Differential ultrasonic imaging for the characterization of lesions induced by high intensity focused ultrasound

High intensity focused ultrasound (HIFU) is an effective technique for noninvasive local creating coagulative necrotic lesions in deep target volumes without damage to the overlaying or surrounding tissues. It is very important to detect and evaluate lesions generated by HIFU during treatment procedures. This study describes the development of several differential ultrasonic imaging techniques to characterize lesions based on estimation of relative changes in tissue properties derived from backscattered RF data. A single, spherical HIFU transducer was used to produce lesions in soft tissues. The RF signals were recorded as outputs from a modified diagnostic ultrasound system. After some preprocessing, the integrated backscatter values, which can be used as an indicator of the microstructure and backscattering property of tissues, were calculated before and after HIFU treatment. The differential integrated backscatter values were subsequently used to form images revealing the lesion areas. The differential attenuation imaging with the same RF data was also performed, which has been proposed by a few researchers. The results of the differential integrated backscatter imaging were compared with that of the differential attenuation imaging and the former method offers some advantages over the latter method. The two methods above are both based on spectrum analysis and would spend much computational time. Therefore, some simple digital differential imaging methods, including absolute difference (AD), sum absolute differences (SAD), and sum squared differences (SSD) algorithms, were also proposed to detect HIFU-induced lesions. However, these methods cannot provide the information of the degree of tissue damage. Experiments in vitro bovine muscle and liver validated the method of differential integrated backscatter imaging for the characterization of HIFU-induced lesions. And the AD, SAD, and SSD algorithms can be implemented in real-time during HIFU therapy to visualize the lesions.     

Identification of denatured and normal biological tissues based on compressed sensing and refined composite multi-scale fuzzy entropy during high intensity focused ultrasound treatment

In high intensity focused ultrasound(HIFU)treatment,it is crucial to accurately identify denatured and normal biological tissues.In this paper,a novel method based on compressed sensing(CS)and refined composite multi-scale fuzzy entropy(RCMFE)is proposed.First,CS is used to denoise the HIFU echo signals.Then the multi-scale fuzzy entropy(MFE)and RCMFE of the denoised HIFU echo signals are calculated.This study analyzed 90 cases of HIFU echo signals,including 45 cases in normal status and 45 cases in denatured status,and the results show that although both MFE and RCMFE can be used to identify denatured tissues,the intra-class distance of RCMFE on each scale factor is smaller than MFE,and the inter-class distance is larger than MFE.Compared with MFE,RCMFE can calculate the complexity of the signal more accurately and improve the stability,compactness,and separability.When RCMFE is selected as the characteristic parameter,the RCMFE difference between denatured and normal biological tissues is more evident than that of MFE,which helps doctors evaluate the treatment effect more accurately.When the scale factor is selected as 16,the best distinguishing effect can be obtained.     

Minimizing abdominal wall damage during high-intensity focused ultrasound ablation by inducing artificial ascites

High-intensity focused ultrasound (HIFU) is becoming an important tool for tumor treatment [especially hepatocellular carcinoma (HCC)] in Asian countries. A HIFU system provides unique advantages of low invasiveness and absence of nonradiation. However, if the target HCC is close to the proximal surface of the liver, HIFU may overheat diaphragm, abdominal wall or skin. To avoid this complication, a method using artificial ascites in the abdominal cavity to separate the liver from the peritoneum, and to serve as a heat sink to cool overlying structures and thereby avoid inducing permanent damage was proposed. Target tissue that was 10 mm below the liver surface was ablated in 12 New Zealand white rabbits: 6 in the experimental group and 6 in the control group. Artificial ascites was established in the experimental group by injecting normal saline into the abdominal cavity until the pressure reached 150 mm H2O. Artificial ascites not only reduced the probability and extent of thermal damage to intervening structures, but also had no adverse affect on the efficacy of HIFU ablation.     

