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.     

The interaction of shockwaves with a vapour bubble in boiling histotripsy: The shock scattering effect

Boiling histotripsy is a High Intensity Focused Ultrasound (HIFU) technique which uses a number of short pulses with high acoustic pressures at the HIFU focus to induce mechanical tissue fractionation. In boiling histotripsy, two different types of acoustic cavitation contribute towards mechanical tissue destruction: a boiling vapour bubble and cavitation clouds. An understanding of the mechanisms underpinning these phenomena and their dynamics is therefore paramount to predicting and controlling the overall size of a lesion produced for a given boiling histotripsy exposure condition. A number of studies have shown the effects of shockwave heating in generating a boiling bubble at the HIFU focus and have studied its dynamics under boiling histotripsy insonation. However, not much is known about the subsequent production of cavitation clouds that form between the HIFU transducer and the boiling bubble. The main objective of the present study is to examine what causes this bubble cluster formation after the generation of a boiling vapour bubble. A numerical simulation of 2D nonlinear wave propagation with the presence of a bubble at the focus of a HIFU field was performed using the k-Wave MATLAB toolbox for time domain ultrasound simulations, which numerically solves the generalised Westervelt equation. The numerical results clearly demonstrate the appearance of the constructive interference of a backscattered shockwave by a bubble with incoming incident shockwaves. This interaction (i.e., the reflected and inverted peak positive phase from the bubble with the incoming incident rarefactional phase) can eventually induce a greater peak negative pressure field compared to that without the bubble at the HIFU focus. In addition, the backscattered peak negative pressure magnitude gradually increased from 17.4 MPa to 31.6 MPa when increasing the bubble size from 0.2 mm to 1.5 mm. The latter value is above the intrinsic cavitation threshold of –28 MPa in soft tissue. Our results suggest that the formation of a cavitation cloud in boiling histotripsy is a threshold effect which primarily depends (a) the size and location of a boiling bubble, and (b) the sum of the incident field and that scattered by a bubble.     

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.     

High-speed observation of cavitation bubble clouds near a tissue boundary in high-intensity focused ultrasound fields

Cavitation bubble clouds generated near a tissue boundary by high-intensity focused ultrasound (HIFU) were studied using high-speed photography. In all, 171 image series were captured during the initial 100 ms of continuous HIFU exposure, which showed that cavitation bubble clouds at the tissue boundary organized into two structures - “cone-shape bubble cloud structure” recorded in 146 image series and “crown-shape bubble cloud structure” recorded in 18 image series. The remaining 7 image series showed the interchanging of these two structures. It was found that when cavitation bubbles first appeared at the tissue boundary, they developed to cone-shape bubble cloud. The cone-shape bubble cloud structure was characterized by a nearly fixed tip in front of the tissue boundary. When the cavitation bubbles initially appeared away from the tissue boundary they evolved into a crown-shape bubble cloud. Deformation of tissue boundary was shown in all the recorded image series.     

Control of the dynamics of a boiling vapour bubble using pressure-modulated high intensity focused ultrasound without the shock scattering effect: A first proof-of-concept study

