Name: real-time monitoring of high intensity focused ultrasound (hifu) ablation of in vitro canine livers using harmonic motion imaging for focused ultrasound (hmifu)
Uploaded: 2015-11-03T11:00:00.000+00:00
Duration: 7 min 38 s
Description: Watch this Scientific Journal Video about Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU a

This work was supported by the National Institutes of Health (R01-EB014496). The authors would like to thank Iason Apostolakis for his contribution to the experiments.

该协议被批准哥伦比亚大学的机构动物护理和使用委员会。所有的数据采集和处理用Matlab环境执行。 1.实验装置<ol><li>在90分钟的脱气离体犬肝脏样本。把肝脏样品中的填充有脱气磷酸盐缓冲溶液（ 图1）罐。固定在一个声吸收用针在肝脏的四肢的肝样品。 </li><li>通过一个圆孔位于93元半球阵列HIFU换能器（治疗）的中心，在4.5 MHz的中心频率的70 mm焦距的深度和插入64元0.32毫米间距，2.5 MHz的中心频率相控阵（成像） 1.7毫米×0毫米焦距的大小11。对齐两个传感器同轴和修复成像传感器到治疗换能器的调整螺丝。 <ol><li>盖上HIFU换能器与AVolume控制聚氨酯膜填充有流动的脱气的水来冷却下来。安装在一个计算机控制的3-D定位的换能器组件。 </li></ol></li><li>的HIFU换能器连接到功能发生器发送具有500毫伏最大振幅为25赫兹的调幅正弦波形。成像传感器连接到使用Matlab软件完全可编程超声系统。 注意:用超声系统相关联的软件和利用Matlab环境必须连接到系统中的计算机上。将50 dB的RF放大器和匹配网络应当放置在HIFU换能器与函数发生器分别放大功率并匹配的阻抗之间。 </li><li>创建一个极性的网格，用Matlab，开始从阵​​列的表面50毫米和40毫米深的在径向方向上具有9.625微米，90°，128线和哪些原点的空间的步骤在方位角方向是FOCUS发散波。限定的发散的波10.24毫米源（孔径大小的一半）的阵列的表面的后面，并集中在横向方向上。 <ol><li>创建一个笛卡尔网格，用Matlab，开始从阵​​列的表面50毫米和40毫米深在与9.625微米，宽20毫米，与64线，为平面波的左右方向的空间的步骤的轴向方向。限定所述阵列的表面上的平面波的来源。对于每一个网格，计算从源的时间的每个点的网格和背面到阵列中的每个元素。 </li></ol></li><li>输入"ReconMat_DW"的发散波成像或"ReconMat_PW"在MATLAB命令窗口平面波成像，然后按"Enter"来创建一个标准的延迟与求和算法，每个网格相关的​​重建矩阵。申请延迟与求和算法的标准基础的每个矢量和检索所述非零点的Elemen所得矩阵 11的TS。分配从所得矩阵获得的稀疏矩阵的相应位置中的非零元素。保存在电脑硬盘上的重建矩阵。 注意:发散和平面波的方法使用两个不同的重建矩阵。 <ol><li>铸造重建矩阵到GPU矩阵。