该项目得到了国家卫生研究所 UH3 NS095554 的支持。技术支持由科学计算和成像研究所的综合生物医学计算中心提供, 部分是由 NIH P41-GM103545、综合生物医学计算中心开发的软件所实现。
感激之情延伸到莱西地板和内森加利在科学计算和成像研究所的制作和编辑的提交视频, 也向特里萨林林为协助的手稿准备。

1. 图像处理
<ol><li>T1 MRI 分割<ol>
<li>下载并安装 FreeSurfer17。假设 T1 MRI 已获得, 并以 DICOM 或 NIFTI 格式。</li>
		<li>键入以下命令以创建病人目录并在 FreeSurfer 中添加他们的 T1 卷:侦察全 patientName-i/全/路径/到/nii
</li>
		<li>键入以下命令以运行 FreeSurfer 的自动分割:侦察全 s patientName-所有
</li>
		<li>使用mri_convert将 "aseg.auto.mgz" 转换为 FreeSurfer 的专有 mgz 格式。</li>
	</ol>
</li>
	<li>扩散加权成像 (DWI)<ol>
<li>下载并安装切片器18。假定已执行了一个 DWI 捕获, 并可作为 DICOM 文件的一叠。 注意: 执行此重建的一个好的命令行工具是 FMRIB 软件库 (FSL)19。在该协议中, FSL 用于在重建前执行回波平面、运动和涡流畸变校正。该分析中使用的 DWI 数据是一系列的 DICOM 文件, 用于41种不同的扩散敏感梯度方向。</li>
		<li>使用切片器中的DWIConverter模块将41个单独的收购重构为单个卷。指定在其中的 DWI 数据所在的输入 Dicom 数据目录。选择DicomToNrrd单选按钮并提供输出 DWI 音量的名称。</li>
		<li>用扩散加权体积掩蔽模块创建张量掩码, 以消除 DTI 估计的背景噪声。将阈值参数保留为默认为0.5。</li>
		<li>使用在上一步中创建的掩码作为扩散张量掩码, 将此单一的 dwi 体积转换为扩散张量 (dti) 体积, 并将dwi 估计为 dti 。将估计参数设置为最小二乘法, 并确保检查了移位负特征值选项。</li>
		<li>以 NRRD 格式保存新创建的 DTI 卷。</li>
	</ol>
</li>
</ol>2. 有限元模型生成
<ol><li>SCIRun<ol>
<li>下载并安装 SCIRun 版本 5 (http://www.sci.utah.edu/software/scirun.html)。SCIRun 是一个解决问题的环境, 用于建模、模拟和可视化科学问题。这是用于创建、解决和与此项目中开发的模型进行交互的计算工作台。 注意: SCIRun 网络是由执行特定任务的各个模块的连接序列构建的。通过由简单模块组成的网络传递数据, 可以进行更复杂的处理和模拟。</li>
	</ol>
</li>
	<li>生成电极几何 注: 在此项目中建模的电极是美敦力3387星展20铅。它是一个圆柱形引线, 四个接触1.5 毫米的高度, 直径1.27 毫米, 间隔1.5 毫米分开。非导电材料将四接触点隔开。<ol>
<li>为星展公司潜在顾客中的每个组件创建一个闭合曲面网格, 以匹配列出的维度。使用两个原始几何图形、圆柱和球体创建整个引线。 注意: 可以在各种3D 建模程序中创建引线几何图形。</li>
		<li>创建一个表面网格的封装层0.5 毫米厚周围的整个铅。</li>
	</ol>
</li>
	<li>创建整个脑网<ol>
<li>加载1部分中创建的脑表面, 作为有限元的外边界。</li>
		<li>创建两个同心盒表面围绕星展集团的领导, 以控制网格密度围绕电极。 注: 星展导线和盒面应沿正 z 轴与位于原点的电极轴的底部对齐。这对于以后电极的旋转和平移是很重要的。</li>
		<li>创建一个点云, 其位于网格的每个不同区域中的单个点。网格的区域有: 轴段、四触点、盒子和脑表面。附加到这些点的值表示该区域网格中每个四面体元素的最大卷约束。这些约束调整, 以控制网格密度在和周围的电极。</li>
		<li>使用 "InterfaceWithTetGen" 模块创建整个脑网。按如下方式设置输入端口: 端口 1: 脑表面 (从 1.1) 端口 2: 区域属性点云, 卷约束 (从 2.3.3) 端口 3: 无 端口 4: 电极模型表面 (从 2.2)</li>
