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>

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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试，以找出最佳传递协议25,26。具体地，耦合图象CFD方法生成的行为和药物颗粒的命运的详细信息，从而提供了深入洞察在减少前鼻药物损失和增加药物剂量到目标。此外，耦合图像的CFD在这项研究中建立的方法可以很容易地修改滴鼻药物输送到其他地区，如鼻窦24。在协议中所概述除以下两种程序类似的程序可以遵循。 （1）这是在2.1.3预定义的感兴趣区域应改为窦，这可以通过以下的协议1.4来实现。 （2）磁铁​​的配置和力量的范围需要调整窦给药。从鼻孔到窦的药物粒子的路径是从从鼻孔到嗅觉显着不同。磁场应作相应的修改，以便使颗粒能够被引导到跟随预定的路径。这个任务可以通过以下方案3.2.1来实现。 有在嗅觉药物传送与此图像-CFD模拟方法的两个关键步骤。第一，开发基于图像的鼻子模型是可以接受的流动粒子的仿真软件（ 例如 ，流利和COMSOL）仍然是一个挑战。它花了超过60小时来重构当前鼻子模型（协议1.3）的表面几何形状。第二，模拟结果表明，磁性颗粒对磁场和粒子释放位置非常敏感;磁铁布局广泛的测试，达到最佳的设计交付（协议3.2.3和3.3.2）之前是必需的。 所有三种给药方案进行了预测，给出改进的嗅觉剂量;然而，改善不同的三种方法之一。这两个被动控制协议（前庭和深插管）似乎不足以达到足够的CNS无剂量在鼻子上造成显著药物损失到其他地区。即使对于最优被动控制协议（ 即 ，吸入的条件下深插管），嗅觉剂量仍然太低（&lt;0.1％），以对于直接鼻子到脑递送的目的实用。主动续在鼻腔药物颗粒的ROLS是不可缺少的。这项研究的限制包括定常流动的假设下，刚性呼吸道墙壁，只有数值模拟，并使用一种鼻气道的几何形状。因此，本研究的结果不能说明主体间的差异。用于药物递送至一个不同的人，在此所提出的设计，预计将有较低的性能。以达到最佳递送至该特定病人，个性化的设计应根据患者的鼻腔几何来配制。 所提出的嗅觉传递协议有直接的鼻子到大脑的药物输送具有重要意义。标准鼻设备递送极低剂量（&lt;1％）到嗅觉区域，该区域已经抢先使用了许多新的基因工程药物用于治疗CNS障碍，如阿尔茨海默氏病和脑肿瘤1,9。所提出的磁致嗅觉交付承诺deliv呃临床显著剂量到嗅觉区域，并且提供绕过血 - 脑屏障的非侵入性实用的方法。此递送系统也可以容易地适于在鼻递送药物到其它地区，如鼻窦，在不同的鼻子模型，或药物具有不同的物理性质。

