Name: evaluating regional pulmonary deposition using patient-specific 3d printed lung models
Uploaded: 2020-11-11T13:00:00.000+00:00
Duration: 7 min 56 s
Description: Watch this Scientific Journal Video about Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models at JoVE.com

作者感谢于峰教授、詹娜·布里德尔博士、伊恩·伍德沃德博士和卢卡斯·阿提亚教授的有益讨论。

1. 准备3D打印实验组件
注:协议中使用的所有软件均在 材料表中注明。此外，所使用的切片软件是特定于 材料表中列出的 3D 打印机:但是，此协议可以扩展到各种立体石刻 （SLA） 3D 打印机。
<ol><li>将患者 CT 扫描转换为 3D 对象 （.stl 文件）。 注:要更详细地讨论这些研究中使用的特定肺模型的几何特征，请参阅冯等人5。<ol>
<li>使用 CT 扫描软件将 CT 扫描渲染为 3D 对象（参见 材料表）。打开 CT 扫描，使用 阈值 工具在空域上创建一个面罩，其设置范围为 -800 到 -1000。使用 3D 预览 工具查看 3D 渲染并导出对象（文件|导出）作为。stl文件。</li>
		<li>将文件导入网格编辑软件（参见 材料表），使用 选择 工具删除任何锯齿状的功能（雕刻|画笔:"收缩/平滑"|属性: 强度 （50）， 大小 （10）， 深度 （0）） 。平滑表面（ctrl+A |变形|平滑|平滑 （0.2）， 平滑量表 （1））.</li>
		<li>在网格编辑软件中，将这些对象的墙壁延长 2 毫米（Ctrl+A |编辑|偏移），并允许内部物体保持空心，使只有墙仍然存在。切片对象（选择|编辑|平面切割）在气管形成一个入口，并在第2代或第3代，对象分支到每个叶创建插座（图1A）。 注:2毫米的厚度是根据 材料表中列出的3D打印机制造商指定的可接受功能尺寸选择的。如果保持模型的内部几何形状，则可以根据可用的 3D 打印机的规格调整此厚度。</li>
	</ol></li>
	<li>修改患者肺模型插座几何形状，以与材料表中列出的先前设计的叶出口盖组件（图1B，C）兼容。<ol>
<li>导入3D对象，复制内部CT扫描，壁厚度为2毫米，在入口和插座打开，进入3D建模软件（见 材料表）作为固体体（打开|网格文件|选项|固体身体）。</li>
		<li>根据每个插座的面部创建平面（插入|参考几何学|飞机）。使用拼接工具，在平面上的草图中跟踪出口的内壁和外壁（素描|斯普林）。</li>
		<li>将气缸（OD 18.5 mm、ID 12.5 mm、H 15.15 mm）连接到模型的内墙和外壁，从而将出口扩展到每个叶的均匀（功能|阁楼老板/基地）。在插座边缘添加一个缺口，以配合盖子（功能|挤压切割|偏移）。 注:盖（图1D）是一个空心圆柱体，匹配插座的尺寸，并有一个架子，与模型插座的档次相互连接。盖子的一端被阻塞，使 ID 小于部分的其余部分，这确保了带刺管连接（图 1E）的紧密配合。带刺管连接是一个带刺锥形，使刺通过帽的开口适合，但其余部分不，允许管连接牢固地适合在帽。因此，帽紧密地贴合在带刺管连接和肺模型（图1F，G）周围。</li>
		<li>根据所需的实验条件修改肺模型的入口。喉咙和咽喉区域可以包括模仿病人，可以自己呼吸（图1B）。气管上方的区域可以使用挤压的切口来模拟呼吸机支架上的插管患者（功能|挤压切割）（图1C）。</li>
	</ol></li>
	<li>3D 打印机制造商提供的切片软件中的定向和支持实验组件。<ol>
<li>将 3D 部分文件导入 3D 打印机切片软件，并选择适当的树脂。使用硬树脂打印肺模型和带刺管连接，以及软树脂打印帽。 注意:用于打印盖子的树脂必须具有弹性特性，使其能够伸展到叶出口，并创建一个密封的密封。</li>
		<li>设置部分方向，以便将任何"岛屿"和未发明的卷最小化。肺模型的最佳方向是叶口面向远离打印平台。确保带刺管连接和盖子都具有面向打印平台的更宽部分。 注:可以查看单个切片，以检查"岛屿"的出现，该部分最初出现在切片中，而不连接到部分的主体。审查功能可用于检查未发明卷的切片，未治愈的树脂在打印过程中可能被困在部分内的区域。"岛屿"和未发明的卷都会降低打印质量，并可能导致打印失败。</li>