	</ol>
</li>
	<li>交互式电极放置 注意: 这一步的目标是使电极在大脑内的任何地方都能轻松移动, 并让系统自动更新新的网格和模拟。<ol>
<li>使用两个级联CreateGeometricTransform模块在 X 和 Y 平面上旋转电极。单击 "旋转", 并将第一个模块设置为1.00 轴Y , 第二个到 1.00轴 X。旋转角度设置为底部滑块,旋转θ (度数)。</li>
		<li>为需要转换的每个转换和对象连接一个TransformMeshWithTransform模块。</li>
		<li>创建一个GenerateSinglePointProbeFromField模块, 并将其几何端口连接到ViewScene模块。通过按住 shift 键和左键单击, 在ViewScene窗口中移动球体。点探头模块在释放时更新球体的位置。 注意: 此位置用于确定应用于电极几何的平移变换。</li>
		<li>使用TransformMeshWithTransform模块将电极几何的每个部分转换为点探头位置。</li>
		<li>将两个旋转变换和从点探针构件到除脑表面以外的每个物体的平移。 注: 所有三的转换都应在每个对象上执行, 然后再管道进入InterfaceWithTetGen模块, 这样啮合算法就知道在新的位置和方向上将大脑内的电极几何网格化。每次在大脑中移动电极时, 都会生成一个新的网格。</li>
	</ol>
</li>
</ol>3. 生物场计算
<ol><li>设置电导率参数<ol>
<li>加载在步骤1中创建的 DTI 卷, 并将数据从步骤2中创建的InterfaceWithTetGen的四面体网格输出设置为使用线性 ("加权") 选项的MapFieldDataFromSourceToDestination 。 注意: 任何各向异性电导率估计都可以在这个步骤中实现。</li>
		<li>使用CalculateFieldData将轴区域电导率设置为 1e-6, 并将触点区域设为1e6。一旦设置了所有的电导率值, 将该字段管入BuildFEMatrix。</li>
	</ol>
</li>
	<li>设置电流/电压源和边界条件<ol>
<li>管在啮合过程中使用的大脑表面从步骤2到SetFieldDataToConstantValue , 并将该值设置为0。这将在整个大脑表面产生一个电压接收器。然后使用InsertVoltageSource将电压值放在InterfaceWithTetGen的四面体网格输出上。</li>
		<li>对于单刺激, 通过计算一个接触面上的ReportFieldInfo模块中的 FieldCenter 值, 在一个联系位置的中心创建一个点。将此点上的字段数据设置为-1 伏。然后使用InsertVoltageSource将点源放置在四面体网格中。 注: 现在有两个四面体网格的副本。一个有电压值设置在大脑表面和一个点源内的联系人。</li>
		<li>加入两个InsertVoltageSource模块的输出, 并将输出ApplyFEMVoltageSource输出BuildFEMatrix。</li>
	</ol>
</li>
	<li>解决正向问题 注: ApplyFEMVoltageSource的输出给出端口1上的刚度矩阵和端口2上的右端矩阵。这是解决方程组所需的两个组成部分。<ol>
<li>将ApplyFEMVoltageSource的两个输出管成SolveLinearSystem。选取共轭梯度解法和雅比法作为预设条件。本模块的输出是求解矩阵, 在四面体网格中每个节点的电压值。</li>
		<li>使用SetFieldData将电压解矩阵放到四面体网格上, 以3D 表示电压分布。</li>
	</ol>
</li>
	<li>等值面可视化<ol>
<li>把SetFieldData的结果管成ExtractSimpleIsosurface。将 UI 打开到 "数量" 选项卡, 并将平均间隔的 isovalues 数设置为10。</li>
		<li>使用ShowField模块并将其连接到ViewScene模块, 以显示等值面为透明, 并将彩虹色图缩放到电压解决方案的最小和最大值。</li>
	</ol>
</li>
</ol>

