Passive Cavitation Detection Research Articles

Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU)

Acoustic cavitation has been shown to play a key role in a wide array of novel therapeutic ultrasound applications. This paper presents a brief discussion of the physics of thermally relevant acoustic cavitation in the context of high-intensity focussed ultrasound (HIFU). Models for how different types of cavitation activity can serve to accelerate tissue heating are presented, and results suggest that the bulk of the enhanced heating effect can be attributed to the absorption of broadband acoustic emissions generated by inertial cavitation. Such emissions can be readily monitored using a passive cavitation detection (PCD) scheme and could provide a means for real-time treatment monitoring. It is also shown that the appearance of hyperechoic regions (or bright-ups) on B-mode ultrasound images constitutes neither a necessary nor a sufficient condition for inertial cavitation activity to have occurred during HIFU exposure. Once instigated at relatively large HIFU excitation amplitudes, bubble activity tends to grow unstable and to migrate toward the source transducer, causing potentially undesirable pre-focal damage. Potential means of controlling inertial cavitation activity using pulsed excitation so as to confine it to the focal region are presented, with the intention of harnessing cavitation-enhanced heating for optimal HIFU treatment delivery. The role of temperature elevation in mitigating bubble-enhanced heating effects is also discussed, along with other bubble-field effects such as multiple scattering and shielding.

Detecting spatially resolved inertial cavitation with a diagnostic ultrasound system

The onset and presence of inertial cavitation in high-intensity focused ultrasound (HIFU) therapy has been identified as an important indicator of energy deposition for therapy planning. A common technique for detecting inertial cavitation is passive cavitation detection, where broadband noise emissions indicative of inertially driven bubbles collapses are detected using a fixed focus transducer. This technique is suboptimal for clinical applications, because most passive cavitation detector (PCD) transducers are tightly focused and thus afford limited spatial coverage of the HIFU focal region. Here, we report on efforts to use a diagnostic ultrasound system as a PCD by operating in passive mode and filtering out the main HIFU frequencies. This approach allows for spatially resolved detection of inertial cavitation throughout the focal region while being insensitive to scattering from voids or bubbles. [Work supported by the Dept. of the Army and the Center for Subsurface Sensing and Imaging Systems.]

Bubble responses to lithotripsy shock waves

The responses of bubbles subjected to a lithotripsy shock wave have been investigated numerically and experimentally to elucidate the role of heat and mass transfer in the underlying dynamics of strongly excited bubbles. Single spherical bubbles were modeled as gas‐vapor bubbles by accounting for liquid compressibility, heat transfer, vapor transport, vapor trapping by noncondensable gases, diffusion of noncondensable gases, and heating of the liquid at the bubble wall. For shock‐wave excitations, the model predicts bubble growth and collapse, followed by rebounds whose durations are significantly affected by vapor trapping. To experimentally test these predictions, bubble rebound durations were measured using passive cavitation detectors, while high‐speed photographs were captured to evaluate the local cavitation field and to estimate radius‐time curves for individual bubbles. Data were acquired for bubbles in water with varying temperature and dissolved gas content. Measurements verify that vapor trapping is an important mechanism that is sensitive to both temperature and dissolved gas content. While this work focuses primarily on individual bubbles, some bubble cloud effects were observed. Analysis with a simple multibubble model provides noteworthy insights. [Work supported by NIH T32‐EB001650, NIH DK43881, and NSBRI SMS00402.]

The correlation between cavitation noise power and bubble-induced heating in high-intensity focused ultrasound

It has been established that inertial cavitation is responsible for elevated heating during high-intensity focused ultrasound (HIFU) application for certain intensity regimes. The contribution of bubble-induced heating can be an important factor to consider, as it can be several times that expected from absorption of the primary ultrasound energy. Working in agar-graphite tissue phantoms with a 1.1-MHz HIFU transducer, an embedded type-E thermocouple, and a 15-MHz passive cavitation detector (PCD), the temperature and cavitation signal near the focus were measured for 5-s continuous wave HIFU insonations. The measured temperature was corrected for heating predicted from the primary ultrasound absorption and the transient thermocouple viscous heating artifact to isolate the temperature rise from the bubble activity. We have found that the temperature rise induced from the bubble activity correlates well with the instantaneous cavitation noise power as indicated by the mean square voltage output of the PCD. The results suggest that careful processing of the cavitation signals could serve as a proxy for measuring the heating contribution from inertial cavitation. [Work supported by the Dept. of the Army (Award No. DAMD17-02-2-0014) and the Center for Subsurface Sensing and Imaging Systems (NSF ERC Award No. EEC-9986821).]

