Safety of ultrasound-guided high-intensity focused ultrasound ablation for diffuse adenomyosis: A retrospective cohort study

ObjectivesTo evaluate the safety of ultrasound-guided high-intensity focused ultrasound (HIFU) ablation for patients with diffuse adenomyosis.MethodsThis was a retrospective cohort study. The data was collected from 417 symptomatic adenomyosis patients who underwent ultrasound-guided HIFU between January 2012 and December 2015 at 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China. Among them were 260 patients with diffuse adenomyosis (Group D) and 157 patients with focal adenomyosis (Group F). All patients underwent contrast-enhanced magnetic resonance imaging (MRI) one week before and the day after HIFU treatment. Successful treatment with HIFU was measured by the non-perfused volume ratio (NPVR). Intraprocedural and postprocedural adverse effects and complications were recorded to assess the safety of the procedure. Patients were followed-up for three months post-treatment. Complications were given a grade A through F according to the SIR Standards.ResultsAll patients successfully completed the procedure, non-perfused regions appeared in 415 (99.5%) patients. The non-perfused volume ratio (NPVR) of Group D was significantly lower than that of Group F (P < 0.05). During the procedure, the odds ratio of skin-burning pain was 1.7 (OR = 1.617, 95% CI: 1.103–2.532), when comparing Group D with Group F, while the odds ratio of inguinal pain was equal to 2.0 (OR = 2.038, 95% CI: 1.161–3.580), when Group F was compared to Group D. 97 patients (23.3%) received nominal therapy due to complications ([Society of interventional radiology, SIR]-B grade), among them, there were 62 cases (23.8%) in Group D and 35 cases (22.3%) in Group F. No significant difference was found between the two groups (P > 0.05) and neither of the reported complications of SIR-C-SIR-F occurred within the two groups.ConclusionsBased on our results, ultrasound-guided HIFU is safe for the treatment of diffuse adenomyosis, and controlling the ablation zone is crucial to ensure patients’ safety.     

MRI-guided focused ultrasound treatments

Focused ultrasound (FUS) allows noninvasive focal delivery of energy deep into soft tissues. The focused energy can be used to modify and eliminate tissue for therapeutic purposes while the energy delivery is targeted and monitored using magnetic resonance imaging (MRI). MRI compatible methods to deliver these exposures have undergone rapid development over the past 10 years such that clinical treatments are now routinely performed. This paper will review the current technical and clinical status of MRI-guided focused ultrasound therapy and discuss future research and development opportunities.     

Weakly nonlinear focused ultrasound in viscoelastic media containing multiple bubbles

To facilitate practical medical applications such as cancer treatment utilizing focused ultrasound and bubbles, a mathematical model that can describe the soft viscoelasticity of human body, the nonlinear propagation of focused ultrasound, and the nonlinear oscillations of multiple bubbles is theoretically derived and numerically solved. The Zener viscoelastic model and Keller–Miksis bubble equation, which have been used for analyses of single or few bubbles in viscoelastic liquid, are used to model the liquid containing multiple bubbles. From the theoretical analysis based on the perturbation expansion with the multiple-scales method, the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation, which has been used as a mathematical model of weakly nonlinear propagation in single phase liquid, is extended to viscoelastic liquid containing multiple bubbles. The results show that liquid elasticity decreases the magnitudes of the nonlinearity, dissipation, and dispersion of ultrasound and increases the phase velocity of the ultrasound and linear natural frequency of the bubble oscillation. From the numerical calculation of resultant KZK equation, the spatial distribution of the liquid pressure fluctuation for the focused ultrasound is obtained for cases in which the liquid is water or liver tissue. In addition, frequency analysis is carried out using the fast Fourier transform, and the generation of higher harmonic components is compared for water and liver tissue. The elasticity suppresses the generation of higher harmonic components and promotes the remnant of the fundamental frequency components. This indicates that the elasticity of liquid suppresses shock wave formation in practical applications.     

