P006 3D Multicellular intestine-on-a-chip model for disease modelling and drug discovery

G. Lo Sasso1, L. Gijzen2, D. Marescotti1, E. Naumovska2, E. Raineri2, A. Nicolas2, H. Lanz2, D. Guerrera1, R. van Vught2, J. Joore2, P. Vulto2, M.C. Peitsch1, J. Hoeng1, D. Kurek2

1Department of System Toxicology, Philip Morris Products SA, Neuchâtel, Switzerland, 2Mimetas BV, Leiden, The Netherlands


One of the major functions of the human intestine is to provide a protective epithelial barrier between the body and digestive environment. Additionally, the interplay of commensal microbes of the gut microbiome with the gut tissue and host immune system significantly contributes to intestinal homeostasis. Crohn’s disease and ulcerative colitis, collectively referred to as inflammatory bowel diseases, are both associated with increased permeability of the epithelial barrier and dysregulated immune response. Great efforts have been made to develop both in vitro and in vivo models of the human intestine in order to understand the development and underlying pathogenesis of IBD. These efforts have provided valuable insights into multiple aspects of the disease. However, none of these models has been able to capture the complexity and multifactorial nature of IBD. Animal models generally fail to accurately predict the efficacy and toxicity of novel compounds in human tissues, while in vitro human intestinal models developed on porous membranes within Transwell inserts fail to accurately recapitulate and mimic key aspects of the in vivo situation.


Here, we present the development and characterisation of a 3D multicellular perfused intestine-on-a-chip model in a microfluidic platform, the OrganoPlate®, and its application for investigating intestinal inflammation. The model described here comprises a coculture of Caco-2 and mucus-secreting HT29-MTX cells in the top compartment of the chip and a coculture of immune-competent cells THP-1 and MUTZ-3 in the bottom compartment, lining a collagen-I ECM in the middle.


We show that the Caco-2 and HT29-MTX coculture form confluent and polarised tubular structures against the collagen-I ECM in the OrganoPlate®, with a stable barrier function over time as well as the capability to secrete mucus. By exposing the cultures to TNFα and/or IL-1β, we were able to induce an inflammatory state, characterised by cytokine release (IL-8) and a decrease in trans-epithelial electrical resistance. Finally, we proved the applicability of the model in screening anti-inflammatory compounds by its reversibility. Using a well-known anti-inflammatory drug, TPCA-1, we were able to prevent cytokine-induced inflammation. This result was evident from the decreased secretion of IL-8 and retention of barrier function in treated cultures, similar to that observed in untreated cultures.


Overall, this complex 3D multicellular perfused intestine-on-a-chip model provides the versatile modularity of mimicking key features of intestinal inflammation and can, therefore, further support drug screening efforts and provide a platform for personalised medicine.