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 border="0" cellpadding="0" cellspacing="0" width="659">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">MIMICS 13</td>
			<td style="width:199px;">Materialise Inc, Ann Arbor, MI</td>
			<td style="width:188px;">MR image segmentation</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">Gambit</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Model development</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">ANSYS ICEMCFD</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Meshing</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">ANSYS Fluent</td>
			<td style="width:199px;">ANSYS Inc, Canonsburg, PA&#160;</td>
			<td style="width:188px;">Fluid and particle simulation</td>
			<td style="width:120px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:152px;">COMSOL Multiphsics</td>
			<td style="width:199px;">COMSOL Inc, Burlington, MA</td>
			<td style="width:188px;">Magnetic particle tracing</td>
			<td style="width:120px;"></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0.02的嗅觉区至0.03秒。很少颗粒（0.22％），存款在上鼻（鼻道）;甚至更少的颗粒（0.007％），到达最上面的嗅粘膜（ 图3C）。高度异质沉积模式进行了预测，通过广泛沉积如图所示增强因子（DEF） 如图3C。这里，DEF表示局部颗粒积累的水平和计算为局部沉积速率超过区域平均沉积速率在 ​​鼻子24中的比率。在这项研究中的数值模型还进行了验证针对可比鼻气道副本获得的实验数据。好协议的数值预测和实验测量（ 图3D）之间实现。 被动控制我:前庭插管 前庭插管协议的仿真结果示于图4中 。对于正面和背面插管例两者，有较强的喷射效果立即喷嘴（ 图4A）的下游。据预计，颗粒释放到前前庭将更有可能存我n中的嗅觉区域比其他区域。考虑背面插管的情况下，主流动通过由喷射效果（ 图4B）引起的真空向下吸入。正如预期的那样，多个药物颗粒相比于背部协议递送到嗅觉区与前插管协议。此外，更集中的沉积在嗅觉区域观测与前释放。最大的DEF值大约是2.5倍后释放。 从图4C中 ，沉积速率的差异是三种情况下（控制，前，后）之间微不足道。然而，一个显着的差异存在于与前释放给显著更高嗅觉剂量，嗅沉积大约两倍背面释放壳体和十倍，该控制的情况下的。 被动控制II:深插管不同的呼吸机动在这个协议中，喷嘴插入靠近嗅粘膜。这种定位成功地绕过了鼻瓣，在鼻子的主要限流区域。三个呼吸条件（吸入，屏气，呼气和）被认为是对他们的嗅觉药物传送的影响。正常的呼吸率（20升/分钟）在两吸入和呼出的条件下使用。在这三种呼吸的条件下，吸入给予最高剂量由浓缩嗅觉沉积（ 图5A），为显示。相比之下，无论是屏气和呼气条件未能产生集中的证言。线索的扩散沉积图案可以在图5B和c，其中只有气流的一小部分进入到嗅觉区域而魔女所示鼻空气动力学来获得RITY向下或者移动到肺（ 图5B）或退出到环境空气中（ 图5C）。特别是，在呼气的情况下颗粒分散在整个鼻通道而没有明显的沉积的热点。相反，吸入的情况下，高的DEF值被限制为仅嗅觉区域，与鼻甲区域观测低DEF值。这是一个理想的沉积图案，因为它会最大化在目标嗅觉区域中的治疗效果，同时减少在其他区域的副作用。 两种递送方法之间的性能（前庭与深插管）进一步相比每如图5D单位面积（％/ cm 2）的沉积速率的函数。嗅觉区域的表面面积为6.8 平方厘米本研究。每单位面积更高的嗅觉剂量与C中的深插管交付omparison前庭插管。具体地，吸入的条件下深插管递送高2.5倍的剂量比，在第一协议中建议的前前庭释放。应当指出的是，沉积的剂量仍需要进入​​脑脊液之前横跨嗅觉上皮扩散。 主动控制:磁致指引 三个几何形状在活性粒子控制的数值实验采用:两板通道找到工作的磁铁强度，理想化的2-D鼻子模型找到基线磁铁布局，并基于图像的3-D鼻子模型来测试性能和细化磁泳指导协议的操作参数; 图6A示出的两个试验在两板通道中的模拟结果。在第一个试验中，我们测试日通过使用磁致力来抵消重力作用，使粒子水平移动而不是下跌的控制粒子运动电子的可行性。到这个目的，我们对信道（ 图6A的上部面板）的顶部施加三个磁体。所得磁场是在底板的上板强和弱。强磁性粒子被吸引向上的磁场强，这充当抵抗重力。当所有三个磁体具有1×10 5 A / m的体积磁化强度和给定的粒径为15μm时，磁泳力是与在信道（ 图6A的上图）的中心线的重力平衡。 