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Hepatology. 2019 Aug 29. doi: 10.1002/hep.30918. [Epub ahead of print]

A Bile Duct-on-a-Chip With Organ-Level Functions.

Du Y1,2, Khandekar G1,2, Llewellyn J1,2, Polacheck W3,4,5, Chen CS4,6,2, Wells RG1,7,8,2.

Author information

1
Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
2
Center for Engineering MechanoBiology, The University of Pennsylvania, Philadelphia, PA.
3
The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA.
4
The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, MA.
5
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC.
6
Tissue Microfabrication Laboratory, Department of Biomedical Engineering, Boston University, Boston, MA.
7
Department of Bioengineering, School of Engineering and Applied Sciences, The University of Pennsylvania, Philadelphia, PA.
8
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Abstract

BACKGROUND AND AIMS:

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are frequently associated with damage to the barrier function of the biliary epithelium. Here, we report on a bile duct-on-a-chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions.

APPROACH AND RESULTS:

We showed that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, that the permeability of the cholangiocyte monolayer was comparable to ex vivo measurements, and that cholangiocytes in the device were mechanosensitive (as demonstrated by changes in calcium flux under applied luminal flow). Permeability decreased significantly when cells formed a compact monolayer with cell densities comparable to those observed in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof-of-concept toxicity studies with the biliary toxin, biliatresone, and the bile acid, glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid.

CONCLUSIONS:

This bile duct-on-a-chip captured essential features of a simplified bile duct in structure and organ-level functions and represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.

PMID:
31465556
PMCID:
PMC7048662
[Available on 2021-02-28]
DOI:
10.1002/hep.30918

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