Modelling mechanisms and treatment of cholangiopathies with a bile duct on a chip

Scientists have developed a new method to study cholangiopathies, which are bile duct disorders, using a human-shaped microfluidic chip. This system recreates the complex bile duct microenvironment and can be used to test potential treatments. To create the chip, researchers printed a collagen-embedded canal and seeded it with patient-derived cholangiocytes, which are the cells that line the bile ducts.

The chip was tested for its ability to maintain a tight, polarized epithelial barrier, which is crucial for preventing the leakage of substances into the bloodstream. The researchers found that certain drugs, such as verapamil and Linerixibat, can effectively reduce the transport of specific molecules across the barrier. However, lipopolysaccharide, a component of bacterial cell walls, caused significant damage to the epithelial barrier, as evidenced by a more than 1000% increase in leakage of small molecules like 3 kDa and 10 kDa dextran, along with the upregulation of inflammatory cytokines.

The study also examined the effects of a toxic compound called Chlorpromazine on the cholangiocytes. The researchers discovered that Chlorpromazine caused dose-dependent toxicity, with different EC50 values (the concentration required to induce a half-maximal effect) for each patient line tested. To investigate potential therapies, the scientists introduced a bile duct disorder called biliatresone and treated it with N-acetyl-L-cysteine.

They observed a dose-dependent improvement in the cholangiocyte phenotype, with viability increasing from 23% to 59% in response to the treatment.