第二次试验测试时更强的磁铁被应用（ 图6A的下图）粒子的轨迹如何变化。在这项试验中，左边两个磁体KEP吨以1×10 5安/米，而右磁体提高到1×10 6 A /微米。因为磁场是在右侧强得多，穿过信道的左半通过了所有的颗粒向上转动其方向，并存放于第三磁体的接近。这个试验证明，当磁泳力足够强，粒子的运动可以被操纵以到达目标部位。 该磁泳指导的性能以理想化的2-D鼻子模型进一步评估。磁铁中的一个行于鼻气道向上吸引铁磁粒子到嗅觉区域的顶部施加。 图4C示出了在鼻孔的前端与不同的磁铁布局释放从一个点的粒子之后粒子的运输和沉积。它表明，颗粒的轨迹向上偏离，由于存在的鼻部（ 图6B）以上磁铁。此外，用适当的磁场强度（在情况3 1×10 6 A / M），从这点沉积在嗅觉区域中的大多数磁泳驱动颗粒（〜92％）。与此相反，一个磁场不足产生较不显着磁响应（例1和2）。在没有磁铁，几乎没有颗粒沉积到嗅觉区即使颗粒将通过嗅觉区域（ 图6B）通过。 在磁泳指导下的3-D鼻子模型的模拟结果示于图7。按照在所述2-D鼻子模型得到的参数，磁体具有体积磁化1×10 6 / m的最初使用。然而，在该初步试验的嗅觉传递没有显示有希望的结果，推测是由于向上磁泳力不足以倒T他粒子运动。以确定为有效嗅觉交付相应磁体强度，各种体积磁化分别由1×10 5 A / m的增量为1×10 6 / m的递增进行测试。据观察，通过增加最大磁化至7.1×10 7 /米，沉积在嗅觉区施用颗粒的约33％，并通过增加至8.1×10 7 /米，约45％在嗅觉存款地区。一个推荐的磁铁布局，包括磁体强度以及所得颗粒的轨迹中， 如图7A所示 。 在推荐的磁铁布局三维鼻子模型预测的嗅觉剂量示于图7B。类似于2-D的情况下，磁泳指导显著改善嗅觉剂量，这点释放优于conventio最终版本从整个鼻孔。用适当的磁泳的指导下，递送嗅觉剂量可以更高数量级的一个甚至两个数量相比，没有磁泳指导（在图7B与&lt; 如图3 0.1％45％）。 图7B还示出的3的变化-D嗅觉剂量作为载体液滴大小的一个函数。没有为ð微不足道的嗅觉沉积&#39;P &lt;10微米或D&#39;P&#39;&gt; 20微米;前者是由于弱磁响应性，而后者则是由于高惯性损失到前鼻。最优嗅觉沉积来自气溶胶中的13的范围内 - 17微米，具有15微米的中值粒径。 <img alt="图1" src="/files/ftp_upload/53902/53902fig1.jpg" /> 图1.人的鼻子模型和嗅觉区的位于鼻腔的顶部，鼻子的复杂结构，防止有效药物输送到标准的设备鼻嗅区。为了研究沉积分布，基于MRI鼻模型分为不同的部分。 LP:低通道，UP:上通道，MM:中鼻道，SM:鼻道，OR:嗅觉区。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/53902/53902fig2.jpg" /> 图2. 三嗅觉传递协议。（A）前庭插管（B）深插管，和（C）的铁磁粒子的磁泳指导。为了达到最佳的嗅觉药物传送，颗粒应沿着鼻通的中间平面行进年龄。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/53902/53902fig3.jpg" /> 。 图3. 控制盒 （A）的气流流线和（B）在不同时刻粒子运动的快照（C）沉积模式是高度异质性，与前鼻高粒子积累;（D）很好的一致性之间实现数值预测和实验测量。 NP:鼻咽<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/53902/53902fig4.jpg" /> <html> 图4. 气流流线和粒子供词前庭插管协议。（A）前插管（B）回插管。嗅觉剂量的比较如图（C）为150 nm和1微米的颗粒。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig4large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图5" src="/files/ftp_upload/53902/53902fig5.jpg" /> 图5. 气流流线，并在三个呼吸条件的粒子沉积深插管。 （A）吸入（B）屏气，和（C）呼气。归一化的嗅觉剂量的比较中不同的协议（每厘米2质量分数）示于（D）中 。S / ftp_upload / 53902 / 53902fig5large.jpg"目标="_空白"&gt;点击此处查看该图的放大版本。 <img alt="图6" src="/files/ftp_upload/53902/53902fig6.jpg" /> 图6. 磁场和粒子轨迹在 （A）两板通道和（B）一个理想化的2-D模型的鼻子。在磁铁附近较暗的颜色代表一个强大的磁场。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig6large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图7" src="/files/ftp_upload/53902/53902fig7.jpg" /> 图7. Magnetophoretc指导在3-D鼻型号:邻（A）磁铁布局和粒子轨迹，和（B）的变化lfactory剂量颗粒大小的函数。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53902/53902fig7large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

