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

• Authors: Yongzhi Qiu, Emory University; Byungwook Ahn, Georgia Institute of Technology; Yumiko Sakurai, Georgia Institute of Technology; Caroline Hansen, Emory University; Reginald Tran, Georgia Institute of Technology; Patrice N. Mimche, University of Utah; Robert G Mannino, Georgia Institute of Technology; Jordan C. Ciciliano, Georgia Institute of Technology; Tracey J. Lamb, University of Utah; Clinton Joiner, Emory University; Solomon F. Ofori-Acquah, University of Pittsburgh; Wilbur Lam, Emory University
• Journal Title: Nature Biomedical Engineering
• Volume: Volume 2, Number 6
• Publisher: Nature Research (part of Springer Nature) | 2018-06-01, Pages 453-463
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41551-018-0224-z
• Subjects: Engineering, Biomedical; Chemistry, Biochemistry
• Keywords: Science & Technology; Technology; Engineering, Biomedical; Engineering; SICKLE-CELL-DISEASE; TUBES IN-VITRO; MICROFLUIDIC NETWORKS; CEREBRAL MALARIA; PERMEABILITY; MICE; VASOOCCLUSION; MICROVESSELS; HYDROGELS; STIFFNESS

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.