Strongly Focused HIFU Transducers With Simultaneous Optical Observation for Treatment of Skin at 20 MHz

High-intensity focused ultrasound (HIFU) transducers are proposed as a new treatment modality for dermatology. The shape and size of pressure fields generated by strongly focused transducers with an f-number equal to 0.75 operating at frequencies up to 20 MHz are analyzed analytically using the Lucas–Muir model and numerically with the wide-angle Khokhlov–Zabolotskaya–Kuznetsov method. The modeling results under quasi-linear conditions are compared against measurements performed in an acoustic tank with the aid of a fiberoptic hydrophone. The size of the focal zone expressed by their depth of focus and focal diameter is found to be directly controlled by their operating frequency and f-number. Devices manufactured for an operating frequency of 20 MHz are characterized by their 6 dB depth of focus of 490 μm and focal diameter of 80.6 µm. The devices are further studied at high power levels using a polyacrylic tissue-mimicking phantom. The devices are equipped with an optical observation system allowing simultaneous treatment and observation of the skin surface. In comparison to conventional cosmetic applications of HIFU, the devices analyzed are concluded to be ideal for treatment of precisely selected and confined layers of the human skin.     

Laser-Induced Fluorescence Thermometry of Heating in Water from Short Bursts of High Intensity Focused Ultrasound

Free field experimental measurements of the temperature rise of water in the focal region of a 2 MHz high intensity focused ultrasound (HIFU) transducer were performed. The transducer was operated in pulse-mode with millisecond bursts, at acoustic intensities of 5 to 18.5 kW/cm² at the focus, resulting in non-linear wave propagation and shock wave formation. Pulsed, planar, laser-induced fluorescence (LIF) was used as a fast rise-time, non-intrusive, temperature measurement method of the water present in the focal region. LIF thermometry is based on calibrating the temperature-dependent fluorescence intensity signal emitted by a passive dye dissolved in water when excited by a pulse of laser light. The laser beam was formed into a thin light sheet to illuminate a planar area in the HIFU focal region. The laser light sheet was oriented transverse to the acoustic axis. Cross-sectional, instantaneous temperature field measurements within the HIFU focal volume showed that the water temperature increased steadily with increasing HIFU drive voltage. Heating rates of 4000–7000°C/s were measured within the first millisecond of the HIFU burst. Increasing the length of the burst initially resulted in an increase in the water temperature within the HIFU focal spot (up to ∼3 ms), after which it steadied or slightly dropped. Acoustic streaming was measured and shown to be consistent with the reduction in heating with increased burst length due to convective cooling. LIF thermometry may thus be a viable non-invasive method for the characterization of HIFU transducers at high power intensities.     

Determination of the Ultrasonic Non-linearity Parameter B/A versus Frequency for Water

For tissue characterization, it is desirable to determine B/A using high-frequency transducers. Moreover, an accurate estimate of B/A at elevated frequencies (or at least the assumption of frequency independence of B/A) is required to evaluate the safety of high-frequency systems. However, common finite-amplitude approaches become increasingly inaccurate at high frequencies. In this article, a practical variation of the finite-amplitude method is proposed which combines experiments with numerical simulations of the Khokhlov–Zabolotskaya–Kuznetsov equation and can be used at elevated frequencies. The results at low frequencies show that the proposed approach is accurate with lower uncertainties compared with the finite-amplitude method because it avoids assumptions and approximations. The measured values of B/A versus frequency for water at 2.25–20 MHz show that there is no statistically significant variation in B/A values with frequency, and therefore the assumption of frequency independence of B/A is realistic.     