高强度聚焦超声经颅脑肿瘤治疗焦域的仿真研究*

为了研究脑组织和脑肿瘤组织在HIFU治疗时形成焦域的特性及坏死肿瘤组织、不同治疗剂量参数以及多次治疗时焦点间距和时间间隔对HIFU形成焦域的影响,本文以脑胶质瘤患者为例,利用患者头颅CT图像数据建立HIFU经颅治疗的仿真模型,基于Westervelt声波非线性传播方程和Pennes生物热传导方程进行HIFU经颅治疗的仿真研究。结果表明,脑组织和脑肿瘤组织内形成HIFU焦域的差异较小,坏死肿瘤组织对HIFU温度场分布有较小影响;辐照声强越大,焦点温升达到同一温度所用时间越短,焦域长短轴越短,颅骨处温升越低;当焦点间距在一定范围内时,第一次辐照形成的温度场分布对第二个焦点温升达到同一温度所需时间影响较大;两次辐照时间间隔对颅骨处温升和两次聚焦形成60?C以上温度分布影响较小。     

Noninvasive treatment efficacy monitoring and dose control for high-intensity focused ultrasound therapy using relative electrical impedance variation

As an effective therapeutic modality, high-intensity focused ultrasound(HIFU) can destroy tumour tissues by thermocoagulation with less metastasis, but it is still limited by inaccurate non-invasive temperature monitoring and efficacy evaluation. A model of electrical impedance measurement during HIFU therapy was established using the temperatureimpedance relationship. Based on the simulations of acoustic pressure, temperature, and electrical conductivity, the impedance of the phantom was calculated and experimentally demonstrated for different values of acoustic power values and treatment time. We proved that the relative impedance variation(RIV) increases linearly with the increasing treatment time at a fixed acoustic power, and the relative impedance variation rate shows a linear relationship with the acoustic power.The RIV and treatment time required for HIFU treatment efficacy are inversely proportional to the acoustic power and the square of acoustic power, respectively. The favourable results suggest that RIV can be used as an efficient indicator for noninvasive temperature monitoring and efficacy evaluation and may provide new strategy for accurate dose control of HIFU therapy.     

应用角谱方法研究聚焦声束在层状生物组织中的非线性声传播

应用角谱方法理论研究了聚焦声束在层状生物组织中的非线性传播特性，将声波分解为角谱，可计算垂直于声轴的任意平面的非线性声场。在圆形平面活塞聚焦换能器的焦区中插入多种生物组织样品，数值计算了样品内部及外部的二次谐波声场，并通过实验测量验证了理论方法的有效性。基于快速傅氏变换的角谱方法可直观地描述非线性声传播，对非线性声成像有指导作用。     

Enhancement and quenching of high-intensity focused ultrasound cavitation activity via short frequency sweep gaps

This letter reports on the use of frequency sweeps to probe acoustic cavitation activity generated by high-intensity focused ultrasound (HIFU). Unprecedented enhancement and quenching of HIFU cavitation activity were observed when short frequency sweep gaps were applied in negative and positive directions, respectively. It was revealed that irrespective of the frequency gap, it is the direction and frequency sweep rate that govern the cavitation activity. These effects are related to the response of bubbles generated by the starting frequency to the direction of the frequency sweep, and the influence of the sweep rate on growth and coalescence of bubbles, which in turn affects the active bubble population. These findings are relevant for the use of HIFU in chemical and therapeutic applications, where greater control of cavitation bubble population is critical.     

随机相控高强度聚焦超声换能器的栅瓣抑制

采用3种随机排列策略形成相控阵元线性排列结构抑制高强度聚焦超声(HIFU)相控阵栅瓣。第1种和第2种策略中阵元基于规则排列随机移动,而第3种策略中阵元则直接进行随机移动,阵元可移动范围依次为:第1种<第2种<第3种。采用瑞利积分和非线性Westervelt方程分别计算了3种策略对应随机相控阵产生的线性和非线性声场,并通过归一化栅瓣最大声压、归一化栅瓣平均声强和归一化旁瓣平均声强3个参量,对栅瓣抑制效果进行评价。结果表明:线性声场中,阵元可移动范围的增加有利于栅瓣抑制,3种随机策略的归一化栅瓣最大声压相比规则排列分别降低30.7%,53.8%和55.8%;非线性声场中对于同一种随机排列策略,随机度的增加可以改善栅瓣抑制效果。例如,第3种随机策略在随机度为0.9时正负压的归一化栅瓣最大声压相比规则排列分别降低55.6%和54.8%。进一步讨论了焦点偏移时随机相控阵的非线性声场,以-8 dB作为栅瓣的安全标准,第2种和第3种随机策略可以满足要求,横向偏移分别为6 mm和10 mm。本文的工作为抑制栅瓣提供了新思路,有利于随机HIFU相控阵的设计优化。     

