Microfluidic Tissue Engineering of Small Airway Injuries

小气道损伤的微流控组织工程

• 批准号: 9260421
• 负责人: JAMES Bernard GROTBERG
• 金额: $ 75.97万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-03 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260421
• 关键词: Acids; Acoustics; Adult Respiratory Distress Syndrome; Animal Model; Atelectasis; Bacterial Infections; Biochemical; Biological Markers; Cell Culture Techniques; Cells; Chemotactic Factors; Clinic; Clinical; Complex; Computer Simulation; Cultured Cells; Development; Environmental air flow; Epithelial Cells; Escherichia coli; Geometry; Goals; Hour; Inflammation Mediators; Inflammatory; Injury; Liquid substance; Lung; Mechanical Stress; Mechanics; Membrane; Microfluidics; Modeling; Pathogenesis; Pathology; Patients; Pattern; Periodicity; Permeability; Pneumonia; Pulmonary Surfactants; Recruitment Activity; Risk Factors; Rodent; Rodent Model; Role; Rupture; Solid; Stimulus; Stress; Stretching; Surface Tension; Testing; Therapeutic Intervention; Tidal Volume; Tissue Engineering; Ventilator; Work; airway epithelium; atelectrauma; design; experimental study; flexibility; improved; in vivo; injured; injured airway; lung injury; macrophage; mechanical force; monocyte; mortality; neutrophil; pressure; prevent; response; stem; surfactant; tool

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?

小气道损伤的微流控组织工程 该项目汇集了微流体、计算和动物模型专业知识来评估相关作用 固体和流体机械应力引起、加剧或诱发小气道上皮损伤。 该提案重点关注小气道，因为它们被认为是急性呼吸道疾病的第一级损害。 呼吸窘迫综合征 (ARDS) (1, 2)。这些航线可能会在疫情期间关闭和重新开放 通气循环，并且可能因称为肺不张伤的相关机制而受伤。由于这些航空公司 都涂有液体衬里，所有关闭和重新打开都涉及液体的形成、传播和破裂 插头。我们之前的工作 (3, 4) 表明，流体/表面张力会传播，特别是， 破裂的液塞是微流体培养的气道上皮细胞致命损伤的一个重要原因， 肺芯片平台。动物模型还表明，由于减少了表面张力， 肺表面活性物质浓度是小气道肺不张的主要原因 (5)，而栓塞破裂 具有声学特征的信号与气道损伤尤其相关 (6)。在此，我们建议确定 肺不张的机制，同时分离出弹性力与流体/表面张力的贡献 实验和计算。我们假设肺不张损伤中的流体/表面张力机械力是 ARDS 的主要贡献者。我们还将测试肺不张伤在加剧额外侮辱中的作用 例如细菌感染和误吸酸，这些都是发生ARDS的直接危险因素。 尽管低潮气量已被证明可以降低 ARDS 患者的死亡率，但开放式呼吸的好处 肺通气概念仍存在争议。开肺结果变化的主要原因之一 通气源于对预防肺不张的最佳方法缺乏了解。了解 小气道肺不张的机制对于制定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 具有重要的临床意义。我们有可能阐明个性化的、适当的 PEEP 水平是否合适 或肺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？流体机械应力与酸的共同作用将如何 误吸或细菌损伤会加剧肺损伤吗？