Platelets on Chip: Studies of Mechanobiology of Platelet-Mediated Thrombosis Enabled by Molecular Fluorescence Sensors Grafted inside Microfluidic Chips

芯片上的血小板：通过微流控芯片内移植的分子荧光传感器实现血小板介导的血栓形成的力学生物学研究

• 批准号: 2204447
• 负责人: Long Que
• 金额: $ 49.21万
• 依托单位: Iowa State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2204447&HistoricalAwards=false
• 关键词: Platelets; Chip; Studies; Mechanobiology; Platelet

The WHO estimates nearly 25 million CVD deaths worldwide in 2020. Thrombosis is the most common pathology causing life-threatening CVDs such as ischemic heart disease, stroke, and venous thromboembolism. Thrombosis is mediated by platelets which are small blood cells normally mediating hemostasis, a process of stopping bleeding. However, during thrombosis, platelets can abnormally adhere on blood vessel walls and aggregate with fibrin to form blood clots that cause heart attacks, strokes, and peripheral vascular disease. Such abnormal platelet adhesion can be initiated by the ruptured cholesterol plaques in blood vessels or by disturbed blood flow at stenoses. Because the local blood flow and shear conditions are important mechanical factors initiating platelet adhesion and activation, studying platelet functions under controllable flow conditions and under controllable pharmacological agents’ treatment is critical for the understanding of the mechanisms of thrombus formation and therapeutics. This award supports fundamental research to develop blood vessel chips, mimicking the microvasculature in human body, that can provide a way to monitor the behaviors of single platelets under tunable fluid flowing profiles with submicron resolution and high sensitivity. This chip also can allow simultaneous studies of the effects of multiple pharmacological agents and their combinations on the platelets, facilitating the drug screen and discovery for thrombus related diseases. Hence, the outcomes from this research will benefit the U.S. society. This research involves several disciplines including microelectromechanical system, microfluidics, biomedical engineering, and biomechanics, allowing broaden participation of women and underrepresented minority students in research, and thus resulting in a positive impact on engineering and science education.The project seeks to develop blood vessel mimicking platforms with quantitative flow control (both flow rate and flow direction), quantitative treatment control of pharmacological agents on platelets, and the ability of monitoring the behaviors of platelets at single cell level. Toward these goals, first, an experimental-theoretical methodology will be established to determine the influence of shear rates and identify the integrin tension sensors with suitable strengths for monitoring the behaviors of platelets. Second, the effects of the in vivo shear rates and the effects of pulsatile flow on platelets will be studied. Finally, the effects of the pharmacological agents and their combinations with varied doses on the platelets will be studied. This research will fill the technical knowledge gap on how to develop a platform suitable for studying the behaviors of platelets in vitro under tunable shearing stresses and pharmacological agents’ treatment in a controlled manner on a chip.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该世卫组织在2020年估计全球近2500万例CVD死亡。血栓形成是最常见的病理，导致威胁生命的CVD，例如缺血性心脏病，中风和静脉血栓主义。血栓形成是由通常介导止血的小血细胞的血小板介导的，这是一种停止出血的过程。但是，在血栓形成期间，血小板可以绝对粘附在血管壁上，并用纤维蛋白聚集，形成血凝块，引起心脏病发作，中风和周围血管疾病。这种异常的血小板粘合剂可以通过血管中的胆固醇斑块或steNose处的分布式血流来引发。由于局部血流和剪切条件是引发血小板粘合剂和激活的重要机械因素，因此在可控制的流动条件下研究血小板功能以及在可控制的药物治疗下的治疗对于理解血栓形成和治疗机制至关重要。该奖项支持开发血管芯片的基本研究，模仿人体的微脉管系统，该研究可以提供一种以亚微米分辨率和高灵敏度的可调液流动剖面下监测单血小板行为的方法。该芯片还可以简单地研究多种药物及其组合对血小板的影响，从而支持药物筛查和针对血栓相关疾病的发现。因此，这项研究的结果将使美国社会受益。这项研究涉及多个学科，包括微电力系统，微型流体，生物医学工程和生物力学，允许妇女的参与和代表性不足的少数群体参与研究，从而对工程和科学的教育产生积极的影响，从而在量化的方向上产生量身定量控制（同时的量化流量控制），从而对流量控制进行了量化方向（均可开发量化的流量控制，从而取得了量化的方向（均可进行量化的流量控制，从而取得了量化的方向（血小板，以及监测单细胞水平血小板行为的能力。朝向这些目标，首先，将建立一种实验理论方法，以确定剪切速率的影响并确定整合素张力传感器，具有适当的优势来监测血小板的行为。其次，将研究体内剪切速率和脉冲流对血小板的影响。最后，将研究药理学剂及其与各种剂量的组合对血小板的影响。这项研究将填补有关如何开发适合于在可调剪切应力和药理学剂治疗中以芯片方式控制血小板行为的平台的技术知识差距。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响评估标准来评估值得支持。