Cavitation mapping by sonochemiluminescence with less bubble displacement induced by acoustic radiation force in a 1.2 MHz HIFU

An acoustic radiation force counterbalanced appliance was employed to map the cavitation distribution in water. The appliance was made up of a focused ultrasound transducer and an aluminum alloy reflector with the exactly same shape. They were centrosymmetry around the focus of the source transducer. Spatial–temporal dynamics of cavitation bubble clouds in the 1.2 MHz ultrasonic field within this appliance were observed in water. And they were mapped by sonochemiluminescence (SCL) recordings and high-speed photography. There were significant differences in spatial distribution and temporal evolution between normal group and counterbalanced group. The reflector could avoid bubble directional displacement induced by acoustic radiation force under certain electric power (⩽50 W). As a result, the SCL intensity in the pre-focal region was larger than that of normal group. In event of high electric power (⩾70 W), most of the bubbles were moving in acoustic streaming. When electric power decreased, bubbles kept stable and showed stripe structure in SCL images. Both stationary bubbles and moving bubbles have been captured, and exhibited analytical potential with respect to bubbles in therapeutic ultrasound.     

The inception of cavitation bubble clouds induced by high-intensity focused ultrasound

In many therapeutic applications of high-intensity focused ultrasound (HIFU) the appearance of cavitation bubbles is unavoidable, whereas the dynamics of the bubbles induced by HIFU have not been clarified. The objective of the present work is to observe the inception process of cavitation bubble clouds generated by HIFU transducer in water using high-speed photography. Sequential images captured within 600 micros after the onset of ultrasound transmission show the dynamics of cavitation bubbles' generation, growth, deformation, expansion and collapse in the focal region. However, when the observation time is narrowed to the initial 145 micros, both the still and streak images reveal that the cavitation bubbles astonishingly stay stable in the focal region for at least 60 micros. The results imply that through adjusting the HIFU exposure time while other physical parameters are appropriately chosen, it might be possible to control the generation of stable cavitation bubbles locally in the focal region.     

Modeling non-spherical oscillations and stability of acoustically driven shelled microbubbles

The oscillation and destruction of microbubbles under ultrasound excitation form the basis of contrast enhanced ultrasound imaging and microbubble assisted drug and gene delivery. A typical microbubble has a size of a few micrometers and consists of a gas core encapsulated by a shell. These bubbles can be driven into surface mode oscillations, which not only contribute to the measured acoustic signal but can lead to bubble destruction. Existing models of surface model oscillations have not considered the effects of a bubble shell. In this study a model was developed to study the surface mode oscillations in shelled bubbles. The effects of shell viscosity and elasticity on the surface mode oscillations were modeled using a Boussinesq-Scriven approach. Simulation was conducted using the model with various bubble sizes and driving acoustic pressures. The occurrence of surface modes and the number of ultrasound cycles needed for the occurrence were calculated. The simulation results show a significant difference between shelled bubbles and shell free bubbles. The shelled bubbles have reduced surface mode amplitudes and a narrower bubble size range within which these modes develop compared to shell free bubbles. The clinical implications were also discussed.     

Effects of nonlinear propagation, cavitation, and boiling in lesion formation by high intensity focused ultrasound in a gel phantom

The importance of nonlinear acoustic wave propagation and ultrasound-induced cavitation in the acceleration of thermal lesion production by high intensity focused ultrasound was investigated experimentally and theoretically in a transparent protein-containing gel. A numerical model that accounted for nonlinear acoustic propagation was used to simulate experimental conditions. Various exposure regimes with equal total ultrasound energy but variable peak acoustic pressure were studied for single lesions and lesion stripes obtained by moving the transducer. Static overpressure was applied to suppress cavitation. Strong enhancement of lesion production was observed for high amplitude waves and was supported by modeling. Through overpressure experiments it was shown that both nonlinear propagation and cavitation mechanisms participate in accelerating lesion inception and growth. Using B-mode ultrasound, cavitation was observed at normal ambient pressure as weakly enhanced echogenicity in the focal region, but was not detected with overpressure. Formation of tadpole-shaped lesions, shifted toward the transducer, was always observed to be due to boiling. Boiling bubbles were visible in the gel and were evident as strongly echogenic regions in B-mode images. These experiments indicate that nonlinear propagation and cavitation accelerate heating, but no lesion displacement or distortion was observed in the absence of boiling.     