Millisecond initiation of boiling by high-intensity focused ultrasound in tissue-mimicking phantoms

Nonlinear propagation effects leading to shock formation at the focus of high-intensity focused ultrasound (HIFU) treatments can accelerate heating and cause rapid boiling in tissue. Boiling can be utilized for targeting the treatment with B-mode ultrasound and should be taken into account when planning the treatment, because bubbles reflect ultrasound and thereby displace and distort the lesion shape. In these experiments, an HIFU transducer of 2-MHz frequency, 4-cm aperture, and 4.5-cm focal length was used to investigate heating effects from shock formation in tissue-mimicking phantoms. The time required to attain 100<th>°C at the focus was calculated with weak shock theory from the peak amplitudes calculated with a KZK-type model, and time to boiling was measured by high-speed video and a 20–MHz passive cavitation detector (PCD) for different values of phantom absorption (both lower than tissue absorption) and HIFU power (100–200 W). Boiling was observed in 3 ms at the highest power level used by the observation of visible bubbles and by a significant change in the PCD time signal and spectrum. [Work supported by NIH DK43881, NSBRI SMS00402, and RFBR.]

Detection of acoustic cavitation in the heart with microbubble contrast agents in vivo: A mechanism for ultrasound-induced arrhythmias

Ultrasound fields can produce premature cardiac contractions under appropriate exposure conditions. The pressure threshold for ultrasound-induced premature contractions is significantly lowered when microbubble contrast agents are present in the vasculature. The objective of this study was to measure directly ultrasound-induced cavitation in the murine heart in vivo and correlate the occurrence of cavitation with the production of premature cardiac contractions. A passive cavitation detection technique was used to quantify cavitation activity in the heart. Experiments were performed with anesthetized, adult mice given intravenous injections of either a contrast agent (Optison) or saline. Murine hearts were exposed to ultrasound pulses (200 kHz, 1 ms, 0.1-0.25 MPa). Premature beats were produced in mice injected with Optison and the likelihood of producing a premature beat increased with increasing pressure amplitude. Similarly, cavitation was detected in mice injected with Optison and the amplitude of the passive cavitation detector signal increased with increasing exposure amplitude. Furthermore, there was a direct correlation between the extent of cavitation and the likelihood of ultrasound producing a premature beat. Neither premature beats nor cavitation activity were observed in animals injected with saline and exposed to ultrasound. These results are consistent with acoustic cavitation as a mechanism for this bioeffect.

Biological and physical mechanisms of HIFU-induced hyperecho in ultrasound images

Guidance and monitoring of high intensity focused ultrasound (HIFU) therapy, using ultrasound imaging, has primarily utilized formation of a hyperechoic region at the HIFU focus. We investigated biologic and physical mechanisms of a hyperecho, as well as safety of this phenomenon, using thermal, acoustic and light microscopy observations. Single, short-duration HIFU pulses (30–60 ms) were able to produce a hyperechoic region at the HIFU focus, 2 cm deep in a rabbit thigh muscle. When hyperechoic regions appeared, inertial cavitation was detected in vivo using a custom-made passive cavitation detection system. Light micrographs showed a large number of cavities (approximately 100/mm 3), 1–10 μm in diameter, in a cytoplasm of cells located at the HIFU focus. Blood congestion was observed around a focal region, indicating an injury of microvasculature. Cellular necrosis was observed at 2 d after the treatment, while healing, scar tissue formation and regeneration were observed at 7 d and 14 d. The results indicate that a possibility of adverse tissue effects has to be taken into consideration when the hyperecho formation, induced by very-short HIFU pulses, is used for pretreatment targeting. (E-mail: adasi@u.washington.edu)