Temperature-Dependent Thermal Properties of ex Vivo Liver Undergoing Thermal Ablation

Thermotherapy uses a heat source that raises temperatures in the target tissue, and the temperature rise depends on the thermal properties of the tissue. Little is known about the temperature-dependent thermal properties of tissue, which prevents us from accurately predicting the temperature distribution of the target tissue undergoing thermotherapy. The present study reports the key thermal parameters (specific heat capacity, thermal conductivity and heat diffusivity) measured in ex vivo porcine liver while being heated from 20°C to 90°C and then naturally cooled down to 20°C. The study indicates that as the tissue was heated, all the thermal parameters resulted in plots with asymmetric quasi-parabolic curves with temperature, being convex downward with their minima at the turning temperature of 35–40°C. The largest change was observed for thermal conductivity, which decreased by 9.6% from its initial value (at 20°C) at the turning temperature (35°C) and rose by 45% at 90°C from its minimum (at 35°C). The minima were 3.567 mJ/(m³?K) for specific heat capacity, 0.520 W/(m.K) for thermal conductivity and 0.141 mm²/s for thermal diffusivity. The minimum at the turning temperature was unique, and it is suggested that it be taken as a characteristic value of the thermal parameter of the tissue. On the other hand, the thermal parameters were insensitive to temperature and remained almost unchanged when the tissue cooled down, indicating that their variations with temperature were irreversible. The rate of the irreversible rise at 35°C was 18% in specific heat capacity, 40% in thermal conductivity and 38.3% in thermal diffusivity. The study indicates that the key thermal parameters of ex vivo porcine liver vary largely with temperature when heated, as described by asymmetric quasi-parabolic curves of the thermal parameters with temperature, and therefore, substantial influence on the temperature distribution of the tissue undergoing thermotherapy is expected.     

Real-Time Monitoring of High-Intensity Focused Ultrasound Thermal Therapy Using the Manifold Learning Method

High-intensity focused ultrasound (HIFU) induces thermal lesions by increasing the tissue temperature in a tight focal region. The main ultrasound imaging techniques currently used to monitor HIFU treatment are standard pulse-echo B-mode ultrasound imaging, ultrasound temperature estimation and elastography-based methods. The present study was carried out on ex vivo animal tissue samples, in which backscattered radiofrequency (RF) signals were acquired in real time at time instances before, during and after HIFU treatment. The manifold learning algorithm, a non-linear dimensionality reduction method, was applied to RF signals which construct B-mode images to detect the HIFU-induced changes among the image frames obtained during HIFU treatment. In this approach, the embedded non-linear information in the region of interest of sequential images is represented in a 2-D manifold with the Isomap algorithm, and each image is depicted as a point on the reconstructed manifold. Four distinct regions are chosen in the manifold corresponding to the four phases of HIFU treatment (before HIFU treatment, during HIFU treatment, immediately after HIFU treatment and 10-min after HIFU treatment). It was found that disorganization of the points is achieved by increasing the acoustic power, and if the thermal lesion has been formed, the regions of points related to pre- and post-HIFU significantly differ. Moreover, the manifold embedding was repeated on 2-D moving windows in RF data envelopes related to pre- and post-HIFU exposure data frames. It was concluded that if mean values of the points related to pre- and post-exposure frames in the reconstructed manifold are estimated, and if the Euclidean distance between these two mean values is calculated and the sliding window is moved and this procedure is repeated for the whole image, a new image based on the Euclidean distance can be formed in which the HIFU thermal lesion is detectable.     

Synergistic Ablation of Liver Tissue and Liver Cancer Cells with High-Intensity Focused Ultrasound and Ethanol

We investigated the combined effect of ethanol and high-intensity focused ultrasound (HIFU), first, on heating and cavitation bubble activity in tissue-mimicking phantoms and porcine liver tissues and, second, on the viability of HepG2 liver cancer cells. Phantoms or porcine tissues were injected with ethanol and then subjected to HIFU at acoustic power ranging from 1.2 to 20.5 W (HIFU levels 1–7). Cavitation events and the temperature around the focal zone were measured with a passive cavitation detector and embedded type K thermocouples, respectively. HepG2 cells were subjected to 4% ethanol solution in growth medium (v/v) just before the cells were exposed to HIFU at 2.7, 8.7 or 12.0 W for 30 s. Cell viability was measured 2, 24 and 72 h post-treatment. The results indicate that ethanol and HIFU have a synergistic effect on liver cancer ablation as manifested by greater temperature rise and lesion volume in liver tissues and reduced viability of liver cancer cells. This effect is likely caused by reduction of the cavitation threshold in the presence of ethanol and the increased rate of ethanol diffusion through the cell membrane caused by HIFU-induced streaming, sonoporation and heating.     