Boiling histotripsy is a promising High-Intensity Focused Ultrasound (HIFU) technique that can be used to induce mechanical tissue fractionation at the HIFU focus via cavitation. Two different types of cavitation produced during boiling histotripsy exposure can contribute towards mechanical tissue destruction: (1) a boiling vapour bubble at the HIFU focus and (2) cavitation clouds in between the boiling bubble and the HIFU source. Control of the extent and degree of mechanical damage produced by boiling histotripsy is necessary when treating a solid tumour adjacent to normal tissue or major blood vessels. This is, however, difficult to achieve with boiling histotripsy due to the stochastic formation of the shock scattering-induced inertial cavitation clouds. In the present study, a new histotripsy method termed pressure-modulated shockwave histotripsy is proposed as an alternative to or in addition to boiling histotripsy without inducing the shock scattering effect. The proposed concept is (a) to generate a boiling vapour bubble via localised shockwave heating and (b) subsequently control its extent and lifetime through manipulating peak pressure magnitudes and a HIFU pulse length. To demonstrate the feasibility of the proposed method, bubble dynamics induced at the HIFU focus in an optically transparent liver tissue phantom were investigated using a high speed camera and a passive cavitation detection systems under a single 10, 50 or 100 ms-long 2, 3.5 or 5 MHz pressure-modulated HIFU pulse with varying peak positive and negative pressure amplitudes from 5 to 89 MPa and −3.7 to −14.6 MPa at the focus. Furthermore, a numerical simulation of 2D nonlinear wave propagation with the presence of a boiling bubble at the focus of a HIFU field was conducted by numerically solving the generalised Westervelt equation. The high speed camera experimental results showed that, with the proposed pressure-modulated shockwave histotripsy, boiling bubbles generated by shockwave heating merged together, forming a larger bubble (of the order of a few hundred micron) at the HIFU focus. This coalesced boiling bubble then persisted and maintained within the HIFU focal zone until the end of the exposure (10, 50, or 100 ms). Furthermore, and most importantly, no violent cavitation clouds which typically appear in boiling histotripsy occurred during the proposed histotripsy excitation (i.e. no shock scattering effect). This was likely because that the peak negative pressure magnitude of the backscattered acoustic field by the boiling bubble was below the cavitation cloud intrinsic threshold. The size of the coalesced boiling bubble gradually increased with the peak pressure magnitudes. In addition, with the proposed method, an oval shaped lesion with a length of 0.6 mm and a width of 0.1 mm appeared at the HIFU focus in the tissue phantom, whereas a larger lesion in the form of a tadpole (length: 2.7 mm, width: 0.3 mm) was produced by boiling histotripsy. Taken together, these results suggest that the proposed pressure-modulated shockwave histotripsy could potentially be used to induce a more spatially localised tissue destruction with a desired degree of mechanical damage through controlling the size and lifetime of a boiling bubble without the shock scattering effect.     

微泡对高强度聚焦超声焦域影响的研究

微泡对高强度聚焦超声(HIFU)治疗具有增效作用,而HIFU治疗中不同声学条件下微泡对HIFU治疗焦域的影响尚不清楚。本文基于声传播方程、Yang-Church气泡运动方程、生物热传导方程、时域有限差分法(FDTD)、龙格-库塔(RK)法数值仿真研究输入功率、激励频率和气泡初始半径对HIFU在含气泡体模中形成焦域的影响,并利用含Sono Vue造影剂的仿组织体模研究进行实验验证。结果表明,增大输入功率、气泡初始半径和升高激励频率均可增大焦域,随着输入功率的增大,焦域形状可能发生变化,而随着激励频率升高和气泡初始半径的增大,焦域会向远离换能器的方向移动。     

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.     

微泡对高强度聚焦超声声压场影响的仿真研究*

微泡对高强度聚焦超声(HIFU)治疗焦域具有增效作用,而HIFU治疗中不同声学条件下微泡对HIFU形成声压场的影响尚不清楚。本文基于气液混合声波传播方程、Keller气泡运动方程、时域有限差分(FDTD)法和龙格-库塔(RK)法数值仿真研究输入声压、激励频率、气泡初始空隙率和气泡初始半径对HIFU形成声压场的影响。研究结果表明,随着输入声压的增大,焦点处声压升高但焦点处最大声压与输入声压的比值减小,焦点位置几乎不变;随着激励频率和气泡初始半径的增大,焦点处声压升高且焦点位置向远离换能器方向移动;随着气泡初始空隙率的增大,焦点处声压降低且焦点位置向换能器方向移动。     

B模式实时成像定量监控超声空化时空行为的研究

提出一种采用B超图像实现高强聚焦超声(HIFU)治疗时声空化的时空量化监控的方法。首先,采用B模式实时成像系统对不同声辐照能量下的HIFU在凝胶仿体中引发的超声空化进行实验监测;接着,利用二维数字图像处理算法消除高强聚焦超声(HIFU)在B超图像中产生的干涉条纹,并在此基础上,对B超成像中观察到的高亮区域的面积变化情况进行量化分析;最后,进一步讨论了驱动声压或脉冲宽度对超声空化产生的高亮区域的生成速度和面积大小的影响。结果显示该方法可以有效去除B超图像中的干涉条纹,并对HIFU引发的空化现象进行实时监测。实验结果还表明辐照声能量的提高将引发更强烈的声空化行为,并且显著缩短HIFU引发的空化泡群的初始生成时间。研究结果对进一步优化HIFU治疗有重要意义。      

