Microfluidic Tissue Engineering of Small Airway Injuries

小气道损伤的微流控组织工程

• 批准号: 7085579
• 负责人: SHUICHI TAKAYAMA
• 金额: $ 59.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085579
• 关键词: bacteria infection mechanism; bioengineering /biomedical engineering; biomaterial interface interaction; biomechanics; biomimetics; cellular pathology; fluid; host organism interaction; hyperoxia; inflammation; lung injury; mechanical stress; microfluidics; respiratory epithelium; tissue /cell culture; tissue engineering

DESCRIPTION (provided by applicant): In diseases that involve mucus secretion and movement in the small airways, such as chronic bronchitis, cystic fibrosis or asthma, liquid plugs form occluding bridges that obstruct the airway and disrupt gas exchange. In response to cough, these bridges move and the airway is reopened, with the transmission of mechanical forces to airway epithelial cells. Similarly, in the setting that involves both the airway and alveolar space, such as pneumonia or congestive heart failure, or mechanical ventilation with low tidal volumes, there is cyclic closure and reopening of smaller airways, which may be recognized as crackle sounds heard easily with a stethoscope. The cellular-level effect of the explosive transient pressure waves created by these reopening events, however, has not previously been investigated despite the likelihood that the associated plug rupture produces large stresses and is a major cause of lung injury. This proposal will investigate, experimentally and theoretically, the detrimental effect of fluid mechanical stresses on airway epithelial cells during airway reopening using a micro-engineered airway. The specific hypothesis is that the movement and rupture of liquid plugs in the small airway system during airway reopening will generate large fluid mechanical stresses and damage airway epithelial cells, and that even normally sub-lethal amounts of fluid mechanical stress will become lethal in the presence of other insults such as bacteria or hyperoxia-mediated inflammation, expanding the region and severity of injury. The specific aims of this proposal are: 1. Design and fabrication of a biomimetic micro fluidic system to perform in vitro culture of airway epithelial cells under physiological air-liquid interface conditions. 2. Generation of liquid plugs with physiological propagation velocities and rupture frequencies within the engineered micro fluidic small airways, and combined computational and experimental assessment of the resulting fluid mechanical stresses and their effect on cell injury. 3. Investigate synergistic cellular damage caused by combination of liquid plug propagation/rupture- mediated fluid mechanical stresses and bacterial infection or hyperoxia-mediated inflammation. Also, evaluate the effect of surfactant as a countermeasure to reduce cellular injuries.

描述（由申请人提供）：在涉及小型气道中粘液分泌和运动的疾病中，例如慢性支气管炎，囊性纤维化或哮喘，液体塞形成了阻塞气道和破坏气体交换的桥梁。为了应对咳嗽，这些桥梁移动并重新开放，随着机械力向气道上皮细胞的传播。同样，在涉及气道和肺泡空间的环境中，例如肺炎或充血性心力衰竭，或潮汐量低的机械通气，较小的气道有循环闭合并重新开放，可以将其识别为带有听觉的crack骨声音。然而，尽管相关的塞子破裂会产生巨大的压力，并且是肺部损伤的主要原因，但这些重新开放事件产生的爆炸性瞬态压力波的细胞水平效应尚未得到研究。该提案将在实验和理论上调查使用微工程气道在气道重新开放过程中流体机械应力对气道上皮细胞的有害作用。具体的假设是，在气道重新开放期间，小型气道系统中液体塞的运动和破裂将产生较大的流体机械应力和损害气道上皮细胞，即使在其他临床上，如细菌或高氧降低了易碎性的施加症状和严重性，即使是通常的亚致死液体机械压力也会变得致命。该提案的具体目的是：1。在生理空气界面条件下，设计和制造仿生微流体系统，以在生理空气界面条件下进行气道上皮细胞的体外培养。 2。在工程微流体小气道中具有生理繁殖速度和破裂频率的液体塞的产生，并将计算和实验性评估结合在一起，对所得的流体机械应力及其对细胞损伤的影响。 3。研究由液体塞繁殖/破裂的液体机械应力和细菌感染或高氧介导的炎症的结合引起的协同细胞损伤。另外，评估表面活性剂的作用是减少细胞损伤的对策。