A Tissue Mimicking Polyacrylamide Hydrogel Phantom for Visualizing Thermal Lesions Generated by High Intensity Focused Ultrasound

An optically transparent tissue-mimicking (TM) phantom whose acoustic properties are close to those of tissue was constructed for visualizing therapeutic effects by high intensity focused ultrasound (HIFU). The TM phantom was designed to improve a widely used standard bovine serum albumin (BSA) polyacrylamide hydrogel (PAG), which attenuated ultrasound far less than tissue and, unlike tissue, did not scatter ultrasound. A modified recipe has been proposed in the study by adding scattering glass beads with diameters of 40–80 μm (0.002% w/v) and by raising the concentration of acrylamide (30% v/v). The TM BSA-PAG constructed has an acoustic impedance of 1.67 MRayls, a speed of sound of 1576 m/s, an attenuation coefficient of 0.52 dB/cm at 1 MHz, a backscattering coefficient of 0.242 × 10⁻³ 1/sr/cm at 1 MHz and a nonlinear parameter (B/A) of 5.7. These parameters are close to those of liver. The thermal and optical properties are almost the same as the standard BSA-PAG. The characteristic features of the thermal lesions by HIFU were observed to be more accurately visualized in the TM BSA-PAG than in the standard BSA-PAG. In conclusion, the proposed TM BSA-PAG acoustically mimics tissue better than the standard BSA-PAG and is expected to be preferentially used for assuring if a clinical HIFU device produces the thermal lesion as planned.     

碘化油与高功率聚焦超声破坏肝组织的协同升温效应研究

本实验首次研究生物组织因素（媒质）对高轼率聚焦超声（HIFU）破坏肝组织的影响。采用国产HIFU样机（1．1MHz）．体外观察其靶区在碘化油或蓖麻油不同媒质存在的温度变化。结果显示：不论在高功率（500W/cm2）和低功率（136W/cm2）超声照射下，碘化油使靶区温度升高显著高于无碘的蓖麻油（P=0．0008和P=0．0004）．提示碘比油与HIFU治疗有协同升温作用。用HIFU（1．1MHz，500W/cm2，20s）照射离体肝组织．发现肝内注射碘化油组靶区温度显著高于注射蓖麻油组（P=0．0239），且前者破坏程度和范围均明显大于后者，提示碘化油配合HIFU治疗肝肿瘤具有潜在的增效、定位和导向作用。     

Thermal properties and changes of acoustic parameters in an egg white phantom during heating and coagulation by high intensity focused ultrasound

A polyacrylamide phantom containing egg white has been proposed previously as an adequate tissue-mimicking material for high intensity focused ultrasound (HIFU) application. In this work, we report on measurements of egg white phantom thermal conductivity and specific heat capacity. We measured changes in acoustical properties which occurred during the heating and the coagulation process. Using a thin thermocouple embedded in the phantom material, we recorded the temperature response in the focus of the ultrasound field during HIFU application and phantom coagulation. The measured values for the thermal conductivity (0.59 +/- 0.06 W/m/ degrees C) and the specific heat capacity (4270 +/- 365 J/kg/ degrees C) are similar to the values of water. The attenuation coefficient decreased in the temperature range between 26 degrees C and 50 degrees C and showed a nonlinear dependence on frequency with an exponent of 1.50 +/- 0.05 that was temperature-independent within the investigated temperature range. Below 65 degrees C, no irreversible changes in material absorption were observed. The coagulation process started at 67 degrees C and no adjacent rapid changes in temperature response were detected. In comparison with the noncoagulated phantom, the coagulated phantom material showed an enhanced absorption and a threefold higher attenuation coefficient at a frequency of 1 MHz.     

