Name: a high-performance compact photoacoustic tomography system for in vivo small-animal brain imaging
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研究由新加坡教育部（ARC2 / 15:M4020238）和新加坡卫生部国家医学研究委员会（NMRC / OFIRG / 0005/2016:M4062012）资助的第二级拨款支持。作者要感谢周伟雄博士为机加工店的帮助。

所有动物实验均按照新加坡南洋理工大学机构动物保护和使用委员会批准的指导方针和规定进行（动物标本编号ARF-SBS / NIE-A0263）。 系统说明<ol><li>将PLD安装在圆形扫描仪内， 如图1a所示。将PLD连接到激光驱动单元（LDU）。 注意:PLD在〜803 nm的波长下提供〜136 ns的脉冲，最大脉冲能量为〜1.42 mJ，重复率高达7 kHz。激光驱动单元（LDU）包括:温度控制器，可变电源，电源（12V）和功能发生器;见材料表。可变电源用于控制激光功率，功能发生器用于改变PLD的重复率。 </li><li>打开PLD激光。将PLD重复率设置为"7,000"Hz通过使用LDU中的函数发生器。通过将可变电源的电压设置为"3.1"V将脉冲能量增加到1.42 mJ。 </li><li>将光扩散器（OD）安装在PLD出口窗口前方，使输出光束均匀， 如图1a所示。 注意:使用细砂粒的扩散器（ 即 1500粒度抛光）。 </li><li>将聚焦的UST安装在UST支架上，使其面向扫描区域的中心， 如图1a所示。 注意:UST的中心频率为2.25 MHz，焦距为1.9 in。 </li><li>将超声波检测仪置于丙烯酸罐内， 如图1a所示。给水箱加水，使UST完全沉浸。 注意:水介质用于将来自大脑（样品）的光声信号耦合到UST。丙烯酸水箱（WT;见材料表）是习惯的- 设计用于小动物成像。水箱设计示意图如图1b所示。 </li><li>使用脉冲发生器/接收器单元（PRU;参见材料表 ）检查样品中的PA信号。 注意:这些信号由12位DAQ卡（参见材料表 ）以100 MS / s采样率数字化，并保存在计算机上。 </li></ol> 2.大鼠脑成像的动物准备注意:上述的PLD-PAT系统被证明用于成像小动物大脑。对于这些实验，使用健康的雌性大鼠（参见材料表 ）。 <ol><li>通过腹膜内注射2mL氯胺酮，1mL的赛拉嗪和1mL的盐水（剂量为0.2mL / 100g）麻醉动物。 </li><li>使用剪发器去除动物头皮上的毛皮。将剃毛膏轻轻涂抹于剃须面毛皮进一步耗尽的区域。 <ol><li> 4-5分钟后使用棉签去除涂抹的霜。 </li><li>将人造泪液用于动物眼睛，以防止由于麻醉和激光照射引起的干燥。 </li></ol></li><li>在实验室插孔上安装配有呼吸面罩的定制动物架（参见材料 表 ）。 </li><li>将动物置于支架上的俯卧位。使用手术胶带将其固定到支架上，以避免动物在成像过程中移动。 </li><li>确保呼吸面罩覆盖大鼠的鼻子和嘴巴以输送吸入麻醉剂。 </li></ol> 3. 体内大鼠脑成像<ol><li> 将呼吸面罩连接到麻醉机。打开麻醉机，将其设置为以0.75％异氟烷提供1.0升/分钟的氧气。 <ol><li>将脉搏血氧仪固定在其上的尾巴来监测动物的生理状态。 </li></ol></li><li> 在大鼠头皮上涂一层无色超声波凝胶。将实验室插孔位置调整到扫描仪的中心。呼吸面罩是定制的，以适应成像窗口。将10％的市售鼻锥切割然后连接到一块手套上。 <ol><li>手动调整实验室插孔的高度，使成像平面位于UST的焦点。 </li></ol></li><li>根据需要在数据采集软件中设置参数（参见材料表）。运行数据采集软件程序开始采集（ 即成像）。 注意:该程序用于旋转UST并收集A线PA信号。收集的A行将保存在计算机上。 </li><li>在整个成像期间观察动物，并在成像完成后进行PAT重建。 </li><li>数据采集​​结束后，使用重建软件程序从A线重建横断面脑图像。 </li><li>关闭麻醉系统，从舞台上取出动物，将其返回笼子，并监视它，直至恢复意识。 注意:例如，如果UST旋转5秒，则PLD提供35,000（= 5×7000）个脉冲，UST收集35,000条A线。通过平均超过70个信号（平均A线= 35,000 / 70 = 500），将35,000条A线减少到500条。 图1c示出了激光脉冲和A线收集的照明。应该使用基于延迟和总和反投影算法的重建程序。 </li></ol><img alt="图1" class="xfigimg" src="/files/ftp_upload/55811/55811fig1.jpg" /> 图1: PLD-PAT系统的示意图。 （ a ）PLD-PAT示意图。 PLD:脉冲激光二极管，CS​​P:电路AM:麻醉机，M:电机，MPU:电机皮带轮单元，LDU:激光驱动单元，PRU:脉冲发生器/接收器单元，UST:超声波换能器，WT:水箱，PF:聚合物膜和DAQ:数据采集​​卡。 （ b ）水箱示意图， 体内小动物脑成像的俯视图（1）和截面图（2）。 A:公制螺丝，B:丙烯酸环状板，C:硅胶"O"形环，D:100μm厚，透明聚乙烯盖。该罐的底部有一个9厘米直径的孔，并用超声光学透明的100μm厚的聚乙烯膜密封。 （ c ）来自PLD和A线的激光脉冲的照明示意图，在5秒的连续扫描时间内收集。 <a href="http://ecsource.jove.com/files/ftp_upload/55811/55811fig1large.jpg" target="_blank">请点击此处查看此图的较大版本。</a>