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

Nanyang Technological University

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

Murine Model of Femoral Artery Wire Injury with Implantation of a Perivascular Drug Delivery Patch

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. While these therapies lead to the rapid restoration of blood flow, these technologies remain limited by restenosis in the case of bare metal stents and angioplasty, or reduced healing and possibly enhanced risk of thrombosis in the case of drug eluting stents. A key pathophysiological mechanism in the formation of restenosis is intimal hyperplasia caused by the activation of vascular smooth muscle cells and inflammation due to arterial stretch and injury. Surgeries that induce arterial injury in genetically modified mice are useful for the mechanistic study of the vascular response to injury but are often technically challenging to perform in mouse models due to the their small size and lack of appropriate sized devices. We describe two approaches for a surgical technique that induces endothelial denudation and arterial stretch in the femoral artery of mice to produce robust neointimal hyperplasia. The first approach creates an arteriotomy in the muscular branch of the femoral artery to obtain vascular access. Following wire injury this arterial branch is ligated to close the arteriotomy. A second approach creates an arteriotomy in the main femoral artery that is later closed through localized cautery. This method allows for vascular access through a larger vessel and, consequently, provides a less technically demanding procedure that can be used in smaller mice. Following either method of arterial injury, a degradable drug delivery patch can be placed over or around the injured artery to deliver therapeutic agents.

We describe a surgical technique that produces wire injury in the femoral artery of mice to induce neointimal hyperplasia to serve as a model testing system for the perivascular delivery of therapeutic compounds for the inhibition of restenosis.

股动脉线损伤的小鼠模型的血管周围给药补丁植入

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. ...

Intraluminal Drug Delivery to the Mouse Arteriovenous Fistula Endothelium

Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The simple murine AVF model was combined with intraluminal administration of drug solution to the venous endothelium at the same time as fistula creation. Technical aspects of this model are discussed. Under general anesthesia, an abdominal incision is made and the aorta and inferior vena cava (IVC) are exposed. The infra-renal aorta and IVC are dissected for clamping. After proximal and distal clamping, the puncture site is exposed and a 25 G needle is used to puncture both walls of the aorta and into the IVC. Immediately after the puncture, a reporter gene-expressing viral vector was infused in the IVC via the same needle, followed by 15 min of incubation. The intraluminal administration method enabled more robust viral gene delivery to the venous endothelium compared to administration by the external route. This novel method of delivery will facilitate studies that explore the role of the endothelium in AVF maturation and enable intraluminal drug delivery at the time of surgical operation.

After puncturing the aorta through the inferior vena cava (IVC) to create an aorto-caval fistula in the mouse, solution containing a drug is infused into the IVC via the same needle, followed by incubation. This method enables more robust drug delivery to the venous endothelium compared to the external route.

腔内药物输送到鼠标动静脉瘘内皮

Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The ...

Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump

Administration sets are delivery tools for the direct application of drugs into the body and are composed of a spike, a drip chamber, tubes, Luer adapters (connectors), a needle cover for protection, and other accessories. Drug sorption to tubes of administration sets is a critical issue in terms of safety and efficacy. Although drug sorption is an important factor in the quality of an administration set, there are no standard evaluation methods for the regulation of drug sorption to the tubes. Here, we describe an evaluation protocol for drug sorption to tubes of administration sets. Tubes made of polyvinyl chloride (PVC)- and non-PVC-based polymeric materials were cut to 1 m in length. Diazepam and tacrolimus were used as model drugs. In the kinetic sorption study, we selected the drug concentration and flow rate based on the clinical usage of these drugs. After the dilution of each drug in a glass bottle, the diluted drug solution was delivered through tubes of administration sets using a pump. Samples were collected in amber vials at appropriate time points and the drugs were analyzed using high-performance liquid chromatography. Drug concentrations and sorption levels to tubes of the administration sets were calculated. Acceptable criteria to ensure the quality of administration sets are recommended.

We report a method for drug sorption evaluation using a pump and model drugs (diazepam and tacrolimus). After drug analysis using high-performance liquid chromatography, drug concentrations and sorption levels in the tubes of administration sets are calculated.

药物吸附的评价PVC-和非PVC为基础的管理管设置在使用泵

Administration sets are delivery tools for the direct application of drugs into the body and are composed of a spike, a drip chamber, tubes, Luer adapters ...

