Microfluidic Tissue Engineering of Small Airway Injuries

微流控组织工程治疗气道小损伤 该项目汇集了微流体，计算和动物模型的专业知识，以评估相关的作用， 固体和流体机械应力导致或加剧或诱发小气道上皮损伤。 这项建议的重点是小气道，因为他们牵连的第一个层次的损害，在急性 呼吸窘迫综合征（ARDS）（1，2）。这些气道可能会在手术期间关闭和重新开放。 可能会因相关的机械损伤而受伤，称为肺不张。由于这些气道 当被液体衬里覆盖时，所有的闭合和再打开都涉及液体的形成、传播和破裂。 插头。我们以前的工作（3，4）表明，流体/表面张力从传播，特别是， 破裂的液塞是对在微流体上培养的气道上皮细胞造成致命损伤的重要原因， 肺芯片平台。动物模型也表明，由于表面张力的降低， 肺表面活性物质浓度是小气道不全损伤的主要原因（5），而塞子破裂 特别与气道损伤有关（6）。在这里，我们建议确定 在分离出弹性力与流体/表面张力的作用时， 实验和计算。我们假设，在肺不张创伤中的流体/表面张力机械力是 是导致ARDS的主要原因我们还将测试在加重额外的侮辱， 如细菌感染和酸吸入，这是发展ARDS的直接危险因素。 尽管低潮气量已被证明可降低ARDS患者的死亡率，但开放式通气的益处 肺通气概念仍存在争议。肺开放手术结果不一的主要原因之一是 通风源于对预防肺不张的最佳方法认识不足。了解 小气道不全损伤的机制对于开发成功的治疗干预措施至关重要， ARDS。虽然我们的主要目标是阐明ARDS病理学的基本机制，但我们的研究结果 重要的临床意义。我们有可能澄清是否个性化，适当水平的PEEP 或复张操作可以预防肺不张，从而减轻ARDS中的肺损伤。 这些目标旨在回答以下关键问题：拉伸与流体的相对贡献是什么？ 机械应力导致肺损伤如何将流体机械应力与酸的组合损伤 吸入或细菌损伤加重肺损伤？

Microfluidic Tissue Engineering of Small Airway Injuries This project brings together microfluidic, computational, and animal model expertise to evaluate the relative roles of solid- and fluid-mechanical stresses causing, or exacerbating, or predisposing injury of small airway epithelia. This proposal focuses on small airways because they are implicated as the first level of damage in acute respiratory distress syndrome (ARDS) (1, 2). These airways are subject to closure and reopening during the ventilatory cycle, and can be injured from the associated mechanics called atelectrauma. Since these airways are coated with a liquid lining, all closure and reopening involves the formation, propagation, and rupture of liquid plugs. Our previous work (3, 4) showed that fluid/surface tension forces from propagating and, especially, rupturing liquid plugs are a significant cause of lethal injury to airway epithelial cells cultured on microfluidic, lung-on-chip platforms. Animal models have also shown that a higher surface tension due to reduction in concentrations of pulmonary surfactants as the major cause of small airway atelectrauma (5), while plug ruptures with acoustical signatures are particularly associated with airway injury (6). Here, we propose to determine the mechanism of atelectrauma while separating out the contributions of elastic vs fluid/surface tension forces in experiment and computations. We hypothesize that fluid/surface tension mechanical forces in atelectrauma are a major contributor to ARDS. We will also test the role of atelectrauma in the exacerbation of additional insults such as, bacterial infection and acid aspiration, which are direct risk factors for the development of ARDS. Although low tidal volumes have been shown to reduce mortality in patients with ARDS, the benefits of the open lung ventilation concept remain controversial. One of the major reasons for the variable results of open lung ventilation stems from the lack of understanding of the best way to prevent atelectasis. Understanding the mechanism of small airway atelectrauma is essential for developing successful therapeutic interventions in ARDS. While our main goal is to clarify fundamental mechanisms underlying ARDS pathology, our findings have significant clinical implications. We have the potential to clarify whether personalized, appropriate levels of PEEP or recruitment maneuvers may prevent atelectrauma and thereby result in mitigation of lung injury in ARDS. The aims are designed to answer key questions such as: What is the relative contribution of stretch versus fluid mechanical stress in causing lung injury? How will combined insults of fluid mechanical stress together with acid aspiration or bacterial insult exacerbate lung injury?