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作者对手稿没有相关的经济利益，也没有其他潜在的利益冲突披露。

该工作提出了使用PLD-PAT系统对大鼠进行体内脑成像的方案。该方案包括成像系统及其对准的详细描述，以及对大鼠脑成像的说明。现有的基于OPO的PAT系统是昂贵且庞大的，并且可以在5-10分钟内提供一个横截面图像。 PLD-PAT系统紧凑，便携，低成本，可在3秒内提供高质量的图像。系统的性能先前在幻影中进行了研究，并与传统的PAT系统25进行了比较 。在这里，相同的PLD-PAT?...

<html>光声层析成像（PAT）是一种混合成像模式，在临床和临床前研究1,2,3,4,5中都有许多应用。在PAT中，纳秒激光脉冲照射生物组织。由组织发色团吸收入射光导致局部温度升高，然后产生以声波形式发射的压力波。超声波检测器在样品周围的各个位置收集光声信号。使用各种算法（诸如延迟和和算法） 6重建光声（PA）信号以产生光声像。 这种混合成像模式提供高分辨率，深层组织成像和高光吸收对比度7 ，class ="xref"&gt; 8。近来，借助于较长波长（〜1,064nm）和称为磷酞菁的外源性造影剂，在鸡胸肉组织中获得〜12cm成像深度9 。这种深度灵敏度远远高于其他光学方法的深度敏感度，如共聚焦荧光显微镜，双光子荧光显微镜， 10光学相干断层扫描等。使用多个波长，PAT可以显示器官的结构和功能变化。对于许多人类疾病，小动物模型已经确立了12,13,14,15 。对于小动物的成像，已经证明了几种方式。在所有这些方法中，PA成像由于上述优点而获得了相当快的关注。 PAT已经显示出在4,16,17,18小动物的组织和器官（ 即心脏，肺，肝脏，眼睛，脾脏，脑，皮肤，脊髓，肾脏等 ）中成像血管的潜力。 PAT是一种成熟的小动物脑成像模式。 PA波由于发色团的光吸收而产生，所以多波长PAT允许总血红蛋白浓度（HbT）和氧饱和度（SO 2 ）的映射19,20,21,22。借助外源性造影剂12,23,24获得脑神经血管成像。 PA模式可以帮助更好地了解大脑健康提供分子和遗传水平的信息。 对于小动物成像，Nd:YAG / OPO激光器被广泛用作PAT激发源。这些激光器以〜10Hz的重复频率25提供〜5ns的近红外脉冲，能量（在OPO输出窗口为〜100mJ）。配备这种激光器的PA系统是昂贵且庞大的，由于激光源的重复率较低，因此可以使用单元件超声换能器（UST）进行低速成像。这种PA系统的典型A线采集时间为每个截面25分钟〜5分钟。具有如此长的测量时间的成像系统对于小动物成像是不理想的，因为难以控制全身成像，时间分辨功能成像等的生理参数。通过采用多个单元件UST，阵列的UST或高重复率激光器，可以提高PA的成像速度系统。仅使用一个单元件UST来收集样品周围的所有PA信号将限制系统的成像速度。以圆形或半圆形几何形式布置的多个单元件UST被演示用于高速，高灵敏度成像技术。基于阵列的UST 26 ，例如线性，半圆形，圆形和体积阵列已经成功地用于实时成像1 。这些基于阵列的UST将增加成像速度并降低测量灵敏度，但是它们昂贵。然而，使用基于阵列的UST的PA系统的成像速度仍受激光器重复率的限制。 脉冲激光技术先进于制造高重复率脉冲激光二极管（PLD）。使用临床超声波平台的PLD证明了7,000帧/秒的B扫描光声成像。这样的PLD可以提高th的成像速度e PAT系统，即使采用单元件UST圆形扫描几何形状。不同于基于阵列的UST，单元件UST更便宜且高度灵敏。在过去十年中，很少有人研究使用高重复率PLD作为PA成像的激发源。已经证明了基于纤维的近红外PLD，用于PA成像的幻影28 。使用低能量PLD 29证明了在人皮肤下约1毫米深度的血管的体内成像。报道了基于PLD的光学分辨率光声显微镜（ORPAM）。使用PLD，以0.43Hz的帧率显示〜1.5cm深的成像。最近，一个PLD-PAT系统被报道，提供的图像在短短的〜3秒和在〜2厘米成像深度的生物组织25,31 。这项研究证明，这样一个低成本，紧凑的系统可以提供高品质甚至高速图像。 PLD-PAT系统可用于高帧率（7,000 fps）光声成像，表面血管成像，手指关节成像，2厘米深的组织成像，小动物脑成像等 。单波长和来自PLD的低脉冲能量脉冲将其应用限于多光谱和深层组织成像。使用与临床前应用相同的PLD-PAT系统对小动物进行实验。这项工作的目的是提供PLD-PAT系统的可视化实验演示，用于小动物的体内 2D横断面脑成像。