输入"SetUpP4_2Flash_4B_streaming_DW"的发散波成像或"SetUpP4_2Flash_4B_streaming_PW"在Matlab的命令窗口，然后按"Enter"来创建使用相控阵由制造商相关的并脚本超声通道数据采集设置文件平面波成像的超声系统。命名安装文件"P4-2Flash_DivergingWave.mat"的发散波成像和"P4-2Flash_PlaneWave.mat"的平面波成像。 注:商业软件包，必须在电脑•安装Ø投重建稀疏矩阵到GPU矩阵。 </li></ol></li><li>使高帧速率的超声数据采集的肝脏开始同时作为HIFU超声系统使用外部触发函数发生器同步。 </li><li>打开Matlab的。运行安装脚本"SetUpP4_2Flash_4B.m"由超声系统制造商使用B模式成像提供。命名创建的安装文件:"P4-2Flash_4B_Bmode.mat"。使用"VSX"命令，在".MAT文件要处理的名称:"提示，输入安装文件"P4-2Flash_4B_Bmode.mat"的名称。移动这两个换能器，并使用B模式显示该出现在计算机屏幕上，以它们在肝脏消融的目标区域放置。目标的区域中的肝脏表面下大约1cm，以避免高超声波衰减因吸收。保存在计算机上的肝脏的常规B模式图像。 注意:在这里，我们两个肝标本进行高强度聚焦超声消融在11个不同的位置通过移动换能器与所述3D定位器为每个消融。 </li></ol> 2.超声数据采集<ol><li>打开Matlab的。使用"VSX"命令，在".MAT文件要处理的名称:"提示，输入安装文件"P4-2Flash_DivergingWave.mat"的名称发散波成像或"P4-2Flash_PlaneWave.mat"的平面波成像。启动HIFU和2分钟的目标区域中应用它。 </li><li>在使用发散波2分钟收购以每秒1000帧的RF信道的数据。另外，在2分钟利用平面波收购以每秒1000帧的RF信道的数据。 </li><li>通过PCI特快电缆将数据传输到主计算机每200帧。或者，对于实时流，使用平面波和TRANSF期间2分钟获取以每秒167帧的RF信道的数据器中的数据到主计算机的每2帧。 注:带套200帧的成像方法提供了每套之间的每个设置，但创造的间隙内高时间分辨率，适用于离线处理。在167 fps的影像处理方法具有较低的时间分辨率，但不创建整个消融时间的任何间隙，并且非常适合实时流。 </li><li>铸造RF信道的数据矩阵与Matlab的单精度GPU矩阵。由重建矩阵相乘RF信道的数据矩阵，以获得重建的RF数据11。 </li></ol> 3.排量成像<ol><li>创建一个6 阶 Butterworth低通于4 MHz的截止频率利用Matlab的DSP系统工具箱过滤器。应用此低通滤波器，以重构RF数据来过滤掉4.5兆赫HIFU组件。 </li><li>估计使用一维归一化互相关的连续帧之间的轴向位移用3.1毫米窗口长度和90％的重叠。 </li><li>创建一个6 阶 Butterworth低通在100赫兹的截止频率利用Matlab的DSP系统工具箱过滤器。用Matlab检索50赫兹振荡频率分量应用此低通滤波器的时间位移的数据。 </li><li>定义感兴趣区域（ROI）的区域作为在-6分贝焦点区域（1.7×0.4毫米，在水中）和位于70毫米背离换能器表面。在提取该ROI的位移数据。消融2分钟作为平均位移和在ROI的位移的标准偏差之间的比率后估计在焦点区域中的位移信噪比（SNR d）所示。 </li><li>提取50赫兹时间位移信号在从位移矩阵数据的焦点。时间位移信号转换的重点放到利用Matlab可听见的声音。 </li></ol>

