Active Cavitation Detection Research Articles

Exploring the Acoustic and Dynamic Characteristics of Phase-Change Droplets.

Acoustic droplet vaporization (ADV) provides the on-demand production of bubbles for use in ultrasound (US)-based diagnostic and therapeutic applications. The droplet-to-bubble transition process has been shown to involve localized internal gas nucleation, followed by a volume expansion of threefold to fivefold and inertial bubble oscillation, all of which take place within a few microseconds. Monitoring these ADV processes is important in gauging the mechanical effects of phase-change droplets in a biological environment, but this is difficult to achieve using regular optical observations. In this study, we utilized acoustic characterization [i.e., simultaneous passive cavitation detection (PCD) and active cavitation detection (ACD)] to investigate the acoustic signatures emitted from phase-change droplets ADV and determined their correlations with the physical behaviors observed using high-speed optical imaging. The experimental results showed that activation with three-cycle 5-MHz US pulse resulted in the droplets (diameter: 3.0- [Formula: see text]) overexpanding and undergoing damped oscillation before settling to bubbles with a final diameter. Meanwhile, a broadband shock wave was observed at the beginning of the PCD signal. The intense fluctuations of the ACD signal revealed that the shock wave arose from the inertial cavitation of nucleated small gas pockets in the droplets. It was particularly interesting that another shock-wave signal with a much lower acoustic frequency (< 2 MHz) was observed at about [Formula: see text] after the first half signal. This signal coincided with the reduction of the ACD signal amplitude that indicated the rebound of the transforming bubble. Since internal gas nucleation is a crucial process of ADV, the first half signal may indicate the occurrence of an ADV event, and the second half signal may further reveal the degrees of expansion and oscillation of the bubble. These acoustic signatures provide opportunities for monitoring ADV dynamics based on the detection of acoustic signals.

Biomedical acoustics research at the Image-Guided Ultrasound Therapeutics Laboratories

The Image-guided Ultrasound Therapeutic Laboratories (IgUTL) are located at the University of Cincinnati in the Heart, Lung, and Vascular Institute, a key component of efforts to align the UC College of Medicine and UC Health research, education, and clinical programs. These laboratories, directed by Christy K. Holland, comprise graduate and undergraduate students, postdoctoral fellows, physician-scientists, and clinical and scientific collaborators in fields including cardiology, neurosurgery, neurology, radiology, and emergency medicine. Holland’s research focuses on biomedical ultrasound including sonothrombolysis, ultrasound-mediated drug and bioactive gas delivery, development of echogenic liposomes, early detection of cardiovascular diseases, and ultrasound-image guided tissue ablation. Imaging algorithms incorporate both passive and active cavitation detection. The Biomedical Acoustics Laboratory within IgUTL, directed by T. Douglas Mast, investigates ultrasound imaging for therapy guidance, including echo decorrelation imaging for monitoring liver cancer ablation and real-time tracking of tongue motion for biofeedback in speech therapy. The Biomedical Ultrasonics and Cavitation Laboratory within IgUTL, directed by Kevin J. Haworth, employs ultrasound-mediated gas scavenging for image-guided treatment of cardiovascular disease, especially reperfusion injury. [Work supported by NIH Grants R01 NS047603, R01 HL135092, R01 HL133334, R01 CA158439, R01 DC017301, and K25 HL133452.]

Study on shock wave-induced cavitation bubbles dissolution process**Project partially supported by the National Natural Science Foundation of China (Grant Nos. 81627802, 81473692, 81673995, 11374155, 11574156, 11474001, 11474161, 11474166, and 11674173), Natural Science Foundation of Jiangsu Province, China (Grant No. BK20151007), and the Qing Lan Project of Jiangsu Province, China.

This study investigated dissolution processes of cavitation bubbles generated during in vivo shock wave (SW)-induced treatments. Both active cavitation detection (ACD) and the B-mode imaging technique were applied to measure the dissolution procedure of biSpheres contrast agent bubbles by in vitro experiments. Besides, the simulation of SW-induced cavitation bubbles dissolution behaviors detected by the B-mode imaging system during in vivo SW treatments, including extracorporeal shock wave lithotripsy (ESWL) and extracorporeal shock wave therapy (ESWT), were carried out based on calculating the integrated scattering cross-section of dissolving gas bubbles with employing gas bubble dissolution equations and Gaussian bubble size distribution. The results showed that (i) B-mode imaging technology is an effective tool to monitor the temporal evolution of cavitation bubbles dissolution procedures after the SW pulses ceased, which is important for evaluation and controlling the cavitation activity generated during subsequent SW treatments within a treatment period; (ii) the characteristics of the bubbles, such as the bubble size distribution and gas diffusion, can be estimated by simulating the experimental data properly.

