Microvasculature-on-a-chip for the long-term study of endothelial barrier dysfunction and microvascular obstruction in disease

Abstract

Alterations in the mechanical properties of erythrocytes occurring in inflammatory and haematological disorders such as sickle-cell disease (SCD) and malaria often lead to increased endothelial permeability, haemolysis and microvascular obstruction. However, the associations among these pathological phenomena remain unknown. Here, we show that a perfusable, endothelialized microvasculature-on-a-chip featuring an interpenetrating-polymer-network hydrogel that recapitulates the stiffness of blood vessel intima, basement membrane self-deposition and self-healing endothelial barrier function for longer than one month enables the real-time visualization, with high spatiotemporal resolution, of microvascular obstruction and endothelial permeability under physiological flow conditions. We found that extracellular haem - a haemolytic by-product - induces delayed yet reversible endothelial permeability in a dose-dependent manner, and demonstrate that endothelial interactions with SCD or malaria-infected erythrocytes cause reversible microchannel occlusion and increased in situ endothelial permeability. The microvasculature-on-a-chip enables mechanistic insight into the endothelial barrier dysfunction associated with SCD, malaria and other inflammatory and haematological diseases. © 2018 The Author(s) 2018, under exclusive licence to Macmillan Publishers Ltd, part of Springer Nature