HIFU治疗中换能器驱动电功率变化机制及规律*

高强度聚焦超声(HIFU)治疗中的驱动电功率对治疗效率起着非常关键的作用,驱动电功率控制的精准性势必会影响治疗的效率和安全性。前期研究表明：HIFU治疗过程中焦域瞬态物理特性的变化会导致换能器的负载阻抗发生变化,进而影响HIFU驱动电功率,但驱动电功率与焦域瞬态物理特性之间的影响关系及规律尚不明确。该文基于电压、电流传感器、空化检测探头和温度传感器等器件,构建了一种HIFU治疗中驱动电功率实时监测及焦域声空化、温度检测系统。基于该实验研究系统,以离体牛心组织作为HIFU辐照对象,分别研究了HIFU焦域温度变化、声空化及组织损伤与驱动电功率之间的变化关系及规律。研究结果表明：当焦域温度升高时,驱动电功率缓慢上升,驱动电功率与温度变化有良好的相关性;当空化产生时,驱动电功率出现明显的波动;当组织出现损伤时,驱动电功率呈陡然下降的变化。三种情景下,驱动电功率变化有明显区别,这有望为区分HIFU治疗过程中焦域处发生损伤和空化以及实时监测靶组织损伤程度提供一种新的解决方案。     

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.     

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.     

Acoustic power measurement of high intensity focused ultrasound in medicine based on radiation force

How to measure the acoustic power of HIFU is one of the most important tasks in its medical application. In the paper a whole series of formula for calculating the radiation force related to the acoustic power radiated by a single element focusing transducer and by the focusing transducer array were given. Various system of radiation force balance (RFB) to measure the acoustic power of HIFU in medicine were designed and applied in China. In high power experiments, the dependence of radiation force acting the absorbing target on the target position at the beam axis of focusing transducer was fined. There is a peak value of "radiation force" acting the absorbing target in the focal region when the acoustic power through the focal plane exceeds some threshold. In order to avoid this big measurement error caused by the 'peak effect' in focal region, the distance between the absorbing target of RFB and the focusing transducer or transducer array was defined to be equal to or less than 0.7 times of the focal length in the National Standard of China for the measurements of acoustic power and field characteristics of HIFU. More than six different therapeutic equipments of HIFU have been examined by RFB for measuring the acoustic power since 1998. These results show that RFB with the absorbing target is valid in the acoustic power range up to 500W with good linearity for the drive voltage squared of focusing transducer or array. The uncertainty of measurement is within +/-15%.     

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.     

Characterization of HIFU transducers designed for sonochemistry application: Cavitation distribution and quantification

Acoustic field distribution was determined in HIFU sonoreactors as well as localization of cavitation activity by crossing different techniques: modeling, hydrophone measurements, laser tomography and SCL measurements. Particular care was taken with quantification of this last technique by pixels or photon counting. Cavitation bubbles generated by HIFU are mainly located on the outer layer of the propagation cone in the post-focal zone. Greatest acoustic activity is not located at the geometrical focal, but corresponds to a high concentration of bubbles zone. On the contrary, the main sonochemical activity shifts slightly toward the transducer, whereas quenching of inertial cavitation is observed directly at the focal. Finally, SCL thresholds have been determined.     

剪切波对HIFU经颅聚焦形成温度场影响的数值仿真研究

在高强度聚焦超声经颅治疗时,既有纵波又有剪切波,为了保障该治疗方法的安全有效性,有必要分析剪切波对HIFU治疗温度场的影响。该文基于人体头颅CT数据和曲率半径为150 mm的256阵元的半球相控换能器建立三维高强度聚焦超声经颅声波传播模型,利用时域有限差分法结合Westervelt声波非线性传播方程、动量方程、质量守恒方程和Pennes生物热传导方程数值仿真其形成温度场,研究在相同输入功率、不同聚焦角度条件下对应阵元数进行激励时,剪切波对换能器形成温度场的影响。结果表明,随换能器聚焦角度减小,在几何焦点处形成的焦域面积逐渐增大,考虑剪切波形成的温度场达到65?C所需时间逐渐延长,焦点前移程度越大;在相同聚焦角度条件下,考虑剪切波的温度场达到65?C所需时间更短,旁瓣更少,在颅骨处的温度更高,对焦点前移几乎没有影响;随换能器聚焦角度减小,考虑剪切波的模型形成的焦域面积变化范围更大;幂指数函数形式对不同聚焦角度下焦域面积大小的拟合优度高,可预测不同聚焦角度换能器形成的焦域面积。     

