Abstract

Organs on a chip is a technology that is often used to mimic the in vivo microenvironment within an organ. In vivo, different forces impact the cell (e.g., peristalsis motion or fluid flow in the intestine), which altogether cause a shear stress that further influences the phenotypical outcome of the cells. With microfluidics, it is possible to mimic these forces to grow the cells in an environment that resembles the in vivo environment. Organs on a chip have the potential to become a valuable tool when it comes to the preclinical evaluation of potential chemotherapeutic agents, thus decreasing the need for animal models. However, the specific conditions for each type of organ on a chip (e.g., brain, liver, intestine) are not uniformly established. Therefore, I tested the effect of different shear stresses on an intestinal epithelium cultured in a microchannel, by varying the rate of perfusion. I found that the ideal shear stress for the integrity of the intestinal epithelium is 0.25 dyn/cm2. I also analyzed the adverse effects of a chemotherapeutic agent, methotrexate, on the intestinal epithelium, by simulating an oral administration of the drug. I determined that methotrexate reduced the levels of the tight junction protein Zonula occludens-1 (ZO-1) within the tight junction between the epithelial cells. Moreover, I found that holes were forming in the tight junctions and that giant multinucleated cells were appearing following a methotrexate treatment. I hypothesized that the formation of these giant multinucleated cells was due to the fusion of neighbour cells, which could lead to holes in the tight junction, leading to an increase in intestinal permeability.