		<li>单独查看每片，为该部分中任何剩余的"岛屿"以及任何悬垂严重的区域添加支撑。导出并查看打印切片，以验证所有区域是否得到适当的支持。</li>
	</ol></li>
	<li>按照制造商的说明打印实验组件并完成后处理。 注:以下所有后处理步骤均特定于 材料表中列出的 3D 打印机。当使用替代打印机或材料时，调整这些步骤以反映制造商的说明。<ol>
<li>对于用软树脂打印的零件，根据制造商规格，用≥99%纯度异丙醇 （IPA） 清洗，以去除多余的未固化树脂，并根据制造商规格在对流烤箱中热固化 8 小时。 注意:在软树脂中打印的零件在打印后可以非常精细，因此在清洁步骤时应特别小心。接触 IPA 应保持在材料溶剂暴露限制以下，以防止部分降解。</li>
		<li>对于用硬树脂打印的零件，用 IPA 清洗以去除多余的未固化树脂，并在紫外线烤箱中固化（365 nm 光在 5-10 mW/cm2），每侧 1 分钟。 注意:为了评估 3D 打印副本的准确性，建议使用印刷部分和 CT 扫描软件的 μCT 扫描来定量地比较原始 3D 渲染和 3D 打印复制品之间的变化。</li>
	</ol></li>
</ol>2. 流量控制管系统组装
<ol><li>螺丝1/4"带刺管配件到歧管的一侧，有6个端口（图2A-6）和一个3/8"带刺管配件到剩余的端口。</li>
	<li>将 1/4" 管子切成所需的长度，并插入推接阀的每一端（图 2A-5）。将每个阀门连接到插入歧管中的 1/4" 配件之一。</li>
	<li>将流量计（图2A-4）连接到每个阀门的另一端。</li>
	<li>将管子系统放置在木板顶部，使多管的单个 3/8"配件延伸至木板边缘。为了固定到位，在木板的一侧添加两个螺丝，然后用电线将歧管连接到螺钉上。</li>
	<li>在每个阀门和流量计周围添加四个螺丝，然后使用电线将每个螺钉固定在木板上（图 2E）。</li>
	<li>使用大约 6" 的 3/8" ID 管，将歧管连接到在线 0.1 μm 孔径大小的真空级过滤器。使用另一个 6" 的 3/8" ID 管将过滤器的另一端连接到流量控制器 注:管子系统只需组装一次。</li>
</ol>3. 带患者肺模型的叶出口盖组装
注意:协议的这一部分必须在每次实验运行之前完成。
<ol><li>将带刺管连接插入盖中，喷嘴通过盖底的开口突出。首先，将椭圆形带刺管连接底座的一端插入盖中。然后，小心地将柔性盖伸到椭圆形底座的另一端，特别注意不要裂开薄底座。 注意:新打印的帽子可能比预期的更硬，并且可以通过沿着盖子内部运行两根手指来伸展。</li>
	<li>切割 10μm 滤纸，使其略大于出口区域。将滤纸折叠在叶出口上，用一只手保持原位。</li>
	<li>另一方面，使用钳子在插座上用带刺管连接将帽子拉伸。按下盖，直到盖的缺口与叶出口上的相应缺口匹配（图 2C）。 注意:在此步骤中撕开滤纸可能会使结果失效，因此在将盖压到插座上时应特别小心以避免过度用力。</li>
	<li>重复所有剩余的叶插座 （图 2D）。</li>
</ol>4. 生成临床相关气流剖面
注意:协议的这一部分必须在每次实验运行之前完成。
<ol><li>将每个肺模型叶出口连接到相应的流量计和阀门的管子，注意不要对带刺管连接施加过多的横向压力。将电子流量计连接到肺模型口入口，以测量肺模型的总气流速率。</li>
	<li>打开流量控制器（图2A-7）和真空泵（图2A-8）。选择流量控制器上的"测试设置"设置，并缓慢地增加流速，直到电子流量计显示所需的总流速率。</li>
	<li>使用阀门（图2E-5），通过五个肺叶中的每一个调整流速:右上（RU）、右中叶（RM）、右下（RL）、左上（LU）和左下（LL）。一旦流表（图2E-4）上显示的叶流速率稳定在所需值，请再次检查电子流量表上的整体流速，以验证系统中没有泄漏。<ol>
<li>如果总流速存在差异，则通过流量控制器降低流速，将所有阀门设置为完全打开的配置，并重复步骤 4.2 和 4.3。 注:此处介绍的结果是利用Sul等人报告的数据，利用全灵感和过期患者肺部的薄片计算断层扫描图像计算得出的，比较了每个肺叶体积的相对变化。结果针对两种不同的流量条件，两种条件的总体入口流量均为 1 L/min。健康的肺叶出口流向每个出口按入口流量的以下百分比分布:LL-23.7%、LU-23.7%、RL-18.7%、RM-14.0%、RU-20.3%。COPD 叶出口流介按入口流量的以下百分比分布于每个出口之间:LL-10.0%、LU-29.0%、RL-13.0%、RM-5.0%、RU-43.0%9、10。</li>