Biomedical research at the image-guided ultrasound therapeutics laboratories

The Image-guided Ultrasound Therapeutic Laboratories (IgUTL) are located at the University of Cincinnati in the Heart, Lung, and Vascular Institute, a key component of efforts to align the UC College of Medicine and UC Health research, education, and clinical programs. These extramurally funded laboratories, directed by Prof. Christy K. Holland, are comprised of graduate and undergraduate students, postdoctoral fellows, principal investigators, and physician-scientists with backgrounds in physics and biomedical engineering, and clinical and scientific collaborators in fields including cardiology, neurosurgery, neurology, and emergency medicine. Prof. Holland’s research focuses on biomedical ultrasound including sonothrombolysis, ultrasound-mediated drug and bioactive gas delivery, development of echogenic liposomes, early detection of cardiovascular diseases, and ultrasound-image guided tissue ablation. The Biomedical Ultrasonics and Cavitation Laboratory within IgUTL, directed by Prof. Kevin J. Haworth, employs ultrasound-triggered phase-shift emulsions (UPEs) for image-guided treatment of cardiovascular disease, especially thrombotic disease. Imaging algorithms incorporate both passive and active cavitation detection. The Biomedical Acoustics Laboratory within IgUTL, directed by Prof. T. Douglas Mast, employs ultrasound for monitoring thermal therapy, ablation of cancer and vascular targets, transdermal drug delivery, and noninvasive measurement of tissue deformation.

Statistics of Acoustically Induced Bubble-Nucleation Events in in Vitro Blood: A Feasibility Study

Bubbles can form in biological tissues through ultrasonic activation of natural gas nuclei. The damaging aftereffects raise safety concerns. However, the population of nuclei is currently unknown, and bubble nucleation is stochastic and thus unpredictable. This study investigates the statistical behavior of bubble nucleation experimentally and introduces a model-based analysis to determine the distribution of nuclei in biological samples—two pig blood samples in vitro. Combined ultra-fast passive and active cavitation detection with a linear array was used to detect nucleation from pulsed ultrasound excitations at 660 kHz. Single nucleation events were detected at peak rarefaction pressures from −3.6 to −24 MPa, and the nucleation probability over the range 0 to 1 was estimated from more than 330 independent acquisitions per sample. Model fitting of the experimental probability revealed that the distribution of nuclei is most likely continuous, and nuclei are rare in comparison to blood cells.

In vivo bubble nucleation probability in sheep brain tissue

Gas nuclei exist naturally in living bodies. Their activation initiates cavitation activity, and is possible using short ultrasonic excitations of high amplitude. However, little is known about the nuclei population in vivo, and therefore about the rarefaction pressure required to form bubbles in tissue. A novel method dedicated to in vivo investigations was used here that combines passive and active cavitation detection with a multi-element linear ultrasound probe (4–7 MHz). Experiments were performed in vivo on the brain of trepanated sheep. Bubble nucleation was induced using a focused single-element transducer (central frequency 660 kHz, f-number = 1) driven by a high power (up to 5 kW) electric burst of two cycles. Successive passive recording and ultrafast active imaging were shown to allow detection of a single nucleation event in brain tissue in vivo. Experiments carried out on eight sheep allowed statistical studies of the bubble nucleation process. The nucleation probability was evaluated as a function of the peak negative pressure. No nucleation event could be detected with a peak negative pressure weaker than −12.7 MPa, i.e. one order of magnitude higher than the recommendations based on the mechanical index. Below this threshold, bubble nucleation in vivo in brain tissues is a random phenomenon.

