这项研究是由密歇根大学创新研究资助P421071和早期职业格兰特P622911资助。

由哈姆纳研究院健康科学和这些图像的使用提供了MRI图像是经弗吉尼亚联邦大学机构审查委员会。 基于图像1.鼻通气准备<ol><li>获得一个健康的不吸烟的53岁的男性（体重73千克和身高173厘米）的磁共振（MR）的图像，包括72冠状断面间距1.5毫米除了跨越鼻孔鼻咽4。 </li><li> 开放式成像程序（ 例如 ，MIMICS） <ol><li>要导入的图片，单击"文件"，"导入图像"。选择MR图像，然后单击"确定"。 </li><li>为了构建三维模型，点击"分割"，那么"门槛"设置-1020和-500之间的灰度范围。点击"分割"，"计算3D"。 </li><li>点击"分割"和"计算折线"。选择3-D身体，并单击"确定"生成定义立体几何折线。导出折线为IGES文件。 </li></ol></li><li> 开放的模型开发软件（ 例如 ，开局） <ol><li>点击"文件"，"导入"，"IGES"将IGES文件导入到程序中。单击右侧面板上的"边缘命令按钮";点击"创建边缘"，然后选择"NURBS"重建平滑的轮廓。 </li><li>点击"脸部命令按钮"，然后单击"窗体面孔"。选择"线框"从边缘建立一个表面。继续构建覆盖整个呼吸道的所有表面。保留鼻腔的解剖细节，如悬雍垂，会厌倍，喉癌窦（ 图1）。点击"文件"，"导出""IGES"导出鼻气道的模型。 </li></ol></li><li> 开放式网格化软件（ 例如 ，ICEM CFD） <ol><li>点击"文件"，"导入几何"，"传统"和"STEP / IES"导入鼻腔气道模型点击"创建部件"的气道表面分为五个不同的区域:鼻前庭，鼻瓣，鼻甲区域，嗅觉和鼻咽部。 </li><li>为了产生呼吸道内的计算网格，单击"网格"，"环球网设置"。指定最大网格尺寸至0.1毫米，点击"应用"。 </li><li>要添加在近壁区的贴体网格，点击"计算网格"，"棱镜网"。指定层5和数量不断扩大的比值为1.25，然后点击"应用"。 </li></ol></li></ol> 2.颗粒的被动控制<ol><li> 前庭插管:前VS。背部 <ol><li>开放的模型开发软件发展与前前庭插管鼻模型。单击"音量"，然后选择"移动/复制"来改变n的位置ebulizer导管5毫米，伸入鼻孔从尖前厅。点击"注入"释放60000粒（150纳米）插入鼻孔。 </li><li>打开流体模拟软件（ 如 ANSYS FLUENT）来计算鼻子内的颗粒沉积速率。为了计算呼吸道内的气流场，通过点击"定义"，"型号"，"粘性"选择层流模型;选择"层流"，"粘性模型"之下。 </li><li>选择"离散相模型"来追踪粒子运动。检查"Saffman升力"下的"离散相模型"。点击"报告"，然后选择"样本轨迹";选择"鼻"，"边界"下，点击"计算"，找到沉积在预定的嗅觉区域的粒子数量。计算淀积速率淀积颗粒的量的进入鼻孔颗粒的量的比率。 </li><li>重复步骤2.1.2 1微米的颗粒。 </li><li>按照步骤2.1.1，插入喷雾喷嘴5毫米深处从鼻孔后面的前庭。重复步骤2.1.2，2.1.3和计算为150纳米的颗粒沉积速率。重复步骤2.1.4为1微米的颗粒（回气管插管）。 </li></ol></li><li> 深插管 <ol><li>按照程序2.1.1插入嗅觉区正下方雾化器导管。从发布喷雾器60000亚微米颗粒（150纳米）。 </li><li>使用液体和仿真软件通过在2.1.2中列出以下类似的程序来计算总的和当地的基础上，鼻子里的颗粒沉积速率。重复此过程为1微米的颗粒。 </li><li>重复上面的步骤，同时锻炼呼吸，控股和呼气，分别为。点击"定义"，然后在"边界条件"，打开边界条件面板。对准两鼻孔呼吸持指定零速度。指定在鼻孔真空压力（200帕）和在出口处为呼气零压力。 </li></ol></li></ol> 3.主动控制:磁致指引<ol><li> 测试在双板通道 <ol><li>打开磁粉跟踪软件（ 例如 ，COMSOL）。单击"几何"和"矩形"打造的双板通道。点击"矩形"，以建立围绕这两个板通道的磁铁。 </li><li>计算粒子轨迹和沉积速率。点击"模式1"，"层流"和"进1";指定入口速度为0.5米/秒。点击"模式1"，"磁场"和"磁保护"，指定三个磁体（1×10 5 A / M）的实力。 </li><li>点击"模式1"，"粒子跟踪的流体流量"和"粒子属性";指定粒径（15微米），密度（1.7为8g /厘米3）。点击"入口"发布3000粒。点击"磁泳队"，指定颗粒相对磁导率（50）。点击"计算"。 </li><li>要了解有多少粒子在选定区域沉积，单击"结果"，"1D情节集团"和"暗算"。计算淀积速率为粒子沉积在一定的区域，以进入几何颗粒的量的量的比率。 </li><li>要调整磁场强度，单击"模型1"，然后"磁场"选择"磁保护"，并在"磁化"改变磁场强度。按1×10 4 / m的增量增加磁场强度，然后点击"计算"。 </li><li>重复此过程，直到对有效的药物输送到嗅觉区域中获得的适当的磁体布置。 </li></ol></li><li> 测试在2-D理想化鼻型 <ol><li>通过将三个磁体为1mm鼻子上述申请在3.1所得到的2-D鼻子模型的磁强度。点击"模式1"，"几何1"来指定磁铁的大小和位置。点击"模式1"，"粒子跟踪的流体流量"，"入口"释放3000颗粒进入左鼻孔。点击"粒子属性"来指定粒径15微米。 </li><li>通过在3.1.2中列出以下类似的程序模拟粒子轨迹和随后的嗅觉递送效率。 </li><li>调整磁铁布局和强度，提高嗅觉提高效率。要调整磁铁的大小和位置，然后单击"模型1"，然后在"几何1";选择感兴趣的磁铁，更改的宽度，深度，高度或X，Y，z的值。按照3.1.5调整磁场强度。 </li></ol></li><li> 测试在3-D解剖精确鼻型 <ol><li>恶魔ORT的3-D鼻通气模式进入磁粉跟踪软件。按照程序3.2.1，放四个磁铁为1mm以上的鼻子和只有一个选择点上释放的15微米的颗粒3000的直径。 </li><li>采用磁粒子跟踪软件来跟踪粒子轨迹，并在3.2.1中列出以下类似的程序计算嗅觉递送效率 - 3.2.3。 </li><li>以下3.2.3，调整磁铁布局和强度在3D模式，提高靶向递送到嗅觉区域。 </li><li>测试颗粒大小为1 - 30微米找到合适的粒径为到嗅觉区域最佳磁泳指导。 </li></ol></li></ol>

