Medical ultrasound with microbubbles

Medical ultrasound with microbubbles

Experimental Thermal and Fluid Science 29 (2005) 255–265 www.elsevier.com/locate/etfs Medical ultrasound with microbubbles Yoichiro Matsumoto *, John...

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Experimental Thermal and Fluid Science 29 (2005) 255–265 www.elsevier.com/locate/etfs

Medical ultrasound with microbubbles Yoichiro Matsumoto *, John S. Allen, Shin Yoshizawa, Teiichiro Ikeda, Yukio Kaneko Department of Mechanical Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan Received 14 September 2003; received in revised form 27 April 2004; accepted 21 May 2004

Abstract In the medical ultrasound applications, microbubbles are closely tied to the diagnostic/therapeutic uses. For diagnostic applications, their sound scattering properties yield improved imaging, when the microbubbles are used as contrast agents. The harmonics and subharmonics responses from the bubbles assist in distinguishing the acoustic scattering of blood from that of the surrounding tissue. The therapeutic use of microbubbles has recently been the subject of much interest. In a HIFU treatment, the heat generated by the bubble motion contributes an enhanced localized heating effect from the ultrasound. In the lithotripsy of renal calculi, the acoustic cloud cavitation contributes to the comminution of the renal stones. In all these applications, it is essential to understand the microbubbles and bubble cloud dynamics. The bubble motion and bubble cloud behavior are strongly influenced by the internal phenomena of the bubbles, such as thermal diffusion, mist formation, mass diffusion and heat and mass transfer through the bubble wall. In our research, bubble and bubble cloud dynamics in the medical ultrasound field have been examined. In this paper numerical results and the new techniques of medical ultrasound applications with microbubbles, microbubble enhanced HIFU and Cavitation Control Lithotripsy (CCL), are highlighted. Ó 2004 Published by Elsevier Inc. Keywords: Medical ultrasound; Microbubble; Acoustic cavitation; Contrast imaging; HIFU; Lithotripsy

1. Introduction Ultrasound is widely applied in the clinical setting, for example ultrasound contrast agent imaging, High Intensity Focused Ultrasound (HIFU), Extracorporeal Shock Wave Lithotripsy (ESWL) and sonodynamic therapy. Some of these applications have a close relation to the dynamic behavior of microbubbles and that of a bubble cloud. In an ultrasound imaging, microbubbles are used as contrast agents. In a HIFU treatment, microbubbles are used to enhance the heating of the tissues. Whereas acoustic cavitation generated by high amplitude ultrasound may cause tissue trauma, and the optimal acoustic parameters need to be determined. The acoustic cloud cavitation has also a close relation*

Corresponding author. Tel.: +81 3 5841 6286/5802 2947; fax: +81 3 3818 0835/5802 2947. E-mail address: [email protected] (Y. Matsumoto). 0894-1777/$ - see front matter Ó 2004 Published by Elsevier Inc. doi:10.1016/j.expthermflusci.2004.05.008

ship with the efficiency of Extracorporeal Lithotripsy. There is a need to better understand the amplitude and the power spectrum of acoustic emission from microbubbles to visualize the tissues and organs, to determine the heat deposition rate for the treatment of tumors and to find the emitted shock pressure from the collapsing bubble cloud. Many researchers have investigated single spherical bubble motion in an infinite liquid and there has been also research where the additional effects, such as compressibility of liquid, deformation of a bubble from the spherical shape near a solid wall and thermal phenomena, are considered. It is well understood that the thermal phenomena inside the bubble significantly influences the bubble motion. The effects of non-equilibrium phase change [1] and thermal diffusion [2,3] on the bubble motion have been discussed. The bubble motions [4,5] have been calculated numerically by using the full equations for mass, momentum and energy in gas and

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liquid phases taking into account the internal phenomena such as thermal and mass diffusion and mist formation due to homogeneous condensation. Not only single bubble dynamics but also bubble cloud dynamics have been investigated [6–13]. Reisman et al. [11] suggested that the formation and focusing of bubbly shock waves, which are formed during the collapse of a cloud, are responsible for the severe noise and damage of cloud cavitation. The behavior of cavitation cloud has been investigated in connection with the severe cavitation damage [12,13] using the set of governing equations for the spherical bubble cloud, where the internal phenomena of each bubble and the compressibility of liquid are taken into account. An inwardly propagating shock wave is formed during the collapse of the bubble cloud and focused at the cloud center [13]. In this paper, the single bubble dynamics and the bubble cloud dynamics in the frequency range of medical ultrasound are examined. New methods for medical ultrasound with microbubbles based on the previous research done in other contexts are discussed. One is the localized enhancement of heating for HIFU therapy using contrast agent microbubbles, and another is Cavitation Control Lithotripsy (CCL) of renal calculi using a method of acoustic cavitation control.