An Adaptive Spectral Estimation Technique to Detect Cavitation in HIFU With High Spatial Resolution

In ultrasound-guided high-intensity focused ultrasound (HIFU) therapy, the changes observed on tissue are subtle during treatment; some ultrasound-guided HIFU protocols rely on the observation of significant brightness changes as the indicator of tissue lesions. The occurrence of a distinct hyperechogenic region (“bright-up”) around the focus is often associated with acoustic cavitation resulting in microbubble formation, but it may indicate different physical events such as larger bubbles from boiling (known to alter acoustic impedance) or sometimes lesion formation. A reliable method to distinguish and spatially localize these causes within the tissue would assist the control of HIFU delivery, which is the subject of this paper. Spectral analysis of the radio frequency (RF) signal underlying the B-mode image provides more information on the physical cause, but the usual techniques that are methods on the Fourier transform require a long series for good spectral resolution and so they give poor spatial resolution. This paper introduces an active spectral cavitation detection method to attain high spatial resolution (0.15 × 0.15 mm per pixel) through a parametric statistical method (ARMA modeling) used on finite-length data sets, which enables local changes to be identified more easily. This technique uses the characteristics of the signal itself to optimize the model parameters and structure. Its performance is assessed using synthesized cavitation RF data, and it is then demonstrated in ex vivo bovine liver during and after HIFU exposure. The results suggest that good spatial and spectral resolution can be obtained by the design of suitable algorithms. In ultrasound-guided HIFU, the technique provides a useful supplement to B-mode analysis, with no additional time penalty in data acquisition.

Stable cavitation in ultrasound image-guided high intensity focused ultrasound therapy

Microbubble activity is significantly involved in both diagnostic and therapeutic aspects of ultrasound image-guided HIFU therapy. Ultrasound interrogation techniques (A-, B-, M-mode, Doppler, harmonic and contrast imaging, and passive and active cavitation detection) were integrated with HIFU. Our results using HIFU devices of 1–5 MHz, and focal, derated intensities of 1,000–10,000 W/cm2, show the formation of microbubbles (about 100 bubbles/mm3, 5–100 microns in size) at the HIFU focus. Boiling, stable, and inertial acoustic cavitation activities were detected during therapy. The presence of bubbles allows the observation of the treatment spot as bright hyperechoic regions in ultrasound images, providing an effective method for guidance and monitoring of therapy. The stable cavitation of microbubbles may provide a mechanism for enhanced HIFU energy delivery, as well as induction of biological responses for stimulation and regulation of specific physiological events such as coagulum and thrombus formation for hemostasis applications, apoptotic activity in treating tumor margins, and stimulation of immune response. Stable cavitation of extrinsic bubbles (contrast agents) is used in detection and localization of internal occult bleeding, using harmonic imaging. There appears to be benefits in utilizing stable cavitation in both diagnostic and therapeutic objectives of ultrasound image-guided HIFU. Funding: DoD, NIH, NSBRI.

Hyperecho in ultrasound images of HIFU therapy: Involvement of cavitation

High-intensity focused ultrasound (US), or HIFU, treatment of soft tissues has been shown to result in a hyperechoic region in B-mode US images. We report on detecting cavitation in vivo in correlation with the appearance of a hyperechoic region. The US system consisted of a HIFU transducer (3.3 MHz), a broadband A-mode transducer for active and passive cavitation detection and an US-imaging probe that were all confocal and synchronized. HIFU, at in situ intensities of 220 to 1710 W/cm 2, was applied for 10 s to pig muscles in vivo. Active and passive cavitation detection results showed a strong correlation between the onset of cavitation and the appearance of a hyperechoic region. Passive cavitation detection results showed that inertial cavitation typically occurred prior (within 0.5 s) to the appearance of a hyperechoic region. The observed cavitation activity confirms that bubbles are present during the formation of a hyperechoic region at the HIFU focus. (E-mail: vaezy@u.washington.edu)

Cavitation detection during ultrasound-assisted thrombolysis in porcine blood clots

Substantial enhancement of recombinant tissue plasminogen activator (rt-PA) mediated thrombolysis can be achieved with exposure of a thrombus to pulsed ultrasound. However, the mechanism of this interaction has not yet been elucidated. In this work cavitation is investigated as a possible mechanism for enhancement in 120-kHz pulsed ultrasound-assisted thrombolysis. Porcine blood clots were immersed in plasma as control and exposed to rt-PA, ultrasound (0.35 MPa, 80% duty cycle, 1667 Hz pulse repetition frequency), or a combination of rt-PA and ultrasound. A confocally aligned active and passive cavitation detection system was employed to detect subharmonic emissions from stable cavitation and broadband superharmonic emissions from inertial cavitation. After exposure, clot mass loss was determined, and clots were subjected to immunohistochemical analysis of fibrin degradation. Spatial investigation of cavitation thresholds inside the clot, on the clot surface, and in the fluid surrounding the clot showed the threshold to be lowest on the clot surface. Stable cavitation was detected in clots exposed to ultrasound alone and a combination of rt-PA and ultrasound. Curiously, inertial cavitation was detected only in samples containing rt-PA. The presence of both stable and inertial cavitation correlated with increased clot mass loss and a distinct pattern of fibrin degradation on histologic evaluation.

