P019 Development of hydrogel systems for targeted rectal delivery of intestinal cells to injured mucosa in inflammatory bowel disease

Abstract

Abstract Background Crohn’s Disease (CD) and Ulcerative Colitis (UC) are Inflammatory Bowel Diseases (IBD) affecting over 6.8 million people worldwide. CD and UC are chronic and progressive diseases, characterised by destructive inflammation of the intestinal tract. IBD management consists of drugs such as steroids, aminosalicylates, immunosuppressants, and biologics that aim to induce disease maintenance and remission. However, frequent, and systemic drug administration leads to limited local effects, severe side effects, and low patient compliance. Ultimately, about 20% of UC and up to 80% of CD patients require surgical colon removal. Thus, new approaches to locally restore the inflamed mucosa and initiate colonic wound repair are required. Human intestinal organoids (HIOs) are 3D cell aggregates derived from primary tissue or stem cells grown in vitro. They demonstrate a similar composition architecture to the primary intestinal tissue. Studies showed that HIOs can engraft into injured colonic mucosa resulting in wound repair. Thus, delivery of HIOs to damaged intestinal epithelium represents a promising therapeutic option in IBD treatment. The project aims to develop hydrogel systems with embedded HIOs and obtain human-relevant information on their efficacy in the restitution of injured colonic mucosa using an improved and human-relevant organ-on-a-chip technology. Methods A series of thermoresponsive hydrogels were fabricated (based on methylcellulose/hyaluronic acid polymers) and characterised. Following the embedment of HIOs into hydrogels, the morphology and viability of HIOs were determined using microscopy and MTT assays. Inflammation was induced through the administration of LPS to the basolateral side of the gut chip. Hydrogel/HIO systems were applied to the apical chip compartment via flow for 24 hours. Subsequently, hydrogel/HIO systems were removed from the chip, and HIO engraftment into injured mucosa was determined utilising permeability (4 kDa dextran) and cytokine release assays (ELISA IL-8). Results Our findings show that the gels were liquid at 25 °C and solidified at 37 °C and demonstrated low cytotoxicity. Additionally, our results suggest that the hydrogel systems had a restorative and possibly protective effect on the villi structures in the gut chip. Microscopy results clearly demonstrated the presence of fully differentiated villi structures in the chips that were treated with the hydrogel/cell systems (Figure 1B). These villi structures were absent in the not-treated chips (Figure 1A). Conclusion This study suggests that development of organoid-based hydrogels that can serve as a safe, effective, and inexpensive therapy (compared to surgery) and significantly improve the treatment of IBD.