Thermal Fixation of Swine Liver Tissue after Magnetic Resonance-Guided High-Intensity Focused Ultrasound Ablation

The aim of this study was to investigate experimental conditions for efficient and controlled in vivo liver tissue ablation by magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU) in a swine model, with the ultimate goal of improving clinical treatment outcome. Histological changes were examined both acutely (four animals) and 1 wk after treatment (five animals). Effects of acoustic power and multiple sonication cycles were investigated. There was good correlation between target size and observed ablation size by thermal dose calculation, post-procedural MR imaging and histopathology, when temperature at the focal point was kept below 90°C. Structural histopathology investigations revealed tissue thermal fixation in ablated regions. In the presence of cavitation, mechanical tissue destruction occurred, resulting in an ablation larger than the target. Complete extra-corporeal MR-guided HIFU ablation in the liver is feasible using high acoustic power. Nearby large vessels were preserved, which makes MR-guided HIFU promising for the ablation of liver tumors adjacent to large veins.     

Modeling of Microbubble-Enhanced High-Intensity Focused Ultrasound

Heat enhancement at the target in a high intensity focused ultrasound (HIFU) field is investigated by considering the effects of the injection of microbubbles in the vicinity of the tumor to be ablated. The interaction between the bubble cloud and the HIFU field is investigated using a 3-D numerical model. The propagation of non-linear ultrasonic waves in the tissue or in a phantom medium is modeled using the compressible Navier–Stokes equations on a fixed Eulerian grid, while the microbubbles dynamics and motion are modeled as discrete singularities, which are tracked in a Lagrangian framework. These two models are coupled to each other such that both the acoustic field and the bubbles influence each other. The resulting temperature rise in the field is calculated by solving a heat transfer equation applied over a much longer time scale. The compressible continuum part of the model is validated by conducting axisymmetric HIFU simulations without microbubbles and comparing the pressure and temperature fields against available experiments. The coupled Eulerian–Lagrangian approach is then validated against existing experiments conducted with a phantom tissue. The bubbles are distributed randomly in a 3-D fashion inside a cylindrical volume, while the background acoustic field is assumed axisymmetric. The presence of microbubbles modifies the ultrasound field in the focal region and significantly enhances heat deposition. The various mechanisms through which heat deposition is increased are then examined. Among these effects, viscous damping of the bubble oscillations is found to be the main contributor to the enhanced heat deposition. The effects of the initial void fraction in the cloud are then sought by considering the changes in the attenuation of the primary ultrasonic wave and the modifications of the enhanced heat deposition in the focal region. It is observed that although high bubble void fractions lead to increased heat deposition, they also cause significant pre-focal heating because of acoustic shielding. The effects of the microbubble cloud size and its location in the focal region are studied, and the effects of these parameters in altering the temperature rise and the location of the temperature peak are discussed. It is found that concentrating the bubbles adjacent to the focus and farther away from the acoustic source leads to effective heat deposition. Finally, the presence of a shell at the bubble surface, as in contrast agents, is seen to reduce heat deposition by restraining bubble oscillations.     

一种用于HIFU聚焦性能评价的仿组织透明体模

目的建立一种用于高强度聚焦超声(HIFU)聚焦性能评价的仿组织透明体模。方法仿组织透明体模主要由聚丙烯酰胺和作为温度敏感指示剂的蛋清混合而成。在B超的监控下使用声功率160W的HIFU在不同的辐照时间下定点辐照体模和新鲜离体牛肝脏,肉眼观察HIFU在体模和新鲜离体牛肝脏中形成的生物学焦域(BFR)形态并测量BFR的长短轴。结果可用肉眼观察HIFU在仿组织透明体模中产生的BFR,其形态呈椭球体,实时超声监控为强回声,BFR的长、短轴随辐照时间的增加而增大。但在相同的辐照参数下,HIFU在仿组织透明体模中产生的BFR的长、短轴小于HIFU在新鲜离体牛肝脏中形成的BFR的长、短轴。结论该仿组织透明体模在用于HIFU聚焦性能的评价方面展示出良好的前景。     

A comparison of the thermal-dose equation and the intensity-time product, Itm, for predicting tissue damage thresholds

