Engineering Smart Solutions for Disorders of the Bladder Urothelium

Urothelial disorders, such as urinary tract infection and bladder cancer, are poorly studied but impose a hefty economic and social burden to society. Urinary tract infection (UTI) is one the most common bacterial infections worldwide, with around 150 million to 250 million cases every year. The incidence of UTI also increases with age and is more common in women. The current gold-standard diagnostic procedure for UTI is the midstream urine culture (MSU), which has been shown to be problematic for detecting all UTI. This is because not all UTI bacteria grow well or reach the established threshold in culture, and because uropathogens are also known to form deep tissue reservoirs which are not detectable in urine. These limitations contribute to the failure to diagnose UTIs correctly which impacts on treatments.
With the global emergence of antibiotic resistant bacteria and the inability of antibiotics to penetrate the urothelium to kill the deep tissue reservoirs, UTIs are becoming a lot more complicated to treat and therefore, more of a burden on society. Current treatment regimens include a 3-7 day course of antibiotics after diagnosis of UTI; however, there is a high recurrence rate. Some patients, particularly in our aging population, develop chronic infections associated with lower urinary tract symptoms (LUTS) that greatly affect their quality of life.
UTI has been known to facilitate the development of bladder cancer. Bladder cancer is the 9th most common malignancy with 150,000 deaths and 400,000 new cases every year worldwide. It is one of the most expensive cancers to treat due to the nature of current treatment procedures.
Non-muscle invasive bladder cancer (NMIBC) treatment involves invasive cystoscopy with instruments to remove the tumour and probes to cauterise the wound with a further round of chemotherapy. Muscle invasive bladder cancer (MIBC) involves a round of Cisplatin-based chemotherapy followed by the complete removal of the bladder (radical cystectomy). For both bladder cancer types, current treatments are costly, extremely invasive and affect the quality of life after treatment, with many MIBC patients needing a stoma and urostomy bag. Also, as many as 50% of MIBC patients die after 5 years following treatment. New bladder cancer treatment regimens are therefore greatly needed.
Research into novel treatments for both UTI and bladder cancer have lagged behind due in part to the use of mouse models, which do not fully recapitulate the full manifestation of human disease. Mouse models also take time to establish and the infection rate is poor. Therefore, developing new models for urothelial disorders is important to understand their basic biology as well as to develop and test new treatments. Our research group has pioneered a human organoid model that has expanded our capabilities for studying urothelial biology and its disorders. In parallel, we have been working with engineers to develop new microencapsulated therapies for chronic UTI which also could be expanded for treatment of bladder cancer.
The main aim of this project is to use cutting-edge engineering solutions to make innovative improvements to the bladder organoid to create a better model for understanding urothelial disorders and for testing new treatments. This includes incorporating the model onto a microfluidic platform (organ-on-a-chip) with perfusion and stretch capacity to enhance its physiological relevance. In addition, we aim to develop new encapsulated therapies for urothelial disorders in the engineering lab of the industrial project partner (AtoCap Ltd), which will involve novel electrospraying methodology.
We hope to provide new engineering solutions to the problems urothelial disorders continue to throw at us. We hope these solutions can provide more favourable treatment options and continue to improve our understanding of urothelial disorders in the future.