Pancreatic Duct Infusion: An Effective and Selective Method of Drug and Viral Delivery

The pancreas is a bifunctional organ with both endocrine and exocrine components. A number of pathologies can afflict the pancreas, including diabetes, pancreatitis, and pancreatic cancer. All three of these diseases mark active areas of study, not only to develop immediate therapy, but also to better understand their pathophysiology. There are few tools to further these areas of study. Pancreatic duct infusion is an important technique that can allow for lineage tracing, gene introduction, and cell line-specific targeting. The technique requires the intricate dissection of the second portion of the duodenum and ampulla, followed by the occlusion of the bile duct and the cannulation of the pancreatic duct. Although the technique is technically challenging at first, the applications are myriad. Ambiguity in the specifics of the procedure between groups highlighted the need for a standard protocol. This work describes the expression of a green fluorescent protein (GFP) within the pancreas after the pancreatic duct infusion of a viral vector expressing GFP versus a sham surgery. The infusion and therefore expression is specific to the pancreas, without expression present in any other tissue type.

Pancreatic duct infusion is an important technique that can allow for lineage tracing, gene introduction, and cell line-specific targeting. A pancreatic duct infusion technique for drug and viral delivery to pancreatic cells is presented here.

胰腺管输液:药物和病毒输送的有效和选择性方法

The pancreas is a bifunctional organ with both endocrine and exocrine components. A number of pathologies can afflict the pancreas, including diabetes, ...

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards. However, to allow the high-throughput analysis of a larger number of patient samples, our group has optimized the reported method through the use of a smaller pore size reverse-phase chromatography column (2.6 &#181;m, C8 100 &#197;; 50 x 2.1 mm) and a gradient solvent system (0-1 min: 40% B; 1-2 min: 40-70% B; 2-2.7 min: held at 70% B; 2.7-2.8 min: 70-90% B; 2.8-4.0 min: 90% B washing; 4.0-4.1 min: 90-40% B; 4.1-6.0 min: held at 40% B) instead of an isocratic elution. The goal of this study was to reduce the HPLC-MS analysis time per sample dramatically from ~15 min to only 6 min per sample, which is essential for the analysis of a large amount of patient samples. This expedient method will be of considerable utility for studies into the exposure-response relationships of these breakthrough CF drugs.

Ivacaftor and ivacaftor-lumacaftor combination are two new CF drugs. However, there is still a dearth of understanding on their PK/PD and pharmacology. We present an optimized HPLC-MS technique for the simultaneous analysis of ivacaftor and its major metabolites, and lumacaftor.

经优化的 LC/ms 方法对囊性纤维化患者 Ivacaftor 及其主要代谢物和 Lumacaftor 的高通量分析

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening ...

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) models based on pBECs in mono-culture (MC), MC with astrocyte-conditioned medium (ACM), and non-contact co-culture (NCC) with astrocytes of porcine or rat origin. pBECs were isolated and cultured from fragments of capillaries from the brain cortices of domestic pigs 5-6 months old. These fragments were purified by careful removal of meninges, isolation and homogenization of grey matter, filtration, enzymatic digestion, and centrifugation. To further eliminate contaminating cells, the capillary fragments were cultured with puromycin-containing medium. When 60-95% confluent, pBECs growing from the capillary fragments were passaged to permeable membrane filter inserts and established in the models. To increase barrier tightness and BBB characteristic phenotype of pBECs, the cells were treated with the following differentiation factors: membrane permeant 8-CPT-cAMP (here abbreviated cAMP), hydrocortisone, and a phosphodiesterase inhibitor, RO-20-1724 (RO). The procedure was carried out over a period of 9-11 days, and when establishing the NCC model, the astrocytes were cultured 2-8 weeks in advance. Adherence to the described procedures in the protocol has allowed the establishment of endothelial layers with highly restricted paracellular permeability, with the NCC model showing an average transendothelial electrical resistance (TEER) of 1249 &#177; 80 &#937; cm2, and paracellular permeability (Papp) for Lucifer Yellow of 0.90 10-6 &#177; 0.13 10-6 cm sec-1 (mean &#177; SEM, n=55). Further evaluation of this pBEC phenotype showed good expression of the tight junctional proteins claudin 5, ZO-1, occludin and adherens junction protein p120 catenin. The model presented can be used for a range of studies of the BBB in health and disease and, with the highly restrictive paracellular permeability, this model is suitable for studies of transport and intracellular trafficking.

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of the protocol is to present an optimized procedure for the establishment of an in vitro blood-brain barrier (BBB) model based on primary porcine brain endothelial cells (pBECs). The model shows high reproducibility, high tightness, and is suitable for studies of transport and intracellular trafficking in drug discovery.

