Human inflammatory bowel disease-on-a-chip for modelling disease progression, cancer initiation and sex-specific effects

nature biomedical engineering Article https://doi.org/10.1038/s41551-026-01686-8 Human inflammatory bowel disease-on-a-chip for modelling disease progression, cancer initiation and sex-specific effects Received: 4 January 2025 Accepted: 15 April 2026 Published online: xx xx xxxx Check for updates Alican Özkan 1,10, Gwenn E. Merry1, David B. Chou 1,2, Ryan R. Posey1, Anna Stejskalova 1, Karina Calderon1, Megan Sperry1, Joshua Piatok1, Viktor Horvath 1,11, Lorenzo E. Ferri3,4, Emanuela Carlotti5, Stuart A. C. McDonald 5, Douglas J. Winton6, Rocco Ricciardi7, Liliana Bordeianou7, Sean Hall1,12, Girija Goyal 1 & Donald E. Ingber 1,8,9 Patients affected by inflammatory bowel disease (IBD) exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here we replicate these IBD hallmarks in human-derived organ-on-a-chip devices lined by colon epithelial cells from individuals with IBD when interfaced with matched fibroblasts, cultured under flow, exposed to peristalsis-like motions and perfused with circulating immune cells. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. In the IBD chip, inflammation and fibrosis are accentuated by peristalsis-like motions and, in female-derived chips, also by exposure to pregnancy-associated hormones. When exposed to carcinogens, the IBD chip shows increased inflammation, gene mutations and chromosome duplication, in contrast to healthy chips. These data suggest that the intestinal stroma, sex hormones and peristalsis-associated mechanical deformations have a key role in driving inflammation, fibrosis and disease progression in male and female individuals with IBD. Inflammation of the intestinal mucosa, including enhanced production of inflammatory cytokines and tissue infiltration with immune cells, along with increased barrier permeability, thinning of the protective mucus layer and fibrosis are central hallmarks of IBDs, such as Crohn’s disease (CD) and ulcerative colitis (UC). These alterations lead to considerable digestive issues and an increased risk of developing colorectal cancer (CRC)1. IBD symptoms also can be more prominent in women2, and they have to control their symptoms before pregnancy because many of these patients experience exacerbations that increase the risk of preterm birth3. Most IBD treatments target immune cells rather than intestinal tissues, and treatment efficacy is variable among patients4. However, interactions between epithelia and underlying stroma also may contribute to inflammation as well as cancer progression5. For example, the presence of a subset of fibroblasts that recruit immune cells to the intestinal stem cell niche is associated with poor prognosis in individuals with CRC6. Inflamed epithelial cells also can undergo Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA. 2Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. 3Thoracic and Upper GI Cancer Research Laboratories, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada. 4Department of Experimental Surgery and Department of Surgery, McGill University, Montreal, Quebec, Canada. 5Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, UK. 6Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK. 7Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. 8Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA. 9Harvard John A. Paulson School of Engineering and Applied Sciences, Boston, MA, USA. 10Present address: AbbVie Bioresearch Center, Worcester, MA, USA. 11Present address: Entact Bio, Watertown, MA, USA. 12Present address: Iovance Therapeutics, Tampa, FL, USA. e-mail: 1 Nature Biomedical Engineering Article an epithelial-to-mesenchymal transition and increase deposition of extracellular matrix (ECM) resulting in intestinal fibrosis that leads to complications, such as bowel stiffening and restriction of luminal fluid flow, which further exacerbate digestive problems in individuals with IBD7,8. Thus, there is a need to gain greater insight into how epithelial–stromal interactions, peristalsis and fluid flow influence IBD development in both male and female patients. However, animal IBD models and in vitro studies with human intestinal cell lines lack direct relevance to the human disease9, and human intestinal organoids cannot be used to address these questions because they lack an epithelial–stromal interface, mucosal barrier, fluid flow, peristalsis motions and immune cells, which are critical organ-level features required to address these questions. In this Article, we leveraged human organ-on-a-chip microfluidic culture technology that recreates tissue–tissue interfaces and a physiologically relevant intestinal microenvironment including dynamic fluid flow, peristalsis-like mechanical deformations and circulating immune cells to confront this challenge10,11. Colon-on-a-chip devices lined by human organoid-derived colonic epithelium cultured under dynamic fluid flow have been used in the past to study mucus layer accumulation and physiology12,13 as well as to identify microbiome metabolites that influence host response to bacterial infections14. In this study, we isolated epithelium and stromal-derived fibroblasts from the same regions of colon from healthy individuals or individuals with IBD and used them to create colon-on-a-chip devices that contained an epithelial–fibroblast interface. We also created heterotypic tissue recombinant chips, measured the effects of applying peristalsis-like motions and flowing immune cells through the stromal channel and studied the effects of female hormones on the IBD state, in addition to modelling cancer progression by exposing the colon-on-a-chip to carcinogens in vitro. Results Establishment of human healthy and IBD colon-on-a-chip devices Patient-specific epithelial organoids and stromal fibroblasts were isolated from surgical resections of the colon of healthy donors and individuals with CD or UC (Supplementary Fig. 1a and Supplementary Information), and the organoids were expanded in Matrigel cultures, while the fibroblasts were cultured on plastic dishes (Supplementary Fig. 1b). To build the human colon-on-a-chip, primary colon epithelial cells and fibroblasts were respectively seeded on the top and bottom surfaces of a porous ECM-coated membrane that separates two parallel channels within a commercially available microfluidic organ-on-a-chip device (Fig. 1a). The cells were allowed to adhere under static conditions for 1 day before flow was initiated. A continuous epithelial monolayer with undulating crypt-like structures when viewed from above (Fig. 1b,c) (...truncated)