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The authors declare that they have no competing financial interests.

HIFU病变的实时监控是非常重要的，以确保适当和有效的病变交付。作为病变形式中，组织变硬和下激励它的运动幅度减小。施加在HIFU的组织的结果的区域中诱导组织位移的声辐射力。在位移的相对变化是组织硬度相对变化的替代。这种技术提供监测HIFU病变不停止在与其它超声基础的方法治疗的优点。在这项研究中（4.5赫兹）的实时监测的时间分辨率比在MR引导HIFU消融（1赫兹）中获得更高。 的超声射频数据的快速处理是用于位移的实时流的关键步骤。图像的重建是处理最慢的步骤。在这个协议中，图像重建的速度进行优化通过获得整个帧USI纳克单个操作。这个操作包括在由以矩阵的RF信道数据相乘。矩阵的唯一的非零元素被分配，以优化计算时间和乘法是在GPU上执行的。一种快速的1-D标准化的互相关方法被用来估计的位移。的80％的窗口的重叠允许良好折衷的计算时间和位移的图像的轴向分辨率之间。 所述发射波束成形的方法，也可以影响位移的图像的质量。 信噪比天得到了发现显著较低发散比使用两样本t检验平面波成像。位移的幅度也较低发散比平面波成像。这可以通过以下事实的发散波的轴线方向不与在整个ROI内HIFU射束对准由于波在扩散性质来解释相对于平面波。找到病变＃3的较低的峰 - 峰位移减少为发散波成像可能是由于一个容器中的大体病理后观察到的病变的中心的存在。找到病变＃4对平面波成像的低信噪比D可以由于焦点到肝脏的表面附近。它也必须要注意的是，衰减由于几何扩散在横向方向上产生的发散波，而不是为平面波可影响运动估计的质量。然而，使用相同的超声换能器时，发散的波成像提供的视图，而不是平面波成像更大的字段，它是感兴趣的连续图象的区域的最大部分以烧蚀。 在这个协议中，相控阵列被用于图像，使得烧蚀区域的仅一个横截面进行成像的位移。甲的2-D阵列传感器可用于图像吨该消融区的，他整个卷。在肝脏的不同位置消融通过移动相对于肝换能器来实现的。波束控制可​​以用高强度聚焦超声探头执行为目标的区域的不同位置进行处理，以允许更适当的定位。除了上述的技术改进，未来的方向包括该方法的临床平移。

High Intensity Focused Ultrasound (HIFU) is a technique that generates temperature elevation at the focal region and can be used to ablate cancerous tissue 1. Temperature elevation at the focus causes thermal lesions in the tissue 2. In order to avoid overtreating a region and to reduce treatment duration, it is imperative to reliably monitor the ablation. Magnetic resonance-guided focused ultrasound (MRgFUS) is the main technique used in clinic to guide and monitor HIFU treatment 3. MRI provides high spatial resolution images of the treated region with tissue displacement or thermal dose but has a frame rate of 0.1-1 Hz and is costly. Several ultrasound-based techniques such as B-mode imaging 4, passive acoustic mapping 5, shear wave imaging 6 and acoustic radiation force impulse 7 have been developed to guide and monitor thermal ablation. However, B-mode imaging and passive acoustic mapping do not provide imaging of mechanical properties of the ablated region which is useful to the operator to improve lesion delivery. 
Shear wave imaging and acoustic radiation force impulse can both characterize the elasticity of the tissue by measuring acoustic radiation force-induced displacements 7,8. However, in both methods, the HIFU treatment is typically interrupted to monitor the ablation. Our group has developed a technique called Harmonic Motion Imaging for Focus Ultrasound (HMIFU) which can monitor the HIFU treatment with ultrasound without stopping the ablation9,10. Briefly, a HIFU transducer sends an amplitude-modulated wave to the region to ablate while simultaneously generating an oscillatory motion in the focal region. A co-axially aligned ultrasound transducer is used to image this oscillation. The magnitude of the induced motion is related to the stiffness of the tissue.
To ensure proper lesion delivery, the temporal resolution of real-time monitoring is of key interest in ablation guidance. Recently, our group has shown real-time streaming of displacement at a frame rate up to 15 Hz, imaged with diverging waves in a narrow field of view and using a fast image reconstruction method 11. Several beamforming techniques can be used to image the displacements. A large field of view can be obtained with diverging wave imaging by changing the delay profile but the axial direction is not aligned with the HIFU beam on the lateral regions and the wave is attenuated due to geometric spreading in the lateral direction, which can affect the quality of the displacement estimation. In contrast, the lateral field of view for plane wave is upper bounded by the active aperture but the axial direction is aligned with the HIFU beam at the focus and there is no geometric spreading in the lateral direction. Depending on the type of application, one or the other imaging method can be selected. The objectives of this protocol are to show how plane wave imaging can provide real-time streaming of displacements images using HMIFU during ablation and to compare the quality of the motion estimation between diverging and plane wave imaging.