	</ol>
</li>
	<li>退出流量控制器的"测试设置"功能，但请打开真空泵。 注意:在设置流速和执行沉积实验之间关闭真空泵可能导致生成的流量配置文件不准确。建议在设定所需的流量后将真空泵留在真空泵上，以完成气溶胶沉积测试。</li>
</ol>5. 向肺模型输送气溶胶
注:必须在烟罩中进行实验，关闭窗框，以尽量减少暴露在雾化器产生的任何气溶胶中。
<ol><li>填充雾化器与所需的荧光颗粒溶液 （图2A-1），并连接到肺模型入口 （图 2B）. 注:此处介绍的结果是使用甲醇中 1:100 稀释 1μm 荧光聚苯乙烯颗粒的 30 mL 得出的。<ol>
<li>要验证实验设置，请将雾化器直接连接到肺模型入口，无需任何定位装置。</li>
		<li>为了测量靶向装置的功效，将雾化器连接到设备，并将设备插入肺模型。</li>
	</ol>
</li>
	<li>将压缩的气管连接到雾化器，并尽可能关闭烟罩窗框。</li>
	<li>设置流控制器运行一个 10s 试用版。在按下启动之前，稍微打开压缩空气阀，开始在雾化器内产生气溶胶。</li>
	<li>按动启动流量控制器，并立即完全打开压缩空气阀。一旦流量控制器达到约9s，开始关闭压缩空气阀。</li>
	<li>压缩空气阀完全关闭后，将雾化器与压缩气管分离，完全关闭烟罩窗框，关闭真空泵，让任何气溶胶从烟斗中清除约 10 分钟。 注意:在完成运行后关闭真空泵非常重要，以防止真空在管道系统内积木。</li>
	<li>等待足够时间后，将肺模型与管系统断开，特别注意不要破裂带刺管连接。</li>
	<li>通过在盖子边缘下运行一对钳子，并轻轻地将其从肺模型上抬起来，取下叶出口盖。</li>
	<li>将滤纸从盖子上取下，放入 24 个井板中，颗粒沉积在底部，朝向板的油井。重复为剩余的插座，并标记与每个叶对应的井。 注意:为了防止任何残余颗粒沉积影响后续实验，在运行之间用 IPA 或适当的溶剂冲洗肺模型和盖组件非常重要。这可以根据需要收集并包含在分析中。此外，还保留日志，以确保使用的所有副本都很少暴露在 IPA 中，以保持部分完整性，并建议在使用前进行视觉部分检查。</li>
</ol>6. 出口滤纸成像
<ol><li>将井板放入数字荧光显微镜中，并将显微镜设置为 4 倍放大和适当的荧光通道。</li>
	<li>目视识别哪个叶的滤纸有最高数量的颗粒沉积，并使用"自动暴露"功能。注意由此产生的曝光和集成时间值。</li>
	<li>将此曝光应用到运行的所有滤镜中，并评估设置是否为过滤器的所有高沉积区域生成满意的图像。 注意:对焦设置可以从筛选器更改为筛选器:但是，必须在相同的曝光设置下分析给定运行的所有滤镜。一次只能有一帧焦点，因此滤纸中的弯曲或撕裂可能会阻止视图中所有沉积的粒子聚焦。通过确保滤纸与井板底部平整，可以避免这种情况。</li>
	<li>在随机位置拍摄每个叶滤纸的至少三张图像，并保存为.tiff文件。</li>
</ol>7. 粒子沉积量化
<ol><li>导入所有滤纸图片，以在给定运行到图像J会话中。</li>
	<li>通过选择图像|将每个图像的类型更改为 8 位 类型|8 位。</li>
	<li>打开具有最高荧光的图片，并选择图像|调整|打开阈值窗口的阈值。调整阈值以最大限度地减少滤纸的背景信号，并清楚地定义粒子的边缘。有关优质和劣质阈值的描述，请参阅图 3。 注意:对于沉积水平高的过滤器，可以在大颗粒群周围观察到由滤纸纤维的光扩散引起的荧光"冠冕"。阈值这些图像时，太大的范围会显示这些组周围的小点或"羽毛状"形状，如 图 3中的"差"阈值图像中所示。这可以通过逐步提高阈值的下限来改进，直到过滤纸纤维发出的信号最小化，而不会遮挡颗粒本身的信号。</li>
	<li>将最高荧光图像的阈值设置传播到所有其他图像。</li>
	<li>通过选择分析|来量化颗粒数量和整个荧光区 分析粒子。 注:使用 Sidak 的多重比较测试和双向 ANOVA 比较数据集。此外，仅使用学生 T 测试假设相等的方差，比较了兴趣叶中的沉积。</li>
</ol>

