Autologous cell engineered bladder augmentation

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Some 3 million people in the UK experience incontinence and the cost of management is over £500 million per annum to the NHS. It can be caused by both congenital anomalies, such as a failure of the bladder in the fetus to form (bladder exstrophy), and acquired conditions such as a loss of the compliance of the bladder (neuropathic bladder) or bladder cancer. For end-stage bladder disease, the most commonly performed surgical procedure to augment or replace the bladder involves incorporating a vascularised, reconfigured segment of bowel (enterocystoplasty). Although this procedure can provide continence and enhance quality of life, it is commonly associated with serious complications, including infections, mucus production and stone formation, and a possible long-term risk of cancer. These complications are primarily due to the fact that bowel mucosa is structurally and physiologically incompatible with the long-term exposure to urine. A number of bladder engineering strategies have been proposed and typically, these rely upon the incorporation of a natural or synthetic biomaterial into the bladder, which may or not be pre-cultured with cells derived from the patient (autologous). Despite some high profile reports, there is little evidence that bladder tissue engineering can yet achieve a functional outcome equivalent to current surgical techniques, and there remains an unmet clinical need. The aim of this programme is to deliver functional bladder reconstruction to patients through an autologous cell engineering strategy. This project will bring together expertise in stem cells and urology (ICH, GOSH, Evelina London Children's Hospital) with urothelial cell biology and bladder tissue engineering (University of York) with the purpose of developing a novel technique for bladder reconstruction that will be applicable in the first instance to patients with bladder exstrophy, but eventually extended to any paediatric or adult patient requiring bladder augmentation. The stages of the project will be to: 1. Prepare a bank of transplant-relevant human epithelial cells for assessment in composite cystoplasty.2. Transplant human epithelial cells into immunosuppressed pigs using the composite cystoplasty procedure and monitor function for 3 & 6 months before sacrifice. Principal outcome measures will be: safety as measured by survival; efficacy as measured by capacity and compliance of the neo-bladder. Secondary measures for this phase will include: surgical morbidity, post-mortem gross anatomy and immunohistological analysis of both the augmented and native mucosa