<table><tbody><tr><td>Pulsed laser diode</td><td>Quantel, France</td><td>QD-Q1910-SA-TEC</td><td>It is the excitation laser source with specifications 803 nm, 1.4 mJ per pulse, 136 ns pulse, 7 kHz maximum, dimentions : 11.0 x 6.0 x 3.6 cm, weight: ~150 gm</td></tr><tr><td>Stepper motor with gearbox</td><td>LIN Engineering (Servo Dynamics)</td><td>Motor: CO-5718-01P, Gearbox: DPL64/1, I = 10 for NEMA 23; power supply PW100-48</td><td>To move the detector holder in a circular geometry. Torque: 2.08 N-m, Rotor inertia: 2.6 kg-cm2</td></tr><tr><td>Ultrasonic pulser/receiver</td><td>Olympus</td><td>5072PR</td><td>To receive, filter and ampligy the PA signal from UST. Its bandwidth is 35 MHz, and gain is &amp;plusmn;59 dB.</td></tr><tr><td>Ultrasound Transducer</td><td>Olympus</td><td>V306-SU-NK-CF1.9IN/Q4200069</td><td>Ultrasonic sensors used for photoacoustic detection. Central freqency 2.25 MHz, 0.5 in, Cylindrical focus 1.9 inch</td></tr><tr><td>PCIe DAQ (Data acquisition) Card</td><td>GaGe</td><td>CSE4227/ A6000610/B0E00610</td><td>12 bit, 100 Ms/s, 2 channels, 1 Gs on board memory, PCIe x16 interface</td></tr><tr><td>Rats</td><td>In Vivos Pte Ltd, Singapore</td><td>NTac:SD, Sprague Dawley / SD</td><td>Female, weight 100 &amp;plusmn;10g</td></tr><tr><td>Acrylic water tank&amp;nbsp;</td><td>NTU workshop</td><td>Custom-made</td><td>It contains the water that acts as an acoustic coupling medium between brain and detector</td></tr><tr><td>Circular Scanner&amp;nbsp;</td><td>NTU workshop</td><td>Custom-made</td><td>Scanner is made out of Alluminum&amp;nbsp;</td></tr><tr><td>Anesthetic Machine</td><td>medical plus pte ltd</td><td>Non-Rebreathing Anaesthesia machine with oxygen concentrator.</td><td>Supplies oxygen and isoflurane to animal</td></tr><tr><td>Pulse Oxymeter portable</td><td>Medtronic</td><td>PM10N with veterinary sensor</td><td>Monitors the pulse oxymetry of the animal</td></tr><tr><td>Ultrasound gel</td><td>Progress/parker acquasonic gel</td><td>PA-GEL-CLEA-5000</td><td>Clear ultrasound gel</td></tr><tr><td>Data acqusison software</td><td>National Instruments Corporation,Austin,TX,USA)</td><td>NI LabVIEW 2015 SP1</td><td>LabVIEW based program was developed in our laboratory for controlling the stepper motor and acquring the PA singnals from the detector</td></tr><tr><td>Data processing software</td><td>Matlab (Mathworks, Natick, MA, USA)</td><td>Matlab R2012b</td><td>Matlab code for reconstruction of PA images was developed in our lab</td></tr><tr><td>Temperature controller&amp;nbsp;</td><td>LaridTech, MO,USA</td><td>MTTC1410</td><td>It will constantly control temperature of the PLD&amp;nbsp;</td></tr><tr><td>12 V power supply&amp;nbsp;</td><td>Voltcraft&amp;nbsp;</td><td>PPS-11810</td><td>To supply operating voltage for PLD</td></tr><tr><td>Variable power supply&amp;nbsp;</td><td>BASETech</td><td>BT-153</td><td>To change the laser output power</td></tr><tr><td>Funtion generator&amp;nbsp;</td><td>Funktionsgenerator</td><td>FG250D</td><td>To change the repetetion rate of the PLD. It will provide TTL signal to synchronize the DAQ with the laser excitation.</td></tr><tr><td>Animal distributor</td><td>In Vivos Pte Ltd, Singapore</td><td></td><td>Animal distributor that supplies small animals for research purpose.</td></tr><tr><td>Animal holder</td><td>NTU workshop</td><td>Custom-made</td><td>Used for holding the animal on its abdomen</td></tr><tr><td>Breathing mask</td><td>NTU workshop</td><td>Custom-made</td><td>Used along with animal holder to supply anesthesia mixture to the animal</td></tr><tr><td>Pentobarbital sodium</td><td>Valabarb</td><td></td><td>Used for euthanizing the animal after the expeirment.</td></tr><tr><td>Optical diffuser</td><td>Thorlabs</td><td>DG10-1500</td><td>Used to to make the laser beam homogeneous</td></tr></tbody></table>