2. Bubble and bubble cloud dynamics in the ultrasound It is well known that the microbubbles behave as non-linear oscillators converting mechanical energy to heat when subjected to an acoustic field. So it is viable to apply the microbubble as an acoustic emitter and a heat transducer for the medical treatments [14]. In order to achieve the effective use of the microbubbles, the behavior of the microbubbles in the ultrasound field should be considered. The emitted sound and the heating effect of the microbubbles are analyzed both numerically using a single bubble model that considers internal thermal phenomena extensively [13]. The simulation of the single bubble motion is extended to investigate pressure wave phenomena with coupled averaged equations for a bubbly liquid, where thermal phenomena inside the bubble and the liquid compressibility are taken into account. Using this set of equations, the bubble cloud dynamics in the ultrasound field are simulated.

sphere pressure, 101.3 kPa, and the initial temperature is 293 K. The bubble oscillation in an ultrasound field is simulated by using the model [13], where the internal thermal phenomena are taken into account under the following assumptions: (l) A bubble maintains spherical shape. (2) The pressure and temperature inside the bubble are uniform except for the boundary layer near the bubble wall, which is thin enough compared with the bubble radius. (3) Vapor and non-condensable gas obey the perfect gas law. (4) The temperature at the bubble wall is equal to that of liquid. (5) Non-condensable gas obeys the HenryÕs law at the bubble wall. (6) Coalescence and fragmentation of mist and slippage between mist and the surrounding gas are ignored. The dynamic equation of the bubble is the Fujikawa and Akamatsu equation [1]. It is solved by using a Runge–Kutta method. Energy equation in liquid phase, diffusion equation of non-condensable gas in liquid, energy conservation equation in gas phase with mist and nucleation rate equation of mist are also solved. Classical theory for generation and growth of mist under quasiequilibrium condition is applied, because the temperature inside the bubble does not change so rapidly [15]. Results are shown in Fig. 1. Fig. 1(a) is the time history of the ambient ultrasound pressure, (b) the bubble radius, (c) the acoustic emission from the bubble. Fig. 1(d) is a FFT analysis of the acoustic emission (Fig. 1(c)). In the FFT analysis, a Hanning window is employed. Acoustic pressure emitted from a bubble, pa is calculated by a formula that is considering water compressibility [1]. It is calculated at 60 mm from the center of a bubble since 60 mm is a typical distance from the surface of ultrasound imaging probe to the focusing point of the probe. Due to the non-linearity, the time history of bubble radius has sharp pointed characteristics at the minimum of radius. This reveals that a bubble oscillates repeatedly with a cycle consisting of slow expansion, rapid shrinkage and rebound. Acoustic pressure from a microbubble shows high pressure when a bubble shrinks and rebounds. The waveform has very sharp-edged shapes and consists of higher harmonic components [16]. FFT analysis shows that the second harmonic is similar in amplitude to the fundamental frequency (3.6 MHz). This second harmonic mode, excited by volumetric oscillation of a microbubble, as is now widely applied to ultrasound contrast techniques.

2.1. Microbubble oscillation in ultrasound field 2.1.1. Non-linear oscillation of a microbubble In this simulation, a bubble is continuously exposed in sinusoidal ultrasound field. Ultrasound frequency, f0, is 3.6 MHz and amplitude is 100 kPa. Initial bubble radius, R0, is 1.0 lm (typical bubble radius of contrast agent) so that the linear resonance frequency of the bubble is 3.6 MHz. Initial ambient pressure, p0, is atmo-

2.1.2. Energy depositions from a microbubble Based on these phenomena, three types of energy depositions from a bubble are considered when the bubble oscillates in an ultrasound field. The first is the thermal conduction, which includes the heat conduction between the gas and the liquid and the latent heat of the vapor inside a bubble. Second is the viscous dissipation. Third is the acoustic emission from a bubble

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Fig. 1. Bubble behavior in the ultrasound field, (a) ambient ultrasound pressure, (b) bubble radius, (c) acoustic emission from the bubble, (d) FFT analysis of the acoustic emission.

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caused by the oscillation of the interface with a finite speed of sound in the fluid. Among the three kinds of the energies, the thermal conduction and viscous dissipation affect the heat near the bubble wall. On the other hand, the energy from acoustic emission travels far away at approximately the sound speed. For the therapeutic use of microbubbles as heat converters, it is important to estimate the three kinds of energy relationship quantitatively. Fig. 2 shows the result of a calculation of three types of the energies from a single air bubble when the amplitude of ambient pressure is 100 kPa at a frequency, 1 MHz. From this graph, the energies become greater near the resonance bubble radius. It is remarkable that the thermal energy is the same order as other two energies, which are viscous and acoustic energies. For sufficiently large values of thermal energy, it is important to consider the thermal phenomena. When the gas species inside a microbubble are different, the bubbleÕs oscillation and internal thermal phenomena change. In Fig. 3 and Fig. 4, the gases inside the bubbles are different. Fig. 3 shows the result of Argon (Ar) gas, and Fig. 4 shows that of sulfur hexafluoride (SF6) gas. In this case of Argon, the ratio of specific heat is 1.67. The temperature in the bubble becomes high, and consequently the