<table><tbody><tr><td>P4-2 Phased array</td><td>ATL</td><td></td><td></td></tr><tr><td>H-178 HIFU transducer</td><td>Sonic Concepts</td><td></td><td></td></tr><tr><td>3-D positioner</td><td>Velmex Inc.</td><td></td><td></td></tr><tr><td>AT33522A function generator</td><td>Agilent Technologies</td><td></td><td></td></tr><tr><td>V-1 ultrasound system</td><td>Verasonics</td><td></td><td></td></tr><tr><td>3100L RF amplifier</td><td>ENI</td><td></td><td></td></tr><tr><td>Matching network</td><td>Sonic Concepts</td><td></td><td></td></tr><tr><td>Degasing system</td><td>Sonic Concepts</td><td></td><td></td></tr><tr><td>Programming software</td><td>Matlab</td><td></td><td></td></tr><tr><td>Jacket software package</td><td>Accelereyes</td><td></td><td></td></tr></tbody></table>

real-time monitoring of high intensity focused ultrasound (hifu) ablation of in vitro canine livers using harmonic motion imaging for focused ultrasound (hmifu)

谐运动成像的聚焦超声（HMIFU）是可以执行和监控高强度聚焦超声（HIFU）消融的技术。的振荡运动在一个93元件和4.5兆赫中心频率的HIFU换能器的焦点通过使用函数发生器施加25赫兹振幅调制的信号生成的。与68kPa峰值压力64元件和2.5兆赫成像换能器被共焦地放置在HIFU换能器获取的射频（RF）信道数据的中心。在这个协议中，使用高强度聚焦超声与对体外犬肝7瓦的声功率热消融的实时监控进行说明。在2分钟HIFU治疗被施加在组织上和烧蚀区域是使用发散或平面波成像高达1000帧/秒成像实时。的RF信道的数据的矩阵乘以一个稀疏矩阵图像重建。视重建场是90°的发散わ已经和20毫米的平面波成像和数据进行采样，在80兆赫。重建是在4.5显示帧速率上的图形处理单元（GPU）执行，以图像在实时的。重构RF数据的一维归一化互相关性被用于估计轴向位移在焦点区域。的峰 - 峰位移的在焦深幅度它表示所述组织的硬化由于病灶的形成热消融过程中降低。位移信噪比（SNR D）在重点领域的平面波是比发散波显示出平面波成像的1.4倍似乎产生更好的置换贴图质量HMIFU比发散波成像。