Minimization of treatment time for in vitro 1.1 MHz destruction of Pseudomonas aeruginosa biofilms by high-intensity focused ultrasound

Medical implants are prone to colonization by bacterial biofilms. Normally, surgery is required to replace the infected implant. One promising noninvasive modality is to destroy biofilms with high-intensity focused ultrasound. In our study, Pseudomonas aeruginosa biofilms were grown on implant-mimicking graphite disks in a flow chamber for 3 days prior to exposing them to ultrasound pulses. Exposure time at each treatment location was varied between 5, 15 and 30 s. Burst period was varied between 1, 3, 6 and 12 milliseconds (ms). The pulses were 20 cycles in duration at 1.1 MHz from a spherically focused transducer (f/1, 63 mm focal length), creating peak compressional and rarefactional pressures at the graphite disk surface of 30 and 13 MPa, respectively. P. aeruginosa were tagged with green fluorescent protein, and killed cells were visualized using propidium iodide before determining the extent of biofilm destruction. The exposure-induced temperature rise was measured to be less than 0.2 °C at the focus, namely the interface between graphite disk and water. Then, the temperature rise was measured at the focus between the graphite disk and a tissue-mimicking phantom to evaluate therapy safety. Two thresholds, of bacteria destruction increase and of complete bacteria removal, respectively, were identified to divide our eight exposure conditions. Results indicated that 30-s exposure and 6-ms pulse period were sufficient to destroy the biofilms. However, the 15-s exposure and 3-ms pulse period were viewed as optimum when considering exposure time, efficacy, and safety.     

Prediction of vascular injury by cavitation microbubbles in a focused ultrasound field

Many studies have shown that microbubble cavitation is one mechanism for vascular injury under ultrasonic excitation. Previous work has attributed vascular damage to vessel expansions and invaginations due to the expansion and contraction of microbubbles. However, the mechanisms of vascular damage are not fully understood. In this paper, we investigate, theoretically and experimentally, the vessel injury due to stress induced by ultrasound-induced cavitation (UIC). A bubble-fluid-vessel coupling model is constructed to investigate the interactions of the coupling system. The dynamics process of vessel damage due to UIC is theoretically simulated with a finite element method, and a focused ultrasound (FU) setup is carried out and used to assess the vessel damage. The results show that shear stress contributes to vessel injury by cell detachment while normal stress mainly causes distention injury. Similar changes in cell detachment in a vessel over time can be observed with the experimental setup. The severity of vascular injury is correlated to acoustic parameters, bubble-wall distance, and microbubble sizes, and the duration of insonation..     

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.     

液体中高强度聚焦超声场及其测量

基于已知文献,文章介绍了液体中高强度聚焦超声场的基本性质,包括传播、频谱、吸收、聚焦、辐射力等特性,描述了它的物理图景和测量方法。     

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

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

Cavitation characteristics of flowing low and high boiling-point perfluorocarbon phase-shift nanodroplets during focused ultrasound exposures

