Name: evaluating regional pulmonary deposition using patient-specific 3d printed lung models
Uploaded: 2020-11-11T13:00:00
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>
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<ol>
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X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gender-related+difference+in+the+upper+airway+dimensions+and+hyoid+bone+position+in+Chinese+Han+children+and+adolescents+aged+6-18+years+using+cone+beam+computed+tomography.">Gender-related difference in the upper airway dimensions and hyoid bone position in Chinese Han children and adolescents aged 6-18 years using cone beam computed tomography.</a> Acta Odontologica Scandinavica. 73 (5), 391-400 (2015).</li><li>Martin, S. E., Mathur, R., Marshall, I., Douglas, N. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effect+of+age,+sex,+obesity+and+posture+on+upper+airway+size.">The effect of age, sex, obesity and posture on upper airway size.</a> European Respiratory Journal. 10 (9), 2087 (1997).</li><li>Xi, J., Longest, P. W., Martonen, T. 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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&#34; 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 &#34;IPA&#34;</td>
		</tr>
		<tr>
			<td>3/8&#34; 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 &#34;flow meter&#34;</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 &#34;slicing software&#34;</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 &#34;nebulizer&#34;, 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 &#34;flow controller&#34;</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 &#34;vacuum pump&#34;</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 &#34;soft resin&#34;</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 &#34;electronic flow meter&#34;</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 &#34;valve&#34;</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 &#34;wooden board&#34;</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 &#34;CT scan software&#34;</td>
		</tr>
		<tr>
			<td>Meshmixer Software</td>
			<td>Autodesk</td>
			<td></td>
			<td>http://www.meshmixer.com/, Referred to in protocol as &#34;mesh editing software&#34;</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 &#34;UV oven&#34;</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 &#34;hard resin&#34;</td>
		</tr>
		<tr>
			<td>PVC Tube for Chemicals</td>
			<td>McMaster Carr</td>
			<td>5231K161</td>
			<td>1/4&#34; ID</td>
		</tr>
		<tr>
			<td>Screws</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SolidWorks Software</td>
			<td>Dassault Syst&#232;mes&#160;SolidWorks Corporation</td>
			<td></td>
			<td>https://www.solidworks.com/, Referred to in protocol as &#34;3D modeling software&#34;</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&#34; 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 ...

This protocol has the potential to drive the development of new targeted pulmonary therapeutics by enabling the pre-clinical predictions of regional deposition. This technique incorporates anatomically accurate lung models, 3D printed from patient's CT scans for the rapid generation of personalized predictive results regarding the efficacy of potential treatments. This technique can be used to develop targeted therapies that minimize off target effects for diseases that are characterized by regional area obstructions such as lung cancer or COPD.After printing the experimental components and completing post-processing as per the manufacturer's instructions, carefully wash the parts printed in soft resin with at least 99%purity isopropyl alcohol to remove any excess uncured resin before thermal curing the parts in a convection oven for eight hours according to the manufacturer's specifications. Then, wash the parts printed in hard resin with the alcohol to remove any excess uncured resin and cure the parts in a UV oven for one minute per side. For lobe outlet cap assembly, insert one end of the oval barbed tubing connection base into the cap before carefully stretching the flexible cap over the other end of the oval base, taking special care not to crack the thin base and with the nozzle protruding through the opening in the cap base.Next, cut 10 microliter filter paper to a size slightly larger than the outlet area and fold the filter paper over the lobe outlet, holding the paper in place with one hand. Then use tweezers in the other hand, to stretch the cap with the barbed tubing connection over the outlet and press the cap down until the notch matches the corresponding notch on the lobe outlet. Before each experimental run, connect each lung model lobe outlet to the tubing of the corresponding flow meter and valve taking care not to apply too much lateral pressure to the barbed tubing connection.Attach the electronic flow meter to the lung model mouth inlet to measure the total airflow rate to the lung model and turn on the flow controller and vacuum pump. In the flow controller, select the test setup setting and slowly increase the flow rate until the electronic flow meter displays the desired total flow rate. Use the valves to adjust the flow rate through the right upper, right middle, right lower, left upper and left lower lung lobes.Once the load flow rates shown on the flow meters are steady at the desired value, check the overall flow rate again on the electronic flow meter to verify that there are no leaks in the system. Then, exit the test setup in the flow controller leaving the vacuum pump on. For aerosol delivery to the lung model, fill a nebulizer with a solution of the desired fluorescent particles and connect the nebulizer to the lung model inlet.To measure the efficacy of the targeting device, insert the device into the lung model and connect the nebulizer to the device. Connect the compressed airline to the nebulizer. Set the flow controller to run for one ten second trial and open the compressed air valve slightly to begin generating an aerosol within the nebulizer.Press start on the flow controller and immediately open the compressed air valve fully. When the flow controller reaches about nine seconds, begin closing the compressed air valve and close the fume hood sash as much as possible. Once the valve is fully closed, disconnect the nebulizer from the compressed airline.Fully close the fume hood sash, shut off the vacuum pump and let any aerosols clear from the fume hood. After about 10 minutes, disconnect the lung model from the tubing system, taking care not to crack the barbed tubing connections and run a pair of tweezers under the edge of each lobe outlet cap to remove the caps from the outlets. Then transfer the filter paper from each cap into individual wells of a 24-well plate particle depositions side down.When all of the filter paper has been collected, place the plate onto the stage of a digital fluorescence microscope and set the microscope to a 4X magnification and the appropriate fluorescence channel. Then take at least three images of the filter paper from each lobe at random locations and save the images as TIF files. Under one liter per minute collection conditions in a healthy lung, ended along effected by COPD, the experimentally determined deposition profile is not statistically different from the clinical data demonstrating that the setup accurately mimics the distribution of air flow to each of the lung lobes.Compared to the non-targeted particle deposition profile, the use of a modified endotracheal tube generates a nearly four fold increase in left lower lobe delivery. In addition to diverting over 96%of the delivered particles to the left lung. Altering the release location setting to target the right lower lobe, this device generates more than double the particle delivery to the right lobe and diverts 94%of the delivered particles to the right lung.Compared to the non-targeted particle deposition profile, the concentric cylinder device causes a nearly three fold increase in left upper lobe delivery in addition to diverting over 87%of the delivered particles to the left lung. Targeting efficiency can also be observed qualitatively by comparing the images of the target lobe filter to the other outlet filters. As illustrated, the most effective targeting method will yield a high particle deposition at the intended lobe of interest and a low deposition at the remaining lobe outlets.It is essential to make sure that components are properly connected to prevent leaks within the system as leaks will impact deposition results. This protocol permits researchers to test potential drug delivery devices for targeting specific regions of the lung prior to clinical trials reducing the cost associated with drug development and efficacy enhancement in human patients.