可以用发散和平面波成像获得HMI排量的实时流期间，高强度聚焦超声消融治疗。 图2是在高强度聚焦超声消融视频截屏显示使用平面波成像技术在体外犬肝脏的声辐射力引起的位移实时显示。的位移以4.5赫兹的显示帧速率流在实时计算机屏幕上。正位移示于红色和负位移为蓝色。病变使用HIFU消融。 图3示出对应于图2的消融后在肝脏中获得的病变被成功交付。 HMI峰值负位移幅度在高强度聚焦超声消融术可以降低成像既发散和平面波成像。 图4显示了 HMI负峰值位移与发散和平面波消融的不同阶段成像。高峰负位移示既没有和有覆盖的B模式更清楚地看到的位移图案和分别地看到目标区域在肝脏中。对应于与平面波（图4C）监测消融的50赫兹的HMI位移声音被合并到视频。 HMI位移振幅由于消融的降低可以被听到，提供了附加的监测工具。 图4也表示该区域的消融。 图5A中兴奋HIFU增加且尺寸5B示出了HMI位移在焦点区域期间分别消融发散和平面波。在HMI位移幅度的降低是既为发散和平面波成像清晰可见。 图6示出了峰-峰值位移降低在肝脏既为发散所有的定位位置（图<html> 6A），面（ 图6B）波成像。的峰 - 峰位移减少为平面波是不显著不同的发散波获得的之一。 平面波成像被发现具有较高的SNRð在焦点比发散波成像。 图7示出了信噪比d在 ROI中在肝脏所有病灶的位置为发散（图7A）和平面（图7B）波成像。平均信噪比d表示飞机比发散波成像的1.7倍。 <img alt="图1" src="/files/ftp_upload/53050/53050fig1.jpg" /> 图1实验装置。该HMIFU系统（A）表示。 （二）图片的实验装置。OM /文件/ ftp_upload / 53050 / 53050fig1large.jpg"目标="_空白"&gt;点击此处查看该图的放大版本。 <img alt="图2" src="/files/ftp_upload/53050/53050fig2.jpg" /> 图2.实时HMI位移。捕获表示在一个犬的肝脏在4.5Hz显示帧频的高强度聚焦超声消融HMI位移与平面波成像的实时流媒体在电脑屏幕上。左侧面板显示过滤HMI位移和右手边的面板显示覆盖在肝脏的预消融B型过滤的HMI位移。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/53050/53050fig3.jpg" /> 图3.病变引起的HIFU，图片下面HIFU治疗病变的中间截面。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/53050/53050fig4.jpg" /> 图4发散和位移的平面波成像。在使用发散波，没有B型叠加（A）犬肝脏高强度聚焦超声消融峰值负HMI位移成像，与B型叠加（B），采用平面波成像无B模式叠加（C）中，用B模式叠加（D）中。对应于与平面波监测（图4C）被合并到视频消融的50赫兹的HMI位移声音<a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig4large.jpg" target="_blank">。P</a>租赁点击此处查看该图的放大版本。 <img alt="图5" src="/files/ftp_upload/53050/53050fig5.jpg" /> 在使用发散HIFU消融（A）和飞机（B）浪成像图5. HMI焦点位移。HMI排量在焦点区域。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图6" src="/files/ftp_upload/53050/53050fig6.jpg" /> 图6.峰-峰值的位移减少。峰-峰值位移在下降过程中高强度聚焦超声消融采用发散（ 一）聚焦区和平面（B）波成像。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig6large.jpg" target="_blank">请</a>点击此处查看该图的放大版本。 <img alt="图7" src="/files/ftp_upload/53050/53050fig7.jpg" /> 图7.位移信噪比，在焦点位移信噪比为发散（A）和飞机（B）浪成像不同消融位置。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53050/53050fig7large.jpg" target="_blank">请点击此处查看该图的放大版本。 。</a>

Watch this Scientific Journal Video about Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU a

Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU

This article describes real-time monitoring of HIFU ablation in canine liver with high frame rate ultrasound imaging using diverging and plane wave imaging. Harmonic Motion Imaging for Focused Ultrasound is used to image the decrease of acoustic radiation force induced displacement in the ablated region.

高强度的实时监控聚焦超声（HIFU）消融<em&gt;体外</em&gt;使用谐运动成像的聚焦超声犬肝脏（HMIFU）

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An ...

real-time-monitoring-high-intensity-focused-ultrasound-hifu-ablation

Universidad San Sebastian

Research

JoVE Journal

Bioengineering

Real-time Monitoring of High Intensity Focused Ultrasound (HIFU) Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU)

9.9K 次观看.  Columbia University. This article describes real-time monitoring of HIFU ablation in canine liver with high frame rate ultrasound imaging using diverging and plane wave imaging. Harmonic Motion Imaging for Focused Ultrasound is used to image the decrease of acoustic radiation force induced displacement in the ablated region.

视频: Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm3&#183;min-1) higher than any other treatment and is independent of perfusion.
The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique.
Fifteen patients were included in phase I&#8211;IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1&#8211;2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2, corresponding to a volume of approximately 7.5 cm3. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.

Here, we present an ablate-and-resect prospective study to evaluate the feasibility, safety, and accuracy of intraoperative high-intensity focused ultrasound ablation in patients undergoing hepatectomy for liver metastases.

术中高强度聚焦超声装置治疗肝转移的可行性、安全性和准确性评价

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% ...