<ol>
	<li>Mistry, A., Stolnik, S., Illum, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nanoparticles+for+direct+nose-to-brain+delivery+of+drugs.">Nanoparticles for direct nose-to-brain delivery of drugs.</a> Int. J. Pharm. 379 (1), 146-157 (2009).</li><li>Alam, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+and+evaluation+of+thymoquinone-encapsulated+chitosan+nanoparticles+for+nose-to-brain+targeting:+a+pharmacoscintigraphic+study.">Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study.</a> Int. J. Nanomedicine. 7 (11), 5705-5718 (2012).</li><li>Shi, H., Kleinstreuer, C., Zhang, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Laminar+airflow+and+nanoparticle+or+vapor+deposition+in+a+human+nasal+cavity+model.">Laminar airflow and nanoparticle or vapor deposition in a human nasal cavity model.</a> J. Biomech. Eng. 128 (5), 697-706 (2006).</li><li>Si, X., Xi, J., Kim, J., Zhou, Y., Zhong, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modeling+of+release+position+and+ventilation+effects+on+olfactory+aerosol+drug+delivery.">Modeling of release position and ventilation effects on olfactory aerosol drug delivery.</a> Respir. Physiol. Neurobiol. 186 (1), 22-32 (2013).</li><li>Si, X., Xi, J., Kim, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+laryngopharyngeal+anatomy+on+expiratory+airflow+and+submicrometer+particle+deposition+in+human+extrathoracic+airways.">Effect of laryngopharyngeal anatomy on expiratory airflow and submicrometer particle deposition in human extrathoracic airways.</a> Open J. Fluid D. 3 (4), 286-301 (2013).</li><li>Xi, J., Longest, P. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Numerical+predictions+of+submicrometer+aerosol+deposition+in+the+nasal+cavity+using+a+novel+drift+flux+approach.">Numerical predictions of submicrometer aerosol deposition in the nasal cavity using a novel drift flux approach.</a> Int. J. Heat Mass Transfer. 51 (23), 5562-5577 (2008).</li><li>Illum, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nasal+drug+delivery:+new+developments+and+strategies.">Nasal drug delivery: new developments and strategies.</a> Drug Discov. Today. 7 (23), 1184-1189 (2002).</li><li>El Taoum, K. K., Xi, J., Kim, J. W., Berlinski, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vitro+evaluation+of+aerosols+delivered+via+the+nasal+route.">In vitro evaluation of aerosols delivered via the nasal route.</a> Respir. Care. 60 (7), 1015-1025 (2015).</li><li>Misra, A., Kher, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Drug+delivery+systems+from+nose+to+brain.">Drug delivery systems from nose to brain.</a> Curr. Pharm. Biotechnol. 13 (12), 2355-2379 (2012).</li><li>Hoekman, J. D., Ho, R. J. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+Localized+Hydrophilic+Mannitol+and+Hydrophobic+Nelfinavir+Administration+Targeted+to+Olfactory+Epithelium+on+Brain+Distribution.">Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution.</a> Aaps Pharmscitech. 12 (2), 534-543 (2011).</li><li>Corley, R. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparative+Computational+Modeling+of+Airflows+and+Vapor+Dosimetry+in+the+Respiratory+Tracts+of+Rat,+Monkey,+and+Human.">Comparative Computational Modeling of Airflows and Vapor Dosimetry in the Respiratory Tracts of Rat, Monkey, and Human.</a> Toxicol. Sci. 128 (2), 500-516 (2012).</li><li>Shi, H., Kleinstreuer, C., Zhang, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modeling+of+inertial+particle+transport+and+deposition+in+human+nasal+cavities+with+wall+roughness.">Modeling of inertial particle transport and deposition in human nasal cavities with wall roughness.</a> J. Aerosol Sci. 38 (4), 398-419 (2007).</li><li>Kleinstreuer, C., Zhang, Z., Donohue, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Targeted+drug-aerosol+delivery+in+human+respiratory+system.">Targeted drug-aerosol delivery in human respiratory system.</a> Annu. Rev. Biomed. Eng. 10 (4), 195-220 (2008).</li><li>Kleinstreuer, C., Zhang, Z., Li, Z., Roberts, W. L., Rojas, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+methodology+for+targeting+drug-aerosols+in+the+human+respiratory+system.">A new methodology for targeting drug-aerosols in the human respiratory system.</a> Int. J. Heat Mass Transfer. 