Functional human 3D microvascular networks on a chip to study the procoagulant effects of ambient fine particulate matter

Abstract

Exposure to ambient fine particulate matter (FPM) has been thought to be associated with cardiovascular disease. However, the pathogenesis remains largely unknown. Animal models have been widely used in toxicological research, but species difference makes it impossible to directly translate discoveries from animals to humans. In this study, we developed a 3D functional human microvascular network in a microfluidic device. The established model enables endothelial cells to form vessel-like microtissues and have physiological functions which are closer to cells in human blood vessels. The perfusable microvasculature allows the delivery of nutrients, and oxygen, as well as flow-induced mechanical stimuli into the luminal space of the endothelium. The microflow effectively mimic the blood flow in human vessels. FPMs were introduced into this physiologically human vessel-like microenvironment following the fluid flow. The vascular toxicity was evaluated based on this organotypic 3D microvessel model. Our results demonstrated that intravascular accumulation of FPM could enhance ROS generation which may further cause endothelial dysfunction by oxidative stress. This is expressed in disorder of NO expression and IL-6 up-regulation. These are expected to enhance endothelial inflammation which might in turn accelerate coagulation that is associated with thrombosis. Human organotypic 3D microvessel models provide a possible bridge for how the research outcomes translate to humans. These models could partly simulate the physiological responses of human vessels to FPM stimulation. This simple and versatile platform can be used for a wide range of applications in vascular physiology studies of particulate matter in the context of cardiovascular disease.