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克里斯托弗 r. Butson 博士曾担任 NeuroPace、高级仿生学、波士顿科学、Intelect 医学、圣裘德医学和功能调节顾问。

该协议展示了降低星展集团患者特定模型的时间负担和计算成本的技术, 使其能够在一定程度上实现模拟结果的近实时反馈。快速反馈使探索一个大的参数空间, 以更好地了解参数变化如何影响模型结果。这些参数包括引线位置、主动触点的选择、振幅、脉冲宽度和激发波形在这些接触处的频率。所建议的工具的主要特点是: 1) 一个简单的用户界面, 以近实时可视化的方式来调整模型参数, 这些参数如何影响仿真, 以及 2) 从一小部分输入中创建模型的自动化: 大脑表面,脑组织电导率张量和电极几何的表面表示法。这种自动化加速了为许多人创建病人特定的模型, 他们有不同的大脑几何和组织电导率, 以及评估插入不同的电极设计到现有的模型的效果。本协议中描述的图像预处理步骤不是完全自动化的, 可能需要一天的处理时间。但是, 一旦完成了从这些步骤生成的数据被认为是静态的, 这意味着在模拟过程中不会修改这些数据。模型创建的自动化是由系统在没有人工努力的情况下将这些数据应用于特定于病人的有限元的能力。SCIRun 网络执行所有的模型生成、仿真、可视化步骤只需要构建一次。因此, 只有图像预处理步骤需要再次执行, 才能为传入的病人生成特定于病人的模型。
建模管线产生结果的性能增益是由网格生成、生物场计算和解的可视化集成到单个软件环境中的。采用自适应网格生成等现有建模技术, 在电极周围产生较高的网格密度, 使电极的密度更低, 从而缩短了有限元的生成和求解时间。该软件 SCIRun 还能实现网格生成和生物字段计算的自动化。使用交互式小部件的用户定义的电极移动会触发新的网格的构造, 并更新电极位置。这包括修改新电极位置的边界条件和电导率值。
电极几何被视为一个自由运动物体内的大脑体积之前, 其位置被纳入有限元。这种网格构造方法的一个关键含义是可以很容易地将多个电极插入模型中。例如, 电极几何的第二个拷贝可以放置几毫米远, 并且两者将包括在有限元中。在最近的研究中, 两个电极被植入近距离治疗多发性硬化震颤13 , 并已用于非人类灵长类实验, 以探索有效的刺激目标21。使用多电极的好处是更好地控制在较大区域内组织产生的电场。刺激与活跃接触在两个电极可以引导电流向目标区域和远离区域, 将导致负面的副作用。更精细地控制刺激在一个更大的区域也是有用的探索不同的刺激地点, 当确切的地点的预期目标是未知的, 像这样的情况下, 许多新兴疗法应用的 DBS。然而, 由于已有较大的参数空间的增加, 确定获得治疗性刺激的参数比单个电极更具挑战性。
我们设想, 这种交互式建模工具可以为星展公司的植入前规划提供好处。对脑组织中刺激程度的反馈可以让外科医生在其手术计划中修改电极位置, 以便为靶区提供治疗性刺激。星展疗法是开发这一工具的主要动力因素, 本文所提出的技术可以应用于任何具有不同刺激或记录范式的有限元生物场模型。刺激疗法, 如经颅直接电流刺激抑郁症22或使用深度电极治疗癫痫23与 DBS 在确定最佳刺激位置, 以实现治疗结果。皮层脑电图, 一种记录技术, 其表面的电极阵列, 以确定癫痫发作的地区, 有一个挑战, 确定在哪里放置电极记录从目标地区的大脑24。所有这些应用都依赖于电极位置, 同时处理电流在脑组织中流动的不确定性。本文所提供的技术减少了生成和使用计算模型的负担, 同时为研究人员和临床医生提供了有意义的反馈, 这些设备不是模型专家。