基于电阻抗层析成像的高强度聚焦超声温度监测技术

作为一种对正常组织无损伤且不易引起癌细胞转移的非入侵肿瘤治疗手段,高强度聚焦超声(HIFU)治疗过程中焦域的温度监测是实现剂量精准控制的关键.本文基于生物组织的温度-电阻抗的关系,将电阻抗层析成像(EIT)和HIFU治疗相结合,提出了一种利用组织焦平面的表面电压实现电阻抗重构的检测技术.建立了HIFU治疗和EIT综合系统模型,在考虑组织的声吸收条件下,对三维Helmholtz方程在柱坐标下的声场计算进行了二维简化,并引入Pennes生物热传导方程来计算HIFU焦域的声压和温升分布特性;引入生物组织的温度-电阻抗关系,基于麦克斯韦电磁场理论,建立了具有温度分布HIFU焦域的电流和电压计算模型,利用恒流注入的边界条件实现电场计算,获得焦平面的表面电压分布.在数值计算中,利用实验聚焦换能器参数,模拟了在固定声功率下组织焦域的声场和温度场分布,以及中心和偏心聚焦条件下不同治疗时刻的电导率分布;然后通过对称电极的循环电流注入,计算了组织模型焦平面内的电流密度和电势分布,获得了焦平面圆周分布的表面电极电压;进一步采用修正的牛顿-拉夫逊算法,利用32×32的表面电极电压实现了焦平面内电导率分布的重建.结果表明,基于温度-电阻抗关系的EIT电导率重建技术不但能准确定位HIFU焦域中心,还能恢复HIFU治疗中焦域的温度分布,证明了EIT用于HIFU治疗中温度监测的可行性,为其疗效评估和剂量控制提供了一种无创电阻抗测量和成像新方法.     

The use of a micro-bubble agent to enhance rabbit liver destruction using high intensity focused ultrasound

Liver tissues in New Zealand rabbits were ablated using high intensity focused ultrasound (HIFU, 14300 W/cm(2), 1.0 MHz). The animals were intravenously administered 0.2 ml of micro-bubble agent in the experimental (n=20) group and an isovolumetric normal saline solution in the control (n=27) group before HIFU treatment which was performed as a linear scan. In both groups, the preselected tissue volumes were destroyed without harming the overlying tissues. Necrosis rate (NR, cm(3)/s) was used to reflect the ablation efficiency, which was the tissue volume of occurring coagulative necrosis per 1s HIFU exposure. NR was improved in the experimental group (0.0570+/-0.0433 vs 0.0120+/-0.0122, P=0.0002). Pathological studies confirmed that there were no residual intact targets within the exposed volume. These findings suggested that the introduction of the micro-bubble agent enhanced HIFU liver destruction.     

球形集声器在生物组织中形成的组织损伤

球形集声器可在亚波长焦域内形成高强度声压,在高强度聚焦超声治疗中具有潜在应用前景.本文结合非线性声传播理论及生物传热学理论,研究球形集声器在生物组织中形成的组织损伤.实验中采用430 kHz,内径为240 mm的球形集声器对肝组织作用,结果表明:集声器表面声压为53 kPa时作用2 s,可以形成小于波长尺度的组织损伤.理论计算结果与实验结果符合得较好,并且理论模型可优化球形集声器的开口孔径.研究结果表明,球形集声器可应用于肿瘤的精细超声治疗.     

Applications of high-intensity focused ultrasound in medicine: Spotlight on neurological applications

High-intensity focused ultrasound (HIFU) has the potential to become a modality of treatment for a wide range of clinical conditions. HIFU enables non-invasive, selective ablation of tissues including tumors and punctured vessels. Another promising area of research within the field of therapeutic ultrasound is the application of HIFU to treat neurological disorders by selectively targeting the brain, spinal cord, or nerves. This paper provides an overview of the current applications of focused ultrasound in medicine with an emphasis on its use in the fields of neurology and neurosurgery.     

New Techniques and Designs of Focusing Piezoelectric Transducers for Ultrasonic Diagnostics and Therapy

New techniques of forming high intensity focused ultrasound (HIFU) fields using dynamic focusing and harmonic multifrequency excitation are developed for ultrasonic diagnostics and therapy. New designs of HIFU transducers based on high-performance composite materials are developed and studied. Finite-element and finite-difference simulations of HIFU transducers and processes of ultrasonic wave propagation in biological tissues are performed. The parameters of piezoceramic materials, piezoelements, and the acoustic fields of focusing ultrasonic transducers are measured. Experiments are performed on biological tissues ex vivo that confirm the efficiency, selectivity, and safety of the developed HIFU transducers and techniques of forming acoustic fields.     

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.     

