Development of a gut-on-a-chip model for pre-clinical testing of drugs for inflammatory bowel disease

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a chronic progressive disorder of the gastrointestinal tract that poses multiple challenges to treatment development due to its multifactorial character. A valid ex vivo research model that properly mimics the in vivo situation is lacking and pivotal to understand disease driving mechanisms and evaluate preclinical compounds. Intestinal organoids already constitute a very promising tool to model IBD and screen development drugs due to their ability to maintain site-specific and patient-specific characteristics. In addition, differentiated intestinal organoids will give rise to all the cell types that populate the crypt, as opposed to cancer-derived cell lines. However, to successfully mimic and evaluate disease mechanisms other characteristics have to be taken into account. For example, simple intestinal organoid cultures cannot be perfused, and the peristalsis motion cannot be reproduced. A possible solution to this problem can be found in the use of gut on a chip platform. Gut-on-a-chip platforms are microfluidic devices lined with living cells cultured under fluid flow and stretching motions. They can recapitulate organ-level physiology and pathophysiology with high fidelity. Seeding this platform with IBD patient-derived intestinal organoids, endothelial cells and immune cells will strongly increase the ability to predict the effects of drugs, xenobiotics and nutritional components on the intestinal epithelium. To summarize, this doctoral project aims at establishing a pre-clinical model representing the complexity of IBD, to enable the study of mechanisms underlying IBD and evaluate preclinical compounds.