Research

JoVE Journal

Bioengineering

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

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 ...

科研

生物工程

Rapid and Low-cost Prototyping of Medical Devices Using 3D Printed Molds for Liquid Injection Molding

医疗器械的使用3D印刷模具的液体注射成型快速，低成本原型

Biologically inert elastomers such as silicone are favorable materials for medical device fabrication, but forming and curing these elastomers using ...

Improving 2D and 3D Skin In Vitro Models Using Macromolecular Crowding

Improving 2D and 3D Skin In Vitro Models Using Macromolecular Crowding

提高2D和3D皮肤<em&gt;体外</em&gt;模型使用大分子拥挤

The glycoprotein family of collagens represents the main structural proteins in the human body, and are key components of biomaterials used in modern ...

Scaling of Engineered Vascular Grafts Using 3D Printed Guides and the Ring Stacking Method

工程血管移植缩放使用3D打印指南和环堆叠方法

Coronary artery disease remains a leading cause of death, affecting millions of Americans. With the lack of autologous vascular grafts available, ...

Fabrication of Custom Agarose Wells for Cell Seeding and Tissue Ring Self-assembly Using 3D-Printed Molds

用 3 d-印刷模具制作细胞播种和组织环自组装用的自定义琼脂糖井

Engineered tissues are being used clinically for tissue repair and replacement, and are being developed as tools for drug screening and human disease ...

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

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 ...

High-resolution Patterned Biofilm Deposition Using pDawn-Ag43

使用 pDawn-Ag43 的高分辨率图案生物膜沉积

Spatial structure and patterning play an important role in bacterial biofilms. Here we demonstrate an accessible method for culturing E. coli biofilms ...

3D Printed Porous Cellulose Nanocomposite Hydrogel Scaffolds

三维印刷多孔纤维素纳米复合水凝胶脚手架

This work demonstrates the use of three-dimensional (3D) printing to produce porous cubic scaffolds using cellulose nanocomposite hydrogel ink, with ...

3D Cell-Printed Hypoxic Cancer-on-a-Chip for Recapitulating Pathologic Progression of Solid Cancer

3D 细胞打印的芯片上低氧癌症，用于回顾固体癌症的病理进展

Cancer microenvironment has a significant impact on the progression of the disease. In particular, hypoxia is the key driver of cancer survival, invasion, ...

Creation of Patient-Specific Silicone Cardiac Models with Applications in Pre-surgical Plans and Hands-on Training

创建患者专用硅胶心脏模型，应用于术前计划和实践培训

Three dimensional&#160;models can be a valuable tool for surgeons as they develop surgical plans and medical fellows as they learn about complex cases. In ...