高强度聚焦超声用于肿瘤治疗的研究

高强度聚焦超声（ＨＩＦＵ）能在短时间内使病变组织的温度升至７０℃以上,导致病变组织凝固坏死,是一种具有巨大潜力的、非侵入的、有效的肿瘤治疗手段。本文对ＨＩＦＵ的动物试验、临床应用及治疗装置的研究情况进行了总结,分析了该技术尚存在的问题,最后展望了其应用前景。     

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。     

High-intensity focused ultrasound for the treatment of liver tumours

High-intensity focused ultrasound (HIFU) has been investigated as a tool for the treatment of cancer for many decades, but is only now beginning to emerge as a potential alternative to conventional therapies. In recent years, clinical trials have evaluated the clinical efficacy of a number of devices worldwide. In Oxford, UK, we have been using the JC HIFU system (HAIFU Technology Company, Chongqing, PR China) in clinical trials since November 2002. This is the first report of its clinical use outside mainland China. The device is non-invasive, and employs an extracorporeal transducer operating at 0.8-1.6 MHz (aperture 12-15 cm, focal length 9-15 cm), operating clinically at Isp (free field) of 5-15 KWcm(-2). The aims of the trials are to evaluate the safety and performance of the device. Performance is being evaluated through two parallel protocols. One employs radiological assessment of response with the use of follow-up magnetic resonance imaging and microbubble-contrast ultrasound. In the other, histological assessment will be made following elective surgical resection of the HIFU treated tumours. Eleven patients with liver tumours have been treated with HIFU to date. Adverse events include transient pain and minor skin burns. Observed response from the various assessment modalities is discussed.     

Low dimensional optimization for in vivo real-time porcine liver motion estimation using ultrasound imaging

This study presents a contribution to the tracking of a moving target during high-intensity focused ultrasound (HIFU) treatment. Indeed, HIFU has proved to be highly efficient in inducing homogeneous and reproducible tumor destruction by thermal coagulation necrosis. However, accurate targeting of human abdominal tumors is difficult to maintain due to the motion induced by breathing. An algorithm is presented to track a region of interest of fixed size in a sequence of images. This algorithm was evaluated on synthetic data and on in vivo sequences of ultrasound liver images acquired using 12 MHz ultrasound imaging probe at a rate of 16 frames/s.The algorithm presented here was derived from the non-linear constant brightness assumption. Since the motion was smooth it was possible to reduce the space of admissible displacements; hence the number of unknown parameters was small compared with the size of the data. The optimal displacement was estimated by a Gauss-Newton method, and the matrix required at each step was assembled by reading the data only once. This algorithm was applied to simulated data, where the true displacement was known and a precise evaluation was possible. The relative error was about 2%. The algorithm was also applied to a video sequence of sonograms acquired during in vivo experiments. These trials were conducted on porcine liver since its size and physiology are similar to humans. Movements were induced by breathing and heart-beating. Two particular frequencies representing breathing (0.26 Hz) and heart beat (1.14 Hz) were identified in the estimated displacement and were correlated with the monitored breathing (0.27 Hz) and electrocardiograms (1.28 Hz). In addition, a region of interest (ROI) modeling the focal zone of a HIFU transducer was tracked along time. Therefore this study provides a mean of determining the location of the targeted region in vivo during HIFU treatments. This can be applied to correct the location of the focal zone accordingly. This method can preferentially be applied to the liver or to any other moving organ.     

Extracorporeal high intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview

The ideal treatment of localized cancer should directly cause an irreversible and complete death of tumor cells without damage to surrounding normal tissue. High intensity focused ultrasound (HIFU) is such a potential treatment, which induces a complete coagulative necrosis of a tumor at depth through the intact skin. The idea that using an extracorporeal source of therapeutic ultrasound was introduced more than 50 years ago [J. Gen. Physiol. 26 (1942) 179]. However, up to now, most of the studies on HIFU have been dealing with animal experiments because this extracorporeal technique is very complicated in clinical applications. The purpose of this study is to introduce Chinese clinical experience of using extracorporeal HIFU for the treatment of patients with various kinds of solid tumor. From December 1997 to October 2001, a total of 1038 patients with solid tumors underwent HIFU ablation in China. Among them, 313 patients were treated at the Chongqing University of Medical Sciences, China. Pathological examination showed that the target region presented clear evidence of cellular destruction. Small blood vessels less than 2 mm in diameter were severely damaged. Follow-up diagnostic imaging revealed that there was no, or reduced, blood supply, and no uptake of radioisotope in the treated tumor after HIFU, both indicating a positive therapeutic response and an absence of viable tumor. Imaging at 6-12 months showed obvious regression of the lesion. Four-year follow-up data were significantly observed in patients with hepatocellular carcinoma, osteosarcoma, and breast cancer. An extremely low major complication rate was noted. It is concluded that HIFU ablation is a safe, effective, and feasible modality for the ablation of carcinomas.     