Ultrasound-enhanced thrombolysis

Substantial enhancement of recombinant tissue plasminogen activator (rt-PA) thrombolysis can be achieved with ultrasound, suggesting its use as an adjunctive treatment in thrombolytic therapy for stroke. This enhancement may be due to acoustic cavitation, thermal effects, forced convection of rt-PA, or biochemical enhancement. The effect of US duty cycle on the lytic efficacy of pulsed 120-kHz ultrasound in a human in vitro clot model was investigated, using a time-lapse microscopic imaging technique. The initial lytic rate increased linearly with duty cycle. In addition, a passive cavitation detection scheme was used to explore stable and inertial cavitation as potential mechanisms for ultrasound-enhanced thrombolysis. Porcine clots were exposed to pulsed ultrasound and rt-PA in vitro for 30 min using four separate ultrasound treatment regimes: (i) no cavitation (0.15 MPa); (ii) stable cavitation alone (0.24 MPa), (iii) stable and inertial cavitation combined (0.36 MPa); or (iv) no ultrasound. Percent clot mass loss after each treatment was used to determine thrombolysis efficacy. Clots exposed to stable cavitation and rt-PA exhibited the highest mass loss. Significant enhancement of thrombolysis correlates with presence of cavitation and stable cavitation appears to play a more important role in the enhancement of thrombolysis.

Intravascular inertial cavitation activity detection and quantification in vivo with Optison

Inertial cavitation (IC) is an important mechanism by which ultrasound (US)-induced bioeffects can be produced. It has been reported that US-induced in vitro mechanical bioeffects with the presence of ultrasound contrast agents (UCAs) are highly correlated with quantified IC “dose” (ICD: cumulated root-mean-squared broadband noise amplitude in the frequency domain). The ICD has also been used to quantify IC activity in ex vivo perfused rabbit ear vessels. The in vivo experiments reported here using a rabbit ear vessel model were designed to: (1) detect and quantify IC activity in vivo within the constrained environment of rabbit auricular veins with the presence of Optison and (2) measure the temporal evolution of microbubble IC activity and the ICD generated during insonation treatment, as a function of acoustic parameters. Preselected regions-of-interest (ROI) in the rabbit ear vein were exposed to pulsed focused US (1.17 MHz, 1 Hz PRF). Experimental acoustic variables included peak rarefaction pressure amplitude ([PRPA]: 1.1, 3.0, 6.5 or 9.0 MPa) and pulse length (20, 100, 500 or 1000 cycles). ICD was quantified based on passive cavitation detection (PCD) measurements. The results show that: (1) after Optison injection, the time to onset of measurable microbubble IC activity was relatively consistent, approximately 20 s; (2) after reaching its peak value, the IC activity decayed exponentially and the half-life decay coefficient (t 1/2) increased with increasing PRPA and pulse length; and (3) the normalized ICD generated by pulsed US exposure increased significantly with increasing PRPA and pulse length. (E-mail: juantu@u.washington.edu)

Correlation between inertial cavitation dose and endothelial cell damage in vivo

Previous in vivo studies have demonstrated that vascular endothelial damage can result when vessels containing gas-based microbubble ultrasound contrast agent (UCA) are exposed to MHz-frequency pulsed ultrasound (US) of sufficient pressure amplitudes, presumably as a result of inertial cavitation (IC). The hypothesis guiding this research was that IC is the primary mechanism by which the vascular endothelium (VE) is damaged when a vessel is exposed to pulsed 1-MHz frequency US in the presence of circulating UCA. The expectation was that a correlation should exist between the magnitude and duration of IC activity and the degree of VE damage. Rabbit auricular vessels were exposed in vivo to 1.17-MHz focused US of variable peak rarefaction pressure amplitude (1, 3, 6.5 or 9 MPa), using low duty factors (0.04% or 0.4%), pulse lengths of 500 or 5000 cycles, with varying treatment durations and with or without infusion of a shelled microbubble contrast agent. A broadband passive cavitation detection system was used to measure IC activity in vivo within the targeted segment of the blood vessel. The magnitude of the detected IC activity was quantified using a previously reported measure of IC dose. Endothelial damage was assessed via scanning electron microscopy image analysis. The results supported the hypothesis and demonstrate that the magnitude of the measured IC dose correlates with the degree of VE damage when UCA is present. These results have implications for therapeutic US-induced vascular occlusion. (E-mail: jooha@u.washington.edu)