a high-performance compact photoacoustic tomography system for in vivo small-animal brain imaging

体内小动物成像在临床前研究中起重要作用。光声层析成像（PAT）是一种新兴的混合成像模式，显示临床前和临床应用的巨大潜力。传统的基于光学参数振荡器的PAT（OPO-PAT）系统体积庞大且昂贵，不能提供高速成像。最近，脉冲激光二极管（PLD）已被成功地证明是PAT的替代激发源。已经成功地证明了脉冲激光二极管PAT（PLD-PAT）用于光声模型和生物组织的高速成像。这项工作提供了使用PLD-PAT的体内脑成像的可视化实验方案。该协议包括紧凑的PLD-PAT系统配置及其描述，用于脑成像的动物准备，以及用于2D横断面大鼠脑成像的典型实验程序。 PLD-PAT系统紧凑且成本低廉有力的，可以提供高速，高品质的成像。提出了以各种扫描速度在体内收集的脑图像。

本节将介绍展示所描述的PLD-PAT系统的能力的体内脑成像结果。为了演示PLD-PAT系统的高速成像能力，进行了两种不同健康大鼠的体内脑成像。 图2以各种扫描速度显示雌性大鼠（93g）的脑图像。 图2a和b显示了在脑区域去除头皮之前和之后的大鼠脑的照片。 PAT成像是非侵入性的（ 即，皮肤和颅骨完整）。通过...

Watch this Scientific Journal Video about A High-performance Compact Photoacoustic Tomography System for In Vivo Small-animal Brain Imaging at JoVE.com

A High-performance Compact Photoacoustic Tomography System for In Vivo Small-animal Brain Imaging

证明了一种用于小动物高速体内脑成像的紧凑型基于脉冲激光二极管的光声层析成像（PLD-PAT）系统。

高性能紧凑型光声层析成像系统<em&gt;体内</em&gt;小动物脑成像

In vivo small-animal imaging has an important role to play in preclinical studies. Photoacoustic tomography (PAT) is an emerging hybrid imaging modality ...

a-high-performance-compact-photoacoustic-tomography-system-for-vivo

Research

JoVE Journal

Bioengineering

A High-performance Compact Photoacoustic Tomography System for In Vivo Small-animal Brain Imaging

10.4K 次观看.  Nanyang Technological University. 证明了一种用于小动物高速体内脑成像的紧凑型基于脉冲激光二极管的光声层析成像（PLD-PAT）系统。 

视频: A High-performance Compact Photoacoustic Tomography System for In Vivo Small-animal Brain Imaging

