Microfluidic tools to investigate pathologies in the blood microcirculation

Abstract

We show how microfluidics technology can be used to fabricate simple and innovative biomimetic tools to shed new light on physiopathological events occurring in the blood microcirculation. Examples of applications are given in the context of the acute respiratory distress syndrome (ARDS), an inflammatory disease of the lung triggered by a massive arrest of white blood cells in the lung microvasculature. The main challenge consists in building relevant micro–devices to reproduce key biological characteristics of blood capillaries. We present a series of tools that permit us to decouple the role of the multiple parameters involved in complex biological events. Straight narrow channels with non–adherent walls are used to characterise the passage of a cell in 4 m wide constrictions in the absence of adhesion, whereas channels covered by endothelial cells allow a quantitative measurement of cell adhesion in the absence of mechanical constraints. We show that incubation of white blood cells in sera of ARDS patients increases their stiffness, confirming the role of stiffness on the abnormal sequestration of white blood cells, whereas we could not bring to light a significant adhesion increase. The multiple branches and constrictions of the blood microvasculature network are mimicked here by series of interconnected crenelled constrictions with different symmetries. In symmetric crenels, cells adopt a stable deformed shape after a few constrictions and travel fast through successive constrictions with a constant orientation. In asymmetric channels, cell orientation and trajectory are perturbed between two constrictions. Unfavourable orientations upon entry can yield temporary or even definitive arrests with the stiffest cells. Finally, we present a new artificial micro–vessel with porous walls to mimic the porosity of real blood vessels. This new tool is useful to observe directly under a microscope the late stages of inflammation in the microvasculature such as immune cells transmigration, or the infection of a micro–vessel by pathogenic bacteria.