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作者没有什么可透露的。

目前用于完全吸入剂量肺药测试的先进设备是下一个发电机冲击器 （NGI），用于测量气溶胶4的空气动力学直径。然后，这个大小的数据用于预测肺生成，气溶胶将沉积基于为健康的成年男性11开发的相关性。不幸的是，这种方法在评估区域肺沉积差异、确定疾病条件对药物输送的影响以及预测不同年龄组、种族和性别12、13、14</sup...

肺癌、慢性阻塞性肺病等许多肺病在疾病特征上表现出区域差异:然而，缺乏治疗技术，以目标药物交付到只有肺1的病区。多个计算流体动态（CFD）模型已经证明，通过识别肺部2，3的特定流线，可以调节药物沉积图谱。我们的实验室正在开发具有区域定位能力的吸入器和内脏（ET）管适配器，以控制气溶胶向患病肺部区域的分布。这些原则推广到临床使用受当前临床前测试能力的限制。众所周知，药物沉积在肺部的确切位置是疗效的最佳预测器:然而，目前的药物评估的可吸入治疗最常预测使用体外体内的粒子大小相关性，只是近似沉积4。此技术不允许任何空间分析来确定不同气道几何形状对通过肺部不同叶的区域分布的影响。此外，这项测试缺乏解剖学上准确的肺几何学，研究人员已经表明，这可能对沉积图5产生重大影响。已作出一些努力，通过增加上呼吸道，将患者特异性肺几何学纳入测试方案:然而，这些方法大多样本气溶胶输送到不同代的肺，而不是每个肺叶6，7，8。下列协议提出了一种高通量的方法，以产生患者特定的肺模型，并能够量化肺9的五个叶中的每个叶的相对粒子沉积。
解剖学上准确的模型肺是由3D打印患者计算断层扫描（CT）扫描产生的。当与一个容易组装的流动系统一起使用时，可以通过每个模型肺叶的相对流率进行独立控制和定制，以模拟不同患者人口统计学和/或疾病状态的相对流率。通过这种方法，研究人员可以在相关的肺几何学中测试潜在治疗方法的有效性，并将每种方法的性能与疾病形态的进展联系起来。在这里，我们实验室开发的两种设备设计通过控制口腔或气管中气溶胶释放的位置来增强所需肺叶沉积的能力。该协议还有可能通过促进对患者CT扫描数据特定于模型肺的治疗效果的快速预测，显著影响患者个性化程序的发展。

<table><tbody><tr><td>1/4&quot; Plastic Barbed Tube Fitting</td><td>McMaster Carr</td><td>5372K111</td><td></td></tr><tr><td>10 um Filter Paper</td><td>Fisher</td><td>1093-110</td><td></td></tr><tr><td>1um Fluorescent Polystyrene Particles</td><td>Polysciences</td><td>15702-10</td><td></td></tr><tr><td>1um Non-Fluorescent Polystyrene Particles</td><td>Polysciences</td><td>8226</td><td></td></tr><tr><td>2-Propanol</td><td>Fisher</td><td>A516-4</td><td>Referred to in protocol as &quot;IPA&quot;</td></tr><tr><td>3/8&quot; Plastic Barbed Tube Fitting</td><td>McMaster Carr</td><td>5372K117</td><td></td></tr><tr><td>Air Flow Meter (1 - 280 mL/min)</td><td>McMaster Carr</td><td>41695K32</td><td>Referred to in protocol as &quot;flow meter&quot;</td></tr><tr><td>Carbon M1 3D Printer</td><td>Carbon 3D</td><td></td><td>https://www.carbon3d.com/, Associated software referred to in protocol as &quot;slicing software&quot;</td></tr><tr><td>Collison Jet Nebulizer</td><td>CH Technologies</td><td>ARGCNB0008 (CN-25)</td><td>6 Jet MRE style horizontal collision with glass jar, Referred to in protocol as &quot;nebulizer&quot;, http://chtechusa.com/Manuals/MRE_Collison_Manual.pdf</td></tr><tr><td>Convection Oven</td><td>Yamato</td><td>DKN602</td><td></td></tr><tr><td>Copley Critical Flow Controller TPK2000 Reve 120V</td><td>MSP Corp</td><td>0001-01-9810</td><td>Referred to in protocol as &quot;flow controller&quot;</td></tr><tr><td>Copley High Capacity Pump Model HCP5</td><td>MSP Corp</td><td>0001-01-9982</td><td>Referred to in protocol as &quot;vacuum pump&quot;</td></tr><tr><td>Cytation</td><td>BioTek</td><td>CYT5MPV</td><td>Multifunctional Spectrophotometer/Fluorescent imager equiped with 4x/20x/40x objectives and DAPI/GFP/TexasRed laser/filter cubes</td></tr><tr><td>EPU40 Resin</td><td>Carbon 3D</td><td></td><td>https://www.carbon3d.com/materials/epu-elastomeric-polyurethane/, Referred to in protocol as &quot;soft resin&quot;</td></tr><tr><td>Filter for vacuum pump</td><td>Whatman</td><td>6722-5000</td><td></td></tr><tr><td>Flow Meter Model DFM 2000</td><td>MSP Corp</td><td>0001-01-8764</td><td>Referred to in protocol as &quot;electronic flow meter&quot;</td></tr><tr><td>ImageJ Software</td><td>ImageJ</td><td></td><td>https://imagej.nih.gov/ij/download.html</td></tr><tr><td>Inline Air Flow Control Valve (Push-to-Connect)</td><td>McMaster Carr</td><td>62005K333</td><td>Referred to in protocol as &quot;valve&quot;</td></tr><tr><td>Inline Filter Devices</td><td>Whatman</td><td>WHA67225000</td><td></td></tr><tr><td>Marine-Grade Plywood Sheet</td><td>McMaster Carr</td><td>62005K333</td><td>Referred to in protocol as &quot;wooden board&quot;</td></tr><tr><td>Materialise Mimics Software</td><td>Materialise</td><td></td><td>https://www.materialise.com/en/medical/mimics-innovation-suite, Referred to in protocol as &quot;CT scan software&quot;</td></tr><tr><td>Meshmixer Software</td><td>Autodesk</td><td></td><td>http://www.meshmixer.com/, Referred to in protocol as &quot;mesh editing software&quot;</td></tr><tr><td>Methanol</td><td>Fisher</td><td>A454-4</td><td></td></tr><tr><td>Opticure LED Cube</td><td>APM Technica</td><td>102843</td><td>Referred to in protocol as &quot;UV oven&quot;</td></tr><tr><td>PR25 Resin</td><td>Carbon 3D</td><td></td><td>https://www.carbon3d.com/materials/uma-urethanemethacrylate, /Referred to in protocol as &quot;hard resin&quot;</td></tr><tr><td>PVC Tube for Chemicals</td><td>McMaster Carr</td><td>5231K161</td><td>1/4&quot; ID</td></tr><tr><td>Screws</td><td></td><td></td><td></td></tr><tr><td>SolidWorks Software</td><td>Dassault Syst&amp;egrave;mes&amp;nbsp;SolidWorks Corporation</td><td></td><td>https://www.solidworks.com/, Referred to in protocol as &quot;3D modeling software&quot;</td></tr><tr><td>Straight Flow Rectangular Manifold</td><td>McMaster Carr</td><td>1125T31</td><td></td></tr><tr><td>Tubing to Flow Controller</td><td>McMaster Carr</td><td>5233K65</td><td>3/8&quot; ID</td></tr><tr><td>Wire</td><td></td><td></td><td></td></tr></tbody></table>