51 (23), 5578-5589 (2008).</li><li>Wilson, I. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+deposition+of+charged+particles+in+tubes,+with+reference+to+the+retention+of+therapeutic+aerosols+in+the+human+lung.">The deposition of charged particles in tubes, with reference to the retention of therapeutic aerosols in the human lung.</a> J. Colloid Sci. 2 (2), 271-276 (1947).</li><li>Wong, J., Chan, H. -. K., Kwok, P. C. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrostatics+in+pharmaceutical+aerosols+for+inhalation.">Electrostatics in pharmaceutical aerosols for inhalation.</a> Ther Deliv. 4 (8), 981-1002 (2013).</li><li>Bailey, A. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+inhalation+and+deposition+of+charged+particles+within+the+human+lung.">The inhalation and deposition of charged particles within the human lung.</a> Journal of Electrostatics. 42 (1), 25-32 (1997).</li><li>Xi, J., Si, X. A., Gaide, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrophoretic+particle+guidance+significantly+enhances+olfactory+drug+delivery:+a+feasibility+study.">Electrophoretic particle guidance significantly enhances olfactory drug delivery: a feasibility study.</a> PLoS ONE. 9 (1), e86593 (2014).</li><li>Martin, A., Finlay, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alignment+of+magnetite-loaded+high+aspect+ratio+aerosol+drug+particles+with+magnetic+fields.">Alignment of magnetite-loaded high aspect ratio aerosol drug particles with magnetic fields.</a> Aerosol Sci. Technol. 42 (4), 295-298 (2008).</li><li>Dames, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Targeted+delivery+of+magnetic+aerosol+droplets+to+the+lung.">Targeted delivery of magnetic aerosol droplets to the lung.</a> Nature Nanotechnology. 2 (8), 495-499 (2007).</li><li>Xi, J., Longest, P. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transport+and+deposition+of+micro-aerosols+in+realistic+and+simplified+models+of+the+oral+airway.">Transport and deposition of micro-aerosols in realistic and simplified models of the oral airway.</a> Ann. Biomed. Eng. 35 (4), 560-581 (2007).</li><li>Longest, P. W., Xi, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effectiveness+of+direct+Lagrangian+tracking+models+for+simulating+nanoparticle+deposition+in+the+upper+airways.">Effectiveness of direct Lagrangian tracking models for simulating nanoparticle deposition in the upper airways.</a> Aerosol Sci. Technol. 41 (4), 380-397 (2007).</li><li>Xi, J., Zhang, Z., Si, X. A., Yang, J., Deng, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimization+of+magnetophoretic-guided+drug+delivery+to+the+olfactory+region+in+a+human+nose+model.">Optimization of magnetophoretic-guided drug delivery to the olfactory region in a human nose model.</a> Biomech. Model. Mechanobiol. In. , (2015).</li><li>Longest, P. W., Hindle, M., Das Choudhuri, S., Xi, J. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+ambient+and+spray+aerosol+deposition+in+a+standard+induction+port+and+more+realistic+mouth-throat+geometry.">Comparison of ambient and spray aerosol deposition in a standard induction port and more realistic mouth-throat geometry.</a> J. Aerosol Sci. 39 (7), 572-591 (2008).</li><li>Xi, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+Testing+of+Electric-Guided+Delivery+of+Charged+Particles+to+the+Olfactory+Region:+Experimental+and+Numerical+Studies.">Design and Testing of Electric-Guided Delivery of Charged Particles to the Olfactory Region: Experimental and Numerical Studies.</a> Curr. Drug Deliv. 13 (9), 1-15 (2015).</li><li>Zhou, Y., Guo, M., Xi, J., Irshad, H., Cheng, Y. -. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nasal+deposition+in+infants+and+children.">Nasal deposition in infants and children.</a> Journal of aerosol medicine and pulmonary drug delivery. 27 (2), 110-116 (2014).</li><li>Xi, J., Yuan, J. E., Si, X. A., Hasbany, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Numerical+optimization+of+targeted+delivery+of+charged+nanoparticles+to+the+ostiomeatal+complex+for+treatment+of+rhinosinusitis.">Numerical optimization of targeted delivery of charged nanoparticles to the ostiomeatal complex for treatment of rhinosinusitis.</a> Int. J. Nanomedicine. 10 (7), 4847-4861 (2015).</li></ol>