Spatial and temporal observation of phase-shift nano-emulsions assisted cavitation and ablation during focused ultrasound exposure

Background: Phase-shift nano-emulsions (PSNEs) with a small initial diameter in nanoscale have the potential to leak out of the blood vessels and to accumulate at the target point of tissue. At desired location, PSNEs can undergo acoustic droplet vaporization (ADV) process, change into gas bubbles and enhance focused ultrasound efficiency. The threshold of droplet vaporization and influence of acoustic parameters have always been research hotspots in order to spatially control the potential of bioeffects and optimize experimental conditions. However, when the pressure is much higher than PSNEs’ vaporization threshold, there were little reports on their cavitation and thermal effects.Object: In this study, PSNEs induced cavitation and ablation effects during pulsed high-intensity focused ultrasound (HIFU) exposure were investigated, including the spatial and temporal information and the influence of acoustic parameters.Methods: Two kinds of tissue-mimicking phantoms with uniform PSNEs were prepared because of their optical transparency. The Sonoluminescence (SL) method was employed to visualize the cavitation activities. And the ablation process was observed as the heat deposition could produce white lesion.Results: Precisely controlled HIFU cavitation and ablation can be realized at a relatively low input power. But when the input power was high, PSNEs can accelerate cavitation and ablation in pre-focal region. The cavitation happened layer by layer advancing the transducer. While the lesion appeared to be separated into two parts, one in pre-focal region stemmed from one point and grew quickly, the other in focal region grew much more slowly. The influence of duty cycle has also been examined. Longer pulse off time would cause heat transfer to the surrounding media, and generate smaller lesion. On the other hand, this would give outer layer bubbles enough time to dissolve, and inner bubbles can undergo violent collapse and emit bright light.     

Visualization and optimization of cavitation activity at a solid surface in high frequency ultrasound fields

Despite the increasing use of high frequency ultrasound in heterogeneous reactions, knowledge about the spatial distribution of cavitation bubbles at the irradiated solid surface is still lacking. This gap hinders controllable surface sonoreactions. Here we present an optimization study of the cavitation bubble distribution at a solid sample using sonoluminescence and sonochemiluminescence imaging. The experiments were performed at three ultrasound frequencies, namely 580, 860 and 1142 kHz. We found that position and orientation of the sample to the transducer, as well as its material properties influence the distribution of active cavitation bubbles at the sample surface in the reactor. The reason is a significant modification of the acoustic field due to reflections and absorption of the ultrasonic wave by the solid. This is retraced by numerical simulations employing the Finite Element Method, yielding reasonable agreement of luminescent zones and high acoustic pressure amplitudes in 2D simulations. A homogeneous coverage of the test sample surface with cavitation is finally reached at nearly vertical inclination with respect to the incident wave.     

Controlled ultrasound tissue erosion: the role of dynamic interaction between insonation and microbubble activity

Previous studies showed that ultrasound can mechanically remove tissue in a localized, controlled manner. Moreover, enhanced acoustic backscatter is highly correlated with the erosion process. "Initiation" and "extinction" of this highly backscattering environment were studied in this paper. The relationship between initiation and erosion, variability of initiation and extinction, and effects of pulse intensity and gas saturation on time to initiation (initiation delay time) were investigated. A 788-kHz single-element transducer was used. Multiple pulses at a 3-cycle pulse duration and a 20-kHz pulse repetition frequency were applied. I(SPPA) values between 1000 and 9000 W/cm2 and gas saturation ranges of 24%-28%, 39%-49%, and 77%-81% were tested. Results show the following: (1) without initiation, erosion was never observed; (2) initiation and extinction of the highly backscattering environment were stochastic in nature and dependent on acoustic parameters; (3) initiation delay times were shorter with higher intensity and higher gas saturation (e.g., the mean initiation delay time was 66.9 s at I(SPPA) of 4000 W/cm2 and 3.6 ms at I(SPPA) of 9000 W/cm2); and (4) once initiated by high-intensity pulses, the highly backscattering environment and erosion can be sustained using a significantly lower intensity than that required to initiate the process.     

