Ulcerative colitis (UC) and Crohn’s disease (CD), collectively known as inflammatory bowel diseases (IBD), are chronic inflammatory disorders of the gastrointestinal tract. IBD is an idiopathic disease characterised by a dysregulated immune response that results in mass-immune cell infiltration and subsequent tissue damage. The mechanisms underpinning the complex pathogenesis of IBD requires further elucidation.
Current therapeutic strategies in IBD primarily target activated leukocytes in order to dampen the immune response, neglecting other critical mediators of inflammation, such as fibroblasts. There now exists irrefutable evidence that fibroblasts are not just bystanders in mucosal inflammation but are pivotal participants in orchestrating the immune response in IBD.1 Although more recent therapies such as biologic agents have shown more success in treating IBD than previous immunosuppressive drugs, 40% of patients elicit no response. Moreover, approximately 90% of clinical trials for investigational new drugs (IND) fail, mainly attributable to the fact that most IND research is carried out in animal models, ex vivo-tissue and oversimplistic in vitro culture methods.2 The scarcity, disease-severity and short-lived nature of IBD tissue ex vivo, low similarity between animal and human tissue, and absence of physiologically relevant in vitro models impedes research progression and subsequent drug development.3,4
We have bioengineered highly reproducible, in vitro models that recapitulate key aspects of the inflamed IBD intestinal mucosa. These constructs utilise a porous polystyrene scaffold membrane to construct lamina-propria-like compartments with an overlying epithelium. Subepithelial fibroblasts within the lamina propria secrete endogenous extracellular matrix (ECM), alongside a co-cultured immune component that simulates the mass immune-cell infiltration observed in IBD. An inflammatory phenotype is induced through addition of appropriate inflammatory stimuli. Inflammatory parameters characteristic of IBD are observed, including endogenous inflammatory cytokine and chemokine secretion, barrier impairment, and ECM remodelling. This in vitro system allows for investigation into complex interplay between epithelial, mesenchymal and immune cells and the resultant effects on barrier function, thus simulating key aspects of IBD.
Through treatment with relevant and well-characterised therapeutic compounds, we further demonstrate the functional potential of the mucosal constructs in obtaining drug efficacy data. Using both prophylactic and therapeutic approaches, we are able to generate datasets that would otherwise be impossible to obtain using ex vivo IBD tissue due to the short-lived nature of ex-vivo assays. This subsequently allows for dissection of the anti-inflammatory effects of the therapeutic compounds within models by analysing changes in inflammatory parameters.
Taken together, our results demonstrate the potential for this novel, bioengineered system to be used for pre-clinical pharmaceutical compound testing in a controlled, reproducible and physiologically relevant environment.
 Barnhoorn MC et al. Stromal cells in the pathogenesis of inflammatory bowel disease. Journal of Crohn's and Colitis, 14(7),(2020)
 Neurath, MF. Current and emerging therapeutic targets for IBD. Nature Reviews Gastroenterology & Hepatology 14.5(2017)
 Kiesler P, Fuss IJ. and Strober W. Experimental models of inflammatory bowel diseases. Cellular and molecular gastroenterology and hepatology, 1(2),(2015)
 McKay DM, Philpott DJ, and Perdue MH. In vitro models in inflammatory bowel disease research—a critical review. Alimentary pharmacology & therapeutics, 11,(1997)