evaluating regional pulmonary deposition using patient-specific 3d printed lung models

肺病靶向疗法的发展受到可预测区域气溶胶输送能力的药物前检测方法的制约。利用 3D 打印生成患者专用肺模型，我们概述了用于量化球状肺沉积的高通量体外实验设置的设计。该系统由市售和 3D 打印组件组合而成，可独立控制肺部每个叶的流速。用荧光显微镜测量荧光气溶胶对每个叶的输送。该协议具有促进呼吸系统疾病个性化药物增长的潜力，因为它能够模拟广泛的患者人口统计学和疾病状态。3D 打印肺模型的几何形状和气流轮廓设置都可以轻松调整，以反映不同年龄、种族和性别患者的临床数据。临床相关的药物输送设备，如此处显示的内分泌管，可以纳入测试设置，以更准确地预测设备将治疗交付目标定向到肺部疾病区域的能力。这种实验设置的多功能性使其能够定制，以反映多种吸入条件，从而提高前结节治疗测试的严格性。

此大小范围（1-5 μm）和流速条件（1-10 L/min）的粒子根据其理论斯托克斯数和体内数据遵循流体流线;因此，在没有定向输送装置的情况下，释放到肺模型中的颗粒会根据流向每个叶的总气流百分比沉积。然后，通过分析患者特异性高分辨率计算机断层扫描 （HRCT） 扫描（HRCT）扫描获得的临床叶流率数据，可以比较每个叶的相对粒子输送量。经验证的实验设置将产生非靶向粒子沉...

Watch this Scientific Journal Video about Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models at JoVE.com

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

我们采用CT扫描衍生的3D打印肺模型和可调谐气流剖面，提出一种高通量体外方法，用于在叶位水平上量化区域肺沉积。

使用患者专用的 3D 打印肺模型评估区域肺沉积

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict ...