作者报告了这项工作没有任何利益冲突。

一个联动图像CFD方法在这项研究中，纳入基于图像的模式发展，以质量网格化，气流模拟和磁性粒子跟踪介绍。多个软件模块实施了这一目的，其中包括医疗图像，重建/解剖学精确气道模型的啮合，和流粒子模拟分割的功能。采用这种数值计算方法，三个鼻内递送协议性能进行了测试，并进行比较。相比， 在体外实验中 ，这种方法是在成本和时间效率更高;由此可进行大量的数字测...

药物输送到嗅觉区可以绕过血-脑屏障，并直接进入大脑，导致药物1,2-的有效摄取和快速行动发作。然而，传统的鼻腔的设备，如鼻泵和喷雾剂经由鼻途径3,4-递送极低剂量到嗅觉区域（&lt;1％）。它主要是由于它是由狭窄的，回旋通路（ 图1）的人的鼻子的复杂的结构。嗅觉区域位于上鼻道，其中仅吸入空气的一小部分可以达到5,6的上方。此外，传统的吸入装置依靠空气动力治疗剂输送到所述目标区7。有超过粒子释放后的运动没有进一步的控制。因此，这些粒子的运输和沉积主要是取决于它们的初始速度和释放的位置。应有向旋绕鼻通道以及缺乏颗粒控制的，大多数药物颗粒被截留在前壁鼻子和不能到达嗅觉区域8。 虽然有鼻设备的选择，对于那些嗅觉针对性交货很少被报道7,9专门设计的。一个例外是Hoekman和何10谁开发的嗅觉优先输送装置以及具备更高的大鼠皮层对血药水平，而不是用鼻子下降。然而，在大鼠缩放沉积的结果对人类并不简单，考虑到这两个品种11之间的广袤的解剖和生理上的差异。使用嗅觉交付标准的鼻设备的改编版本时存在着诸多限制。一个主要缺陷是，只有药物的一个非常小的部分可被输送到嗅粘膜，通过该药物可能进入脑。数值模拟预测，鼻内施用纳米颗粒小于0.5％所用的嗅觉区3,5-沉积。淀积速率是即使对微米颗粒12低（0.007％）。为了使鼻子到脑递送临床可行，嗅觉沉积速率，必须显著改善。 存在改善嗅觉交付几种可能的方法。一种方法是通过Kleinstreuer 等人 13提出作为在一个区域上沉积的颗粒主要是由在入口一个特定区域中的智能吸入器的想法，也可以通过在入口处从某些区域仅释放他们提供颗粒到目标部位。智能递送技术已经显示出，以产生一个更有效的肺递送比常规方法。13,14这是假设，这个智能输送想法也可在鼻内药物递送应用到我的mProve剂量到嗅粘膜。通过释放颗粒进入在鼻孔开口和从鼻腔内的不同深度位置不同，改进的嗅觉递送效率和前鼻降低药物浪费是可能的。 另一个可能的方法是积极控制使用各种字段的力，如电场或磁场力的鼻腔内的颗粒运动。带电粒子的电控制已被建议用于靶向药物递送到人的鼻子和肺部15-17。习等人 18数值测试的带电粒子的电指导的性能和预测显著改善嗅觉的剂量。同样地，用适当的磁场铁磁药物颗粒的指导也有到目标粒子嗅粘膜的潜力。吸入剂的行为，如果铁磁性，可以通过适当的施加磁力改变<suP&gt; 19。达梅斯等人 20表明，它是实际的目标铁磁粒子，以在小鼠肺特定区域。通过封装的治疗剂的超顺磁性氧化铁纳米颗粒，在小鼠中的一个肺沉积强磁场的影响下被显著增加相比，其他肺20。 颗粒假设是球形的，并从150纳米至30微米的直径范围。控制方程为21: （1） <img alt="式（1）" src="/files/ftp_upload/53902/53902eq1.jpg" />上述公式描述如果放在磁场中受阻力，重力，Saffman升力22纳米粒子布朗力，磁致力支配的粒子的运动。此处，V i是粒子速度u i是流速，τp是粒子响应时间，C c是坎宁安修正系数，α是空气/颗粒密度比。为了有效地引导鼻内施用的药物到嗅觉区域，有必要对所施加的磁泳力，以克服这两种颗粒的惯性和重力。在这项研究中，20％的磁赤铁矿的复合（γ- 的 Fe 2 O 3，4.9克/厘米3）和80％的活性剂被假定，这给的近似1.78克/ cm 3的密度和50的相对导磁率。了γ-Fe 2 O 3的选择是由于其低细胞毒性的。铁（3+）离子广泛存在于人体和略高离子浓度不会引起显著副作用23。

<table><tbody><tr><td>MIMICS 13</td><td>Materialise Inc, Ann Arbor, MI</td><td>MR image segmentation</td><td></td></tr><tr><td>Gambit</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Model development</td><td></td></tr><tr><td>ANSYS ICEMCFD</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Meshing</td><td></td></tr><tr><td>ANSYS Fluent</td><td>ANSYS Inc, Canonsburg, PA&amp;nbsp;</td><td>Fluid and particle simulation</td><td></td></tr><tr><td>COMSOL Multiphsics</td><td>COMSOL Inc, Burlington, MA</td><td>Magnetic particle tracing</td><td></td></tr></tbody></table>

modeling and simulations of olfactory drug delivery with passive and active controls of nasally inhaled pharmaceutical aerosols

有在神经学病症的治疗中直接鼻子到大脑的药物输送的许多优点。然而，它的应用是由极低递送效率（&lt;1％），以直接连接大脑嗅粘膜的限制。它是开发新颖的技术，以更有效地对嗅觉区域递送神经药物是至关重要的。本研究的目的是建立一个数值平台来模拟和改善鼻内嗅觉药物传送。一个联动图像CFD方法，提出了原料合成基于图像的模式发展，以质量啮合，流体模拟，和磁粉跟踪。用这种方法，三个鼻内递送协议性能进行了数值评估和比较。呼吸机动，磁铁布局，磁场强度，药物释放的位置，并在嗅觉剂量粒径的影响进行了数值研究。 从Simulations，我们发现，在临床显著嗅觉剂量（高达45％），使用磁铁布局和选择性的药物释放的组合是可行的。用量的64倍更高的交付与磁致指导的情况相比，没有它的情况进行了预测。但是，经鼻吸入气雾剂到嗅觉区域的精确导向，由于磁电泳的不稳定性质，以及嗅觉剂量患者 - ，设备，平台，和粒子有关的因素的高灵敏度仍然具有挑战性。