科研

癌症研究

Fetal Mouse Cardiovascular Imaging Using a High-frequency Ultrasound (30/45MHZ) System

Congenital heart defects (CHDs) are the most common cause of childhood morbidity and early mortality. Prenatal detection&#160;of the underlying molecular mechanisms of CHDs is&#160;crucial for inventing new preventive and therapeutic strategies. Mutant mouse models are powerful tools to discover new&#160;mechanisms&#160;and environmental stress modifiers that drive cardiac development and their potential&#160;alteration in CHDs. However, efforts to establish the causality of these putative contributors have been limited to histological&#160;and molecular studies&#160;in non-survival animal experiments, in which&#160;monitoring the key physiological and hemodynamic parameters is&#160;often absent. Live imaging technology has become an essential tool to establish the&#160;etiology of CHDs. In particular,&#160;ultrasound imaging can be used prenatally without surgically exposing the fetuses,&#160;allowing maintaining&#160;their baseline physiology while monitoring the impact of environmental stress&#160;on the hemodynamic and structural aspects of cardiac chamber development. Herein, we use the High-Frequency Ultrasound (30/45)&#160;system to examine the cardiovascular system in fetal mice at E18.5 in utero at the baseline and in response to prenatal hypoxia exposure. We demonstrate the feasibility of the system to measure cardiac chamber size, morphology, ventricular function, fetal heart rate, and umbilical artery flow indices, and their alterations in fetal mice exposed to systemic chronic hypoxia in utero in real time.

Fetal Mouse Cardiovascular Imaging Using a High-frequency Ultrasound 30/45MHZ System

High-frequency ultrasound imaging of the fetal mouse has improved imaging resolution and can provide precise non-invasive characterization of cardiac development and structural defects. The protocol outlined herein is designed to perform real-time fetal mice echocardiography in vivo.

用高频超声 (30/45 mhz) 系统对胎儿小鼠进行心血管成像

Congenital heart defects (CHDs) are the most common cause of childhood morbidity and early mortality. Prenatal detection&#160;of the underlying molecular ...

发育生物学

Controllable Nucleation of Cavitation from Plasmonic Gold Nanoparticles for Enhancing High Intensity Focused Ultrasound Applications

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) for the controllable nucleation of cavitation in tissue-mimicking gel phantoms. This in vitro protocol was developed to demonstrate the feasibility of this approach, for both enhancement of imaging and therapeutic applications for cancer. The same apparatus can be used for both imaging and therapeutic applications by varying the exposure duration of the HIFU system. For short duration exposures (10 &#181;s), broadband acoustic emissions were generated through the controlled nucleation of inertial cavitation around the gold nanoparticles. These emissions provide direct localization of nanoparticles. For future applications, these particles may be functionalized with molecular-targeting antibodies (e.g. anti-HER2 for breast cancer) and can provide precise localization of cancerous regions, complementing routine diagnostic ultrasound imaging. For continuous wave (CW) exposures, the cavitation activity was used to increase the localized heating from the HIFU exposures resulting in larger thermal damage in the gel phantoms. The acoustic emissions generated from inertial cavitation activity during these CW exposures was monitored using a passive cavitation detection (PCD) system to provide feedback of cavitation activity. Increased localized heating was only achieved through the unique combination of nanoparticles, laser light and HIFU. Further validation of this technique in pre-clinical models of cancer is necessary.

This protocol demonstrates the controllable nucleation of cavitation in gel phantoms, through simultaneous exposure to both near-infrared pulsed laser light and high intensity focused ultrasound (HIFU). The cavitation activity can then be used for enhancing imaging and/or therapeutic uses of HIFU.

等离子金纳米粒子空化的可控核增强高强度聚焦超声应用

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) ...

工程学

Evaluating Targeting Accuracy in the Focal Plane for an Ultrasound-guided High-intensity Focused Ultrasound Phased-array System

Phased arrays are increasingly used as high-intensity focused ultrasound (HIFU) transducers in the existing extracorporeal ultrasound-guided HIFU (USgHIFU) systems. The HIFU transducers in such systems are usually spherical in shape with a central hole where a US imaging probe is mounted and can be rotated. The image on the plane of treatment can be reconstructed through the image sequence acquired during the rotation of the probe. Therefore, the treatment plan can be made on the reconstructed images. In order to evaluate the targeting accuracy in the focal plane of such systems, the protocol of a method using a bovine muscle and marker-embedded phantom is described. In the phantom, four solid balls at the corners of a square resin model serve as the reference markers in the reconstructed image. The target should be moved so that both its center and the center of the square model can coincide according to their relative positions in the reconstructed image. Swine muscle with a thickness of about 30 mm is placed above the phantom to mimic the beam path in clinical settings. After sonication, the treatment plane in the phantom is scanned and the boundary of the associated lesion is extracted from the scanned image. The targeting accuracy can be evaluated by measuring the distance between the centers of target and lesion, as well as three derivative parameters. This method cannot only evaluate the targeting accuracy of the target consisting of multiple focal spots rather than a single focal spot in a clinically relevant beam path of the USgHIFU phased-array system, but it can be also used in the preclinical evaluation or regular maintenance of USgHIFU systems configured with phased-array or self-focused HIFU transducer.