Three-dimensional Optical-resolution Photoacoustic Microscopy

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As the mainstays of in vivo three-dimensional (3-D) optical microscopy, single-/multi-photon fluorescence microscopy and optical coherence tomography (OCT) have demonstrated their extraordinary sensitivities to fluorescence and optical scattering contrasts, respectively. However, the optical absorption contrast of biological tissues, which encodes essential physiological/pathological information, has not yet been assessable. 
The emergence of biomedical photoacoustics has led to a new branch of optical microscopy optical-resolution photoacoustic microscopy (OR-PAM)1, where the optical irradiation is focused to the diffraction limit to achieve cellular1 or even subcellular2 level lateral resolution. As a valuable complement to existing optical microscopy technologies, OR-PAM brings in at least two novelties. First and most importantly, OR-PAM detects optical absorption contrasts with extraordinary sensitivity (i.e., 100%). Combining OR-PAM with fluorescence microscopy3 or with optical-scattering-based OCT4 (or with both) provides comprehensive optical properties of biological tissues. Second, OR-PAM encodes optical absorption into acoustic waves, in contrast to the pure optical processes in fluorescence microscopy and OCT, and provides background-free detection. The acoustic detection in OR-PAM mitigates the impacts of optical scattering on signal degradation and naturally eliminates possible interferences (i.e., crosstalks) between excitation and detection, which is a common problem in fluorescence microscopy due to the overlap between the excitation and fluorescence spectra. 
Unique for optical absorption imaging, OR-PAM has demonstrated broad biomedical applications since its invention, including, but not limited to, neurology5, 6, ophthalmology7, 8, vascular biology9, and dermatology10. In this video, we teach the system configuration and alignment of OR-PAM as well as the experimental procedures for in vivo functional microvascular imaging.

Optical-resolution photoacoustic microscopy (OR-PAM) is an emerging technology capable of imaging optical absorption contrasts in vivo with cellular resolution and sensitivity. Here, we provide a visualized instruction on the experimental protocols of OR-PAM, including system configuration, system alignment, typical in vivo experimental procedures, and functional imaging schemes.

三维光学分辨率的光声显微镜

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As ...

科研

生物工程

Computed Tomography-guided Time-domain Diffuse Fluorescence Tomography in Small Animals for Localization of Cancer Biomarkers

Small animal fluorescence molecular imaging (FMI) can be a powerful tool for preclinical drug discovery and development studies1. However, light absorption by tissue chromophores (e.g., hemoglobin, water, lipids, melanin) typically limits optical signal propagation through thicknesses larger than a few millimeters2. Compared to other visible wavelengths, tissue absorption for red and near-infrared (near-IR) light absorption dramatically decreases and non-elastic scattering becomes the dominant light-tissue interaction mechanism. The relatively recent development of fluorescent agents that absorb and emit light in the near-IR range (600-1000 nm), has driven the development of imaging systems and light propagation models that can achieve whole body three-dimensional imaging in small animals3.
Despite great strides in this area, the ill-posed nature of diffuse fluorescence tomography remains a significant problem for the stability, contrast recovery and spatial resolution of image reconstruction techniques and the optimal approach to FMI in small animals has yet to be agreed on. The majority of research groups have invested in charge-coupled device (CCD)-based systems that provide abundant tissue-sampling but suboptimal sensitivity4-9, while our group and a few others10-13 have pursued systems based on very high sensitivity detectors, that at this time allow dense tissue sampling to be achieved only at the cost of low imaging throughput. Here we demonstrate the methodology for applying single-photon detection technology in a fluorescence tomography system to localize a cancerous brain lesion in a mouse model.
The fluorescence tomography (FT) system employed single photon counting using photomultiplier tubes (PMT) and information-rich time-domain light detection in a non-contact conformation11. This provides a simultaneous collection of transmitted excitation and emission light, and includes automatic fluorescence excitation exposure control14, laser referencing, and co-registration with a small animal computed tomography (microCT) system15. A nude mouse model was used for imaging. The animal was inoculated orthotopically with a human glioma cell line (U251) in the left cerebral hemisphere and imaged 2 weeks later. The tumor was made to fluoresce by injecting a fluorescent tracer, IRDye 800CW-EGF (LI-COR Biosciences, Lincoln, NE) targeted to epidermal growth factor receptor, a cell membrane protein known to be overexpressed in the U251 tumor line and many other cancers18. A second, untargeted fluorescent tracer, Alexa Fluor 647 (Life Technologies, Grand Island, NY) was also injected to account for non-receptor mediated effects on the uptake of the targeted tracers to provide a means of quantifying tracer binding and receptor availability/density27. A CT-guided, time-domain algorithm was used to reconstruct the location of both fluorescent tracers (i.e., the location of the tumor) in the mouse brain and their ability to localize the tumor was verified by contrast-enhanced magnetic resonance imaging.
Though demonstrated for fluorescence imaging in a glioma mouse model, the methodology presented in this video can be extended to different tumor models in various small animal models potentially up to the size of a rat17.