控制案例: 图3显示了气流场和粒子沉积在鼻腔气道与标准鼻装置。它清楚地表明，从正面鼻孔气流通风到上通道和气流从背部鼻孔朝向鼻底（ 图3A）。气溶胶颗粒观察移动中位数通道较快和较慢的壁附近，形成在平均流动方向的气溶胶前面。气溶胶粒子可以进入正常呼吸的条件下鼻孔（20升/分钟）（ 图3B）后达到0.0...

Watch this Scientific Journal Video about Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols at JoVE.com

Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

This manuscript reviews the modeling and simulations of different protocols to deliver medications to the olfactory region in image-based nasal airway models. Multiple software modules are used to develop the anatomically accurate nose model, generate computational mesh, simulate nasal airflows, and predict particle deposition at the olfactory region.

建模与嗅觉药物传送的模拟与鼻吸入气雾剂药品的被动和主动控制

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the ...

modeling-simulations-olfactory-drug-delivery-with-passive-active

Universidad de Cartagena UDEC

Research

JoVE Journal

Medicine

10.8K 次观看.  California Baptist University. This manuscript reviews the modeling and simulations of different protocols to deliver medications to the olfactory region in image-based nasal airway models. Multiple software modules are used to develop the anatomically accurate nose model, generate computational mesh, simulate nasal airflows, and predict particle deposition at the olfactory region. 

视频: Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to stimulate microcirculation. The choice of delivery method for these agents is important because the route of administration profoundly affects the bioactivity and efficacy of these agents1,2. In this article, we demonstrate how to locally administer a substance in ischemic hindlimbs by using a catheterized osmotic pump. This pump can deliver a fixed volume of aqueous solution continuously for an allotted period of time. We also present our mouse model of unilateral hindlimb ischemia induced by ligation of the common femoral artery proximal to the origin of profunda femoris and epigastrica arteries in the left hindlimb. Lastly, we describe the in vivo cannulation and ligation of the infrarenal abdominal aorta and perfusion of the hindlimb vasculature with Microfil, a silicone radiopaque casting agent. Microfil can perfuse and fill the entire vascular bed (arterial and venous), and because we have ligated the major vascular conduit for exit, the agent can be retained in the vasculature for future ex vivo imaging with the use of small specimen micro-CT3.

We show here the in vivo insertion of an osmotic pump for constant local drug delivery and the creation of hindlimb ischemia in a mouse model. Moreover, the hindlimb vasculature is perfused with Microfil, a silicone radiopaque agent, to prepare for micro-computed tomography (micro-CT) imaging.

药物输送到微型计算机断层扫描成像缺血后肢血管灌注与微滤渗透

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to ...

科研

医学

Controlled Odor Mimic Permeation Systems for Olfactory Training and Field Testing

The Controlled Odor Mimic Permeation System (COMPS) was developed to provide a convenient field testing method of odor delivery at controlled and reproducible rates. COMPS are composed of an odorant of interest on an absorbent material sealed inside of a permeable polymer bag. The permeable layer allows for a constant release of the odorant over a given amount of time. The permeable bag is further stored in a secondary, impermeable bag. The double-containment procedure allows for equilibration of the odorant from the permeable bag but within the impermeable outer layer, resulting in an instant and reproducible source of odorant vapor upon removal from the outer packaging. COMPS are used in both olfactory testing for experimental scenarios and for olfactory detection training, such as with detection canines. COMPS can be used to contain a wide range of odorants (e.g., narcotics powders) and provide a controlled release of the associated odorants. Odor availability from COMPS is expressed in terms of permeation rate (i.e., the rate of the odorant vapor released from a COMPS per unit time) and is typically measured by gravimetric means. The permeation rate for a given mass or volume of odorant can be adjusted as needed by varying the bag thickness, surface area, and/or polymer type. The available odor concentration from a COMPS can also be measured by headspace analysis techniques such as solid phase microextraction with gas chromatography/mass spectrometry (SPME-GC/MS).

