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

Iowa State University, Ames IA

Investigators

Abstract

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 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.