一种基于猪脑内皮细胞的体外血脑屏障模型的改进方法

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) ...

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity

The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could interfere with the chemotherapeutic efficacy of the primary drugs. This is especially true for the drug cisplatin, whose anticancer actions are attenuated by antioxidants which provide adequate protection against hearing loss. Other current or potential otoprotective agents could pose a similar problem, if administered systemically. The application of various biologicals or protective agents directly to the cochlea would allow for high levels of these agents locally with limited systemic side effects. In this report, we demonstrate a trans-tympanic method of delivery of various drugs or biological reagents to the cochlea, which should enhance basic science research on the cochlea and provide a simple way of directing the use of otoprotective agents in the clinics. This report details a method of trans-tympanic drug delivery and provides examples of how this technique has been used successfully in experimental animals to treat cisplatin ototoxicity.

We present a technique for localized administration of drugs through the trans-tympanic route into the cochlea. Drug delivery through this route would not interfere with the anti-cancer efficacy of the chemotherapeutic drugs such as cisplatin.

经鼓膜药物治疗耳毒性的临床研究

The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could ...

A Rat Carotid Artery Pressure-Controlled Segmental Balloon Injury with Periadventitial Therapeutic Application

Cardiovascular disease remains the leading cause of death and disability worldwide, in part due to atherosclerosis. Atherosclerotic plaque narrows the luminal surface area in arteries thereby reducing adequate blood flow to organs and distal tissues. Clinically, revascularization procedures such as balloon angioplasty with or without stent placement aim to restore blood flow. Although these procedures reestablish blood flow by reducing plaque burden, they damage the vessel wall, which initiates the arterial healing response. The prolonged healing response causes arterial restenosis, or re-narrowing, ultimately limiting the long-term success of these revascularization procedures. Therefore, preclinical animal models are integral for analyzing the pathophysiological mechanisms driving restenosis, and provide the opportunity to test novel therapeutic strategies. Murine models are cheaper and easier to operate on than large animal models. Balloon or wire injury are the two commonly accepted injury modalities used in murine models. Balloon injury models in particular mimic the clinical angioplasty procedure and cause adequate damage to the artery for the development of restenosis. Herein we describe the surgical details for performing and histologically analyzing the modified, pressure-controlled rat carotid artery balloon injury model. Additionally, this protocol highlights how local periadventitial application of therapeutics can be used to inhibit neointimal hyperplasia. Lastly, we present light sheet fluorescence microscopy as a novel approach for imaging and visualizing the arterial injury in three-dimensions.

The rat carotid artery balloon injury mimics the clinical angioplasty procedure performed to restore blood flow in atherosclerotic vessels. This model induces the arterial injury response by distending the arterial wall, and denuding the intimal layer of endothelial cells, ultimately causing remodeling and an intimal hyperplastic response.

大鼠胡萝卜动脉压力控制段气球损伤与腹腔ventit 治疗应用

Cardiovascular disease remains the leading cause of death and disability worldwide, in part due to atherosclerosis. Atherosclerotic plaque narrows the ...

Intratracheal Administration of Dry Powder Formulation in Mice

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper introduces a noninvasive method of intratracheal delivery of dry powder formulation in mice. A dry powder loading device that consists of a 200 &#181;L gel loading pipette tip connected to an 1 mL syringe via a three-way stopcock is presented. A small amount of dry powder (1-2 mg) is loaded into the pipette tip and dispersed by 0.6 mL of air in the syringe. Because pipette tips are disposable and inexpensive, different dry powder formulations can be loaded into different tips in advance. Various formulations can be evaluated in the same animal experiment without device cleaning and dose refilling, thereby saving time and eliminating the risk of cross-contamination from residual powder. The extent of powder dispersion can be inspected by the amount of powder remaining in the pipette tip. A protocol of intubation in mouse with a custom-made light source and a guiding cannula is included. Proper intubation is one of the key factors that influences the intratracheal delivery of dry powder formulation to the deep lung region of the mouse.

Dry powder formulations for inhalation have great potential in treating respiratory diseases. Before entering human studies, it is necessary to evaluate the efficacy of the dry powder formulation in preclinical studies. A simple and noninvasive method of the administration of dry powder in mice through the intratracheal route is presented.

小鼠干粉配方的内经管理

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper ...