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.     

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.     

Cavitation clouds created by shock scattering from bubbles during histotripsy

Histotripsy is a therapy that focuses short-duration, high-amplitude pulses of ultrasound to incite a localized cavitation cloud that mechanically breaks down tissue. To investigate the mechanism of cloud formation, high-speed photography was used to observe clouds generated during single histotripsy pulses. Pulses of 5-20 cycles duration were applied to a transparent tissue phantom by a 1-MHz spherically focused transducer. Clouds initiated from single cavitation bubbles that formed during the initial cycles of the pulse, and grew along the acoustic axis opposite the propagation direction. Based on these observations, we hypothesized that clouds form as a result of large negative pressure generated by the backscattering of shockwaves from a single bubble. The positive-pressure phase of the wave inverts upon scattering and superimposes on the incident negative-pressure phase to create this negative pressure and cavitation. The process repeats with each cycle of the incident wave, and the bubble cloud elongates toward the transducer. Finite-amplitude propagation distorts the incident wave such that the peak-positive pressure is much greater than the peak-negative pressure, which exaggerates the effect. The hypothesis was tested with two modified incident waves that maintained negative pressure but reduced the positive pressure amplitude. These waves suppressed cloud formation which supported the hypothesis.     

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.     

High-speed observation of cavitation bubble cloud structures in the focal region of a 1.2 MHz high-intensity focused ultrasound transducer

Cavitation bubble clouds in the focal region of HIFU play important roles in therapeutic applications of HIFU. Temporal evolution and spatial distribution of cavitation bubble clouds generated in the focal region of a 1.2 MHz single element concave HIFU transducer in water are investigated by high-speed photography. It is found that during the initial 600 micro s insonation cavitation bubble clouds organize to the "screw-like structure" or "cap-like structure". The screw-like structure is characterized by a nearly fixed tip at the geometrical focus of the HIFU transducer, and the cap-like structure is marked by a dent formed in the direction of ultrasound transmission. After 600 micro s, another two structures are recorded - "streamer structure" and "cluster structure". The streamer structure is also featured by a nearly fixed bottom position at the focus, while the cluster structure is distinguished by agglomerations of bubbles around the focus.     

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

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

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。      

Numerical modelling of acoustic cavitation threshold in water with non-condensable bubble nuclei

Numerical modelling of acoustic cavitation threshold in water is presented taking into account non-condensable bubble nuclei, which are composed of water vapor and non-condensable air. The cavitation bubble growth and collapse dynamics are modeled by solving the Rayleigh-Plesset or Keller-Miksis equation, which is combined with the energy equations for both the bubble and liquid domains, and directly evaluating the phase-change rate from the liquid and bubble side temperature gradients. The present work focuses on elucidating acoustic cavitation in water with a wide range of cavitation thresholds (0.02–30 MPa) reported in the literature. Computations for different nucleus sizes and acoustic frequencies are performed to investigate their effects on bubble growth and cavitation threshold. The numerical predictions are observed to be comparable to the experimental data in the previous works and show that the cavitation threshold in water has a wide range depending on the bubble nucleus size.     

Effects of acoustic parameters on bubble cloud dynamics in ultrasound tissue erosion (histotripsy)

High intensity pulsed ultrasound can produce significant mechanical tissue fractionation with sharp boundaries ("histotripsy"). At a tissue-fluid interface, histotripsy produces clearly demarcated tissue erosion and the erosion efficiency depends on pulse parameters. Acoustic cavitation is believed to be the primary mechanism for the histotripsy process. To investigate the physical basis of the dependence of tissue erosion on pulse parameters, an optical method was used to monitor the effects of pulse parameters on the cavitating bubble cloud generated by histotripsy pulses at a tissue-water interface. The pulse parameters studied include pulse duration, peak rarefactional pressure, and pulse repetition frequency (PRF). Results show that the duration of growth and collapse (collapse cycle) of the bubble cloud increased with increasing pulse duration, peak rarefactional pressure, and PRF when the next pulse arrived after the collapse of the previous bubble cloud. When the PRF was too high such that the next pulse arrived before the collapse of the previous bubble cloud, only a portion of histotripsy pulses could effectively create and collapse the bubble cloud. The collapse cycle of the bubble cloud also increased with increasing gas concentration. These results may explain previous in vitro results on effects of pulse parameters on tissue erosion.     

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。     

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.     

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.     

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.     

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。     

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.     