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Research

JoVE Journal

Bioengineering

4.2K 次观看.  University of Delaware. 我们采用CT扫描衍生的3D打印肺模型和可调谐气流剖面，提出一种高通量体外方法，用于在叶位水平上量化区域肺沉积。

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

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

In the present study, we combined an in vitro 3D lung tumor model with an in silico model to optimize predictions of drug response based on a specific mutational background. The model is generated on a decellularized porcine scaffold that reproduces tissue-specific characteristics regarding extracellular matrix composition and architecture including the basement membrane. We standardized a protocol that allows artificial tumor tissue generation within 14 days including three days of drug treatment. Our article provides several detailed descriptions of 3D read-out screening techniques like the determination of the proliferation index Ki67 staining&#39;s, apoptosis from supernatants by M30-ELISA and assessment of epithelial to mesenchymal transition (EMT), which are helpful tools for evaluating the effectiveness of therapeutic compounds. We could show compared to 2D culture a reduction of proliferation in our 3D tumor model that is related to the clinical situation. Despite of this lower proliferation, the model predicted EGFR-targeted drug responses correctly according to the biomarker status as shown by comparison of the lung carcinoma cell lines HCC827 (EGFR -mutated, KRAS wild-type) and A549 (EGFR wild-type, KRAS-mutated) treated with the tyrosine-kinase inhibitor (TKI) gefitinib. To investigate drug responses of more advanced tumor cells, we induced EMT by long-term treatment with TGF-beta-1 as assessed by vimentin/pan-cytokeratin immunofluorescence staining. A flow-bioreactor was employed to adjust culture to physiological conditions, which improved tissue generation. Furthermore, we show the integration of drug responses upon gefitinib treatment or TGF-beta-1 stimulation - apoptosis, proliferation index and EMT - into a Boolean in silico model. Additionally, we explain how drug responses of tumor cells with a specific mutational background and counterstrategies against resistance can be predicted. We are confident that our 3D in vitro approach especially with its in silico expansion provides an additional value for preclinical drug testing in more realistic conditions than in 2D cell culture.

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

We present a three-dimensional (3D) lung cancer model based on a biological collagen scaffold to study sensitivity towards non-small-cell-lung-cancer-(NSCLC)-targeted therapies. We demonstrate different read-out techniques to determine the proliferation index, apoptosis and epithelial-mesenchymal transition (EMT) status. Collected data are integrated into an in silico model for prediction of drug sensitivity.

一种混合的3D组织工程<em&gt;体外</em&gt; /<em&gt;在硅片</em在具体的突变背景预测药物的有效性&gt;肺肿瘤模型

In the present study, we combined an in vitro 3D lung tumor model with an in silico model to optimize predictions of drug response based on a specific ...

科研

生物工程

A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection

Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection

Human tuberculosis infection is a complex process, which is difficult to model in vitro. Here we describe a novel 3D human lung tissue model that recapitulates the dynamics that occur during infection, including the migration of immune cells and early granuloma formation in a physiological environment.

关于功能研究的三维人体肺组织模型<em&gt;结核分枝杆菌</em&gt;感染

Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us ...

免疫与感染

Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease

Human lung development and disease has been difficult to study due to the lack of biologically relevant in vitro model systems. Human induced pluripotent stem cells (hiPSCs) can be differentiated stepwise into 3D multicellular lung organoids, made of both epithelial and mesenchymal cell populations. We recapitulate embryonic developmental cues by temporally introducing a variety of growth factors and small molecules to efficiently generate definitive endoderm, anterior foregut endoderm, and subsequently lung progenitor cells. These cells are then embedded in growth factor reduced (GFR)-basement membrane matrix medium, allowing them to spontaneously develop into 3D lung organoids in response to external growth factors. These whole lung organoids (WLO) undergo early lung developmental stages including branching morphogenesis and maturation after exposure to dexamethasone, cyclic AMP and isobutylxanthine. WLOs possess airway epithelial cells expressing the markers KRT5 (basal), SCGB3A2 (club) and MUC5AC (goblet) as well as alveolar epithelial cells expressing HOPX (alveolar type I) and SP-C (alveolar type II). Mesenchymal cells are also present, including smooth muscle actin (SMA), and platelet-derived growth factor receptor A (PDGFR&#945;). iPSC derived WLOs can be maintained in 3D culture conditions for many months and can be sorted for surface markers to purify a specific cell population. iPSC derived WLOs can also be utilized to study human lung development, including signaling between the lung epithelium and mesenchyme, to model genetic mutations on human lung cell function and development, and to determine the cytotoxicity of infective agents.

The article describes step wise directed differentiation of induced pluripotent stem cells to three-dimensional whole lung organoids containing both proximal and distal epithelial lung cells along with mesenchyme.

从诱导多能干细胞生成3D全肺类器官，用于模拟肺发育生物学和疾病

Human lung development and disease has been difficult to study due to the lack of biologically relevant in vitro model systems. Human induced pluripotent ...

