CAREER: Mechanobiology of Microbubble Induced Cellular Injury in the Pulmonary System

职业：微泡引起的肺系统细胞损伤的力学生物学

• 批准号: 0852417
• 负责人: Samir Ghadiali
• 金额: $ 37.42万
• 依托单位: Ohio State University Research Foundation -DO NOT USE
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0852417&HistoricalAwards=false
• 关键词: CAREER; Mechanobiology; Microbubble; Induced; Cellular

CBET-0747760, GhadialiMicrobubble flows are an important area of research in the biomedical sciences. Important applications of microbubbles include the enhancement of ultrasound images, drug delivery and cancer treatment. However, microbubbles can also cause significant cellular and tissue damage in the cardiopulmonary system. For example, patients suffering from acute lung injury (AcLI) cannot breathe on their own due to the collapse and fluid occlusion of small pulmonary airways. These patients must be placed on a mechanical ventilator in order to survive. However, the microbubbles generated during ventilation can exacerbate the existing lung injury. As a result, the mortality rate for AcLI is very high (30-40%). Microbubbles have been shown to impart complex fluid mechanical forces to the epithelial cells (EpC) which line airway walls. Depending on the EpC's biophysical properties, these forces may result in cell death and disruption of the epithelium. In addition, these fluid mechanical forces may also be transduced into injurious biological responses including the up-regulation of inflammatory pathways and altered surfactant secretion. However, the exact mechanisms responsible for microbubble induced cellular injury in the pulmonary system are not known. The research objective of this CAREER project is to use a combination of computational and experimental techniques from the biological, engineering and mathematical sciences to fill this knowledge gap.The PI will develop multi-scale, fluid-structure computational models of cellular deformation and detachment during microbubble flows. These models will be used to quantify mechanical parameters which are difficult to measure experimentally (i.e. cell deformation). The PI will also utilize an in-vitro, microfluidic cell culture system and sophisticated microscopy techniques to ascertain the biological response of EpCs to microbubble flows (i.e. protein expression). The correlation of computational and experimental results will be use to identify the biomechanical mechanisms responsible for microbubble induced cellular injury. The significance of this research is that once we understand the mechanisms responsible for cellular injury, this information can be used to develop novel pharmaco-protective therapies for AcLI that minimize ventilation induced lung injury by altering specific cellular and/or molecular properties.The main educational objective of this proposal is to develop a bioengineering workforce that not only understands the interaction between engineering and biological systems but can also translate this knowledge into commercially viable and life-saving medical products. The PI will collaborate with local medical device companies to solve real-world design issues and will play a key role in developing industrially sponsored bioengineering projects within Lehigh University's Integrated Product Development program. As a part of this program, the PI will advise multi-disciplinary student teams who will work closely with their industry sponsor to develop design plans and prototypes that satisfy technical, business and regulatory requirements. These hands-on, industrially sponsored projects will provide students with the team-work skills most valued by employers and first-hand knowledge of the complex issues involved in developing commercially viable and life-saving medical products.

微泡流动是生物医学研究的一个重要领域。微泡的重要应用包括超声图像增强、药物输送和癌症治疗。然而，微泡也会对心肺系统造成严重的细胞和组织损伤。例如，急性肺损伤（AcLI）患者由于小气道塌陷和液体闭塞而不能自主呼吸。这些病人必须戴上机械呼吸机才能生存。然而，通气过程中产生的微泡会加重已有的肺损伤。因此，AcLI的死亡率非常高（30-40%）。研究表明，微泡可对气道壁上皮细胞（EpC）施加复杂的流体力学力。根据EpC的生物物理特性，这些力可能导致细胞死亡和上皮破坏。此外，这些流体机械力也可能被转导成有害的生物反应，包括炎症途径的上调和表面活性剂分泌的改变。然而，微泡诱导肺系统细胞损伤的确切机制尚不清楚。这个CAREER项目的研究目标是结合生物、工程和数学科学的计算和实验技术来填补这一知识空白。PI将开发微泡流动过程中细胞变形和脱离的多尺度流体结构计算模型。这些模型将用于量化难以通过实验测量的机械参数（即细胞变形）。PI还将利用体外微流体细胞培养系统和复杂的显微镜技术来确定EpCs对微泡流动的生物学反应（即蛋白质表达）。计算结果和实验结果的相关性将用于确定微泡诱导细胞损伤的生物力学机制。这项研究的意义在于，一旦我们了解了细胞损伤的机制，这些信息就可以用于开发新的AcLI药物保护疗法，通过改变特定的细胞和/或分子特性，最大限度地减少通气引起的肺损伤。这项建议的主要教育目标是培养生物工程劳动力，他们不仅了解工程和生物系统之间的相互作用，而且还能将这些知识转化为商业上可行的和拯救生命的医疗产品。PI将与当地医疗设备公司合作，解决现实世界的设计问题，并将在利哈伊大学综合产品开发计划中开发工业赞助的生物工程项目中发挥关键作用。作为该项目的一部分，PI将为多学科学生团队提供建议，这些学生团队将与他们的行业赞助商密切合作，开发满足技术、商业和监管要求的设计计划和原型。这些由工业界赞助的实际操作项目将为学生提供雇主最重视的团队合作技能，以及开发商业上可行和挽救生命的医疗产品所涉及的复杂问题的第一手知识。