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thermal conduction through the bubble wall becomes larger than with the other two energies. On the other hand, in the case of SF6, the ratio of specific heat is 1.09. The bubble behaves almost isothermally, so the temperature rise is not so high, instead the bubble radius violently changes [17]. In this case, the viscous dissipation and acoustic emission are large in comparison with the thermal one. The SF6 bubble radiates at a subharmonic when the bubble radius is about 6 lm. For these reasons, the Argon bubble deposits the thermal energy effectively, and a microbubble that includes the gas such as Argon has a greater potential to play a role in therapeutic use. On the other hand, a bubble that

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contains the gas such as SF6 can radiate the acoustic energy strongly and can be more effectively used for a diagnostic application. 2.2. Bubble cloud oscillation in an ultrasound field For medical applications of ultrasound, it is necessary to discuss acoustic cavitation that is induced by focused ultrasound. It has been suggested that cavitation may induce serious trauma to the tissues of human body and its occurrence disturbs ultrasound propagation by scattering and absorbing energy [18]. However, cavitation can be used as an energy transducer if there is enough control of the cavitation bubbles. Damage to tissues results from cavitation erosion producing extraordinary high pressures at a very small spatial area in the body. A discernable disturbance of the ultrasound propagation indicates enhanced heating is possible if there is enough control of microbubblesÕ volumetric vibrations in the ultrasound field. To utilize their energy efficiently, their behavior in an ultrasound field must be understood. In foregoing section, a single bubble motion in an ultrasound field was discussed, and it was revealed that its oscillations are complicated. In this section, we discuss numerical simulation of the volumetric change of a cluster of microbubbles, a bubble cloud. The acoustic emission from the bubble cloud is intricately more complicated than a single bubble. 2.2.1. Concept of a bubble cloud Inside a bubble cloud, a shock wave propagates in the bubbly flow. Kameda et al. clarified that internal phenomena have much influence on shock wave propagation [19] and in certain cases the compressibility of liquid cannot be ignored depending on state of bubble motion [20]. A very high pressure of O(108)–O(109) Pa emerges near the center of cloud cavitation when it collapses violently. In such a case compressibility of liquid must be taken into account. Therefore, to analyze collapsing phenomena of a bubble cloud precisely, internal phenomena of a bubble and liquid compressibility are needed. Considering such phenomena, Shimada et al. numerically simulated a bubble cloud. They concluded that when a bubble cloud collapses, very high pressure is emitted from each of the bubbles near the center of the bubble cloud and the variation of the pressure is at a very high frequency [13]. 2.2.2. Assumptions The model of each of the bubbles is basically the same as that is used in a former numerical simulation of a single bubble [13]. Bubbles in the cloud shrink violently so that gases in a bubble cannot be treated as ideal. For simplification, ambient temperature rise and mass transfer of non-condensable gases were not considered. To sum up, the following assumptions are employed in

the numerical simulation: (l) The bubble cloud and each bubble oscillate maintaining spherical symmetry. (2) Bubbly liquid is treated as a continuum fluid. (3) Coalescence and fragmentation of bubbles are ignored. (4) The pressure and temperature inside the bubble are uniform except for the thin boundary layer near the bubble wall, which is thin compared with the bubble radius. (5) Temperature at the bubble wall is equal to that of liquid. (6) Mass of non-condensable gas inside a bubble is constant. (7) Gases inside a bubble obey the van der Waals gas law. (8) Coalescence and fragmentation of mist inside a bubble are ignored. Then we consider the thermal behavior inside the bubble and the pressure wave phenomena in the bubble cloud in detail, namely, the evaporation and condensation of liquid at the bubble wall, heat transfer through the bubble wall and the compressibility of liquid. The equation of motion of the spherical bubble cloud interface is the Keller equation [21]. Volumetric change of bubble is solvable if pressure at the surface of the cloud is given. Therefore pressure waves in a bubble cloud should be determined. In a bubble cloud, mass conservation equation, momentum conservation equation of bubbly flow and conservation equation of number density of bubbles are also solved. Tait equation is employed as the equation of the liquid state. 2.2.3. Frequency response of a bubble cloud Acoustic cavitation induced by ultrasound is considered to be strongly dependent on ultrasound frequency. In medical applications, the typical frequency of ultrasound is around 0.5–5 MHz.When ultrasound frequency is 4 MHz, wavelength is about 0.4 mm in water and approximately the same in the human body. Focal region is considered to be around 2–4 times of wavelength. In this simulation, we assume that region of acoustic cavitation is 0.75 mm in radius, and radius of a bubble is 1.0 lm (natural frequency is about 4 MHz). Calculation conditions are shown in Table 1. Fig. 5 is the frequency response of the bubble cloud from 1 kHz to 10 MHz. It shows a maximum pressure inside the bubble at the center of the cloud. Resonance frequency of the bubble cloud is about 110 kHz (Dp = 100 kPa), less than natural frequency, 147 kHz, that of linear bubble cloud. The variance of the bubble