深部脑刺激 (DBS) 是一种已建立的治疗运动障碍, 如必要的震颤1和帕金森病2。这项治疗也被调查为一个潜在的治疗越来越多的疾病, 包括创伤性脑损伤3, 抽动秽语综合征4, 抑郁症5。星展系统需要外科植入电极导致在局部脑区进行刺激, 以调节正在进行的神经活动6。电极的位置和刺激参数都对调节神经元回路产生治疗效果有一定的影响。小的位置变化可能会影响治疗窗口, 可能会增加不良副作用的可能性, 在治疗效果达到7,8,9。在实践中, 通常很难预测刺激对神经活动的影响;因此, 这一治疗效果的窗口是在病人的基础上确定的, 因为刺激装置是由临床医生8,9编程。随着新一代星展设备的推出, 这个过程变得更加复杂。例如, 新的引线设计正在引入更多的联系人10,11,12, 在某些情况下, 多个潜在顾客被植入近距离13。因此, 有必要能够探索和预测 DBS 在一个大的和不断增长的参数空间的影响。
计算建模和分析可用于预测星展集团在患者特定基础上的生理和临床效果。这些模型使用有限元建模 (FEM) 建立三维表示的脑组织和生物物理特性的植入电极。有限元生物场模型已成功地用于预测星展14的影响, 但到目前为止, 这些都是耗时和计算成本高昂的产生。需要新的建模技术来跟上星展设备日益增长的复杂性。这些病人特定的模型应提供近实时视觉反馈的影响, 星展集团的潜在位置或刺激参数的变化。用户将在几秒钟内获得有关潜在顾客位置和刺激设置的反馈, 从而在几分钟内继续改进铅的放置过程。病人特异性是通过结合病人的解剖, 他们的大脑的形状和大小, 当建立有限元和应用他们的大脑的生物物理特性, 如各向异性组织电导率。各向异性电导率描述了电流将如何通过不同的大脑区域传播, 并且可以非侵入性测量整个大脑类似于典型的磁共振图像 (MRI)。
星展的建模方法不使用病人特定的信息可以提供快速, 但不准确的预测刺激效应, 由于广义几何和电导率的大脑组织。在这种方法中, 对所有患者使用单一的有限元, 预测的神经活动可以提前计算。由于每个个体都建立了一个新的有限元模型, 因此不能对特定的病人进行泛化和预计算。这些模型需要更多的努力来构建, 但可以更准确。有几个因素限制了这些模型的生成和使用速度: 1) 在模型生成管线开始时修改参数, 如电极位置, 需要手动更新所有后续步骤;和 2) 建模管道中的步骤不易相互集成, 需要在多个软件包之间传递数据。通常, 我们要评估许多不同的情况, 如电极位置, 刺激参数, 或电极设计。为了提供有意义的反馈, 这些变化对患者将接受的治疗效果的影响, 这些结果应该是准确的, 并迅速产生。
我们的目标是提供新的技术, 以建立病人特定的模型, 利用通用模型获得的速度和自动化许多管道步骤, 以创建一个交互式建模环境, 提供近实时视觉对 DBS 效应的反馈。交互式模拟允许用户在不关注模型构造细节的情况下快速测试预测并获得结果。这是有益的, 当有一个大的参数空间来探索, 这些参数如何影响模拟是不确定的。我们将描述在处理管道中的步骤, 以产生交互式的, 病人特定的有限元模型的磁共振成像 (MRI) 收购。利用本文概述的工具和技术, 可以减少创建有限元生物场模型的时间成本, 并提供一种方法, 使这些模型可供没有建模专家的研究人员和临床医生使用。
该协议描述了如何从获得的 MRI 容量中构建病人特定的有限元模型, 然后模拟星展电极引起的电场。创建这些模型的主要步骤是: 1) 建立一个代表患者大脑和植入电极的有限元模型 (FEM), 2) 增加大脑的生物物理特性, 并将星展设备的刺激参数限定为有限元, 3) 解决在模型中由电极产生的电压。需要两种成像方式来建立星展模拟的病人特定模型。T1 MRI 用于构建脑表面、心室和特定细胞核的分割。扩散加权成像 (DWI) 是一种水扩散率测量方法, 用于估计整个脑组织15的扩散张量。将扩散张量转换成电导率张数, 以体素为基础, 将组织的非均匀、各向异性生物物理特性量化为16。通过求解泊松方程, 通过有限元法简化到线性方程组的线性系统, 计算出电极所引起的整个脑部的电压分布, 其中a是刚度矩阵,表示网格的电导率和几何, x是网格中每个节点的电压解, b根据边界条件和电流源进行修改。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr >
			<td >FreeSurfer</td>
			<td >Athinoula A. Martinos Center for Biomedical Imaging</td>
			<td ></td>
			<td ><a href="https://surfer.nmr.mgh.harvard.edu/">https://surfer.nmr.mgh.harvard.edu/</a></td>
		</tr>
		<tr >
			<td >3D Slicer</td>
			<td >BWH, Harvard University</td>
			<td ></td>
			<td><a href="https://www.slicer.org/">https://www.slicer.org/</a></td>
		</tr>
		<tr >
			<td >SCIRun&#160;</td>
			<td >University of Utah Center for Integrative Biomedical Computing</td>
			<td ></td>
			<td><a href="http://www.sci.utah.edu/cibc-software/scirun.html">http://www.sci.utah.edu/cibc-software/scirun.html</a></td>
		</tr>
	</tbody>
</table>

targeting neuronal fiber tracts for deep brain stimulation therapy using interactive, patient-specific models

深部脑刺激 (DBS), 其中包括插入电极, 以提供刺激到局部大脑区域, 是一个既定的治疗运动紊乱, 并正在应用于越来越多的疾病。计算建模已成功地用于预测 DBS 的临床效果;然而, 需要新的建模技术来跟上星展设备日益增长的复杂性。这些模型还需要快速准确地生成预测。该项目的目标是开发一个图像处理管道, 将结构磁共振成像 (MRI) 和扩散加权成像 (DWI) 纳入一个交互式的, 病人的具体模型, 以模拟的影响, DBS。虚拟星展导线可以放置在病人模型内, 以及主动接触和刺激设置, 在那里铅位置或方向的变化产生一个新的有限元网格和解决生物场问题近实时,timespan 大约10秒。该系统还能够在接近接近度的情况下模拟多个引线, 以便在不同的引线上通过不同的阳极和阴极对电流进行转向。本文提出的技术减少了生成和使用计算模型的负担, 同时为研究人员或临床医生提供了对电极位置、电极设计和刺激配置的影响的有意义的反馈。谁可能不会建模专家。