Correlation of cavitation with ultrasound enhancement of thrombolysis

Pulsed ultrasound, when used as an adjuvant to recombinant tissue plasminogen activator (rt-PA), has been shown to enhance thrombolysis in the laboratory as well as in clinical trials for the treatment of ischemic stroke. The exact mechanism of this enhancement has not yet been elucidated. In this work, stable and inertial cavitation (SC and IC) are investigated as possible mechanisms for this enhancement. A passive cavitation detection scheme was utilized to measure cavitation thresholds at 120 kHz (80% duty cycle, 1667 Hz pulse repetition frequency) for four host fluid and sample combinations: plasma, plasma with rt-PA, plasma with clot and plasma with clot and rt-PA. Following cavitation threshold determination, clots were exposed to pulsed ultrasound for 30 min in vitro using three separate ultrasound treatment regimes: (1) no cavitation (0.15 MPa), (2) SC alone (0.24 MPa) or (3) SC + IC combined (0.36 MPa) in the presence of rt-PA. Percent clot mass loss after each treatment was used to determine thrombolysis efficacy. The highest percent mass loss was observed in the stable cavitation regime (26%), followed by the combined stable and inertial cavitation regime (20.7%). Interestingly, the percent mass loss in clots exposed to ultrasound without cavitation (13.7%) was not statistically significantly different from rt-PA alone (13%) [ p > 0.05]. Significant enhancement of thrombolysis correlates with presence of cavitation and stable cavitation appears to play a more important role in the enhancement of thrombolysis. (E-mail: saurabhdattas@yahoo.com)

Interpreting passive cavitation detection signals during high-intensity focused ultrasound (HIFU)

Inertial cavitation is known to be associated with significantly enhanced rates of heating during cancer treatment by high-intensity focused ultrasound (HIFU). However, during prolonged exposure, the cavitation region gradually shifts towards the HIFU transducer, causing shielding of the original focus. It is hoped that controlling the HIFU field to constrain cavitation to the focal region will lead to sustained enhanced focal heating, thus reducing treatment times and improving treatment resolution. Monitoring of cavitation can be achieved during insonation by using a focussed passive cavitation detector (PCD) to listen for broadband noise emissions resulting from microbubble collapse. The ability to effectively control the cavitation field relies on accurate interpretation of the PCD data. During HIFU exposure of a tissue-mimicking material, it was noted that the frequency content of the PCD signal shifted downwards with increasing phantom propagation path length to the PCD, as a result of depth-dependent attenuation. This has significant implications for the effective sensing volume of the PCD. In addition, it was noted that separate analysis of the peak and rms time-domain PCD values provides an incomplete description of inertial cavitation activity, but that combining these two parameters enables a better understanding of bubble cloud dynamics.

Nonlinear mechanisms of heating by high-intensity focused ultrasound

Two major nonlinear mechanisms are known to influence HIFU heating: acoustic nonlinearity and cavitation. Heating may also result in formation of boiling vapor bubbles that grow much larger than the cavitation bubbles. The relevant role of these phenomena was investigated experimentally and numerically in a gel phantom. HIFU pressure thresholds for shock formation, cavitation, and boiling were measured using a fiber-optic probe hydrophone, passive cavitation detection, ultrasound and optical imaging, and thermocouples. The KZK and Bio-heat equations were employed to simulate experimental conditions. Elevated static pressure was applied to suppress bubbles and increase the boiling temperature, thus isolating the pure effect of acoustic nonlinearity in comparison of heating between short, high-amplitude and long, low-amplitude pulses of equal average intensity. The experimental results indicated that both nonlinear mechanisms accelerated lesion production with acoustic nonlinearity responsible for the greater effect. It was observed that lesion distortion and migration was due to boiling detected in as little as 40 ms within the center of the lesion, in agreement with nonlinear acoustic simulations. These data indicate that acoustic nonlinearity and the boiling play a significant role earlier in HIFU treatments than previously anticipated. [Work supported by the NSBRI-SMS00402, RFBR, NIH FIRCA and DK43881.]