Effect of polymer surface activity on cavitation nuclei stability against dissolution.

The persistence of acoustic cavitation in a pulsed wave ultrasound regime depends upon the ability of cavitation nuclei, i.e., bubbles, to survive the off time between pulses. Due to the dependence of bubble dissolution on surface tension, surface-active agents may affect the stability of bubbles against dissolution. In this study, measurements of bubble dissolution rates in solutions of the surface-active polymer poly(propyl acrylic acid) (PPAA) were conducted to test this premise. The surface activity of PPAA varies with solution pH and concentration of dissolved polymer molecules. The surface tension of PPAA solutions (55-72 dynes/cm) that associated with the polymer surface activity was measured using the Wilhelmy plate technique. Samples of these polymer solutions then were exposed to 1.1 MHz high intensity focused ultrasound, and the dissolution of bubbles created by inertial cavitation was monitored using an active cavitation detection scheme. Analysis of the pulse echo data demonstrated that bubble dissolution time was inversely proportional to the surface tension of the solution. Finally, comparison of the experimental results with dissolution times computed from the Epstein-Plesset equation suggests that the radii of residual bubbles from inertial cavitation increase as the surface tension decreases.

Active cavitation detection of asymmetrical inertial cavitation

The active cavitation detector (ACD) developed in Bob Apfel’s laboratory has often been employed to quantify pressure thresholds for inception of symmetrical inertial cavitation of microbubbles. In the current application, however, a 30-MHz ACD interrogates individual echo-contrast agent bubbles adhering to a Mylar(TM) sheet that are driven into asymmetrical (jet-producing) collapse by a 1-MHz toneburst (&amp;gt;1 MPa pp). The resulting ACD output suggests that asymmetrical bubble collapse is slower than symmetrical collapse, producing less total radiated acoustic power. ACD output mixed with reference sinusoids at 30 MHz and low pass filtered yields Doppler signals that may be useful in quantifying asymmetrical collapses under biomedically relevant conditions, such as on endothelial walls.

When is a bubble a bubble?: The subtleties of cavitation threshold detection at MHz frequencies

Detecting the onset of cavitation induced by short-pulse ultrasound at MHz frequencies is tricky business, for one must be positioned to observe the genesis and evolution of a single micron-sized bubble lasting as short as one acoustic cycle. The observation is rarely accomplished directly. Rather, investigators often rely on indirect evidence of cavitation activity manifested by physical effects such as noise (a.k.a. passive cavitation detection), light emission, and mechanical damage. These techniques are noise limited, and investigators frequently measure a threshold for ‘‘detectable’’ cavitation. Another approach is to actively probe the medium with a high-frequency acoustic beam, and watch for anomalous backscatter associated with bubble activity. This technique, often termed active cavitation detection, can be quite sensitive, which is part of the problem; transient disturbances in the medium can be mistaken for bona fide cavitation activity. Such errors are often associated with, say, the motion of solid particles in a test liquid that is put into motion by acoustic radiation forces or entrained by acoustic streaming. In all cases, the ability to detect and monitor minute, spurious cavitation activity is limited by noise, clutter, or reverberation. These issues are discussed, examples given, and potential solutions proposed. [Work supported by DARPA.]

Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz

Inertial cavitation is hypothesized to be a mechanism by which ultrasound (US) accelerates the dissolution of human blood clots when the clot is exposed to a thrombolytic agent such as tissue plasminogen activator (t-PA). To test this hypothesis, radiolabeled fibrin clots were exposed or sham-exposed in vitro to 1 MHz c.w. US in a rotating sample holder immersed in a water-filled tank at 37°C. Percent clot dissolution after 60 min of US exposure was assessed by removing the samples, centrifuging, and measuring the radioactivity of the supernatant fluid relative to the pelletized material. To suppress acoustic cavitation, the exposure tank was contained within a hyperbaric chamber capable of pneumatic pressurization to 10 atmospheres (gauge). Various combinations of static pressure (0, 2, 5, and 7.5 atm gauge), US (0 or 4 W/cm 2 SATA), and t-PA (0 or 10 μg/mL) were employed, showing statistically significant reductions in thrombolytic activity as static pressure increased. To gain further insight, an active cavitation detection scheme was employed in which 1-μs duration tonebursts of 20-MHz US (< 1 kPa peak negative pressure, 1 Hz PRF) were used to interrogate clots subjected to US and static pressure. Results of this cavitation detection scheme showed that scattering from within the clot and broadband acoustic emissions that were both present during insonification were significantly reduced with application of static pressure. However, only about half of the acceleration of thrombolysis due to US could be removed by static pressure, suggesting the possibility of other mechanisms in addition to inertial cavitation.