在本议定书的末尾提供了创建病人特定模型所需的所有输入: 脑表面、电极几何和电导率张量。还应该创建一个 SCIRun 网络, 将所有输入集成起来, 建立一个有限元模型, 并模拟诱导的生物场。该模拟模型允许在大脑中的电极运动和参数的修改, 如主动接触或刺激幅度。
图 1演示了在多个电极位置模拟和比较光纤激活预测的能力。在该协议中没有显示出从扩散成像中产生的光纤束, 但这种分析可以用任何确定性纤维束成像方法进行。位置2预测, 与位置1相比, 在所有触点上, 目标纤维束在较低的刺激振幅下更健壮地活化。该分析用于星展手术的规划阶段, 确定电极轨迹, 有效地刺激靶纤维通路。
该系统的一个新特点是能够快速切换模型中的电极几何, 并能够在接近彼此的情况下模拟多个引线。这两种方法都用于对电极周围电场的形状和转向提供更大的控制。图 2显示了轴对称和定向星展集团铅之间的纤维活化预测的比较, 同时研究了铅的位置, 以刺激中心丘脑纤维通路和避免附近地区, 如感官核.对于相同的电极轨迹, 我们可以看到定向引线能够引导纤维活化到目标区域, 同时避免刺激不受欢迎的纤维。这种分析可以用来确定什么时候需要改变的设备, 病人将接受星展治疗, 以避免刺激附近地区, 会诱发不必要的副作用。这种方法有助于靶向丘脑核治疗帕金森病的症状, 同时避免附近的内囊。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57292/57292fig1.jpg"> 图 1: 电极位置的比较和目标纤维活化的预测.预测刺激振幅的总纤维束活化 (-0.5 v 到-5.0 v) 和所有四触点为两个不同的电极位置。<a href="https://www.jove.com/files/ftp_upload/57292/57292fig1large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/57292/57292fig2.jpg"> 图 2: 中心丘脑纤维束活化预测与轴对称和定向星展集团线索的比较.(A)可视化美敦力3387圆柱星展集团铅和智人定向星展集团铅与激活功能计算的目标中央丘脑纤维束为一个单一的单刺激幅度。(B)(i)通过星展集团的铅和纤维束进行横断面切片。(ii)跨截面积的二维投影, 以识别星展集团的铅、靶纤维和纤维以避免。(C)在两个目标纤维和避免纤维之间的活化扩散, 以刺激振幅增加为轴对称和定向星展集团铅。给定刺激振幅的活化纤维以红色显示, 而未激活的纤维以蓝色显示。(D)汇编 C 组中显示的所有模拟, 显示了在光纤束的所有区域内预测的刺激阈值。<a href="https://www.jove.com/files/ftp_upload/57292/57292fig2large.jpg">请单击此处查看此图的较大版本.</a>

Watch this Scientific Journal Video about Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models at JoVE.com

Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

该项目的目标是开发一个交互式的, 病人特定的建模管道, 以模拟的影响, 深脑刺激在近实时, 并提供有意义的反馈, 这些设备如何影响神经活动的大脑。

应用交互式、患者特异性模型对神经纤维束进行深部脑刺激治疗的靶向性

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for ...

targeting-neuronal-fiber-tracts-for-deep-brain-stimulation-therapy

Universidad San Sebastian

Research

JoVE Journal

Bioengineering

8.8K 次观看.  University of Utah. 该项目的目标是开发一个交互式的, 病人特定的建模管道, 以模拟的影响, 深脑刺激在近实时, 并提供有意义的反馈, 这些设备如何影响神经活动的大脑。

视频: Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

High-resolution Fiber-optic Microendoscopy for in situ Cellular Imaging

Many biological and clinical studies require the longitudinal study and analysis of morphology and function with cellular level resolution. Traditionally, multiple experiments are run in parallel, with individual samples removed from the study at sequential time points for evaluation by light microscopy. Several intravital techniques have been developed, with confocal, multiphoton, and second harmonic microscopy all demonstrating their ability to be used for imaging in situ 1. With these systems, however, the required infrastructure is complex and expensive, involving scanning laser systems and complex light sources. Here we present a protocol for the design and assembly of a high-resolution microendoscope which can be built in a day using off-the-shelf components for under US$5,000. The platform offers flexibility in terms of image resolution, field-of-view, and operating wavelength, and we describe how these parameters can be easily modified to meet the specific needs of the end user.
We and others have explored the use of the high-resolution microendoscope (HRME) in in vitro cell culture 2-5, in excised 6 and living animal tissues 2,5, and in human tissues in vivo 2,7. Users have reported the use of several different fluorescent contrast agents, including proflavine 2-4, benzoporphyrin-derivative monoacid ring A (BPD-MA) 5, and fluoroscein 6,7, all of which have received full, or investigational approval from the FDA for use in human subjects. High-resolution microendoscopy, in the form described here, may appeal to a wide range of researchers working in the basic and clinical sciences. The technique offers an effective and economical approach which complements traditional benchtop microscopy, by enabling the user to perform high-resolution, longitudinal imaging in situ.