The Controlled Odor Mimic Permeation System is a simple, field-portable, low-cost method of odor delivery for olfactory testing and training. It is constructed of an odorant retained on an adsorbent material and contained inside of a permeable polymer bag allowing controlled release of the odorant vapor over time.

用于嗅觉训练和现场测试的受控气味模拟渗透系统

The Controlled Odor Mimic Permeation System (COMPS) was developed to provide a convenient field testing method of odor delivery at controlled and ...

化学

Disposable Dosators for Pulmonary Insufflation of Therapeutic Agents to Small Animals

Development of new therapeutic products requires efficacy testing in an animal model. The pulmonary route of administration can be utilized to deliver drugs locally and systemically. Evaluation of dry powder aerosols necessitates an efficient dispersion mechanism to maintain high concentrations in an exposure chamber or for direct endotracheal administration. While solutions exist to expose animals by passive inhalation to dry powder aerosols, most require masses of powder in large excess of the dose delivered. This precludes conducting early feasibility studies as insufficient drug is available at the research or early development stage to support the dose delivery requirements for conventional aerosol delivery systems. When designing an aerosol drug product, aerodynamic performance can relate directly to delivery efficiency and efficacy. Dispersion of powder into an aerosol requires energy input sufficient to overcome interparticulate forces, and particle engineering approaches can substantially improve aerosol performance. We have developed a dispersion system (dosator) which can aerosolize engineered dry powder aerosols efficiently for the purpose of direct pulmonary insufflation, dispersion into an exposure system or generation for analytical purposes.

During development of drugs for pulmonary delivery, it is necessary to evaluate pharmacokinetics and efficacy in an animal model. We present a method to build a disposable aerosol dispersion system from of-the-shelf components that can be used to administer intrapulmonary dry powder aerosol to rodents.

一次性充填机对治疗药物的肺吹入小动物

Development of new therapeutic products requires efficacy testing in an animal model. The pulmonary route of administration can be utilized to deliver ...

Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and bronchodilator drugs. Despite the availability of multiple treatments, both diseases are growing public health concerns. The majority of asthma patients are well controlled on current inhaled therapies but a substantial number of patients with severe asthma are not. Asthma affects an estimated 300 million people worldwide and approximately 20 percent have a severe form of the disease. In contrast to asthma, there are few effective therapies for COPD. An estimated 10% of the population has COPD and the trend in death rates is increasing for COPD while decreasing for other major diseases. Although developing drugs for inhaled delivery is challenging, the nose-only inhalation unit enables direct delivery of novel drugs to the lung of rodents for pre-clinical efficacy and safety/toxicology studies. Inhaled drug delivery has multiple advantages for respiratory diseases, where high concentration in the lung improves efficacy and minimizes systemic side effects. Inhaled corticosteroids and bronchodilators benefit from these advantages and inhaled delivery may also hold potential for future biologic therapies. The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs of rodents, key data required before initiating clinical development.

The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs; key data enabling clinical inhaled drug development.

干粉和药品的雾化吸入气雾剂递送小鼠使用鼻只曝光系统

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and ...

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.

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 ...

生物工程

Real-time In Vitro Monitoring of Odorant Receptor Activation by an Odorant in the Vapor Phase

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. This is why the olfaction community is committed to &#34;de-orphanize&#34;&#160;these receptors. Conventional in vitro systems used to identify odorant-OR interactions have utilized incubating cell media with odorant, which is distinct from the natural detection of odors via vapor odorants dissolution into nasal mucosa before interacting with ORs. Here, we describe a new method that allows for real-time monitoring of OR activation via vapor-phase odorants. Our method relies on measuring cAMP release by luminescence using the Glosensor assay. It bridges current gaps between in vivo and in vitro approaches and provides a basis for a biomimetic volatile chemical sensor.

Physiologically, odorant receptors are activated by odorant molecules inhaled in the vapor phase. However, most in vitro systems utilize liquid phase odorant stimulation. Here, we present a method that allows real-time in vitro monitoring of odorant receptor activation upon odorant stimulation in vapor phase.

气相臭受体活化的实时体外监测

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition ...