Direct evidence of cavitation in vivo from diagnostic ultrasound

Recent increases in the pressure output of diagnostic ultrasound scanners have led to an interest in establishing thresholds for bioeffects in many organs including the lungs of mammals. Damage may be mediated by inertial cavitation, yet there have been no such direct observations in vivo. To explore the hypothesis of cavitation-based bioeffects from diagnostic ultrasound, research has been performed on the thresholds of damage in rat lungs exposed to 4.0-MHz pulsed Doppler and color Doppler ultrasound. A 30-MHz active cavitation detection scheme complementing these studies provides the first direct evidence of cavitation in vivo from diagnostic ultrasound pulses.

In vitro measurements of inertial cavitation thresholds in human blood

Inertial cavitation thresholds were measured in human blood exposed to pulsed ultrasound. Freshly drawn blood, bank blood and aqueous dilutions of both were used in this experimental study. Micrometer-sized polystyrene particles were used as extra potential nuclei in some samples. Focused transducers with megahertz center frequencies (2.5 MHz, 4.3 MHz) were employed to generate pulsed ultrasound to induce cavitation. Specially designed cells for hosting the blood samples were made to adapt to the experimental environment. Cavitation threshold measurements were achieved by using an active cavitation detection scheme which utilizes a highly focused transducer with a much higher center frequency (30 MHz). In 50% diluted blood samples, when no polystyrene particles were added to the samples, the threshold for cavitation was about 4.1 MPa at 2.5 MHz, while no cavitation was detected at 4.3 MHz. Generally, the measured thresholds decrease in samples with lower volume concentration of red blood cells or when polystyrene particles were added to the samples. Results show that the measured thresholds in some circumstances are in the range of output pressure of diagnostic ultrasound instrumentation; but for whole, freshly drawn blood, our apparatus was unable to detect cavitation, even at 6.3 MPa.

Active cavitation detection of microbubble echocontrast agents in blood

Apfel’s active cavitation detector [Roy etal., J. Acoust. Soc. Am. 87, 2451–2458 (1990)] has been improved to allow quantification of microbubble activity in reconstituted human blood. One-microsecond-long 20-MHz tone bursts are scattered from microbubbles undergoing transient cavitation at the focus of a pulsed 1-MHz transducer. The host medium consists either of human red blood cells suspended in autologous plasma or platelet-rich plasma, with various concentrations of microbubble-based echocontrast agent present. The microbubble activity inferred from the backscattered tone bursts is compared to measured bioeffects (hemolysis, platelet aggregation) in order to determine the physical basis for cavitational damage of blood components. Current results as a function of system parameters will be presented. [Work supported by NSF MSS-9253777.]

Acoustic scattering from transient, micron‐sized cavitation bubbles

If cavitation occurs in vivo due to the application of medical ultrasound, it is likely to be difficult to observe. Concern rests less with the destruction of biological cells and more with the more subtle subcellular injuries that could result in damage to components responsible for cell reproduction. Cavitation on the scale of single biological cells—microcavitation—can be observed in vitro by scattering high‐frequency ultrasound (30 MHz) off of single transient cavitation bubbles. An active cavitation detection (ACD) has been used to determine the onset conditions (e.g., cavitation thresholds) in vitro for water with various artificial cavitation nuclei. More recently, the same scattering technique has been employed to observe the radius versus time characteristics of transient cavitation bubbles of one or more cycles. Reports on both threshold measurements and attempts to measure quantitative radius versus time histories of individual bubbles will be presented. The results will be presented in the general context of the joint Yale‐National Center for Physical Acoustics collaborative effort to assess the safety of diagnostic ultrasound. [Work supported by the National Institutes of Health through Grant 4R01‐CA39374.]