Optical and acoustic monitoring of bubble cloud dynamics at a tissue-fluid interface in ultrasound tissue erosion

Short, high-intensity ultrasound pulses have the ability to achieve localized, clearly demarcated erosion in soft tissue at a tissue-fluid interface. The primary mechanism for ultrasound tissue erosion is believed to be acoustic cavitation. To monitor the cavitating bubble cloud generated at a tissue-fluid interface, an optical attenuation method was used to record the intensity loss of transmitted light through bubbles. Optical attenuation was only detected when a bubble cloud was seen using high speed imaging. The light attenuation signals correlated well with a temporally changing acoustic backscatter which is an excellent indicator for tissue erosion. This correlation provides additional evidence that the cavitating bubble cloud is essential for ultrasound tissue erosion. The bubble cloud collapse cycle and bubble dissolution time were studied using the optical attenuation signals. The collapse cycle of the bubble cloud generated by a high intensity ultrasound pulse of 4-14 micros was approximately 40-300 micros depending on the acoustic parameters. The dissolution time of the residual bubbles was tens of ms long. This study of bubble dynamics may provide further insight into previous ultrasound tissue erosion results.     

An acoustic backscattering technique for the detection of transient cavitation produced by microsecond pulses of ultrasound

An acoustic backscattering technique for detecting transient cavitation produced by 10-microseconds-long pulses of 757-kHz ultrasound is described. The system employs 10-microseconds-long, 30-MHz center frequency tone bursts that scatter from cavitation microbubbles. Experiments were performed with suspensions of hydrophobic polystyrene spheres in ultraclean water. Transient cavitation threshold pressures measured with the active cavitation detector (ACD) were always less than or equal to those measured using a passive acoustic detection scheme. The measured cavitation thresholds decreased with increasing dissolved gas content and increasing suspended particle concentration. Results also show that ultrasonic irradiation of the polystyrene sphere suspensions by the ACD lowered the threshold pressure measured with the passive detector. A possible mechanism through which suspensions of hydrophobic particles might nucleate bubbles is presented.     

Phase transitions of nanoemulsions using ultrasound: experimental observations

The ultrasound-induced transformation of perfluorocarbon liquids to gases is of interest in the area of drug and gene delivery. In this study, three independent parameters (temperature, size, and perfluorocarbon species) were selected to investigate the effects of 476-kHz and 20-kHz ultrasound on nanoemulsion phase transition. Two levels of each factor (low and high) were considered at each frequency. The acoustic intensities at gas bubble formation and at the onset of inertial cavitation were recorded and subsequently correlated with the acoustic parameters. Experimental data showed that low frequencies are more effective in forming and collapsing a bubble. Additionally, as the size of the emulsion droplet increased, the intensity required for bubble formation decreased. As expected, perfluorohexane emulsions require greater intensity to form cavitating bubbles than perfluoropentane emulsions.     

