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Microvasculature on a chip: study of the Endothelial Surface Layer and the flow structure of Red Blood Cells

Abstract : Microvasculatures-on-a-chip, i.e. in vitro models that mimic important features of microvessel networks, have gained increasing interest in recent years. Such devices have allowed investigating pathophysiological situations involving abnormal biophysical interactions between blood cells and vessel walls. Still, a central question remains regarding the presence, in such biomimetic systems, of the endothelial glycocalyx. The latter is a glycosaminoglycans-rich surface layer exposed to blood flow, which plays a crucial role in regulating the interactions between circulating cells and the endothelium. Here, we use confocal microscopy to characterize the layer expressed by endothelial cells cultured in microfluidic channels. We show that, under our culture conditions, endothelial cells form a confluent layer on all the walls of the circuit and display a glycocalyx that fully lines the lumen of the microchannels. Moreover, the thickness of this surface layer is found to be on the order of 600 nm, which compares well with measurements performed ex or in vivo on microcapillaries. Furthermore, we investigate how the presence of endothelial cells in the microchannels affects their hydrodynamic resistance and the near-wall motion of red blood cells. Our study thus provides an important insight into the physiological relevance of in vitro microvasculatures. Interactions between circulating blood components and vessel walls are central to the immune 1,2 and inflamma-tory 3,4 response, and to processes such as angiogenesis 5,6 or hemostasis 7. These interactions result from a complex and highly regulated interplay between specific biomolecular adhesion mechanisms at cell/wall interfaces 1,3,8 , chemoattractant expression 2,9 , mechanical properties of the cells 10,11 , and fluid stresses arising from hemody-namics 10–13. Anomalous interactions between blood cells and the endothelium, i.e. the cellular layer lining the internal lumen of blood vessels, are known to be associated with a number of blood and vascular disorders such as thrombosis, atherosclerosis, diabetes mellitus, or sickle cell anemia 3,14. In vitro studies have proven to be extremely useful in order to unravel the respective roles of mechanical, biochemical and biophysical factors that govern some vascular pathologies 15–18. These studies typically rely on microfluidic tools to create networks of channels that recapitulate the microvasculature properties. Such in vitro investigations present several important advantages for the rational studies of blood dynamics, cell trafficking and microvascular functions: (i) they solve technical and ethical issues encountered when working on animal models 19 , (ii) microchannels are made from transparent materials and facilitate the use of advanced and high-resolution microscopy techniques, and (iii) experiments are performed under tightly controlled fluid composition and flow conditions. However, these advantages often come at the cost of a partial loss of physiological relevance, in particular regarding cell/wall interactions. To overcome this limitation, several works have proposed designs of in vitro microvasculatures that mimic not only the architecture, but also the surface properties of blood microvessels: endothelial cells have been cultured in microcircuits, made of silicone elastomer or hydrogels, in order to form a confluent monolayer on their walls, thus providing perfusable channels bearing a model endothe-lium, while displaying two-or three-dimensional network architectures 20–31. Such in vitro microvasculatures have 1 Univ.
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Daria Tsvirkun, Alexei Grichine, Alain Duperray, Chaouqi Misbah, Lionel Bureau. Microvasculature on a chip: study of the Endothelial Surface Layer and the flow structure of Red Blood Cells. Scientific Reports, Nature Publishing Group, 2017, 7, pp.45036. ⟨10.1038/srep45036⟩. ⟨inserm-01498626⟩

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