This study describes a protocol to evaluate the targeting accuracy in the focal plane of an ultrasound-guided high-intensity focused ultrasound phased-array system.

超声引导高强度聚焦超声相控阵系统焦平面定位精度的评价

Phased arrays are increasingly used as high-intensity focused ultrasound (HIFU) transducers in the existing extracorporeal ultrasound-guided HIFU ...

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Presented here is a protocol to use controlled hyperthermia, generated by magnetic resonance-guided high intensity focused ultrasound, to trigger drug release from temperature-sensitive liposomes in a rhabdomyosarcoma mouse model.

磁共振引导的高强度聚焦超声产生热疗:小鼠横纹肌肉瘤模型中的可行治疗方法

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time ...

Real-Time Intravital Multiphoton Microscopy to Visualize Focused Ultrasound and Microbubble Treatments to Increase Blood-Brain Barrier Permeability

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain.
Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method.

This protocol describes the surgical and technical procedures that enable real-time in vivo multiphoton fluorescence imaging of the rodent brain during focused ultrasound and microbubble treatments to increase blood-brain barrier permeability.

实时活体内多光子显微镜可可视化聚焦超声和微气泡处理，以提高血脑屏障通透性

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles ...

生物工程

Multi-timescale Microscopy Methods for the Characterization of Fluorescently-labeled Microbubbles for Ultrasound-Triggered Drug Release

Microbubble contrast agents hold great promise for drug delivery applications with ultrasound. Encapsulating drugs in nanoparticles reduces systemic toxicity and increases circulation time of the drugs. In a novel approach to microbubble-assisted drug delivery, nanoparticles are incorporated in or on microbubble shells, enabling local and triggered release of the nanoparticle payload with ultrasound. A thorough understanding of the release mechanisms within the vast ultrasound parameter space is crucial for efficient and controlled release. This set of presented protocols is applicable to microbubbles with a shell containing a fluorescent label. Here, the focus is on microbubbles loaded with poly(2-ethyl-butyl cyanoacrylate) polymeric nanoparticles, doped with a modified Nile Red dye. The particles are fixed within a denatured casein shell. The microbubbles are produced by vigorous stirring, forming a dispersion of perfluoropropane gas in the liquid phase containing casein and nanoparticles, after which the microbubble shell self-assembles. A variety of microscopy techniques are needed to characterize the nanoparticle-stabilized microbubbles at all relevant timescales of the nanoparticle release process. Fluorescence of the nanoparticles enables confocal imaging of single microbubbles, revealing the particle distribution within the shell. In vitro ultra-high-speed imaging using bright-field microscopy at 10 million frames per second provides insight into the bubble dynamics in response to ultrasound insonation. Finally, nanoparticle release from the bubble shell is best visualized by means of fluorescence microscopy, performed at 500,000 frames per second. To characterize drug delivery in vivo, the triggered release of nanoparticles within the vasculature and their extravasation beyond the endothelial layer is studied using intravital microscopy in tumors implanted in dorsal skinfold window chambers, over a timescale of several minutes. The combination of these complementary characterization techniques provides unique insight into the behavior of microbubbles and their payload release at a range of time and length scales, both in vitro and in vivo.

The presented protocols can be used to characterize the response of fluorescently-labeled microbubbles designed for ultrasound-triggered drug delivery applications, including their activation mechanisms as well as their bioeffects. This paper covers a range of in vitro and in vivo microscopy techniques performed to capture the relevant length and timescales.

