Self-assembled human arteriole-on-a-chip for arterial functionality testing and disease modeling

Abstract

In recent years, various vascularized organ-on-a-chip models have been designed for drug development and screening, and many of them have also advanced to serve as disease models for studying infectious diseases and gene disorders. Currently, most vascular models are capillary-like structures with only a layer of endothelium. Some of them may have pericytes to support the vessel structure. However, there are very limited studies on developing the complex structure of the arteries. In this study, we report a physiological approach to develop self-assembled arterioles in a microfluidic device, providing an in vitro model for human arterioles. First, we use human umbilical artery endothelial cells (HUAECs) and smooth muscle cells (HUSMCs) to create a vessel network through vasculogenesis and angiogenesis. Then, a 1 Hz oscillating pressure is applied to create two different levels of wall shear stress on the vessel network to stimulate arteriogenesis. Using this method, self-assembled arterioles are successfully developed in a microfluidic chip with HUAEC endothelium wrapped by HUSMCs and a basement membrane. The experimental studies show that vessel networks under high shear stress tend to grow over time. Furthermore, the concurrent formation of primary vessels with enlarging diameters and regression of secondary vessels with thinning diameters can be observed, suggesting that cyclic shear flow is a critical physiological stimulus in arteriole development. Finally, we verified the functionality of the developed arterioles. Vasodilation and vasoconstriction can be stimulated by administering varying dopamine concentrations into the arteriole chip, suggesting they are functional arterioles. We also demonstrated that thrombosis can be induced within the developed arterioles on the chip, suggesting that this device can serve as a viable in vitro human arteriole model for studying arterial thrombosis.