神经科学

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain barrier. However, there have been few reports regarding not only the quantitative analysis but also optimal administration conditions and dosing regimens for investigations of nose-to-brain delivery. The limited progress in research on nose-to-brain pathway mechanisms using rodents represents a significant impediment in terms of designing nose-to-brain delivery systems for candidate drugs.
To gain some headway in this regard, we developed and evaluated two novel methods of stable intranasal administration under inhalation anesthesia for experimental animals. We also describe a method for the evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radio-labeled [14C]-inulin (molecular weight: 5,000) as a model substrate of water-soluble macromolecules.
Initially, we developed a pipette-based intranasal administration protocol using temporarily openable masks, which enabled us to perform reliable administration to animals under stable anesthesia. Using this system, [14C]-inulin could be delivered to the brain with little experimental error.
We subsequently developed an intranasal administration protocol entailing reverse cannulation from the airway side through the esophagus, which was developed to minimize the effects of mucociliary clearance (MC). This technique led to significantly higher levels of [14C]-inulin, which was quantitatively detected in the olfactory bulb, cerebrum, and medulla oblongata, than the pipette method. This appears to be because retention of the drug solution in the nasal cavity was substantially increased by active administration using a syringe pump in a direction opposite to the MC into the nasal cavity.
In conclusion, the two methods of intranasal administration developed in this study can be expected to be extremely useful techniques for evaluating pharmacokinetics in rodents. The reverse cannulation method, in particular, could be useful for evaluating the full potential of nose-to-brain delivery of drug candidates.

Here, we describe two novel methods of stable intranasal administration under inhalation anesthesia with minimal physical stress for experimental animals. We also describe a method for quantitative evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radiolabeled [14C]-inulin as a model substrate of water-soluble macromolecules.

吸入麻醉下鼻内给药评价鼻腔给脑药物的新方法

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain ...

气味对通过呼吸同步嗅觉计评估的大脑兴奋性的影响

Combining a Breath-Synchronized Olfactometer with Brain Simulation to Study the Impact of Odors on Corticospinal Excitability and Effective Connectivity

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals and humans. Recently, studies using electroencephalography and transcranial magnetic stimulation (TMS) have demonstrated a strong link between processing in the olfactory system and activity in the motor cortex in humans. To better understand the interactions between the olfactory and the motor systems and to overcome some of the previous methodological limitations, we developed a new method combining an olfactometer that synchronizes the random order presentation of odorants with different hedonic values and the TMS (single- and dual-coil) triggering with nasal breathing phases. This method allows probing the modulations of corticospinal excitability and effective ipsilateral connectivity between the dorsolateral prefrontal cortex and the primary motor cortex that could occur during pleasant and unpleasant odor perception. The application of this method will allow for objectively discriminating the pleasantness value of an odorant in a given participant, indicating the biological impact of the odorant on brain effective connectivity and excitability. In addition, this could pave the way for clinical investigations in patients with neurological or neuropsychiatric disorders who may exhibit&#160;odor hedonic alterations and maladaptive approach-avoidance behaviors.

作者聚焦：探索嗅觉对皮质脊髓兴奋性的影响 - 神经学研究的见解和创新 

This paper describes using a breath-synchronized olfactometer to trigger single- and dual-coil transcranial magnetic stimulation (TMS) during odorant presentation synchronized to human nasal breathing. This combination allows us to objectively investigate how pleasant and unpleasant odors impact corticospinal excitability and brain-effective connectivity in a given individual.

将呼吸同步嗅觉计与大脑模拟相结合，研究气味对皮质脊髓兴奋性和有效连接性的影响

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals ...

建模与嗅觉药物传送的模拟与鼻吸入气雾剂药品的被动和主动控制

摘要

探索更多视频

此视频中的章节

药物输送到微型计算机断层扫描成像缺血后肢血管灌注与微滤渗透

用于嗅觉训练和现场测试的受控气味模拟渗透系统

一次性充填机对治疗药物的肺吹入小动物

干粉和药品的雾化吸入气雾剂递送小鼠使用鼻只曝光系统

使用患者专用的 3D 打印肺模型评估区域肺沉积

气相臭受体活化的实时体外监测

吸入麻醉下鼻内给药评价鼻腔给脑药物的新方法

将呼吸同步嗅觉计与大脑模拟相结合，研究气味对皮质脊髓兴奋性和有效连接性的影响

将呼吸同步嗅觉计与大脑模拟相结合，研究气味对皮质脊髓兴奋性和有效连接性的影响

将呼吸同步嗅觉计与大脑模拟相结合，研究气味对皮质脊髓兴奋性和有效连接性的影响