Modelling catheter-associated bladder mucosal adhesion and microtrauma using a human urothelial microtissue model

Animal models have been used to investigate urinary tract catheters, but most do not accurately recapitulate human bladder physiology nor support different types of catheters. Recent advances in three-dimensional models mimicking tissue microenvironments have improved our understanding of human tissue development and allowed us to model many diseases. Here, our objective was to characterise bladder urothelial mucoadhesion and microtrauma associated with intermittent catheterisation. We employed our three- dimensional Urine-tolerant Human Urothelial model (3D-UHU) to investigate two different intermittent catheter types, a polyvinylpyrrolidone (PVP)-coated catheter (PVP-CC), and a coating-free integrated amphiphilic surfactant (IAS) catheter. We showed that pressing catheters onto the models for two minutes caused compression of the 3D-UHU model in contact regions, with disruption of urothelial umbrella cells detected by immunofluorescence staining of surface markers uroplakin III, cytokeratin-20 and chondroitin sulphate, alongside occasional effacement of apical surfaces exposing intermediate layers. PVP-CC had a significantly higher number of urothelial cells adhered to its surface after catheter removal compared with IAS. Moreover, application and removal of PVP-CC caused a decrease in transepithelial electrical resistance, suggesting barrier disruption, whereas IAS did not cause a statistically different effect. However, no change in paracellular permeability rates assessed by FITC-dextran were observed in models after application of catheter pieces. Finally, compression of models induced trauma-triggered inflammatory cytokine responses. Specifically, we observed increased secretion of the pro- inflammatory cytokine IL-1β as well as the cell adhesion molecule CEACAM1 after exposure to PVP-CC compared with IAS. Our findings suggest that the IAS catheter damaged the epithelium less than the PVP-CC catheter. These data demonstrate that the 3D-UHU model holds promise as an alternative to animal models for investigating the effects of urinary catheters on the urothelium.