Thermal dose is the most generally accepted concept for estimating temperature-related tissue damage thresholds in high-intensity focused ultrasound (HIFU) procedures. However, another approach based on the intensity-time product I t^m = D has been used, where D is a tissue-dependent damage threshold, I is the spatial-peak, temporal-average intensity and t is time. In this study, these two approaches were compared analytically by substituting a well-known soft-tissue solution for temperature vs. time into the thermal dose equation. From power law fits of I vs. t, m was found to fall between about 0.3 and 0.8. In terms of the intensity required for cell death for a given exposure time, the standard deviation of the error between the full thermal-dose formulation and the I t^m = D prediction based upon the power-law fit was less than 5% for focal beam diameters up to 3 mm. Thus, for the practical range of HIFU parameters examined, the intensity-time product relationship is equivalent to the thermal dose formulation. (E-mail: gerald.harris@fda.hhs.gov)     

Using the acoustic interference pattern to locate the focus of a high-intensity focused ultrasound (HIFU) transducer

One of the main problems encountered when using conventional B-mode ultrasound (US) for targeting and monitoring purposes during ablation therapies employing high-intensity focused US (HIFU) is the appearance of strong interference in the obtained diagnostic US images. In this study, instead of avoiding the interference noise, we demonstrate how we used it to locate the focus of the HIFU transducer in both in vitro tissue-mimicking phantoms and an ex vivo tissue block. We found that when the B-mode image plane coincided with the HIFU focal plane, the interference noise was maximally converged and enhanced compared with the off-focus situations. Stronger interference noise was recorded when the angle (alpha) between the US image plane and the HIFU axis was less than or equal to 90 degrees. By intentionally creating a target (group of bubbles) at the 3.5-MHz HIFU focus (7.1 mm in length and 0.7 mm in diameter), the position of the maximal noise convergence coincided well with the target. The difference between the predicted focus and the actual one (bubbles) on x and z axes (axes perpendicular to the HIFU central axis, Fig. 1) were both about 0.9 mm. For y axis (HIFU central axis), the precision was within 1.0 mm. For tissue block ablation, the interference noise concentrated at the position of maximal heating of the HIFU-induced lesions. The proposed method can also be used to predict the position of the HIFU focus by using a low intensity output scheme before permanent changes in the target tissue were made.     

Measurements of bubble-enhanced heating from focused, MHz-frequency ultrasound in a tissue-mimicking material.

Time-resolved measurements of the temperature field in an agar-based tissue-mimicking phantom insonated with a large aperture 1-MHz focused acoustic transducer are reported. The acoustic pressure amplitude and insonation duration were varied. Above a critical threshold acoustic pressure, a large increase in the temperature rise during insonation was observed. Evidence for the hypothesis that cavitation bubble activity in the focal zone is the cause of enhanced heating is presented and discussed. Mechanisms for bubble-assisted heating are presented and modeled, and quantitative estimates for the thermal power generated by viscous dissipation and bubble acoustic radiation are given.     

MRI监控高强度聚焦超声辐照升温的有效性和准确性研究

目的探讨高强度聚焦超声（HIFU）辐照过程中,MRI靶区温度监控的有效性和准确性。方法HIFU辐照离体牛肝组织,对比MRI的温度图（T—Map）显示坏死区域与实际解剖坏死区域面积,以检验T—Map监控的有效性;HIFU辐照仿组织透明体模,对比MRI所测温度与光纤传感器所测温度。结果T—Map所示的坏死区面积和实际坏死区面积出现统计学差异（P〉0．05）的概率约为25％;对小于1℃／s的缓慢温度变化,MRI和光纤的测温结果较为一致,二者的平均差异在2．6℃以内;而对于剧烈的温度变化,二者的平均差异达到5℃以上。结论MRI的T—Map可对靶区坏死情况提供一定的参考信息,但结果并不完全可靠,同时MRI测温的精确性还有待进一步加强。     

