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

Alterations in the mechanical properties of erythrocytes occurring in inflammatory and haematological disorders such as sicklecell 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.