基于分数导数研究高强度聚焦超声的非线性声场

在高强度聚焦超声(high intensity focused ultrasound, HIFU) 的研究中, 生物组织的衰减和色散性质会对声能量的空间分布产生影响. 本文提出应用分数导数修正非线性Khokhlov-Zabolotskaya-Kuznetsov (KZK)方程, 研究生物组织中非线性HIFU声场. 对三种生物仿体的衰减和声速色散的理论实验研究表明分数导数应用的可行性, 在此基础上通过数值仿真分析研究了衰减及声速随频率的变化对HIFU焦域分布的影响. 研究结果表明, 在计算强非线性聚焦超声时, 由于高次谐波的强色散作用, 引入分数导数来解决生物组织特殊的衰减以及色散问题可进一步提高HIFU治疗的安全性. 关键词： 分数导数 声衰减 色散 高强度聚焦超声     

Ultrasound responsive block copolymer micelle of poly(ethylene glycol)–poly(propylene glycol) obtained through click reaction

The well-defined amphiphilic poly(ethylene glycol)-block-poly(propylene glycol) copolymer containing 1, 2, 3-triazole moiety and multiple ester bonds (PEG-click-PPG) was prepared by click reaction strategy. The PEG-click-PPG copolymer can self-assemble into spherical micelles in aqueous solution. It is found that high intensity focused ultrasound (HIFU) can open the copolymer PEG-click-PPG micelles and trigger the release of the payload in the micelle. The multiple ester bonds introduced in the junction point of the copolymer chain through click reactions were cleaved under HIFU, and leads to the disruption of the copolymer micelle and fast release of loaded cargo. The click reaction provides a convenient way to construct ultrasound responsive copolymer micelles with weak bonds.     

基于回波平移序列的快速三维磁共振温度成像方法

高强度聚焦超声（HIFU）是一种无创的热消融疗法，为保证其安全性和有效性，需要一种精度高、速度快的测温方法在其治疗过程中对温度进行监控.基于质子共振频率位移（PRFS）的磁共振温度成像（MRT）对温度具有较高的灵敏度，且与温度具有良好的线性关系，因此常被用于引导HIFU治疗.然而在实际应用中，HIFU治疗的最大隐患在于可能造成表皮灼伤，并且灼伤区域可能与焦点区域相隔较远.因此MRT的监控范围十分重要.本文基于三维回波平移成像序列，结合可控混叠的空间并行成像技术，实现了时间分辨率为3 s的快速三维温度成像.为了验证该方法的精度，本文首先设计了仿体降温实验，利用光纤温度计验证回波平移序列测温的准确度和精确度.然后在室温条件下扫描离体猪肉组织，对比加速前后的MRT的测温精确度.在HIFU加热条件下扫描离体猪肉组织，对比加速前后的MRT的测温准确度.结果显示，本文提出的方法可以在3 s内完成三维温度精准测量，对于HIFU治疗的安全监控具有重要意义.     

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.     

时间反转方法用于高强度聚焦超声的焦点偏移补偿

传统的高强度聚焦超声(HIFU)治疗中实际焦点和预设焦点容易出现偏移,为考察时间反转方法对HIFU治疗中焦点偏移的补偿效果,采用时域有限差分方法求解Westervelt方程,建立高强度聚焦声场数值模型。数值计算得到在人体软组织中进行HIFU治疗时,采用时间反转方法后焦点偏移距离最大仅为1.6 mm。脂肪层厚度及声源强度改变对时间反转聚焦精度影响不大,F数(焦点距离同换能器孔径的比值)降低时,焦点偏移减小。研究表明在人体软组织吸收系数和非线性系数范围内,时间反转方法可有效补偿焦点偏移,达到更好的聚焦效果。      

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.