Diffuse fluorescence tomography offers a relatively low-cost and potentially high-throughout approach to preclinical in vivo tumor imaging. The methodology of optical data collection, calibration, and image reconstruction is presented for a computed tomography-guided non-contact time-domain system using fluorescent targeting of the tumor biomarker epidermal growth factor receptor in a mouse glioma model.

电脑断层导引的时域漫荧光体层摄影术在小动物的肿瘤生物标志物的本土化

Small animal fluorescence molecular imaging (FMI) can be a powerful tool for preclinical drug discovery and development studies1. However, light ...

医学

Universal Hand-held Three-dimensional Optoacoustic Imaging Probe for Deep Tissue Human Angiography and Functional Preclinical Studies in Real Time

The exclusive combination of high optical contrast and excellent spatial resolution makes optoacoustics (photoacoustics) ideal for simultaneously attaining anatomical, functional and molecular contrast in deep optically opaque tissues. While enormous potential has been recently demonstrated in the application of optoacoustics for small animal research, vast efforts have also been undertaken in translating this imaging technology into clinical practice. We present here a newly developed optoacoustic tomography approach capable of delivering high resolution and spectrally enriched volumetric images of tissue morphology and function in real time. A detailed description of the experimental protocol for operating with the imaging system in both hand-held and stationary modes is provided and showcased for different potential scenarios involving functional and molecular studies in murine models and humans. The possibility for real time visualization in three dimensions along with the versatile handheld design of the imaging probe make the newly developed approach unique among the pantheon of imaging modalities used in today&#8217;s preclinical research and clinical practice.

We provide herein a detailed description of the experimental protocol for imaging with a newly developed hand-held optoacoustic (photoacoustic) system for three-dimensional functional and molecular imaging in real time. The demonstrated powerful performance and versatility may define new application areas of the optoacoustic technology in preclinical research and clinical practice.

通用型手持式三维光声成像探测深部组织人力造影和功能的临床前研究中实时

The exclusive combination of high optical contrast and excellent spatial resolution makes optoacoustics (photoacoustics) ideal for simultaneously ...

Non-invasive Parenchymal, Vascular and Metabolic High-frequency Ultrasound and Photoacoustic Rat Deep Brain Imaging

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central nervous system of small animals. However, transdermal and transcranial neuroimaging is frequently affected by low sensitivity, image aberrations and loss of space resolution, requiring scalp or even skull removal before imaging. To overcome this challenge, a new protocol is presented to gain significant insights in brain hemodynamics by photoacoustic and high-frequency ultrasounds imaging with the animal skin and skull intact. The procedure relies on the passage of ultrasound (US) waves and laser directly through the fissures that are naturally present on the animal cranium. By juxtaposing the imaging transducer device exactly in correspondence to these selected areas where the skull has a reduced thickness or is totally absent, one can acquire high quality deep images and explore internal brain regions that are usually difficult to anatomically or functionally describe without an invasive approach. By applying this experimental procedure, significant data can be collected in both sonic and optoacoustic modalities, enabling to image the parenchymal and the vascular anatomy far below the head surface. Deep brain features such as parenchymal convolutions and fissures separating the lobes were clearly visible. Moreover, the configuration of large and small blood vessels was imaged at several millimeters of depth, and precise information were collected about blood fluxes, vascular stream velocities and the hemoglobin chemical state. This repertoire of data could be crucial in several research contests, ranging from brain vascular disease studies to experimental techniques involving the systemic administration of exogenous chemicals or other objects endowed with imaging contrast enhancement properties. In conclusion, thanks to the presented protocol, the US and PA techniques become an attractive noninvasive performance-competitive means for cortical and internal brain imaging, retaining a significant potential in many neurologic fields.

The present work describes a new protocol to perform non-invasive high-frequency ultrasound and photoacoustic based imaging on rat brain, to efficiently visualize deep subcortical regions and their vascular patterns by directing signals on skull foramina naturally present on animal cranium.

非侵入性的脑实质，血管和代谢高频超声和光声大鼠深脑成像

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central ...

