of optimally sized UCAs were found to be lower than the threshold for subharmonic emissions for either single cycle or steady state acoustic excitations. Because the thresholds of both subharmonic emissions and UCA rupture are linearly dependent on frequency, an index of the form ICAV = Pr/f (where Pr is the peak rarefactional pressure in MPa and f is the frequency in MHz) was derived to gauge the likelihood of subharmonic emissions due to stable cavitation activity nucleated from UCAs. [ABSTRACT FROM AUTHOR]

Recent investigations of cavitation in fluids pressurized up to 30 MPa found that the intensity of light emissions increased by 1000-fold over that measured for single bubble sonoluminescence. A series of measurements is reported here to extend this original work by resolving the static pressure dependence of the shock wave and light emissions from the first and the most energetic collapses, along with the total shock wave energy and light emissions for the event. Each of these parameters was found to increase with the static pressure of the fluid. Furthermore, the energy of these shock wave and light emissions was found to increase in proportion to the stored acoustic energy in the system. These findings were corroborated using the Gilmore equation to numerically compute the work done by the liquid during the bubble collapse. The overall findings suggest that the increased collapse strength at high static pressure is due to the increased tension required to generate inertial cavitation, and not an increased pressure gradient between the interior of the vaporous bubble and the surrounding liquid. [ABSTRACT FROM AUTHOR]

In order to model possible effects of cavitation on bone structure, the formation of cavitation along an acoustically reflective PVC surface was studied. The bubbles were generated by a commerical therapeutic transducer (1 MHz), for both water and agar gel mediums. Bubble formation and activity were monitored using light scattering techniques: a HeNe laser was directed through the medium, and the transmitted light was detected using an optical power meter. The data show a decline in cavitation activity further from the surface and offer suggestive evidence of a boundary layer. Temporal saturation is also evident in both mediums, though an anomalous increase in transmitted light for the agar medium suggests the possibility of pressure variations due to microstreaming. Analysis of the microstreaming pattern was subsequently performed at lower frequencies in order to allow visualization with a standard laboratory microscope. [ABSTRACT FROM AUTHOR]

Although primarily known as an ablative modality, histotripsy can increase the efficacy of lytic therapy in a retracted venous clot model. Bubble cloud oscillations are the primary mechanism of action for histotripsy, and the type of bubble activity is dependent on the pulse duration. A retracted human venous clot model was perfused with and without the thrombolytic recombinant tissue plasminogen activator (rt-PA). The clot was exposed to histotripsy pulses of single- or five-cycle duration and peak negative pressures of 0-30 MPa. Bubble activity within the clot was monitored via passive cavitation imaging. The combination of histotripsy and rt-PA was more efficacious than rt-PA alone for single- and five-cycle pulses with peak negative pressures of 25 and 20 MPa, respectively. For both excitation schemes, the detected acoustic emissions correlated with the degree of thrombolytic efficacy. These results indicate that rt-PA and single- or multicycle histotripsy pulses enhance thrombolytic therapy. [ABSTRACT FROM AUTHOR]