HIFU-induced cavitation and heating in ex vivo porcine subcutaneous fat

The present study is motivated by the fact that there are no published studies quantifying cavitation activity and heating induced by ultrasound in adipose tissue and that there are currently no reliable techniques for monitoring successful deposition of ultrasound energy in fat in real time. High-intensity focused ultrasound (HIFU) exposures were performed in excised porcine fat at four different frequencies (0.5, 1.1, 1.6 and 3.4 MHz) over a range of pressure amplitudes and exposure durations. The transmission losses arising from reflection at the skin interface and attenuation through skin and fat were quantified at all frequencies using an embedded needle hydrophone. A 15 MHz passive cavitation detector (PCD) coaxial to the HIFU transducer was used to capture acoustic emissions emanating from the focus during HIFU exposures, while the focal temperature rise was measured using minimally invasive needle thermocouples. Repeatable temperature rises in excess of 10°C could be readily instigated across all four frequencies for acoustic intensities (Ispta) in excess of 50 W/cm² within the first 2 s of exposure. Even though cavitation could not be initiated at 1.1, 1.6 and 3.4 MHz over the in situ peak rarefactional (p_-) pressure range 0-3 MPa explored in the present study, inertial cavitation activity was always initiated at 0.5 MHz for pressures greater than 1.6 MPa (p_-) and was found to enhance focal heat deposition. A good correlation was identified between the energy of broadband emissions detected by the PCD and the focal temperature rise at 0.5 MHz, particularly for short 2 s exposures, which could be exploited as a tool for noninvasive monitoring of successful treatment delivery. (E-mail: zoe.kyriakou@eng.ox.ac.uk)     

Ultrasound Doppler Monitoring of Soft Tissues In Vitro and Tissue Phantoms Heating and Thermal Destruction Induced by Acoustic Remote Palpation

The rise of shear strain value under temperature increase in biological tissue samples in vitro and tissue phantoms was studied and the range of shear modulus and viscosity calculated. It has been shown that the acoustic radiation force-based methods with the usage of ultrasound Doppler probing provides the potential ability of noninvasive real-time monitoring of tissues' ultrasound thermal destruction process. At that, the thermal destruction is possible under action of wave beam that creates the radiation force and local tissue displacements so that tissue ablation and acoustic remote palpation could be realized by means of the same ultrasound transducer. The experiments were performed using gelatin-based tissue-mimicking phantoms and freshly excised samples of bovine muscle tissue. It was determined also that fluctuating pattern of detected displacement amplitude variation is the indicator of the phase transitions beginning in the heated field of soft tissue or tissue phantom. (Email: Evgenij.A.Barannik@univer.kharkov.ua; barannik@pht.univer.kharkov.ua)     

生物学焦域的概念及在高强度聚焦超声切除组织中的作用

本实验研究和比较了高强度聚焦超声(HIFU)所致体内深部组织凝固性坏死灶的形状和大小.结果显示参照同样的治疗参数,HIFU所致凝固性坏死灶的大小和形状在体内和体外有较大的差异.体内体积与治疗参数、靶组织的结构、功能和运动有密切关系.与物理学焦域比较,凝固性坏死灶体积亦可能命名为HIFU的生物学焦域.     

聚焦超声换能器的频率和曲率半径对生物学焦域的影响

目的探讨聚焦超声换能器的物理参数——频率(f)、曲率半径(R)对生物学焦域的影响．为优化设计适合临床应用的聚焦超声换能器提供实验依据。方法运用JC-A型Haifu聚焦超声肿瘤治疗系统，使用3种聚焦超声换能器，以一定的超声剂量定点辐照新鲜离体牛肝脏．辐照结束后沿凝固性坏死最大面剖开，测量生物学焦域的长、短轴和体积。结果对于任一种聚焦超声换能器，辐照深度一定时。生物学焦域的体积随换能器辐射声功率、辐照时间的增大而增大。在一定的换能器辐射声功率和辐照时间下．辐照深度一定时，当聚焦超声换能器其他物理参数固定时．生物学焦域的体积随换能器频率的增大而增大，而生物学焦域的形态指数随频率的增大而减小；而当聚焦超声换能器的其他物理参数固定时．生物学焦域的体积和形态指数随透镜曲率半径的增大而增大。结论生物学焦域除了与声功率、辐照时间、辐照深度以及组织结构、功能状态有关外，还与聚焦超声换能器的物理参数如频率(f)、曲率半径(R)有关。在临床运用中，应根据临床方案优化设计适合临床应用的一定频率(f)和曲率半径(R)的聚焦超声换能器。