High-resolution Fiber-optic Microendoscopy for in situ Cellular Imaging

In many biological and clinical situations it is advantageous to study cellular processes as they evolve in their native microenvironment. Here we describe the assembly and use of a low-cost fiber-optic microscope which can provide real time imaging in cell culture, animal studies, and clinical patient studies.

高分辨率光纤内窥镜为原位细胞成像

Many biological and clinical studies require the longitudinal study and analysis of morphology and function with cellular level resolution.  ...

科研

生物工程

Impulsive Pressurization of Neuronal Cells for Traumatic Brain Injury Study

A novel impulsive cell pressurization experiment has been developed using a Kolsky bar device to investigate blast-induced traumatic brain injury (TBI). We demonstrate in this video article how blast TBI-relevant impulsive pressurization is applied to the neuronal cells in vitro. This is achieved by using well-controlled pressure pulse created by a specialized Kolsky bar device, with complete pressure history within the cell pressurization chamber recorded. Pressurized neuronal cells are inspected immediately after pressurization, or further incubated to examine the long-term effects of impulsive pressurization on neurite/axonal outgrowth, neuronal gene expression, apoptosis, etc. We observed that impulsive pressurization at about 2 MPa induces distinct neurite loss relative to unpressurized cells. Our technique provides a novel method to investigate the molecular/cellular mechanisms of blast TBI, via impulsive pressurization of brain cells at well-controlled pressure magnitude and duration.

A novel impulsive cell pressurization experiment has been developed using a Kolsky bar device to investigate the molecular/cellular mechanisms of blast-induced traumatic brain injury.

创伤性脑损伤研究神经细胞的脉冲增压

A novel impulsive cell pressurization experiment has been developed using a Kolsky bar device to investigate blast-induced traumatic brain injury (TBI). ...

Patient-specific Modeling of the Heart: Estimation of Ventricular Fiber Orientations

Patient-specific simulations of heart (dys)function aimed at personalizing cardiac therapy are hampered by the absence of in vivo imaging technology for clinically acquiring myocardial fiber orientations. The objective of this project was to develop a methodology to estimate cardiac fiber orientations from in vivo images of patient heart geometries. An accurate representation of ventricular geometry and fiber orientations was reconstructed, respectively, from high-resolution ex vivo structural magnetic resonance (MR) and diffusion tensor (DT) MR images of a normal human heart, referred to as the atlas. Ventricular geometry of a patient heart was extracted, via semiautomatic segmentation, from an in vivo computed tomography (CT) image. Using image transformation algorithms, the atlas ventricular geometry was deformed to match that of the patient. Finally, the deformation field was applied to the atlas fiber orientations to obtain an estimate of patient fiber orientations. The accuracy of the fiber estimates was assessed using six normal and three failing canine hearts. The mean absolute difference between inclination angles of acquired and estimated fiber orientations was 15.4 &deg;. Computational simulations of ventricular activation maps and pseudo-ECGs in sinus rhythm and ventricular tachycardia indicated that there are no significant differences between estimated and acquired fiber orientations at a clinically observable level.The new insights obtained from the project will pave the way for the development of patient-specific models of the heart that can aid physicians in personalized diagnosis and decisions regarding electrophysiological interventions.

A methodology to estimate ventricular fiber orientations from in vivo images of patient heart geometries for personalized modeling is described. Validation of the methodology performed using normal and failing canine hearts demonstrate that that there are no significant differences between estimated and acquired fiber orientations at a clinically observable level.

病人的具体建模之心:的心室纤维方向估计

Patient-specific  simulations of heart (dys)function aimed at personalizing cardiac therapy are hampered  by the absence of in vivo imaging technology for ...

Transplantation of Induced Pluripotent Stem Cell-derived Mesoangioblast-like Myogenic Progenitors in Mouse Models of Muscle Regeneration

Patient-derived iPSCs could be an invaluable source of cells for future autologous cell therapy protocols. iPSC-derived myogenic stem/progenitor cells similar to pericyte-derived mesoangioblasts (iPSC-derived mesoangioblast-like stem/progenitor cells: IDEMs) can be established from iPSCs generated from patients affected by different forms of muscular dystrophy. Patient-specific IDEMs can be genetically corrected with different strategies (e.g. lentiviral vectors, human artificial chromosomes) and enhanced in their myogenic differentiation potential upon overexpression of the myogenesis regulator MyoD. This myogenic potential is then assessed in vitro with specific differentiation assays and analyzed by immunofluorescence. The regenerative potential of IDEMs is further evaluated in vivo, upon intramuscular and intra-arterial transplantation in two representative mouse models displaying acute and chronic muscle regeneration. The contribution of IDEMs to the host skeletal muscle is then confirmed by different functional tests in transplanted mice. In particular, the amelioration of the motor capacity of the animals is studied with treadmill tests. Cell engraftment and differentiation are then assessed by a number of histological and immunofluorescence assays on transplanted muscles. Overall, this paper describes the assays and tools currently utilized to evaluate the differentiation capacity of IDEMs, focusing on the transplantation methods and subsequent outcome measures to analyze the efficacy of cell transplantation.