Measuring bubble dynamics in lithotripsy using a high-speed camera

The primary goal of this study was to examine bubble dynamics in shock wave lithotripsy and experimentally obtain the radius-time (r-t) profile. A piezoelectric array was employed as a shock wave (SW) source. The focal waveform (as measured with a fiber optic probe hydrophone) was double-peaked with two shocks: leading peak pressure 65±3 MPa and second peak 30±3 MPa. The negative phase in between had a peak p−=−16±2 MPa. The cavitation field was monitored using a dual passive cavitation detector consisting of two 1-MHz focused transducers. The second peak of the SW inhibited cavitation limiting the characteristic time to less than 60 μs. A high-speed camera (up to 10 million frames per second) with a spatial resolution of 2 μm/pixel was used to measure bubble dynamics. The camera could record 14 frames that were timed to measure the growth and collapse phases of the bubbles. The bubbles were initially spherical but became aspherical and exhibited jetting as they collapsed. The bubble radius was estimated from the area of bubble in each snapshot from which r-t curves were constructed and compared to calculations using the Gilmore formulation. The maximum radius ranged from 150 to 300 μm. [Work supported by NIH.]

Customization of acoustic output in lithotripsy using a piezoelectric transducer array

A piezoelectric array was employed to examine the role of waveform shaping on stone fragmentation in lithotripsy. The array consisted of 170 elements placed on the inner surface of a 15-cm-radius spherical cap. Each element was driven independently using 170 individual pulsers—each capable of generating 1.2 kV. The acoustic field was characterized using a fiber optic probe hydrophone with a bandwidth of 30 MHz and a spatial resolution of 100 μm. When all elements were driven simultaneously, the focal waveform was a shock wave with peak pressures p+=65±3 MPa and p−=−16±2 MPa and the focal region was cigar shaped: 13 mm long and 2 mm wide. The firing of group of elements was adjusted so that each groups focused to different locations in the geometric focal plane. This method allowed the width of the focal region to be broadened albeit with decrease in peak pressure: for a 3-mm-wide region p+=32 MPa and for a 4-mm focal region p+=25 MPa. Waveform shaping was used to enhance or suppress cavitation effects where cavitation activity was observed using a dual passive cavitation detector consisting of two 1-MHz focused transducers. Stone fragmentation was assessed by treating artificial stones with fixed number of shock waves. [Work supported by NIH.]

Quantitative measurements of acoustic emissions from cavitation at the surface of a stone in response to a lithotripter shock wave

Measurements are presented of acoustic emissions from cavitation collapses on the surface of a synthetic kidney stone in response to shock waves (SWs) from an electrohydraulic lithotripter. A fiber optic probe hydrophone was used for pressure measurements, and passive cavitation detection was used to identify acoustic emissions from bubble collapse. At a lithotripter charging voltage of 20 kV, the focused SW incident on the stone surface resulted in a peak pressure of 43 +/- 6 MPa compared to 23 +/- 4 MPa in the free field. The focused SW incident upon the stone appeared to be enhanced due to the acoustic emissions from the forced cavitation collapse of the preexisting bubbles. The peak pressure of the acoustic emission from a bubble collapse was 34 +/- 15 MPa, that is, the same magnitude as the SWs incident on the stone. These data indicate that stresses induced by focused SWs and cavitation collapses are similar in magnitude thus likely play a similar role in stone fragmentation.

Inertial cavitation dose produced in ex vivo rabbit ear arteries with optison® by 1-mhz pulsed ultrasound

Previous in vitro studies have shown that ultrasound-induced mechanical bioeffects with contrast agents present are highly correlated with inertial cavitation (IC) “dose” ( Chen et al. 2003a, 2003c). The ex vivo experiments conducted here addressed the following hypotheses: 1. IC activity can be generated by insonating perfused rabbit ear blood vessel, and 2. the IC “dose” developed during insonation treatment can be reliably measured and will vary with varying acoustic parameters and Optison® concentration. Ex vivo rabbit auricular arteries were perfused with Optison® suspensions and then exposed to 1.1-MHz pulsed focused ultrasound. Experimental variables included peak negative acoustic pressure (0.2 MPa to 5.2 MPa), pulse-repetition frequency (5, 50 or 500 Hz), pulse length (50, 100, 500 or 1000 cycles), and Optison® volume concentration (0, 0.2, 0.5 or 1%). Cavitation activity was quantified as IC dose, based on passive cavitation detection measurements. The results show that: 1. The IC pressure threshold decreases with higher concentrations of Optison®, and 2. IC dose increases significantly with increasing acoustic pressure, Optison® concentration, pulse length or with decreasing pulse-repetition frequency. (E-mail: juantu@u.washington.edu)

Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity

Acoustic emission was monitored during focused ultrasound exposures in conjunction with an ultrasound contrast agent (Optison®) in order to determine if cavitation activity is associated with the induction of blood–brain barrier disruption (BBBD). Thirty-four locations were sonicated (frequency: 260 kHz) at targets 10 mm deep in rabbit brain (N = 9). The sonications were applied at peak pressure amplitudes ranging from 0.11 to 0.57 MPa (burst length: 10 ms; repetition frequency of 1 Hz; duration: 20 s). Acoustic emission was recorded with a focused passive cavitation detector. This emission was recorded at each location during sonications with and without Optison®. Detectable wideband acoustic emission was observed only at 0.40 and 0.57 MPa. BBBD was observed in contrast MRI after sonication at 0.29–0.57 MPa. The appearance of small regions of extravasated erythrocytes appeared to be associated with this wideband emission signal. The results thus suggest that BBBD resulting from focused ultrasound pulses in the presence of Optison® can occur without indicators for inertial cavitation in vivo, wideband emission and extravasation. If inertial cavitation is not responsible for the BBBD, other ultrasound/microbubble interactions are likely the source. A significant increase in the emission signal due to Optison® at the second and third harmonics of the ultrasound driving frequency was found to correlate with BBBD and might be useful as an online method to indicate when the disruption occurs.

Ultrasonic contrast agent shell rupture detected by inertial cavitation and rebound signals

Determining the rupture pressure threshold of ultrasound contrast agent microbubbles has significant applications for contrast imaging, development of therapeutic agents, and evaluation of potential bioeffects. Using a passive cavitation detector, this work evaluates rupture based on acoustic emissions from single, encapsulated, gas-filled microbubbles. Sinusoidal ultrasound pulses were transmitted into weak solutions of Optison at different center frequencies (0.9, 2.8, and 4.6 MHz), pulse durations (three, five, and seven cycles of the center frequencies), and peak rarefactional pressures (0.07 to 5.39 MPa). Pulse repetition frequency was 10 Hz. Signals detected with a 13-MHz, center-frequency transducer revealed postexcitation acoustic emissions (between 1 and 5 micros after excitation) with broadband spectral content. The observed acoustic emissions were consistent with the acoustic signature that would be anticipated from inertial collapse followed by "rebounds" when a microbubble ruptures and thus generates daughter/free bubbles that grow and collapse. The peak rarefactional pressure threshold for detection of these emissions increased with frequency (e.g., 0.53, 0.87, and 0.99 MPa for 0.9, 2.8, and 4.6 MHz, respectively; five-cycle pulse duration) and decreased with pulse duration. The emissions identified in this work were separated from the excitation in time and spectral content, and provide a novel determination of microbubble shell rupture.

Cavitation detection during shock-wave lithotripsy

A system was built to detect cavitation in pig kidney during shock-wave lithotripsy (SWL) with a Dornier HM3 lithotripter. Active detection using echo on B-mode ultrasound, and passive cavitation detection using coincident signals on confocal orthogonal receivers, were used to interrogate the renal collecting system (urine) and the kidney parenchyma (tissue). Cavitation was detected in urine immediately upon shock-wave (SW) administration in urine or urine plus X-ray contrast agent but, in native tissue, cavitation required hundreds of SWs to initiate. Localization of cavitation was confirmed by fluoroscopy, sonography and by thermally marking the kidney using the passive cavitation detection receivers as high-intensity focused ultrasound sources. Cavitation collapse times in tissue and native urine were about the same, but less than in urine after injection of X-ray contrast agent. The finding that cavitation occurs in kidney tissue is a critical step toward determining the mechanisms of tissue injury in SWL. (E-mail: bailey@apl.washington.edu)