高强度聚焦超声(HIFU)——一门多学科的研究课题

高强度聚焦超声(high intensity focused ultrasound,简称HIFU)已作为一种无创外科工具而应用于门诊治疗肿瘤。文章介绍了它的基本原理、有关的研究现状和存在的问题,以及对今后研究工作的建议。文章特别强调高强度聚焦超声是一门多学科的综合研究课题,需要各方面的科学工作者通力协作。     

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。     

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.     

Characterization of a fiber-optic displacement sensor for measurements in high-intensity focused ultrasound fields

A fiber-optic sensor is presented that is capable of measuring the particle displacement in high-intensity focused ultrasound (HIFU) fields. For this probe, a secondary calibration was performed, and the resulting complex frequency response is discussed. As a first practical application, the setup was used to measure the pressure in the field of a weakly focusing ultrasound transducer. The result is compared with that of a membrane hydrophone measurement. The feasibility of measurements in HIFU fields is demonstrated by means of measurements of the spatial distribution of the peak particle velocity within the focus of a HIFU transducer and of the dependence of the peak values on the acoustical power level.     

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。     

Nonlinear absorption in biological tissue for high intensity focused ultrasound

In recent years the propagation of the high intensity focused ultrasound (HIFU) in biological tissue is an interesting area due to its potential applications in non-invasive treatment of disease. The base principle of these applications is the heat effect generated by ultrasound absorption. In order to control therapeutic efficiency, it is important to evaluate the heat generation in biological tissue irradiated by ultrasound. In his paper, based on the Khokhlov-Zabolotkaya-Kuznetsov (KZK) equation in frequency-domain, the numerical simulations of nonlinear absorption in biological tissues for high intensity focused ultrasound are performed. We find that ultrasound thermal transfer effect will be enhanced with the increasing of initial acoustic intensity due to the high harmonic generation. The concept of extra absorption factor is introduced to describe nonlinear absorption in biological tissue for HIFU. The theoretical results show that the heat deposition induced by the nonlinear theory can be nearly two times as large as that predicated by linear theory. Then, the influence of the diffraction effect on the position of the focus in HIFU is investigated. It is shown that the sound focus moves toward the transducer compared with the geometry focus because of the diffraction of the sound wave. The position of the maximum heat deposition is shifted to the geometry focus with the increase of initial acoustic intensity because the high harmonics are less diffraction. Finally, the temperature in the porcine fat tissue changing with the time is predicated by Pennes' equation and the experimental results verify the nonlinear theoretical prediction.     

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.     

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.     

格子玻尔兹曼方法对不同张角聚焦声束的建模

高强度聚焦超声(HIFU)是一种新型的无创治疗肿瘤新技术,其中换能器声场数值计算能够为HIFU治疗提供重要的依据。传统非线性KZK和SBE模型广泛应用于换能器声场数值计算,但依然存在某些不足。我们采用一种介观尺度的新型流体力学方法,即格子Boltzmann方法(LBM),基于2维9离散速度(D2Q9)格子构建了轴对称多弛豫参数LBM模型,并通过调节弛豫参数分析其对模型的影响;利用该模型对两个具有不同张角的球面聚焦换能器的声场进行数值模拟,并与KZK和SBE模型的计算结果进行比较。结果表明LBM模型能够很好地描述超声波的激发和传播机制,从流体力学的角度描述聚焦声场的分布,具有清晰的物理意义,且计算过程不受换能器张角的限制,在换能器声场的理论分析和模拟计算及其在HIFU治疗中的应用有着积极的意义。      

Calibration and measurement issues for therapeutic ultrasound

This review paper examines some of the issues relating to calibration and measurement of therapeutic medical ultrasonic equipment (MUE). This is not intended to be an all-encompassing review of all aspects of characterising therapeutic ultrasound. Instead it concentrates on issues related to the acoustic output of two applications: physiotherapy and high intensity focused ultrasound surgery (HIFUS or HIFU; also referred to as high intensity therapeutic ultrasound, HITU). Physiotherapy has a well-established standards infrastructure for calibration: the requirements are small in number and well-defined. The issue for physiotherapy is not so much 'How to calibrate?' but rather, 'How to ensure that equipment IS calibrated?' The situation in the much newer area of HIFU is very different: the first steps towards writing standards are just starting and even the very basic questions of what to measure and with what type of sensor are open for debate. Readers whose main interest is in other ultrasound therapies will find ideas of relevance to their own specialty.     