A novel method for estimating the focal size of two confocal high-intensity focused ultrasound transducers

Estimating the focal size and position of a high-intensity focused ultrasound (HIFU) transducer remains a challenge since traditional methods, such as hydrophone scanning or schlieren imaging, cannot tolerate high pressures, are directional, or provide low resolution. The difficulties increase when dealing with the complex beam pattern of a multielement HIFU transducer array, e.g., two transducers facing each other. In the present study we show a novel approach to the visualization of the HIFU focus by using shockwave-generated bubbles and a diagnostic B-mode scanner. Bubbles were generated and pushed by shock waves toward the HIFU beam, and were trapped in its pressure valleys. These trapped bubbles moved along the pressure valleys and thereby delineated the shape and size of the HIFU beam. The main and sidelobes of 1.1- and 3.5 MHz HIFU beams were clearly visible, and could be measured with a millimeter resolution. The combined foci could also be visualized by observing the generation of sustained inertial cavitation and enhanced scattering. The results of this study further demonstrate the possibility of reducing the inertial cavitation threshold by the local introduction of shock wave-generated bubbles, which might be useful when bubble generation and cavitation-related bioeffects are intended within a small region in vivo.     

Spatial-temporal dynamics of cavitation bubble clouds in 1.2 MHz focused ultrasound field

Cavitation bubbles have been recognized as being essential to many applications of ultrasound. Temporal evolution and spatial distribution of cavitation bubble clouds induced by a focused ultrasound transducer of 1.2 MHz center frequency are investigated by high-speed photography. It is revealed that at a total acoustic power of 72 W the cavitation bubble cloud first emerges in the focal region where cavitation bubbles are observed to generate, grow, merge and collapse during the initial 600 μs. The bubble cloud then grows upward to the post-focal region, and finally becomes visible in the pre-focal region. The structure of the final bubble cloud is characterized by regional distribution of cavitation bubbles in the ultrasound field. The cavitation bubble cloud structure remains stable when the acoustic power is increased from 25 W to 107 W, but it changes to a more violent form when the acoustic power is further increased to 175 W.     

The Relationship of Cavitation to the Negative Acoustic Pressure Amplitude in Ultrasonic Therapy

The relationship between the cavitation and acoustic peak negative pressure in the high-intensity focused ultrasound(HIFU)Held is analyzed in water and tissue phantom.The peak negative pressure at the focus is determined by a hybrid approach combining the measurement with the simulation.The spheroidal beam equation is utilized to describe the nonlinear acoustic propagation.The waveform at the focus is measured by a fiber optic probe hydrophone in water.The relationship between the source pressure amplitude and the excitation voltage is determined by fitting the measured ratio of the second harmonic to the fundamental component at the focus,based on the model simulation.Then the focal negative pressure is calculated for arbitrary voltage excitation in water and tissue phantom.A portable B-mode ultrasound scanner is applied to monitor HIFU-induced cavitation in real time,and a passive cavitation detection(PCD)system is used to acquire the bubble scattering signals in the HIFU focal volume for the cavitation quantification.The results show that:(1)unstable cavitation starts to appear in degassed water when the peak negative pressure of HIFU signals reaches 13.5 MPa;and(2)the cavitation activity can be detected in tissue phantom by B-mode images and in the PCD system with HIFU peak negative pressures of 9.0 MPa and 7.8 MPa,respectively,which suggests that real-time B-mode images could be used to monitor the cavitation activity in two dimensions,while PCD systems are more sensitive to detect scattering and emission signals from cavitation bubbles.     

Selective aggregation by ultrasonic standing waves through gas nuclei on the particle surface

Gas nuclei in water are usually too small to be directly observed. They will grow into bubbles under the negative pressure, which is called cavitation (heterogeneous cavitation). In this study, the gas nuclei in the hydrophilic and hydrophobic silica particle suspension were investigated using the transient cavitation threshold measured by a high-intensity focused ultrasound (HIFU). The transient cavitation bubbles were also observed by a high-speed camera. The results showed that the nuclei only exist on the surface of hydrophobic particles. Furthermore, the aggregation experiments revealed that the aggregates were only formed in the hydrophobic silica suspension by ultrasonic standing waves (USW) at 200 kHz. This distinct difference was mainly due to the formation of gas nuclei on hydrophobic silica particles, which grew and coalesced into stable bubbles under the 200 kHz USW. The aggregation process in suspension was observed by a CCD camera. Moreover, the cavitation thresholds and acoustic radiation forces were analyzed to explain the mechanism of the acoustic aggregation. This study showed a very promising acoustic method for the selective aggregation of hydrophobic particles, which might be efficiently used in the mineral separation industry.     