发育生物学

3D Printing of Preclinical X-ray Computed Tomographic Data Sets

Three-dimensional printing allows for the production of highly detailed objects through a process known as additive manufacturing. Traditional, mold-injection methods to create models or parts have several limitations, the most important of which is a difficulty in making highly complex products in a timely, cost-effective manner.1 However, gradual improvements in three-dimensional printing technology have resulted in both high-end and economy instruments that are now available for the facile production of customized models.2 These printers have the ability to extrude high-resolution objects with enough detail to accurately represent in vivo images generated from a preclinical X-ray CT scanner. With proper data collection, surface rendering, and stereolithographic editing, it is now possible and inexpensive to rapidly produce detailed skeletal and soft tissue structures from X-ray CT data. Even in the early stages of development, the anatomical models produced by three-dimensional printing appeal to both educators and researchers who can utilize the technology to improve visualization proficiency. 3, 4 The real benefits of this method result from the tangible experience a researcher can have with data that cannot be adequately conveyed through a computer screen. The translation of pre-clinical 3D data to a physical object that is an exact copy of the test subject is a powerful tool for visualization and communication, especially for relating imaging research to students, or those in other fields. Here, we provide a detailed method for printing plastic models of bone and organ structures derived from X-ray CT scans utilizing an Albira X-ray CT system in conjunction with PMOD, ImageJ, Meshlab, Netfabb, and ReplicatorG software packages.

Using modern plastic extrusion and printing technologies, it is now possible to quickly and inexpensively produce physical models of X-ray CT data taken in a laboratory. The three -dimensional printing of tomographic data is a powerful visualization, research, and educational tool that may now be accessed by the preclinical imaging community.

基础X射线计算机断层数据的三维打印设置

Three-dimensional printing allows for the production of highly detailed objects through a process known as additive manufacturing.  Traditional, ...

生物学

Generation of Human 3D Lung Tissue Cultures (3D-LTCs) for Disease Modeling

Translation of novel discoveries to human disease is limited by the availability of human tissue-based models of disease. Precision-cut lung slices (PCLS) used as 3D lung tissue cultures (3D-LTCs) represent an elegant and biologically highly relevant 3D cell culture model, which highly resemble in situ tissue due to their complexity, biomechanics and molecular composition. Tissue slicing is widely applied in various animal models. 3D-LTCs derived from human PCLS can be used to analyze responses to novel drugs, which might further help to better understand the mechanisms and functional effects of drugs in human tissue. The preparation of PCLS from surgically resected lung tissue samples of patients, who experienced lung lobectomy, increases the accessibility of diseased and peritumoral tissue. Here, we describe a detailed protocol for the generation of human PCLS from surgically resected soft-elastic patient lung tissue. Agarose was introduced into the bronchoalveolar space of the resectates, thus preserving lung structure and increasing the tissue&#39;s stiffness, which is crucial for subsequent slicing. 500 &#181;m thick slices were prepared from the tissue block with a vibratome. Biopsy punches taken from PCLS ensure comparable tissue sample sizes and further increase the amount of tissue samples. The generated lung tissue cultures can be applied in a variety of studies in human lung biology, including the pathophysiology and mechanisms of different diseases, such as fibrotic processes at its best at (sub-)cellular levels. The highest benefit of the 3D-LTC ex vivo model is its close representation of the in situ human lung in respect of 3D tissue architecture, cell type diversity and lung anatomy as well as the potential for assessment of tissue from individual patients, which is relevant to further develop novel strategies for precision medicine.

Generation of Human 3D Lung Tissue Cultures 3D-LTCs for Disease Modeling

Here, we present a protocol for the preparation of agarose-filled human precision-cut lung slices from resected patient tissue that are suitable for generating 3D lung tissue cultures to model human lung diseases in biological and biomedical studies.

用于疾病建模的人三维肺组织培养 (3D-LTCs) 的生成

Translation of novel discoveries to human disease is limited by the availability of human tissue-based models of disease. Precision-cut lung slices (PCLS) ...

医学

Development and Evaluation of 3D-Printed Cardiovascular Phantoms for Interventional Planning and Training

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training physicians&#39; wire-skills as well as improving planning of interventional procedures. The aim of this study was to develop a manufacturing process of patient-specific 3D-printed models for cardiovascular interventions.
To create a 3D-printed elastic phantom, different 3D-printing materials were compared to porcine biological tissues (i.e., aortic tissue) in terms of mechanical characteristics. A fitting material was selected based on comparative tensile tests and specific material thicknesses were defined. Anonymized contrast-enhanced CT-datasets were collected retrospectively. Patient-specific volumetric models were extracted from these datasets and subsequently 3D-printed. A pulsatile flow loop was constructed to simulate the intraluminal blood flow during interventions. Models&#39; suitability for clinical imaging was assessed by x-ray imaging, CT, 4D-MRI and (Doppler) ultrasonography. Contrast medium was used to enhance visibility in x-ray-based imaging. Different catheterization techniques were applied to evaluate the 3D-printed phantoms in physicians&#39; training as well as for pre-interventional therapy planning.
Printed models showed a high printing resolution (~30 &#181;m) and mechanical properties of the chosen material were comparable to physiological biomechanics. Physical and digital models showed high anatomical accuracy when compared to the underlying radiological dataset. Printed models were suitable for ultrasonic imaging as well as standard x-rays. Doppler ultrasonography and 4D-MRI displayed flow patterns and landmark characteristics (i.e., turbulence, wall shear stress) matching native data. In a catheter-based laboratory setting, patient-specific phantoms were easy to catheterize. Therapy planning and training of interventional procedures on challenging anatomies (e.g., congenital heart disease (CHD)) was possible.
Flexible patient-specific cardiovascular phantoms were 3D-printed, and the application of common clinical imaging techniques was possible. This new process is ideal as a training tool for catheter-based (electrophysiological) interventions and can be used in patient-specific therapy planning.