神经科学

Switchable Acoustic and Optical Resolution Photoacoustic Microscopy for In Vivo Small-animal Blood Vasculature Imaging

Photoacoustic microscopy (PAM) is a fast-growing invivo imaging modality that combines both optics and ultrasound, providing penetration beyond the optical mean free path (~1 mm in skin) with high resolution. By combining optical absorption contrast with the high spatial resolution of ultrasound in a single modality, this technique can penetrate deep tissues. Photoacoustic microscopy systems can have either a low acoustic resolution and probe deeply or a high optical resolution and probe shallowly. It is challenging to achieve high spatial resolution and large depth penetration with a single system. This work presents an AR-OR-PAM system capable of both high-resolution imaging at shallow depths and low-resolution deep-tissue imaging of the same sample in vivo. A lateral resolution of 4 &#181;m with 1.4 mm imaging depth using optical focusing and a lateral resolution of 45 &#181;m with 7.8 mm imaging depth using acoustic focusing were successfully demonstrated using the combined system. Here,&#160;in vivo&#160;small-animal blood vasculature imaging is performed to demonstrate its biological imaging capability.

Switchable Acoustic and Optical Resolution Photoacoustic Microscopy for In Vivo Small-animal Blood Vasculature Imaging

Here a switchable acoustic resolution (AR) and optical resolution (OR) photoacoustic microscopy (AR-OR-PAM) system capable of both high resolution imaging at shallow depth and low resolution deep tissue imaging on the same sample in vivo is demonstrated.

可切换声光学分辨率光声显微镜<em&gt;体内</em&gt;小动物血液血管成像

Photoacoustic microscopy (PAM) is a fast-growing invivo imaging modality that combines both optics and ultrasound, providing penetration beyond the ...

Hand-held Clinical Photoacoustic Imaging System for Real-time Non-invasive Small Animal Imaging

Translation of photoacoustic imaging into the clinic is a major challenge. Handheld real-time clinical photoacoustic imaging systems are very rare. Here, we report a combined photoacoustic and clinical ultrasound imaging system by integrating an ultrasound probe with light delivery for small animal imaging. We demonstrate this by showing sentinel lymph node imaging in small animals along with minimally invasive real-time needle guidance. A clinical ultrasound platform with access to raw channel data allows the integration of photoacoustic imaging leading to a handheld real-time clinical photoacoustic imaging system. Methylene blue was used for sentinel lymph node imaging at 675 nm wavelength. Additionally, needle guidance with dual modal ultrasound and photoacoustic imaging was shown using the imaging system. Depth imaging of up to 1.5 cm was demonstrated with a 10 Hz laser at a photoacoustic imaging frame rate of 5 frames per second.

A clinical handheld photoacoustic imaging system will be demonstrated for real-time non-invasive small animal imaging.

手持式实时非侵入性小动物成像的临床光声成像系统

Translation of photoacoustic imaging into the clinic is a major challenge. Handheld real-time clinical photoacoustic imaging systems are very rare. Here, ...

Pulsed Laser Diode-Based Desktop Photoacoustic Tomography for Monitoring Wash-In and Wash-Out of Dye in Rat Cortical Vasculature

Photoacoustic (PA) tomography (PAT) imaging is an emerging biomedical imaging modality useful in various preclinical and clinical applications. Custom-made circular ring array-based transducers and conventional bulky Nd:YAG/OPO lasers inhibit translation of the PAT system to clinics. Ultra-compact pulsed laser diodes (PLDs) are currently being used as an alternative source of near-infrared excitation for PA imaging. High-speed dynamic in vivo imaging has been demonstrated using a compact PLD-based desktop PAT system (PLD-PAT). A visualized experimental protocol using the desktop PLD-PAT system is provided in this work for dynamic in vivo brain imaging. The protocol describes the desktop PLD-PAT system configuration, preparation of animal for brain vascular imaging, and procedure for dynamic visualization of indocyanine green (ICG) dye uptake and clearance process in rat cortical vasculature.&#160;

A compact pulsed laser diode-based desktop photoacoustic tomography (PLD-PAT) system is demonstrated for high-speed dynamic in vivo imaging of small animal cortical vasculature.

基于脉冲激光二极管的桌面光声层析成像在大鼠皮质血管内监测染料的洗入和洗脱

Photoacoustic (PA) tomography (PAT) imaging is an emerging biomedical imaging modality useful in various preclinical and clinical applications. ...

Dual Raster-Scanning Photoacoustic Small-Animal Imager for Vascular Visualization

Imaging of vascular networks on small animals has played an important role in basic biomedical research. Photoacoustic imaging technology has great potential for application in the imageology of small animals. The wide-field photoacoustic imaging of small animals can provide images with high spatiotemporal resolution, deep penetration, and multiple contrasts. Also, the real-time photoacoustic imaging system is desirable to observe the hemodynamic activities of small-animal vasculature, which can be used to research the dynamic monitoring of small-animal physiological features. Here, a dual-raster-scanning photoacoustic imager is presented, featuring a switchable double-mode imaging function. The wide-field imaging is driven by a two-dimensional motorized translation stage, while the real-time imaging is realized with galvanometers. By setting different parameters and imaging modes, in vivo visualization of small-animal vascular network can be performed. The real-time imaging can be used to observe pulse change and blood flow change of drug-induced, etc. The wide-field imaging can be used to track the growth change of tumor vasculature. These are easy to be adopted in various areas of basic biomedicine research.

A dual raster-scanning photoacoustic imager was designed, which integrated wide-field imaging and real-time imaging.

用于血管可视化的双栅格扫描光声小动物成像仪

Imaging of vascular networks on small animals has played an important role in basic biomedical research. Photoacoustic imaging technology has great ...

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 ...

缺血性卒中的无创综合 PAUSAT 全脑成像

Integrated Photoacoustic, Ultrasound, and Angiographic Tomography (PAUSAT) for NonInvasive Whole-Brain Imaging of Ischemic Stroke

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging technologies: photoacoustic, ultrasound, and angiographic tomography (PAUSAT). Combining these three modalities helps acquire multi-spectral photoacoustic tomography (PAT) of the brain blood oxygenation, high-frequency ultrasound imaging of the brain tissue, and acoustic angiography of the cerebral blood perfusion. The multi-modal imaging platform allows the study of cerebral perfusion and oxygenation changes in the whole mouse brain after stroke. Two commonly used ischemic stroke models were evaluated: the permanent middle cerebral artery occlusion (pMCAO) model and the photothrombotic (PT) model. PAUSAT was used to image the same mouse brains before and after a stroke and quantitatively analyze both stroke models. This imaging system was able to clearly show the brain vascular changes after ischemic stroke, including significantly reduced blood perfusion and oxygenation in the stroke infarct region (ipsilateral) compared to the uninjured tissue (contralateral). The results were confirmed by both laser speckle contrast imaging and triphenyltetrazolium chloride (TTC) staining. Furthermore, stroke infarct volume in both stroke models was measured and validated by TTC staining as the ground truth. Through this study, we have demonstrated that PAUSAT can be a powerful tool in noninvasive and longitudinal preclinical studies of ischemic stroke.

作者聚焦：用于缺血性卒中的无创全脑成像的集成光声、超声和血管造影断层扫描 （PAUSAT）  

This work demonstrates the use of a multimodal ultrasound-based imaging platform for noninvasive imaging of ischemic stroke. This system allows for the quantification of blood oxygenation through photoacoustic imaging and impaired perfusion in the brain through acoustic angiography.

集成光声、超声和血管造影断层扫描 （PAUSAT） 用于缺血性卒中的无创全脑成像

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging ...

高性能紧凑型光声层析成像系统

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三维光学分辨率的光声显微镜

电脑断层导引的时域漫荧光体层摄影术在小动物的肿瘤生物标志物的本土化

通用型手持式三维光声成像探测深部组织人力造影和功能的临床前研究中实时

非侵入性的脑实质，血管和代谢高频超声和光声大鼠深脑成像

可切换声光学分辨率光声显微镜

手持式实时非侵入性小动物成像的临床光声成像系统

基于脉冲激光二极管的桌面光声层析成像在大鼠皮质血管内监测染料的洗入和洗脱

用于血管可视化的双栅格扫描光声小动物成像仪

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

集成光声、超声和血管造影断层扫描（PAUSAT）用于缺血性卒中的无创全脑成像

高性能紧凑型光声层析成像系统

摘要

探索更多视频

此视频中的章节

三维光学分辨率的光声显微镜

电脑断层导引的时域漫荧光体层摄影术在小动物的肿瘤生物标志物的本土化

通用型手持式三维光声成像探测深部组织人力造影和功能的临床前研究中实时

非侵入性的脑实质，血管和代谢高频超声和光声大鼠深脑成像

可切换声光学分辨率光声显微镜

手持式实时非侵入性小动物成像的临床光声成像系统

基于脉冲激光二极管的桌面光声层析成像在大鼠皮质血管内监测染料的洗入和洗脱

用于血管可视化的双栅格扫描光声小动物成像仪

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

集成光声、超声和血管造影断层扫描 （PAUSAT） 用于缺血性卒中的无创全脑成像

集成光声、超声和血管造影断层扫描（PAUSAT）用于缺血性卒中的无创全脑成像