Impact of cavitation on lesion formation induced by high intensity focused ultrasound

High intensity focused ultrasound(HIFU) has shown a great promise in noninvasive cancer therapy. The impact of acoustic cavitation on the lesion formation induced by HIFU is investigated both experimentally and theoretically in transparent protein-containing gel and ex vivo liver tissue samples. A numerical model that accounts for nonlinear acoustic propagation and heat transfer is used to simulate the lesion formation induced by the thermal effect. The results showed that lesions could be induced in the samples exposed to HIFU with various acoustic pressures and pulse lengths. The measured areas of lesions formed in the lateral direction were comparable to the simulated results, while much larger discrepancy was observed between the experimental and simulated data for the areas of longitudinal lesion cross-section. Meanwhile,a series of stripe-wiped-off B-mode pictures were obtained by using a special imaging processing method so that HIFUinduced cavitation bubble activities could be monitored in real-time and quantitatively analyzed as the functions of acoustic pressure and pulse length. The results indicated that, unlike the lateral area of HIFU-induced lesion that was less affected by the cavitation activity, the longitudinal cross-section of HIFU-induced lesion was significantly influenced by the generation of cavitation bubbles through the temperature elevation resulting from HIFU exposures. Therefore, considering the clinical safety in HIFU treatments, more attention should be paid on the lesion formation in the longitudinal direction to avoid uncontrollable variation resulting from HIFU-induced cavitation activity.     

Sonoluminescence characterization of inertial cavitation inside a BSA phantom treated by pulsed HIFU

The aim of this study was to investigate the inertial cavitation inside a phantom treated by pulsed HIFU (pHIFU). Basic bovine serum albumin (BSA) phantoms without any inherent ultrasound contrast agents (UCAs) or phase-shift nano-emulsions (PSNEs) were used. During the treatment, sonoluminescence (SL) recordings were performed to characterize the spatial distribution of inertial cavitation adjacent to the focal region. High-speed photographs and thermal coagulations, comparing with the SL results, were also recorded and presented. A series of pulse parameters (pulse duration (PD) was between 1 and 23 cycles and pulse repetition frequency (PRF) was between 0.5 kHz and 100 kHz) were performed to make a systematic investigation under certain acoustic power (APW). Continuous HIFU (cHIFU) investigation was also performed to serve as control group. It was found that, when APW was 19.5 W, pHIFU with short PD was much easier to form SL adjacent to the focal region inside the phantom, while it was difficult for cHIFU to generate cavitation bubbles. With appropriate PD and PRF, the residual bubbles of the previous pulses could be stimulated by the incident pulses to oscillate in a higher level and even violently collapse, resulting to enhanced physical thermogenesis. The experimental results showed that the most violent inertial cavitation occurs when PD was set to 6 cycles (5 μs) and PRF to 10 kHz, while the highest level of thermal coagulation was observed when PD was set to 10 cycles. The cavitational and thermal characteristics were in good correspondence, exhibiting significant potentiality regarding to inject-free cavitation bubble enhanced thermal ablation under lower APW, compared to the conventional thermotherapy.     

Ultrasound line-by-line scanning method of spatial–temporal active cavitation mapping for high-intensity focused ultrasound

This paper presented an ultrasound line-by-line scanning method of spatial–temporal active cavitation mapping applicable in a liquid or liquid filled tissue cavities exposed by high-intensity focused ultrasound (HIFU). Scattered signals from cavitation bubbles were obtained in a scan line immediately after one HIFU exposure, and then there was a waiting time of 2 s long enough to make the liquid back to the original state. As this pattern extended, an image was built up by sequentially measuring a series of such lines. The acquisition of the beamformed radiofrequency (RF) signals for a scan line was synchronized with HIFU exposure. The duration of HIFU exposure, as well as the delay of the interrogating pulse relative to the moment while HIFU was turned off, could vary from microseconds to seconds. The feasibility of this method was demonstrated in tap-water and a tap-water filled cavity in the tissue-mimicking gelatin–agar phantom as capable of observing temporal evolutions of cavitation bubble cloud with temporal resolution of several microseconds, lateral and axial resolution of 0.50 mm and 0.29 mm respectively. The dissolution process of cavitation bubble cloud and spatial distribution affected by cavitation previously generated were also investigated. Although the application is limited by the requirement for a gassy fluid (e.g. tap water, etc.) that allows replenishment of nuclei between HIFU exposures, the technique may be a useful tool in spatial–temporal cavitation mapping for HIFU with high precision and resolution, providing a reference for clinical therapy.     

Modeling cavitation nucleation from laser-illuminated nanoparticles subjected to acoustic stress

In an earlier work by Farny et al. [ARLO 6, 138-143 (2005).] it was demonstrated that the acoustic cavitation threshold in a tissue mimicking gel phantom can be lowered from 4.5 to ～1 MPa by "seeding" the optically transparent phantom with light absorptive gold nanoparticles and irradiating these absorbers with nanosecond pulses of laser light at intensities less than 10 mJ/cm(2). As a follow-up study, a three-stage numerical model was developed to account for prenucleation heating, the nucleation and formation of the vapor cavity, and the resulting vapor bubble dynamics. Through examination of the radius-time evolution of the cavity, the combined thresholds for laser radiant exposure and acoustic peak pressure required to induce inertial cavitation are deduced. It is found that the threshold pressure decreases when laser exposure increases; but the rate depends on exposure levels and the size of the particle. Investigations of the roles of particle size and laser pulse length are performed and optimum choices for these parameters determined in order to obtain inertial cavitation at the lowest possible acoustic pressure and laser intensity.