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

CBET-0747760，Ghadiali微气泡流是生物医学科学的一个重要研究领域。微泡的重要应用包括增强超声图像、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)患者由于小肺气道塌陷和液体阻塞而无法自主呼吸。这些患者必须戴上机械呼吸机才能存活。然而，在通风过程中产生的微泡会加剧现有的肺损伤。因此，ACLI的死亡率非常高(30%-40%)。微泡已被证明可以将复杂的流体机械力传递给排列在气道壁上的上皮细胞(EPC)。根据EPC的生物物理性质，这些力可能会导致细胞死亡和上皮细胞破裂。此外，这些流体机械力也可能被转化为损伤性的生物反应，包括炎症途径的上调和表面活性物质分泌的改变。然而，微泡导致肺系统细胞损伤的确切机制尚不清楚。这一职业项目的研究目标是利用生物、工程和数学科学的计算和实验技术相结合的方法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分离的多尺度、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力学参数(即细胞变形)。PI还将利用体外微流控细胞培养系统和先进的显微技术来确定内皮祖细胞对微泡流动(即蛋白质表达)的生物反应。计算结果和实验结果的相关性将被用来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，这些信息就可以用来开发新的药物保护疗法，通过改变特定的细胞和/或分子特性，将机械通气引起的肺损伤降至最低。这项建议的主要教育目标是培养一支生物工程队伍，不仅了解工程和生物系统之间的相互作用，而且还可以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将与当地医疗器械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内开发行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，这些团队将与行业赞助商密切合作，制定满足技术、商业和监管要求的设计计划和原型。这些实践性的、工业赞助的项目将为学生提供雇主最重视的团队合作技能，以及开发具有商业可行性和拯救生命的医疗产品所涉及的复杂问题的第一手知识。

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.