Physical mechanisms of the therapeutic effect of ultrasound (a review)

Therapeutic ultrasound is an emerging field with many medical applications. High intensity focused ultrasound (HIFU) provides the ability to localize the deposition of acoustic energy within the body, which can cause tissue necrosis and hemostasis. Similarly, shock waves from a lithotripter penetrate the body to comminute kidney stones, and transcutaneous ultrasound enhances the transport of chemotherapy agents. New medical applications have required advances in transducer design and advances in numerical and experimental studies of the interaction of sound with biological tissues and fluids. The primary physical mechanism in HIFU is the conversion of acoustic energy into heat, which is often enhanced by nonlinear acoustic propagation and nonlinear scattering from bubbles. Other mechanical effects from ultrasound appear to stimulate an immune response, and bubble dynamics play an important role in lithotripsy and ultrasound-enhanced drug delivery. A dramatic shift to understand and exploit these nonlinear and mechanical mechanisms has occurred over the last few years. Specific challenges remain, such as treatment protocol planning and real-time treatment monitoring. An improved understanding of the physical mechanisms is essential to meet these challenges and to further advance therapeutic ultrasound.     

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     

Simulation of three-dimensional nonlinear fields of ultrasound therapeutic arrays

A novel numerical model was developed to simulate three-dimensional nonlinear fields generated by high intensity focused ultrasound (HIFU) arrays. The model is based on the solution to the Westervelt equation; the developed algorithm makes it possible to model nonlinear pressure fields of periodic waves in the presence of shock fronts localized near the focus. The role of nonlinear effects in a focused beam of a two-dimensional array was investigated in a numerical experiment in water. The array consisting of 256 elements and intensity range on the array elements of up to 10 W/cm² was considered. The results of simulations have shown that for characteristic intensity outputs of modern HIFU arrays, nonlinear effects play an important role and shock fronts develop in the pressure waveforms at the focus.     

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.     

组织凝固性坏死对基于纵向弛豫时间的磁共振测温的影响

高强度聚焦超声（High Intensity Focused Ultrasound,HIFU）治疗肿瘤时,为了保证治疗的安全性和有效性,需要对组织温度分布进行实时监测.磁共振成像（Magnetic Resonance Imaging,MRI）具有对温度敏感的成像参数,可以无创检测组织温度.本文结合组织相变对测温的影响,探讨了磁共振测温（Magnetic Resonance Thermometry,MRT）技术能否用于实时监控HIFU治疗.利用两态快速交换模型,提出在组织凝固性坏死的相变前后,MRI的纵向弛豫时间（T₁）参数与组织温度之间具有不同关系.并通过实验验证了上述假设.相对于传统的磁共振测温方法模型,本文考虑了HIFU治疗过程中组织相变对检测温度的影响,对利用磁共振测温引导HIFU治疗具有重要的参考价值.     

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.     

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.     

The affection on the tissue lesions of difference frequency in dual-frequency high-intensity focused ultrasound (HIFU)

The lesions induced by dual-frequency high-intensity focused ultrasound (HIFU) in freshly excised porcine livers were investigated and compared with the lesions induced by conventional single-frequency HIFU. The results have shown that using different exposure time resulted in lesions of different sizes in both dual-frequency and single-frequency HIFU modes at the same intensity level (ISAL = 808 W cm(-2)), but the dimensions of lesions in dual-frequency mode were obviously larger than those in single-frequency mode. A much possible explanation was suggested for the results and the possibilities of applications in the future were also discussed in brief.     

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.