Induced pluripotent stem cell (iPSC)-derived myogenic progenitors are promising candidates for cell therapy strategies to treat muscular dystrophies. This protocol describes transplantation and functional measurements required to evaluate the engraftment and differentiation of iPSC-derived mesoangioblasts (a type of muscle progenitors) in mouse models of acute and chronic muscle regeneration.

在肌肉再生的老鼠模型中移植诱导多能干细胞衍生的中生代细胞样肌原体

Patient-derived iPSCs could be an invaluable source of cells for future autologous cell therapy protocols. iPSC-derived myogenic stem/progenitor cells ...

Production and Targeting of Monovalent Quantum Dots

The multivalent nature of commercial quantum dots (QDs) and the difficulties associated with producing monovalent dots have limited their applications in biology, where clustering and the spatial organization of biomolecules is often the object of study. We describe here a protocol to produce monovalent quantum dots (mQDs) that can be accomplished in most biological research laboratories via a simple mixing of CdSe/ZnS core/shell QDs with phosphorothioate DNA (ptDNA) of defined length. After a single ptDNA strand has wrapped the QD, additional strands are excluded from the surface. Production of mQDs in this manner can be accomplished at small and large scale, with commercial reagents, and in minimal steps. These mQDs can be specifically directed to biological targets by hybridization to a complementary single stranded targeting DNA. We demonstrate the use of these mQDs as imaging probes by labeling SNAP-tagged Notch receptors on live mammalian cells, targeted by mQDs bearing a benzylguanine moiety.

We provide detailed instructions for the preparation of monovalent targeted quantum dots (mQDs) from phosphorothioate DNA of defined length. DNA wrapping occurs in high yield, and therefore, products do not require purification. We demonstrate the use of the SNAP tag to target mQDs to cell-surface receptors for live-cell imaging applications.

生产和目标单价量子点

The multivalent nature of commercial quantum dots (QDs) and the difficulties associated with producing monovalent dots have limited their applications in ...

Solid Lipid Nanoparticles (SLNs) for Intracellular Targeting Applications

Nanoparticle-based delivery vehicles have shown great promise for intracellular targeting applications, providing a mechanism to specifically alter cellular signaling and gene expression. In a previous investigation, the synthesis of ultra-small solid lipid nanoparticles (SLNs) for topical drug delivery and biomarker detection applications was demonstrated. SLNs are a well-studied example of a nanoparticle delivery system that has emerged as a promising drug delivery vehicle. In this study, SLNs were loaded with a fluorescent dye and used as a model to investigate particle-cell interactions. The phase inversion temperature (PIT) method was used for the synthesis of ultra-small populations of biocompatible nanoparticles. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylphenyltetrazolium bromide (MTT) assay was utilized in order to establish appropriate dosing levels prior to the nanoparticle-cell interaction studies. Furthermore, primary human dermal fibroblasts and mouse dendritic cells were exposed to dye-loaded SLN over time and the interactions with respect to toxicity and particle uptake were characterized using fluorescence microscopy and flow cytometry. This study demonstrated that ultra-small SLNs, as a nanoparticle delivery system, are suitable for intracellular targeting of different cell types.

Solid Lipid Nanoparticles SLNs for Intracellular Targeting Applications

In this study, a method for synthesizing ultra-small populations of biocompatible nanoparticles was described, as well as several in vitro methods by which to assess their cellular interactions.

固体脂质纳米粒（前哨淋巴结）细胞内定位的应用

Nanoparticle-based delivery vehicles have shown great promise for intracellular targeting applications, providing a mechanism to specifically alter ...

Transmission of Multiple Signals through an Optical Fiber Using Wavefront Shaping

The transmission of multiple independent optical signals through a multimode fiber is accomplished using wavefront shaping in order to compensate for the light distortion during the propagation within the fiber. Our methodology is based on digital optical phase conjugation employing only a single spatial light modulator, where the optical wavefront is individually modulated at different regions of the modulator, one region per light signal. Digital optical phase conjugation approaches are considered to be faster than other wavefront shaping approaches, where (for example) a complete determination of the wave propagation behavior of the fiber is performed. In contrast, the presented approach is time-efficient since it only requires one calibration per light signal. The proposed method is potentially appropriate for spatial division multiplexing in communications engineering. Further application fields are endoscopic light delivery in biophotonics, especially in optogenetics, where single cells in biological tissue have to be selectively illuminated with high spatial and temporal resolution.