Here we present development of a mock circulation setup for multimodal therapy evaluation, pre-interventional planning, and physician-training on cardiovascular anatomies. With the application of patient-specific tomographic scans, this setup is ideal for therapeutic approaches, training, and education in individualized medicine.

干预规划和培训的3D打印心血管幻影的开发与评估

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training ...

A Personalized 3D-Printed Model for Preoperative Evaluation in Thyroid Surgery

The anatomic structure of the surgical area of thyroid cancer is complex. It is very important to comprehensively and carefully evaluate the tumor location and its relation with the capsule, trachea, esophagus, nerves, and blood vessels before operation. This paper introduces an innovative 3D-printed model establishment method based on computerized tomography (CT) DICOM images. We established a personalized 3D-printed model of the cervical thyroid surgery field for each patient who needed thyroid surgery to help clinicians evaluate the key points and difficulties of the surgery and select the operation methods of key parts as a basis. The results showed that this model is conducive to preoperative discussion and the formulation of operation strategies. In particular, as a result of the clear display of the recurrent laryngeal nerve and parathyroid gland locations in the thyroid operation field, injury to them can be avoided during surgery, the difficulty of thyroid surgery reduced, and the incidence of postoperative hypoparathyroidism and complications related to recurrent laryngeal nerve injury reduced too. Moreover, this 3D-printed model is intuitive and aids communication for the signing of informed consent by patients before surgery.

Here, a new method of establishing a personalized 3D-printed model for preoperative evaluation of thyroid surgery is proposed. It is conducive to preoperative discussion, reducing the difficulty of thyroid surgery.

用于甲状腺手术术前评估的个性化3D打印模型

The anatomic structure of the surgical area of thyroid cancer is complex. It is very important to comprehensively and carefully evaluate the tumor ...

用于肺结节诊断和治疗的 3D 重建

A 3D Digital Model for the Diagnosis and Treatment of Pulmonary Nodules

The three-dimensional (3D) reconstruction of pulmonary nodules using medical images has introduced new technical approaches for diagnosing and treating pulmonary nodules, and these approaches are progressively being acknowledged and adopted by physicians and patients. Nonetheless, constructing a relatively universal 3D digital model of pulmonary nodules for diagnosis and treatment is challenging due to device differences, shooting times, and nodule types. The objective of this study is to propose a new 3D digital model of pulmonary nodules that serves as a bridge between physicians and patients and is also a cutting-edge tool for pre-diagnosis and prognostic evaluation. Many AI-driven pulmonary nodule detection and recognition methods employ deep learning techniques to capture the radiological features of pulmonary nodules, and these methods can achieve a good area under-the-curve (AUC) performance. However, false positives and false negatives remain a challenge for radiologists and clinicians. The interpretation and expression of features from the perspective of pulmonary nodule classification and examination are still unsatisfactory. In this study, a method of continuous 3D reconstruction of the whole lung in horizontal and coronal positions is proposed by combining existing medical image processing technologies. Compared with other applicable methods, this method allows users to rapidly locate pulmonary nodules and identify their fundamental properties while also observing pulmonary nodules from multiple perspectives, thereby providing a more effective clinical tool for diagnosing and treating pulmonary nodules.

作者聚焦:用于肺结节诊断和治疗的 3D 数字模型  

The objective of this study is to develop a novel 3D digital model of pulmonary nodules that serves as a communication bridge between physicians and patients and is also a cutting-edge tool for pre-diagnosis and prognostic evaluation.

用于肺结节诊断和治疗的三维数字模型

The three-dimensional (3D) reconstruction of pulmonary nodules using medical images has introduced new technical approaches for diagnosing and treating ...

使用患者专用的 3D 打印肺模型评估区域肺沉积

摘要

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此视频中的章节

一种混合的3D组织工程

关于功能研究的三维人体肺组织模型

从诱导多能干细胞生成3D全肺类器官，用于模拟肺发育生物学和疾病

基础X射线计算机断层数据的三维打印设置

用于疾病建模的人三维肺组织培养 (3D-LTCs) 的生成

干预规划和培训的3D打印心血管幻影的开发与评估

用于甲状腺手术术前评估的个性化3D打印模型

用于肺结节诊断和治疗的三维数字模型

用于肺结节诊断和治疗的三维数字模型

用于肺结节诊断和治疗的三维数字模型