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）：在涉及小气道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，液塞形成阻塞桥，阻塞气道并破坏气体交换。为了应对咳嗽，这些桥移动并重新打开气道，并将机械力传递到气道上皮细胞。类似地，在涉及气道和肺泡腔的情况下，例如肺炎或充血性心力衰竭，或低潮气量的机械通气，较小气道会循环关闭和重新打开，这可能会被识别为容易听到的爆裂声。听诊器。然而，尽管相关的栓塞破裂可能会产生巨大的应力并且是肺损伤的主要原因，但以前尚未研究过这些重新开放事件产生的爆炸性瞬态压力波的细胞水平影响。该提案将从实验和理论上研究使用微工程气道重新打开气道期间流体机械应力对气道上皮细胞的有害影响。具体假设是，气道重新开放期间小气道系统中液体塞的移动和破裂将产生巨大的液体机械应力并损伤气道上皮细胞，并且即使正常情况下亚致死量的液体机械应力在存在时也会变得致命。其他损伤，如细菌或高氧介导的炎症，扩大了损伤的区域和严重程度。该提案的具体目标是： 1.设计和制造仿生微流体系统，以在生理气液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内生成具有生理传播速度和破裂频率的液体塞，并对所产生的流体机械应力及其对细胞损伤的影响进行综合计算和实验评估。 3. 研究由液塞传播/破裂介导的流体机械应力和细菌感染或高氧介导的炎症相结合引起的协同细胞损伤。此外，还评估表面活性剂作为减少细胞损伤的对策的效果。