We demonstrate the transmission of multiple independent signals through a multimode fiber using wavefront shaping employing a single spatial light modulator. By modulating the wavefront for each signal individually, spatially separated foci are transmitted. Potential applications are multiplexed data transfer in communications engineering and endoscopic light delivery in biophotonics.

通过光纤使用波前整形多个信号的传输

The transmission of multiple independent optical signals through a multimode fiber is accomplished using wavefront shaping in order to compensate for the ...

Protocol for MicroRNA Transfer into Adult Bone Marrow-derived Hematopoietic Stem Cells to Enable Cell Engineering Combined with Magnetic Targeting

While CD133+ hematopoietic stem cells (SCs) have been proven to provide high potential in the field of regenerative medicine, their low retention rates after injection into injured tissues as well as the observed massive cell death rates lead to very restricted therapeutic effects. To overcome these limitations, we sought to establish a non-viral based protocol for suitable cell engineering prior to their administration. The modification of human CD133+ expressing SCs using microRNA (miR) loaded magnetic polyplexes was addressed with respect to uptake efficiency and safety as well as the targeting potential of the cells. Relying on our protocol, we can achieve high miR uptake rates of 80&#8211;90% while the CD133+ stem cell properties remain unaffected. Moreover, these modified cells offer the option of magnetic targeting. We describe here a safe and highly efficient procedure for the modification of CD133+ SCs. We expect this approach to provide a standard technology for optimization of therapeutic stem cell effects and for monitoring of the administered cell product via magnetic resonance imaging (MRI).

This protocol illustrates a safe and efficient procedure to modify CD133+ hematopoietic stem cells. The presented non-viral, magnetic polyplex-based approach may provide a basis for the optimization of therapeutic stem cell effects as well as for monitoring the administered cell product via magnetic resonance imaging.

MicroRNA 移植成人骨髓造血干细胞促进细胞工程与磁性靶向结合的协议

While CD133+ hematopoietic stem cells (SCs) have been proven to provide high potential in the field of regenerative medicine, their low retention rates ...

Patient-Specific Polyvinyl Alcohol Phantom Fabrication with Ultrasound and X-Ray Contrast for Brain Tumor Surgery Planning

Phantoms are essential tools for clinical training, surgical planning and the development of novel medical devices. However, it is challenging to create anatomically accurate head phantoms with realistic brain imaging properties because standard fabrication methods are not optimized to replicate any patient-specific anatomical detail and 3D printing materials are not optimized for imaging properties. In order to test and validate a novel navigation system for use during brain tumor surgery, an anatomically accurate phantom with realistic imaging and mechanical properties was required. Therefore, a phantom was developed using real patient data as input and 3D printing of molds to fabricate a patient-specific head phantom comprising the skull, brain and tumor with both ultrasound and X-ray contrast. The phantom also had mechanical properties that allowed the phantom tissue to be manipulated in a similar manner to how human brain tissue is handled during surgery. The phantom was successfully tested during a surgical simulation in a virtual operating room.
The phantom fabrication method uses commercially available materials and is easy to reproduce. The 3D printing files can be readily shared, and the technique can be adapted to encompass many different types of tumor.

This protocol describes the fabrication of a patient specific skull, brain and tumor phantom. It uses 3D printing to create molds, and polyvinyl alcohol (PVA-c) is used as the tissue mimicking material.

患者特异性聚乙烯酒精幻影制造与超声波和X射线对比脑肿瘤手术规划

Phantoms are essential tools for clinical training, surgical planning and the development of novel medical devices. However, it is challenging to create ...

Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict regional aerosol delivery. Leveraging 3D printing to generate patient-specific lung models, we outline the design of a high-throughput, in vitro experimental setup for quantifying lobular pulmonary deposition. This system is made with a combination of commercially available and 3D printed components and allows the flow rate through each lobe of the lung to be independently controlled. Delivery of fluorescent aerosols to each lobe is measured using fluorescence microscopy. This protocol has the potential to promote the growth of personalized medicine for respiratory diseases through its ability to model a wide range of patient demographics and disease states. Both the geometry of the 3D printed lung model and the air flow profile setting can be easily modulated to reflect clinical data for patients with varying age, race, and gender. Clinically relevant drug delivery devices, such as the endotracheal tube shown here, can be incorporated into the testing setup to more accurately predict a device&#8217;s capacity to target therapeutic delivery to a diseased region of the lung. The versatility of this experimental setup allows it to be customized to reflect a multitude of inhalation conditions, enhancing the rigor of preclinical therapeutic testing.

We present a high-throughput, in vitro method for quantifying regional pulmonary deposition at the lobe level using CT scan-derived, 3D printed lung models with tunable air flow profiles.