Autologous cell engineered bladder augmentation

英国约有300万人患有尿失禁，NHS每年的管理成本超过5亿英镑。它可以由先天性异常引起，例如胎儿中膀胱形成失败（膀胱外翻），以及后天条件，例如膀胱顺应性丧失（神经性膀胱）或膀胱癌。对于终末期膀胱疾病，最常进行的增加或替换膀胱的外科手术涉及合并血管化的重新配置的肠段（肠膀胱成形术）。虽然这种手术可以提供治疗并提高生活质量，但它通常与严重的并发症有关，包括感染，粘液产生和结石形成，以及癌症的长期风险。这些并发症主要是由于肠粘膜在结构和生理上与长期暴露于尿液不相容。已经提出了许多膀胱工程化策略，并且通常，这些策略依赖于将天然或合成生物材料掺入膀胱中，其可以或不可以与源自患者的细胞（自体的）一起预培养。尽管有一些高调的报道，但几乎没有证据表明膀胱组织工程可以实现与当前手术技术等同的功能结果，并且仍然存在未满足的临床需求。该计划的目的是通过自体细胞工程策略为患者提供功能性膀胱重建。该项目将汇集干细胞和泌尿学（ICH，GOSH和UCLH）与尿路上皮细胞生物学和膀胱组织工程（约克）的专业知识，旨在开发一种新的膀胱重建技术，该技术首先适用于膀胱外翻患者，但最终扩展到所有需要膀胱扩大的患者。该项目的阶段将首先是开发方法，以确定和分离最合适的自体上皮细胞来源的情况下，膀胱外翻。为了实现这一目标，将分离和表征来自正常和患病膀胱以及来自颊粘膜活检的细胞。上皮细胞的扩增将使用“良好生产规范”技术进行，这是用于药品的标准方法，为转化到临床提供现成的途径。将人细胞异种移植到24头猪中用于膀胱增大，并在移植后3个月和6个月获得功能和组织学数据。主要结局指标将是：通过生存率测量的安全性;通过新膀胱的容量和顺应性测量的疗效。这一阶段的次要指标包括：手术发病率、增强和天然粘膜的尸检免疫组织学分析以及“反向翻译”结果指标，其中细胞行为的观察用于开发关于干细胞/细胞功能性植入的假设。

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 foetus to form (bladder exstrophy), and acquired conditions such as a lost 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 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 and UCLH) with urothelial cell biology and bladder tissue engineering (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 all patients requiring bladder augmentation. The stages of the project will be firstly to develop methods to identify and isolate the most appropriate source of autologous epithelial cells in the case of bladder exstrophy. To meet this aim, cells derived from normal and diseased bladder and from biopsies of buccal mucosa will be isolated, and characterized. Expansion of the epithelial cells will be conducted using "Good Manufacturing Practices" techniques, a standard methodology used for pharmaceutical products, to provide a ready route for translation to the clinic. Human cells will be xenogeneic transplanted in 24 pigs for bladder augmentation and functional and histological data will be obtained at 3 and 6 months after transplantation. 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 immunohistological analysis of both the augmented and native mucosa, and also 'reverse translational' outcome measures, where observations of cellular behaviour are used to develop hypotheses about stem cell/cell functional engraftment in these settings in vivo.