用于表征用于超声触发药物释放的荧光标记微气泡的多时间尺度显微镜方法

Microbubble contrast agents hold great promise for drug delivery applications with ultrasound. Encapsulating drugs in nanoparticles reduces systemic ...

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (&#62;500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma.
In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs.
Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

The blood-brain barrier (BBB) can be temporarily disrupted with microbubble-mediated focused ultrasound (FUS). Here, we describe a step-by-step protocol for high-throughput BBB opening in vivo using a modular FUS system accessible for non-ultrasound experts.

高通量图像引导立体定向神经导航和聚焦超声系统，用于在啮齿动物中打开血脑屏障

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a ...

神经科学

Ultrafast Doppler Ultrasound for Hepatic Microvasculature Analysis in Mice

Imaging and Quantification of the Hepatic Vasculature of Mice Using Ultrafast Doppler Ultrasound

Non-invasive in vivo imaging of the vasculature is a powerful tool for studying disease mechanisms in rodents. To achieve high sensitivity imaging of the microvasculature using Doppler ultrasound methods, imaging modalities employing the concept of ultrafast imaging are preferred. By increasing the frame rate of the ultrasound scanner to thousands of frames per second, it becomes possible to improve the sensitivity of the blood flow down to 2 mm/s and to obtain functional information about the microcirculation in comparison to a sensitivity of around 1 cm/s in conventional Doppler modes. While Ultrafast Doppler ultrasound (UFUS) imaging has become adopted in neuroscience, where it can capture brain activity through neurovascular coupling, it presents greater challenges when imaging the vasculature of abdominal organs due to larger motions linked to breathing. The liver, positioned anatomically under the diaphragm, is particularly susceptible to out-of-plane movement and oscillating respiratory motion. These artifacts not only adversely affect Doppler imaging but also complicate the anatomical analysis of vascular structures and the computation of vascular parameters. Here, we present a qualitative and quantitative imaging analysis of the hepatic vasculature in mice by UFUS. We identify major anatomical vascular structures and provide graphical illustrations of the hepatic macroscopical anatomy, comparing it to an in-depth anatomical assessment of the hepatic vasculature based on Doppler readouts. Additionally, we have developed a quantification protocol for robust measurements of hepatic blood volume of the microvasculature over time. To contemplate further research, qualitative vascular analysis provides a comprehensive overview and suggests a standardized terminology for researchers working with mouse models of liver disease. Furthermore, it offers the opportunity to apply ultrasound as a non-invasive complementary method to inspect hepatic vascular defects in vivo and measure functional microvascular alterations deep within the organ before unraveling blood vessel anomalies at the micron scale levels using ex vivo staining on tissue sections.

Ultrafast Doppler ultrasound (UFUS) with high spatial resolution (100 &#956;m) and sensitivity represents a suitable noninvasive imaging modality for obtaining a comprehensive qualitative overview of the hepatic vasculature. UFUS also facilitates quantitative measurements of the microvasculature, aiming to enhance our understanding of vascular disease mechanisms.

Non-invasive in vivo imaging of the vasculature is a powerful tool for studying disease mechanisms in rodents. To achieve high sensitivity imaging of the ...

医学

Focus Ultrasound Based Microbubble Mediated Blood-Brain Barrier Opening: A Technique to Create Localized Transient Openings in Blood-Brain Barrier of Mouse by Sonoporation

Source: Haumann, R. et al. <a href="https://www-jove-com.bdigitaluss.remotexs.co/video/61269" target="_blank">A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents.</a> J. Vis. Exp. (2020)
This video describes a method of temporarily disrupting the blood-brain barrier (BBB) by creating transient openings using microbubble-mediated focused ultrasound (FUS). These transient local BBB openings can eventually be used to deliver larger-sized drug molecules directly into the brain parenchyma.

基于聚焦超声的微泡介导的血脑屏障开口:一种通过超声在小鼠血脑屏障中创建局部瞬时开口的技术

Source: Haumann, R. et al. A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in ...

高强度的实时监控聚焦超声（HIFU）消融

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