仿生的微流体模型肺呼吸腺泡航空公司
Summary
Soft-lithography was utilized to produce a representative true-scale model of pulmonary alveolated airways that expand and contract periodically, mimicking physiological breathing motion. This platform recreates respiratory acinar flows on a chip, and is anticipated to facilitate experimental investigation of inhaled aerosol dynamics and deposition in the pulmonary acinus.
Abstract
在肺腺泡深度量化呼吸流动特性，以及它们如何影响吸入烟雾传输是针对优化药物吸入技术以及预测肺泡潜在有毒大气颗粒的沉积图案的关键。在这里，软光刻技术用于在在光学系统访问重现生理腺泡流动现象的真实解剖长尺度制造复杂腺泡样气道结构。微流体器件具有5代与周期性扩张和收缩的墙壁分岔蜂窝状的管道。壁的致动是通过改变内部周围都从侧面和该装置的顶部的薄的PDMS腺泡通道壁充满水的腔室中的压力来实现的。在对比普通多层微流体装置，其中需要的几个的PDMS模具堆叠，提出以制造顶部的简单方法通过嵌入注射器的筒段成PDMS模具腔。这种新颖的微流控的设置提供了生理呼吸运动而这又引起特点腺泡空气流动。在目前的研究中，微粒子图像测速（μPIV）与液体悬浮颗粒来定量这种空气流根据流体力学相似性匹配。 μPIV结果和预期腺泡流现象之间的良好的一致性表明微流体平台可能在不久的将来作为体外工具一个有吸引力的，调查在肺部的腺泡区域直接空降代表粒子输运和沉积。
Introduction
在末节呼吸流量动态的细致的量化，肺部蜂窝状的区域是朝着在肺腺泡理解气流混合，并预测在最深的气道吸入1-3气溶胶的命运至关重要。在寻 求改进和靶向给药吸入治疗剂的局部肺站点4,5以及用于全身递送新策略一方面寻址吸入颗粒污染物的危害或相反时，这后一方面是特别关注的。
迄今为止，在深肺腺泡区域呼吸流量已经典型地使用计算流体动力学（CFD），或者与按比例增加的实验模型中体外以下液力相似性匹配调查在硅片 。在过去的几十年中，CFD方法已经被越来越多地应用于研究腺泡流动现象，从SINGLË肺泡模型6,7和蜂窝状的管道8-12更详细的在硅片模型捕捉解剖学逼真腺泡树形结构与蜂窝状的管道多代，最多几百个人肺泡13-15。
总之，数字的努力已经在上随后腺泡气流模式的呼吸运动过程中的作用和室壁运动的影响力脱落光的关键。在没有呼吸运动，静态肺泡功能循环的腔表现出腺泡管和肺泡6,7之间的空气对流不交流中流动;换句话说，肺泡流将被完全从流动腺泡树木内分离空气的交换将来自扩散机制唯一结果。与肺泡域的环状扩张的存在，然而，肺泡流拓扑大幅度修改和地区环境部门一道内部肺泡lting流动模式紧密并列沿着腺泡树的肺泡的位置（ 例如 ，近端与远端世代）。
特别是，已经假设在肺泡流动模式强烈肺泡的比率的影响的模拟到乳腺导管的流速，使得肺腺泡树中，其中，该比值是比较大的以下跨越树结构，特征质量守恒近端世代复杂的循环不可逆的流体迹线肺泡腔内流动。随着每更深腺泡产生，肺泡到导管流量的比例逐渐降低，使得远端腺泡几代表现出更多的径向流线一样是让人联想到通货膨胀简单和气球通缩的。随着现代影像学检查，肺部影像学资料16，啮齿类动物，包括大鼠和小鼠的17，进步已经引起了一些第一CFD SIMUL的在重建肺泡解剖，重建腺泡流动ations。尽管有这样的希望的进展，这些最近的研究仍局限于终端肺泡囊只有18，19或周围的单一管道20几个肺泡解决气流的现象。其结果是，在腺泡呼吸流动现象的国家的最先进的调查仍然受到研究侧重于腺泡环境2的通用解剖风格的几何形状为主。
在实验方面，不同的设置，设有带一个或几个肺泡气道已经发展了很多年21-24。然而，存在分叉蜂窝状航空公司是能够通过在呼吸样的方式扩张和收缩模仿生理呼吸没有实验模型。由于缺乏手头有吸引力的实验平台，腺泡运输现象的研究仍然是有限的问候valida婷计算的研究和批判，仍然实验数据可用的缺乏。 近年来 ，Ma 等人 （2009）构建了由三个腺泡世代的腺泡的按比例增大的刚性壁模型;然而，在这个模型中缺乏壁运动的限制了其能力来捕获呼吸的条件下实际的肺泡流动模式。
其他规模扩大的实验，包括基于从投副本解剖数据移动壁模型，最近推出的25;然而，由于该模型仅捕获的最后两个腺泡世代（ 即 ，终端囊），它未能捕获表征更近侧腺泡世代复杂再循环流动。的规模扩大的实验后面的这些例子进一步强调这种做法的持续限制。具体而言，没有现成的试验迄今已证实从循环的假设过渡到沿径向流腺泡从而确认假设流拓扑结构的数值预测在现实肺腺泡树木7，15最关键的存在。也许，规模扩大的实验调查可吸入颗粒搬运和沉积动力学26极其有限的，由于匹配所有相关的非困难维参数（ 例如 ，粒子扩散，临界传输机制亚微米颗粒，是完全可以忽略不计）。