This work investigated and compared the dynamic cavitation characteristics between low and high boiling-point phase-shift nanodroplets (NDs) under physiologically relevant flow conditions during focused ultrasound (FUS) exposures at different peak rarefactional pressures. A passive cavitation detection (PCD) system was used to monitor cavitation activity during FUS exposure at various acoustic pressure levels. Root mean square (RMS) amplitudes of broadband noise, spectrograms of the passive cavitation detection signals, and normalized inertial cavitation dose (ICD) values were calculated. Cavitation activity of low-boiling-point perfluoropentane (PFP) NDs and high boiling-point perfluorohexane (PFH) NDs flowing at in vitro mean velocities of 0–15 cm/s were compared in a 4-mm diameter wall-less vessel in a transparent tissue-mimicking phantom. In the static state, both types of phase-shift NDs exhibit a sharp rise in cavitation intensity during initial FUS exposure. Under flow conditions, cavitation activity of the PFH NDs reached the steady state less rapidly compared to PFP NDs under the lower acoustic pressure (1.35 MPa); at the higher acoustic pressure (1.65 MPa), the RMS amplitude increased more sharply during the initial FUS exposure period. In particular, the RMS-time curves of the PFP NDs shifted upward as the mean flow velocity increased from 0 to 15 cm/s; the RMS amplitude of the PFH ND solution increased from 0 to 10 cm/s and decreased at 15 cm/s. Moreover, amplitudes of the echo signal for the low boiling-point PFP NDs were higher compared to the high boiling-point PFH NDs in the lower frequency range, whereas the inverse occurred in the higher frequency range. Both PFP and PFH NDs showed increased cavitation activity in the higher frequency under the flow condition compared to the static state, especially PFH NDs. At 1.65 MPa, normalized ICD values for PFH increased from 0.93 ± 0.03 to 0.96 ± 0.04 and from 0 to 10 cm/s, then decreased to 0.86 ± 0.05 at 15 cm/s. This work contributes to our further understanding of cavitation characteristics of phase-shift NDs under physiologically relevant flow conditions during FUS exposure. In addition, the results provide a reference for selecting suitable phase-shift NDs to enhance the efficiency of cavitation-mediated ultrasonic applications.     

Comparisons among sensitivities of different tumor cells to focused ultrasound in vitro

This study is to test the sensitivities of different tumor cells to ultrasound irradiation at the frequency of 2.2 MHz for 60 s duration, and investigate the potential mechanism underlying different sensitivities. Three murine tumor models with distinct aggressiveness (S180, H-22 and EAC) were exposed to ultrasound to evaluate their sonodynamic efficiencies, and several biological parameters such as cell membrane permeability, lipid peroxidation (LPO), ultra-structure observation, intracellular reactive oxygen species (ROS) and mitochondria membrane potential (MMP) were analyzed after exposures. The results showed that cellular responses of different cells were distinct, of interest to note, the aggressive S180 cells were much more sensitive than others, whereas EAC cells were relatively more resistant to ultrasound irradiation. The direct comparisons among different types of cells indicate that the sono-sensitization seems to depend on the physiological and chemical properties of tumor cells. Perhaps sections of cell membrane became destabilized following the initial radical attack and LPO reaction, which caused S180 cells more susceptible to mechanical stresses during sonolysis. This study provides important implications for cancer therapy.     

Numerical simulations of partial elements excitation for hemispherical high-intensity focused ultrasound phased transducer

The hemispherical phased transducer maximizes the coverage of the skull and the ultrasonic energy per unit area of the skull is minimized, thereby reducing the risk of skull burns, but the transducer has a small focal area adjustment range, increasing the focal length of treatment is an urgent question for this type of transducer. In this paper, a three-dimensional high-intensity focused ultrasound (HIFU) transcranial propagation model is established based on the human head structure. The finite difference time domain (FDTD) is combined with the Westervelt acoustic wave nonlinear propagation equation and Penne's biological heat conduction equation for numerical simulation of the sound pressure field and temperature field. Forming a treatable focal area in a small-opening hemispherical transducer with a small amount of numerical simulation calculation focusing at a set position to determine the minimum partial excitation area ratio of focusing. And then, applying these preliminary results to a large-opening diameter hemispherical transducer and the temperature field formed by it or full excitation is studied. The results show that the focus area with the excitation area ratio of less than 22% moves forward to the transducer side when the excitation sound is formed. When the excitation area ratio is greater than or equal to 23%, it focuses at the set position. In the case of partial incentives, using 23% of the partial array, the adjustable range of the treatable focal area formed in the three-dimensional space is larger than that of the full excitation.     

Lysis of Chlamydomonas reinhardtii by high-intensity focused ultrasound as a function of exposure time

Efficient lysis of microalgae for lipid extraction is an important concern when processing biofuels. Historically, ultrasound frequencies in the range of 10–40 kHz have been utilized for this task. However, greater efficiencies might be achievable if higher frequencies could be used. In our study, we evaluated the potential of using 1.1 MHz ultrasound to lyse microalgae for biofuel production while using Chlamydomonas reinhardtii as a model organism. The ultrasound was generated using a spherically focused transducer with a focal length of 6.34 cm and an active diameter of 6.36 cm driven by 20 cycle sine-wave tone bursts at a pulse repetition frequency of 2 kHz (3.6% duty cycle). The time-average acoustic power output was 26.2 W while the spatial-peak-pulse-average intensity (I_SPPA) for each tone burst was 41 kW/cm². The peak compressional and rarefactional pressures at the focus were 102 and 17 MPa, respectively. The exposure time was varied for the different cases in the experiments from 5 s to 9 min and cell lysis was assessed by quantifying the percentage of protein and chlorophyll release into the supernate as well as the lipid extractability. Free radical generation and lipid oxidation for the different ultrasound exposures were also determined. We found that there was a statistically significant increase in lipid extractability for all of the exposures compared to the control. The longer exposures also completely fragmented the cells releasing almost all of the protein and chlorophyll into the supernate. The cavitation activity did not significantly increase lipid oxidation while there was a minor trend of increased free radical production with increased ultrasound exposure.     

Feasibility study of high intensity focused ultrasound (HIFU) for the treatment of hydatid cysts of the liver

This study evaluates the feasibility of using high intensity focused ultrasound (HIFU) for the treatment of hydatid cysts of the liver. HIFU ablation was carried out in 62 patients with echinococcosis of the liver. The mean age of patients was 40.76 ± 14.84 (range: 17–72 years). The effectiveness of the treatment was monitored in real-time by changes in the gray-scale, and by morphological studies, computed tomography, magnetic resonance imaging, and ultrasound.Criteria for evaluating the effectiveness of treatment in real time were outlines. Cytomorphological picture of destructive changes of parasitic elements was presented as well. Loss of embryonic elements of the parasite was observed at the subcellular level after HIFU-ablation and underlines the effectiveness of HIFU.     

高强聚焦超声(HIFU)加热活体组织中的温度分布

在高强聚焦超声(HIFU)加热的情况下,利用多针射频(RF)测温装置测量活体组织内的温度分布,结果表明,温度梯度依赖于局部温度,温度越高,梯度越大。此外,本文还研究了血流对温度梯度的影响,结果似乎证实了理论预测,即血流(或血液灌注)减缓了温度(梯度)的变化。     

Spatial distribution of sonoluminescence and sonochemiluminescence generated by cavitation bubbles in 1.2 MHz focused ultrasound field

An intensified charge coupled device (ICCD) camera was used to observe the spatial distribution of sonoluminescence (SL) and sonochemiluminescence (SCL) generated by cavitation bubbles in a 1.2 MHz focused ultrasound (FU) field in order to investigate the mechanisms of acoustic cavitation under different sonication conditions for FU therapeutic applications.It was found that SL emissions were located in the post-focal region. When the intensity of SL and SCL increased as the power rose, the growth of SCL was much higher than that of SL. In the post-focal region, the SCL emissions moved along specific paths and formed branch-like streamers. At the beginning of the ultrasound irradiation, cavitation bubbles generated SCL in both the pre-focal and the post-focal region. When the electrical power or the sonication time increased, the SCL in the post-focal region increased and became higher than that in the pre-focal region. The intensity of SCL in the focal region is usually the weakest because of “oversaturation”.The spatial distribution of SCL near a tissue boundary differed from that obtained in free fields. It organized into special structures under different acoustic amplitudes. When the electrical power was relatively low, the SCL emission was conical shape which suggested a standing wave formation at the tissue-fluid boundary. When the electrical power exceeded a certain threshold, only a bright spot could be captured in the focus. The cavitation bubbles which centralized in the focus concentrated energy and hindered the formation of standing waves. With rising electrical power at high levels, besides a bright spot in the focus, there were some irregular light spots in pre-focal region, which indicated some cavitation bubbles or small bubble clusters achieved the threshold of SCL and induced the reaction with the luminol solution.