High intensity focused ultrasound-induced gene activation in solid tumors

In this work, the activation of heat-sensitive trans-gene by high-intensity focused ultrasound (HIFU) in a tumor model was investigated. 4T1 cancer cells (2 x 10(6)) were inoculated subcutaneously in the hind limbs of Balb/C mice. The tumors were subsequently transducted on day 10 by intratumoral injection of a heat-sensitive adenovirus vector (Adeno-hsp70B-Luc at 2 x 10(8) pfu/tumor). On day 11, the tumors were heated to a peak temperature of 55, 65, 75, or 85 degrees C within 10-30 s at multiple sites around the center of the tumor by a 1.1- or 3.3-MHz HIFU transducer. Inducible luciferase gene expression was increased from 15-fold to 120-fold of the control group following 1.1-MHz HIFU exposure. Maximum gene activation (120-fold) was produced at a peak temperature of 65-75 degrees C one day following HIFU exposure and decayed to baseline within 7 days. HIFU-induced gene activation (75 degrees C-10 s) could be further improved by using a 3.3-MHz transducer and a dense scan strategy to 170-fold. Thermal stress, rather than nonthermal mechanical stress, was identified as the primary physical mechanism for HIFU-induced gene activation in vivo. Overall, these observations open up the possibility for combining HIFU thermal ablation with heat-regulated gene therapy for cancer treatment.     

A feasibility study of temperature rise measurement in a tissue phantom as an alternative way for characterization of the therapeutic high intensity focused ultrasonic field

The feasibility that temperature field measurements in vitro as an alternative way to characterize the high intensity focused ultrasound (HIFU) field used in therapeutic applications has been explored in a phantom study. Thermocouples (copper-constantan, diameter 0.125 mm) are embedded in a phantom filled with tissue mimicking material that simulates the thermal and acoustic properties of soft-tissue. The temperature rises as a function of ultrasound exposure time near the focus of a HIFU transducer (1.1 MHz, active radius a = 32 mm, geometric focal length = 62 mm) of various acoustic powers up to 30 W are measured and compared with predicted values using a simple nonlinear Gaussian model. The experimental results can be explained well by the model if no acoustic cavitation takes place. When the acoustic power become higher (>5 W) and the local temperature elevation >15 °C and the local temperature is >40 °C at the focal point, cavitation vapor bubbles appear. The presence of the cavitation bubbles may increase the temperature rise rate initially. The bubble aggregates may form along the beam axis under sonication and then eventually makes the temperature elevation reach a saturated value. When acoustic cavitation occurs, the bubble-assisted enhancement of the initial temperature rise (exposure time t < 2 s) can still be predicted by the theory.     

Bubble size distribution in acoustic droplet vaporization via dissolution using an ultrasound wide-beam method