Table 1 Calculation conditions of a bubble cloud Initial cloud radius, Rc0 Initial bubble radius,Rb0 Initial void fraction, a0 Initial ambient pressure, p0 Initial temperature, T0 Amplitude of ambient pressure, Dp Variation range of frequency Natural frequency of a bubble cloud

0.75 mm 1.0 lm 0.1% 101.3 kPa 293 K 10, 50, 100 kPa 1 kHz–10 MHz 147 kHz

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cloud radius is very small. Different from a single bubble, volume of the bubble cloud hardly changes. An increase of the amplitude of ambient pressure has little influence on volumetric oscillation of the bubble cloud. In contrast, at the center of the bubble cloud, the pressure of the center bubble reaches around 500 MPa, in the case the forcing frequency is at the resonance and the pressure amplitude is 100 kPa. It far surpasses the case of a single bubble. A little volumetric change of the bubble cloud makes a pressure wave at the surface, and this pressure wave propagates toward the center of the bubble cloud. The pressure wave focuses at the center and bubbles near the center collapse violently. Matsumoto [22] discusses the process of shock wave propagation in a bubble cloud in more detail. Fig. 5 also indicates that the frequency response of the bubble cloud has strong dependence on the amplitude of the ambient ultrasound pressure. At 10 kPa in amplitude, the pressure of the center of the bubble cloud is small. In the case of 50 kPa, although pressure reaches 2 MPa, the range of frequency that gains a high-pressure response is very narrow (less than 100 kHz). However, at 100 kPa of ambient amplitude, the range of frequencies that reach higher pressures becomes very broad. The bound is more than 10 MPa at 50–200 kHz in frequency. This means that it is possible to control the collapsing phenomenon of cavitation bubbles in ultrasound field. The size of the bubble cloud and that of bubbles in it are determined by the frequency of ultrasound (excitation frequency). If the frequency is selected carefully, it is technically possible to concentrate high energy in spatially restricted area in a media such as water or human tissue.

microbubbles in medical ultrasound such as ultrasound imaging, sonodynamic therapy [25] have been investigated and applied. Recently microbubbles attract much attention as heat transducers for the medical ultrasound application [18,26]. There are reports of in vivo enhancement of tissue heating can be done in the existence of acoustic cavitation produced by HIFU [14] and contrast agent [27]. In the field of the bubble dynamics, it is known that the microbubble is an energy converter of mechanical energy to heat when subjected to an acoustic field. If the heat deposited from microbubbles is effectively utilized, the treatment for a tumor can be achieved with less intense ultrasound, and accordingly a less invasive and more effective therapy might be developed. In order to achieve a more effective use of the microbubbles, we need to better comprehend the behavior of the microbubbles in the ultrasound field. The behavior in the ultrasound field is very complicated and the various phenomena may occur: non-linear oscillation, collapse, break-up, and coalescence. Therefore, an experimental analysis in conjunction with the numerical simulations discussed in the foregoing section is needed. 3.1. Experiment of microbubble heating 3.1.1. Experimental conditions In this section, some results of the experiments are shown and the heating effect of microbubbles is discussed. Fig. 6 shows the experimental set-up [17]. The concave PZT ceramics diaphragms that have the natural frequencies of 2.17 MHz is used as the ultrasound transducer. The diameter of the transducer is 40 mm, and focal length is also 40 mm. The polyacrylamide gel is placed in the ultrasound field. In the gel a cylindrical space whose depth is 10 mm and diameter is 10 mm is created. In this space, pure water or the liquid with LevovistÒ, one of the contrast agents,are injected. In order to measure the temperature distribution, a thermal liquid crystal sheet (TLC sheet) is used, and this sheet

3. Microbubble enhanced high intensity focused ultrasound High Intensity Focused Ultrasound (HIFU) is used in the treatment for cancer [23,24], whereas the use of

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Fig. 6. Set-up of the microbubble heating experiment.

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Fig. 7. Temperature distribution measured with a thermal liquid crystal sheet after 60 s ultrasound irradiation (ultrasound frequency 2.17 MHz, amplifier output 5 W), (a) water, (b) Levovist Ò (30 mg/ml).

has the temperature sensitivity range from 40 to 45 °C. The camera is set above the test section and the temperature distribution is monitored. The temperature at the focus is measured by thermocouple. The initial temperature of the test section is fixed at 37 °C.

3.1.3. Heating effect of microbubbles The temperature at the focus was measured by the thermocouple. Fig. 8 shows the time history of the tem65 Levovist (30 mg/ml) Levovist (3.0 mg/ml) Levovist (0.3 mg/ml) no bubbles

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3.1.2. Temperature distribution around focal region Fig. 7 shows the result of the temperature distribution with a TLC sheet after 60 s ultrasound irradiation. The frequency of ultrasound is 2.17 MHz and the output power from the amplifier is 5 W. These pictures were taken from above, so the cylindrical space is under the sheet. Fig. 7(a) shows the temperature distribution in the case of pure water, and in this case, the temperature rise occurs only at the ultrasound focal region. On the other hand, in Fig. 7(b) the spatial region of high temperature is larger. In the case of LevovistÒ, at first only the ultrasound focal region is heated, and the region where the microbubbles are located gradually also becomes heated. As the microbubbles absorb the ultrasound energy and oscillate, the surrounding water is heated more quickly.

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Fig. 9. Relationship between the number density of bubbles and the temperature rise (ultrasound frequency 2.17 MHz, amplifier output 30 W, ultrasound irradiation 60 s).

perature at the focus. LevovistÒ is made by dissolving the galactose, so the density of microbubbles is controlled by changing the weight of galactose. The output power from the amplifier is 30 W. Increasing the number density of bubbles, the temperature rise increases. Fig. 9 shows the relation between the number density of bubbles and the temperature rise. In this graph, the temperature rises linearly at the region of low density. As the density becomes larger, the rise in temperature becomes saturated. It is hypothesized that different phenomena occurs in this region above a certain density. One possibility is a shielding effect of microbubbles acting as a bubble cloud as has been hypothesized previously [18].

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In the HIFU application, high intensity ultrasound causes acoustic cavitation near the focal area. The violent collapse of cavitation bubbles has the potential of

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inducing tissue trauma [28], especially in the case in which the bubbles form a cloud, though the process is not well understood. The maximum pressure in the cloud on the order of GPa has been reported both in numerical [13] and experimental [29] studies from other fields. On the other hand in the study of ESWL, the complex effects of cavitation have been known in the early stage of its research history [30] and many researchers have investigated the role of the cavitation in ESWL previously. These studies were conducted on the tissue damage [28], and on the stone comminution acceleration [31]. Recently, cavitation control techniques by applying novel shock wave combinations have been proposed, and effective results have been achieved [32,33]. However, the main force that breaks the stone is still considered to be the incident plane shock wave which has a 10–60 mm focal region. Moreover, the cavitation collapse is thought to only complement the stone comminution process. If the cavitation phenomena are well controlled in time and space only at the stone surface, the extremely high-energy and high-pressure concentration can be utilized as the main mechanism of renal stone disintegration. By utilizing two frequency ultrasound, Extracorporeal Focused Ultrasound Lithotripsy (Cavitation Control Lithotripsy: CCL) is being developed. The method can erode and chip away the renal stone. By the violent collapse that is induced by the HIFU. The cavitation phenomena are well controlled in time and space only at the stone surface. Thus, the stone disintegration is solely contributed by cavitation erosion. In this section, the concept of the method and the phenomena in the CCL protocol are explained and the results of the stone crushing are also discussed. 4.1. Schematics of acoustic cavitation control Fig. 10 shows the schematic of Cavitation Control Lithotripsy (CCL) [34,35]. CCL method is comprised of two different frequencies of ultrasound. First, higher frequency ultrasound is focused at the stone surface (Fig. 10-1). It has a range about 1–15 MHz in its frequency for a shorter wavelength than the characteristic length of the renal stone. It creates a hemispherical bubble cloud consisting of very tiny bubbles only at the stone surface (Fig. 10-2). Immediately after the higher frequency is stopped, a short pulse of lower frequency ultrasound that has 100 kHz–1 MHz in its frequency is focused at the hemispherical bubble cloud (Fig. 103). The lower one forces the bubble cloud to oscillate near resonance (Fig. 10-4). Accompanying the forced oscillation of bubble cloud, a shock wave propagates inward from the hemispherical bubble cloud [13,36] (Fig. 10-5). At the center of the bubble cloud, the bubbles near the center collapse violently while they emit an extremely high-pressure wave that reaches order of GPa

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Fig. 10. Schematic of cloud cavitation control.

Fig. 11. Typical cavitation control waveform using two frequency ultrasound. A short pulse of low frequency ultrasound immediately follows a high frequency ultrasound irradiation.

[13]. Therefore, only at the stone surface, the stone is crushed with a high-energy concentration and also with the minimum amount of cavitation resulting in scooplike indentations (Fig. 10-6). Fig. 11 is the typical cavitation control ultrasound waveform. As indicated previously, high frequency ultrasound (bubble cloud creator) is immediately followed by low frequency ultrasound (cloud collapse inducer). The interval time should be long enough to dissolve all of the cavitation bubble into liquid. If this scheme can be finely controlled within the cavitation area in space and the occurrence time of the bubble cloud collapse, a lithotripsy method utilizing only cavitation erosion might be developed that produces less tissue damage and more smaller stone fragments than conventional ESWL. 4.2. Behavior of the bubble cloud in CCL method In this section, the observed bubble cloud phenomena in the CCL cycle are discussed. Fig. 12 shows the experimental set-up. The concave PZT ceramics diaphragms

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Fig. 12. Set-up of the acoustic cavitation experiment.

that have the natural frequencies of 545 kHz are used for the ultrasound transducer. They transmit higher amplitude of ultrasound at the frequencies of (2n + l) times of the fundamental frequencies than the other frequencies. Appropriate higher order harmonics coupled with fundamental frequency is used to realize CCL waveform (Fig. 11) by one PZT transducer. The maximum output voltage of CCL waveform is 1.6 kV in its peak-to-peak amplitude. The aluminum ball or artificial stone, which is used as the crushing test material of the ESWL machine, is fixed at the focus point. The cavitation phenomena at the focal point of the ultrasound are photographed by an ultra high-speed camera (IMACON200, DRS Hadland). It has the ability to take 16 frames with 5 ns exposure time and 5 ns in the minimum frame interval. IMOTEC needle hydrophone is placed near the focal region to detect the synchronized signal of the shock wave emitted by the cavitation collapse. 4.2.1. High frequency focusing phase: a stable bubble cloud Fig. 13 shows the photographs of the bubble cloud forced into oscillation. Immediately after 100 ls irradiation of 2.74 MHz ultrasound, 545 kHz pulse ultrasound

Fig. 13. High-speed photography of a forced collapse of cloud cavitation (camera interframe 275 ns, exposure 100 ns). 2.74 MHz ultrasound induced cloud cavitation is forced to collapse at the 3rd frame by 545 kHz ultrasound.

is focused upon the cloud. As shown in Fig. 13 in the first frame, after 100–200 ls irradiation of the 2.74 MHz ultrasound, stable bubble clouds are observed. As the bubble cloud growth in size, almost the entire pressure wave is scattered at its surface, so it does not proceed into the cavitation cloud. At some point, the bubble cloud stops growing and becomes a stable size. The stable bubble cloud is observed in various ultrasound frequencies, then there is a strong relationship between the size of the bubble cloud and ultrasound wavelength [35]. At the focal point, because the standing wave field is created by the incident and reflected ultrasound wave, the size of stable bubble cloud is considered to be dependent on the wavelength of ultrasound. It indicates that the sizes of the area generated by the bubble cloud can be controlled with respect to the ultrasound frequency, i.e., in the focused ultrasound field, acoustic cavitation at the solid surface can be well controlled in space. 4.2.2. Low frequency focusing phase: Collapse of a bubble cloud Fig. 13 also shows the stable bubble cloud forced to collapse by 545 kHz ultrasound. The bubble cloud shrinks at the positive phase of the 545 kHz ultrasound decreasing each bubble radii, and as seen in the 3rd frame, the bubble cloud collapses. Shadowgraph photography of cloud collapse is shown in Fig. 14. The shock wave propagation from bubble cloud is observed. Fig. 14 corresponds to the phenomena that occurred immediately after the third frame of Fig. 13, for a different frequency, strong shock wave propagating outward from the bubble cloud is seen. Fig. 15 shows the acoustic signal that is taken 1.6 mm away from the focal point. The shock wave signal of cloud cavitation collapse is captured at about 3.3 ls. The maximum pressure was about 3 MPa at 1.6 mm away. The standard deviation of the occurrence time of the peak amplitude is 65 ns. It is noted that the repro-

Fig. 14. Shadowgraph photography of the shock wave emitted from the collapse of cloud cavitation (camera exposure 5 ns). A spherical shock wave propagates outward from the cloud cavitation.

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Fig. 15. Shock wave signal of the cloud cavitation collapse; the hydrophone is placed 1.6 mm away from the focal point of the focused ultrasound.

ducibility of the cloud collapsing phenomena is very high. It is concluded that cloud cavitation collapsing phenomena can be well controlled in time and space with a high pressure and energy concentration at the solid surface. 4.3. In vitro stone crushing tests In this section, the crushing tests of model stone, which are used as the test material of ESWL machine, are discussed. The repetition frequency of the ultrasound pulse and the amplifier voltage are fixed at 20 Hz and 1.6 kV (peak-to-peak). To investigate the advantages of the CCL method, three types of waveform were applied to the cylindrical model stones. Fig. 16 shows the results. The waveforms are (a) high frequency, (b) low frequency and (c) high and low frequency combination (CCL waveform; Fig. 11). For case (a), little erosion is visible at a depth of 1

Fig. 16. Model stone crushing test: (a) high frequency only, 3.82 MHz, 50 ls; (b) low frequency only, 545 kHz, 2 cycles; (c) CCL waveform, 3.82 MHz, 50 ls + 545 kHz, 2 cycles.

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mm. In case (b), more erosion is visible than in (a) at a depth of 2 mm. Two cycles of low frequency follow the high frequency 50 ls irradiation in (c). The depth of the scoop indentation reaches 6 mm. In this case, a very acute hole is created by the cloud cavitation collapse. These results show that by controlling acoustic cavitation phenomena, high-pressure and high-energy concentration is realized within fine spatial and timing resolution. The estimated total break up time by CCL is comparable to the conventional ESWL methods. Also the resulting fragments are small enough (1 mm) to pass through the urethra.

5. Conclusions In the medical ultrasound field for both in diagnostic and therapeutic applications, microbubble and acoustic cavitation has recently been the subject of much interest. The single bubble and the bubble cloud dynamics at the frequency range of medical ultrasound are discussed. New methods for medical ultrasound with microbubbles based on their nonlinear dynamics are outlined. One is localized enhancement of heating for HIFU therapy using a microbubble contrast agent, and the other is Cavitation Control Lithotripsy (CCL) for the renal stone disintegration using a method of acoustic cavitation control. A single bubble motion in an ultrasound field is simulated taking the internal thermal phenomena into account. The higher harmonics of the ultrasound field are observed in the emitted sound from the microbubbles. Also the type of gas species inside the bubble has a significant influence on the bubble motion and the energy deposition from a bubble. The heat deposited near a bubble in the ultrasound field, from thermal and viscous losses, can be utilized for the localized enhancement of heating of HIFU treatment. Injecting the microbubbles at the ultrasound focal region of the HIFU treatment, the region is heated more effectively compared with ultrasound alone. The temperature rise is saturated above a certain density of bubbles. Acoustic cloud cavitation is simulated using a set of governing equations for the motion of a spherical bubble cloud. An inwardly propagating shock wave is formed during the collapse of the bubble cloud and focused in the cloud center. This creates a violent bubble collapse. The pressure waves emitted from bubbles at the cloud center area are amplified greatly when the driving pressure wave oscillates at the resonance frequency of the cloud. The maximum pressure emitted from the bubbles at the cloud center becomes much higher than that of a single bubble. The response curve of the emitted pressure from the bubbles at the center of

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the cloud is broadened with respect to the ultrasound amplitude. An extracorporeal lithotripsy method, Cavitation Control Lithotripsy (CCL) is being developed by utilizing two frequency focused ultrasound. By controlling cloud cavitation phenomena, high-energy and high-pressure concentrations at the stone surface are obtained. The cavitation phenomena are well controlled both in time and space. The occurrence time of the bubble cloud collapse can be controlled with a high reproducibility, and the cavitation area that is generated by high frequency ultrasound can be controlled for a restricted area at the stone surface. The model stone is efficiently chipped away. The stone comminution mechanism is attributed solely to the cavitation erosion. Compared with conventional ESWL, the spatial range of cavitation is narrower and input energy is also smaller. The CCL method has the potential to provide a less invasive and more controllable lithotripsy system. Single bubble and bubble cloud dynamics are intrinsically related to medical ultrasound applications. Further complementary numerical and experimental investigations should contribute to the progress of these applications. References [1] S. Fujikawa, T. Akamatsu, Effect of the non-equilibrium condensation of vapour on the pressure wave produced by the collapse of a bubble in a liquid, J. Fluid Mech. 97 (3) (1980) 481–512. [2] R.I. Nigumatulin, N.S. Khabeev, F.B. Nagiev, Dynamics, heat and mass transfer of vapor gas bubbles in liquid, Int. J. Heat Mass Transfer 24 (6) (1981) 1033–1044. [3] V. Kamath, A. Prosperetti, Numerical integration methods in gas bubble dynamics, J. Acoust. Soc. Am. 85 (1989) 1538–1548. [4] Y. Matsumoto, F. Takemura, Influence of internal phenomena on gas bubble motion (effects of thermal diffusion phase change on the gas–liquid interface and mass diffusion between vapor and noncondensable gas in the collapsing phase), JSME Int. J. B-37 (2) (1994) 288–296. [5] F. Takemura, Y. Matsumoto, Influence of internal phenomena on gas bubble motion (effects of transport phenomena and mist formation inside bubble in the expanding phase), JSME Int. J. B-37 (4) (1994) 736–745. [6] Y. Kawanami, H. Kato, H. Yamaguchi, M. Tanimura, Y. Tagaya, Mechanism and control of cloud cavitation, J. Fluids Eng., ASME 119 (4) (1997) 788–794. [7] K.A. Mørch, Cavitation and inhomogeneities, in: On the Collapse of Cavity Cluster in Flow Cavitation, Springer-Verlag, 1980, pp. 95–100. [8] R. Omta, Oscillation of a cloud of bubbles of small and not so small amplitude, J. Acoust. Soc. Am. 82 (1987) 1018–1033. [9] G.L. Chahine, R. Duraiswami, Bubble nuclei measurement via an inverse acoustic scattering technique, ASME J. Fluids Eng. 114 (1992) 680–686. [10] H. Soyama, H. Kato, R. Oba, Cavitation observation of severely erosive vortex cavitation arising in a centrifugal pump, in: Proc. of the Third Mech. E. Conf. on Cavitation, 1992, pp. 103–110.

[11] G.E. Reisman, Y.C. Wang, C.E. Brennen, Observations of shock waves in cloud cavitation, J. Fluids Mech. 335 (1998) 255–283. [12] Y. Matsumoto, M. Shimada, Dynamics of cavitation bubble cloud, ASME FEDSM97-3267, 1997. [13] M. Shimada, T. Kobayashi, Y. Matsumoto, Dynamics of cloud: cavitation and cavitation erosion, ASME FEDSM99-6775, 1999. [14] S.D. Sokka, R. King, K. Hynynen, MRI-guided gas bubble enhanced ultrasound heating in in vivo rabbit thigh, Phys. Med. Biol. 48 (2003) 223–241. [15] J. Frenkel, Kinetic Theory of Liquids, Oxford University Press, New York, 1946. [16] S. Yoshizawa, K. Sugiyama, Y. Matsumoto, Acoustic emission from microbubbles in ultrasound field, in: Proc. 4th Int. Symposium on Cavitation, Pasadena, California, 2001. [17] Y. Kaneko, T. Higaki, T. Maruyama, Y. Matsumoto, The effect of microbubbles as a heat transducer, in: Proc. 3rd ISTU, Lyon, France, 2003, pp. 55–60. [18] R.G. Holt, R.A. Roy, et al., Bubbles and HIFU: the Good, the bad, and the ugly, in; Proc. 2nd ISTU, 2002, pp. 120–131. [19] M. Kameda, Y. Matsumoto, Shock waves in a liquid containing small gas bubbles, Phys. Fluids 8 (2) (1996) 322–335. [20] M. Kameda, N. Shimaura, F. Higashino, Y. Matsumoto, Shock waves in a uniform bubbly flow, Phys. Fluids 10 (10) (1998) 2661– 2668. [21] J.B. Keller, I.I. Kolodner, Damping of underwater explosion bubble oscillation, J. Appl. Phys. 27 (1) (1956) 1152–1161. [22] Y. Matsumoto, Bubble and bubble cloud dynamics, in: 15th ISNA, 1999, pp. 65–74. [23] G.R. Ter Haar, Acoustic surgery, Phys. Today 54 (16) (2002) 29– 34. [24] L.A. Crum, Acoustic hemostasis, in: Proc. 15th ISNA, 1999, pp. 13–22. [25] S. Umemura, K. Kawabata, K. Sasaki, In vitro and in vivo enhancement of sonodynamically active cavitation by secondharmonic superimposition, J. Acoust. Soc. Am. 101 (1997) 569– 577. [26] S. Umemura, K. Kawabata, K. Hashiba, Enhancement of ultrasound absorption by microbubbles for therapeutic application, in: Ultrasonic Symposium, 2001. [27] N.T. Sanghvi, F.J. Fry, et al., High intensity focused ultrasound treatment of prostate Tissue in the presence of us contrast agent, J. Ultrason. Med 14 (1995) S17. [28] P.A. Evan et al., Kidney damage and renal functional changes are minimized by waveform control that suppresses cavitation in shock wave lithotripsy, J. Urol. 168 (2002) 1556–1562. [29] H. Kato, A. Konno, M. Maeda, H. Yamaguchi, Possibility of quantitative prediction of cavitation erosion without model test, Trans. ASME J. Fluids Eng. 118 (1996) 582–588. [30] L.A. Crum, Cavitation microjets as a contributory mechanism for renal calculi disintegration in ESWL, J. Urol. 140 (1988) 1587– 1590. [31] S. Zhu, P. Zhong, et al., The role of stress waves and cavitation in stone comminution in shock wave lithotripsy, Ultrasound Med. Biol. 28 (5) (2002) 661–671. [32] X. Xi, P. Zhong, Improvement of stone fragmentation during shock-wave lithotripsy using a combined EH/PEAA shock-wave generator––in vivo experiments, Ultrasound Med. Biol. 26 (3) (2000) 457–467. [33] D.L. Sokolov, M.R. Bailey, L.A. Crum, Use of a dual-pulse lithotripter to generate a localized and intensified cavitation field, J. Acoust. Soc. Am. 110 (2001) 1685–1695. [34] Y. Matsumoto, S. Yoshizawa, T. Ikeda, Dynamics of bubble cloud in focused ultrasound, in: Proc. 2nd ISTU, ISBN 0-73540125-X, Seattle, America, 2002, pp. 290–299.

Y. Matsumoto et al. / Experimental Thermal and Fluid Science 29 (2005) 255–265 [35] T. Ikeda, M. Tosaki, Y. Matsumoto, M. Ohta, T. Kitamura, Renal stone comminution utilizing cloud cavitation erosion, in: Proc. 3rd ISTU, Lyon, France, 2003, pp. 49–54.

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[36] Y. Matsumoto, S. Yoshizawa, Behavior of bubble cluster in ultrasound field, Int. J. Numer. Methods Fluids (Special issue) based on WCCM5 in Vienna, 7–12 July 2002, in press.