Human microphysiological model of chemotherapy-induced intestinal injury and repair for predictive toxicology

Julia will work with industry partner MEPSGEN to adapt their commercially available microphysiological system for use as a model of the human small intestine in gastrointestinal toxicology studies. By incorporating organoid-derived cells, her team will establish a system capable of reproducing chemotherapy-induced mucositis, an inflammatory injury of the intestinal lining that is typically studied in animal models. The team will characterise how intestinal barrier damage and repair occur within the in vitro system. These responses will be compared with 2D models and existing in vivo data, providing insight into mechanisms of treatment-related intestinal toxicity. 

Intestinal mucositis is one of the most debilitating side effects of chemotherapy, resulting from chemotherapeutic-induced inflammation and pathophysiological changes in the intestinal mucosa. These arise from stem-cell apoptosis and dysregulated epithelial renewal, leading to loss of barrier integrity and severe symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and malnutrition. Up to 40-100% of patients receiving chemotherapy experience intestinal mucositis (Dahlgren et al., 2021). Current models rely heavily on animal studies, which poorly mimic human intestinal injury and repair due to species-specific differences, thereby limiting their translational potential. Existing 2D in vitro models based on simple cell lines lack physiological relevance, and no current systems can reliably replicate chemotherapy-induced mucositis.  

This project aims to adapt MEPSGEN’s microphysiological system (MPS) to emulate the human small intestine with its crypt-villus architecture by integrating organoid-derived intestinal and endothelial cells within a two-compartment perfusable chip, establishing the first translational model in this field. Small intestinal tissue formation and chemotherapeutic effects will be analysed via immunofluorescence (IF) imaging using key markers Lgr5⁺ (intestinal stem cells), CK20 (differentiated enterocytes), MUC2 (goblet cells), and ZO-1 (tight junctions). Injury will be induced with 5-fluorouracil (5-FU) and irinotecan. Barrier disruption will be quantified by transepithelial electrical resistance (TEER) and dextran permeability assays, while inflammatory activation will be assessed via IL-6 ELISA. Repair will be characterised by Lgr5⁺ renewal, ZO-1 reappearance, and TEER recovery. Data will be benchmarked against conventional 2D (Caco-2) models and in vivo datasets to evaluate translational predictivity.  

This project will deliver a novel, human-relevant intestinal model, providing mechanistic insight into intestinal toxicity and driving more predictive, reproducible, and animal-reducing research workflows both in the short and long term.