Characterization of HIFU transducers designed for sonochemistry application: Acoustic streaming

Cavitation distribution in a High Intensity Focused Ultrasound sonoreactors (HIFU) has been extensively described in the recent literature, including quantification by an optical method (Sonochemiluminescence SCL). The present paper provides complementary measurements through the study of acoustic streaming generated by the same kind of HIFU transducers. To this end, results of mass transfer measurements (electrodiffusional method) were compared to optical method ones (Particle Image Velocimetry). This last one was used in various configurations: with or without an electrode in the acoustic field in order to have the same perturbation of the wave propagation. Results show that the maximum velocity is not located at the focal but shifted near the transducer, and that this shift is greater for high powers. The two cavitation modes (stationary and moving bubbles) are greatly affect the hydrodynamic behavior of our sonoreactors: acoustic streaming and the fluid generated by bubble motion. The results obtained by electrochemical measurements show the same low hydrodynamic activity in the transducer vicinity, the same shift of the active focal toward the transducer, and the same absence of activity in the post-focal axial zone. The comparison with theoretical Eckart’s velocities (acoustic streaming in non-cavitating media) confirms a very high activity at the “sonochemical focal”, accounted for by wave distortion, which induced greater absorption coefficients. Moreover, the equivalent liquid velocities are one order of magnitude larger than the ones measured by PIV, confirming the enhancement of mass transfer by bubbles oscillation and collapse close to the surface, rather than from a pure streaming effect.     

Study of a peak in cavitation activity from HIFU exposures using TA fluorescence

Methods of measuring the sound field and focal region of a 1.05 MHz high intensity focused ultrasound (HIFU) are described in this paper. 1.05 MHz pulsed HIFU with intensity 2400 W/cm(2) with a 1:1 duty cycle ("on" phase equaled "off" phase) was used to irradiate terephthalic acid (TA). Pulse periods of 0.5 ms, 1 ms, 3.3 ms, 10 ms, 15 ms, 33 ms, 0.1s and 1s were used. The irradiation time was 2 min. To indicate the intensity of inertial cavitation activity, the fluorescence intensity of hydroxyterephthalic acid (HTA) was measured. The result shows that the cavitation activity of pulsed HIFU peaks at a pulse period of 10 ms, cavitation activity is significantly greater for pulse periods from 2 to 20 ms than for others.     

Directional transport and random motion of particles in ALF ultrasonic cavitation structure

The motion of particles of different properties and sizes in ALF ultrasonic cavitation structure is investigated experimentally with high-speed photography. Particles tend to transport along the bubble chain and move towards the focus repeatedly and predictably in ALF cavitation structures. Particles at the focus aggregate and separate alternately over time. The separation of particles mainly occurs in the expansion process of cavitation bubbles, while the movement and aggregation of particles mostly take place during the collapse stage. The directional transport of particles along the bubble chain of ALF cavitation cloud and the random aggregation and dispersion at the focus of ALF are all related to the cavitation bubbles attached to the particles. The directional transportation (predictable, repeatable and pipeline-free) and aggregation of particles in ALF cavitation clouds may be used in special occasions, for example, drug delivery and targeted therapy.     

Modification of the ultrasound induced activity by the presence of an electrode in a sonoreactor working at two low frequencies (20 and 40 kHz). Part I: Active zone visualization by laser tomography

Sonoelectrochemical experiments differ from sonochemical ones by the introduction of electrodes in the sonicated reaction vessel. The aim of the study is to characterize the changes of the ultrasonic activity induced by the presence of an electrode located in front of the transducer. The scope of our investigations concerns two low frequencies vibration modes: 20 and 40 kHz. For this purpose, two laser visualization techniques have been used. The first part of the study, described in the present paper (part I), deals with the laser tomography technique which provides an accurate picture of the reactor actives zones, related to numerous cavitation events. For each frequency, two parameters were studied: the electrical power supplied to the transducer and the electrode transducer distance. At both frequencies, without electrode, we can observe distinct zones corresponding to cavitation production and stationary waves establishment. When increasing the input power, bubble clouds tend to form a unique cloud near the transducer. In presence of the electrode, bubble cavitation clouds are largely influenced by the obstacle. The second part of the paper (part II) will describe the Particle Image Velocimetry (P.I.V.) technique which allows to measure the velocity vector field in the fluid portion between the horn and the electrode.