与正在进行的实验挑战，允许在复杂移动壁的呼吸气流和粒子动力学研究新的实验平台腺泡网络追捧。在这里， 体外模型腺泡解剖学风格的介绍。该微流体平台模拟肺腺泡直接代表腺泡规模流动，拓宽和范围日益扩大肺微流体模型27，包括支气管液塞-FLOWS 28-30和肺泡-毛细血管屏障31。
即，本设计采用了简化的五代蜂窝状气道树周期性膨胀和收缩壁，其中，环状运动是通过控制压力围绕薄的PDMS侧壁并且其中所述顶壁是由一个额外的水而变形的水室内部实现的室直接坐在腺泡结构之上。不像普通的多层微流体装置，该室被简单地通过嵌入的PDMS装置内的注射器的筒部形成的，并且不需要制备额外的PDMS模具。
这里介绍的小型化方法提供了一种用于再现复杂腺泡结构与相比，规模扩大的模式，同时捕捉腺泡流环境的基本特征移动壁的简单和灵活的手段。此平台可用于FLOW¯¯可视化使用航空（见下文代表性的成果）内的流体悬浮颗粒。在不久的将来，该模型将与空气中的颗粒可用于研究吸入腺泡粒子动力学。
Protocol
Representative Results
Discussion
这里介绍的微流体平台腺泡的一个重要特点是它重现生理逼真的呼吸运动是引起生理流动分布和速度腺泡内管和肺泡内的能力。因为微流体通道具有相对低的长宽比产生（ 即 ， 宽 深 / 小时 ≈3.9，其中，w，d是所述管道的宽度，h是所述管道高度），所测量的流量显示更多柱塞样流动特性相比预期的抛物线流量分布，将存在于循?…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
This work was supported in part by the European Commission (FP7 Program) through a Career Integration Grant (PCIG09-GA-2011-293604), the Israel Science Foundation (Grant nr. 990/12) and the Technion Center of Excellence in Environmental Health and Exposure Science (TCEEH). Microfabrication of microfluidic chips was conducted at the Micro-Nano Fabrication Unit (MNFU) of the Technion and supported by a seed grant from the Russel Berrie Institute of Nanotechnology (RBNI) at Technion. The authors thank Avshalom Shai for assistance during deep reactive ion etching (DRIE) and Molly Mulligan and Philipp Hofemeier for helpful discussions.
Materials
| Polydimethylsiloxane (PDMS) and curing agent | Dow Corning | (240)4019862 | SYLGARD® 184 SILICONE ELASTOMER KIT |
| Plastipak 2 ml syringe | BD | 300185 | |
| Norm-Ject Luer slip 1 ml syringe | Henke Sass Wolf | 4010-200V0 | |
| 1mm Biopsy punch | Kai Medical | BP-10F | |
| Laboratory Corona Treater | Electro-Technic Products | BD-20AC | |
| PHD Ultra Syringe pump | Harvard apparatus | 703006 | |
| Dyed red rqueous fluorescent particles | Thermo-Scientific | Uncatalloged 0.86 µm beads were used | |
| Glycerin AR | Gadot | 830131320 | |
| FlowMaster MITAS micro-particle image velocimetry (µPIV) system | LaVision | 1108630 |
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