Performance and efficiency of numerous cavitation enhanced applications in a wide range of areas depend on the cavitation bubble size distribution. Therefore, cavitation bubble size estimation would be beneficial for biological and industrial applications that rely on cavitation. In this study, an acoustic method using a wide beam with low pressure is proposed to acquire the time intensity curve of the dissolution process for the cavitation bubble population and then determine the bubble size distribution. Dissolution of the cavitation bubbles in saline and in phase-shift nanodroplet emulsion diluted with undegassed or degassed saline was obtained to quantify the effects of pulse duration (PD) and acoustic power (AP) or peak negative pressure (PNP) of focused ultrasound on the size distribution of induced cavitation bubbles. It was found that an increase of PD will induce large bubbles while AP had only a little effect on the mean bubble size in saline. It was also recognized that longer PD and higher PNP increases the proportions of large and small bubbles, respectively, in suspensions of phase-shift nanodroplet emulsions. Moreover, degassing of the suspension tended to bring about smaller mean bubble size than the undegassed suspension. In addition, condensation of cavitation bubble produced in diluted suspension of phase-shift nanodroplet emulsion was involved in the calculation to discuss the effect of bubble condensation in the bubble size estimation in acoustic droplet vaporization. It was shown that calculation without considering the condensation might underestimate the mean bubble size and the calculation with considering the condensation might have more influence over the size distribution of small bubbles, but less effect on that of large bubbles. Without or with considering bubble condensation, the accessible minimum bubble radius was 0.4 or 1.7 μm and the step size was 0.3 μm. This acoustic technique provides an approach to estimate the size distribution of cavitation bubble population in opaque media and might be a promising tool for applications where it is desirable to tune the ultrasound parameters to control the size distribution of cavitation bubbles.     

The effect of acoustically-induced cavitation on the permeance of a bullfrog urinary bladder

It is well known that ultrasound enhances drug delivery to tissues, although there is not a general consensus about the responsible mechanisms. However, it is known that the most important factor associated with ultrasonically-enhanced drug permeance through tissues is cavitation. Here we report results from research conducted using a experimental approach adapted from single bubble sonoluminescence experiments which generates very well defined acoustic fields and allows controlled activation and location of cavitation. The experimental design requires that a biological tissue be immersed inside a highly degassed liquid media to avoid random bubble nucleation. Therefore, live frog bladders were used as the living tissue due to their high resistance to hypoxia. Tissue membrane permeance was measured using radiolabeled urea. The results show that an increase in tissue permeance only occurs when cavitation is present near the tissue membrane. Moreover, confocal microscopy shows a direct correlation between permeance increases and physical damage to the tissue.     

Quantitative estimation of ultrasound beam intensities using infrared thermography-Experimental validation

Infrared (IR) thermography is a technique that has the potential to rapidly and noninvasively determine the intensity fields of ultrasound transducers. In the work described here, IR temperature measurements were made in a tissue phantom sonicated with a high-intensity focused ultrasound (HIFU) transducer, and the intensity fields were determined using a previously published mathematical formulation relating intensity to temperature rise at a tissue/air interface. Intensity fields determined from the IR technique were compared with those derived from hydrophone measurements. Focal intensities and beam widths determined via the IR approach agreed with values derived from hydrophone measurements to within a relative difference of less than 10%, for a transducer with a gain of 30, and about 13% for a transducer with a gain of 60. At axial locations roughly 1 cm in front (pre-focal) and behind (post-focal) the focus, the agreement with hydrophones for the lower-gain transducer remained comparable to that in the focal plane. For the higher-gain transducer, the agreement with hydrophones at the pre-focal and post-focal locations was around 40%.     

Physical mechanisms of the therapeutic effect of ultrasound (a review)

Therapeutic ultrasound is an emerging field with many medical applications. High intensity focused ultrasound (HIFU) provides the ability to localize the deposition of acoustic energy within the body, which can cause tissue necrosis and hemostasis. Similarly, shock waves from a lithotripter penetrate the body to comminute kidney stones, and transcutaneous ultrasound enhances the transport of chemotherapy agents. New medical applications have required advances in transducer design and advances in numerical and experimental studies of the interaction of sound with biological tissues and fluids. The primary physical mechanism in HIFU is the conversion of acoustic energy into heat, which is often enhanced by nonlinear acoustic propagation and nonlinear scattering from bubbles. Other mechanical effects from ultrasound appear to stimulate an immune response, and bubble dynamics play an important role in lithotripsy and ultrasound-enhanced drug delivery. A dramatic shift to understand and exploit these nonlinear and mechanical mechanisms has occurred over the last few years. Specific challenges remain, such as treatment protocol planning and real-time treatment monitoring. An improved understanding of the physical mechanisms is essential to meet these challenges and to further advance therapeutic ultrasound.