Autologous cell engineered bladder augmentation

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

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.
Thestages 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

Technical Summary

1. Sourcing of autologous cells. Bladder mucosa will be harvested from children undergoing bladder
procedures according to ethical approval. Buccal mucosa epithelium will be obtained from discarded
tissue during urethral reconstruction (ethical approval granted). Cells will be isolated and expanded
using established techniques and tested for their capacity to express differentiation-associated
markers and develop functional barrier properties by measuring trans-epithelial electrical resistance
and permeability to urea and water. Human urothelial and buccal epithelial cells will be
produced/banked for transplantation into pigs.
2. The harvest of differentiated sheets and suitable carrier for transport and delivery will be refined.
3. Establish a porcine experimental surgical model of composite cystoplasty. A vascularised, deepithelialized,
seromuscular colonic segment will be developed in a total of 20 immunosuppressed
pigs. After isolation, the patch will receive a tissue-engineered epithelial sheet in association with inert
carrier (Vicryl mesh) to facilitate epithelial sheet transfer and surgical attachment. The pigs will be
divided into 2 groups (10 animals each): one set will receive a bladder augment with a patch built with
tissue derived from healthy urothelium; the second will undergo augmentation using tissue from
buccal mucosal epithelium. The animals will be sacrificed at 6 months post-augment. The assessment
will include voiding behaviour records and post-mortem immunohistological analysis of both the
augmented and native mucosaXenogeneic transplant of human epithelial cells into 20 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.

Planned Impact

The aim of this programme is to deliver a functional bladder reconstruction, through a cell/tissue engineering strategy, to children who require increased bladder capacity. Bladder exstrophy is a major congenital anomaly that affects the growth and function of the bladder. Despite improvement of the surgical techniques, the need for bladder augmentation in bladder exstrophy patients, in order to achieve an adequate bladder capacity is reported in up to 70% of children.
In the last 7 years at GOSH and Evelina, 106 children underwent a bladder augmentation and of those 26 were exstrophy patients (GOSH).
In general, the incidence of neonates born with bladder exstrophy or other congenital malformations is increasing and the results of the operations currently used for their correction are often disappointing, leaving these children with profound disabilities and poor quality of life. This has significant deleterious effects on both the family and the community. While the main focus the work of our group is on the bladder exstrophy, the use of a surrogate epithelium, such as the buccal mucosa here proposed, may have an impact also for other indications where bladder augmentation is required but autologous urothelium cannot be used, such as for neuropathic bladders and bladder cancer patients. The evidence suggests an increasing trend in the incidence of this malignancy in recent years. In 2000, worldwide, 336,000 patients were diagnosed with bladder cancer. Bladder augmentation is part of the armoury of the urologist / paediatric urologist in the treatment of urinary incontinence. Urinary incontinence is associated with tremendous costs and results in medical and psychological morbidity and adverse effects on quality of life. In general, urinary incontinence, secondary to congenital and acquired diseases, is experienced by some 3 million people in the UK and the cost of management is over £500 million per annum to the NHS. At the moment, although bladder augmentationcan provide continence and enhance quality of life, it is commonly associated with serious complications, such as mucus production, formation of stones, recurrent urinary infection, metabolic imbalance and for some, in the long term, malignant change. Management of these complications can require additional medication, bladder washouts and occasionally hospitalisation treatment. The aim of this project is to provide a safe alternative to bowel segments for augment the bladder that will improve clinical outcomes and the quality of life for these patients and their families by reducing their risk of serious sequelae. This in turn will reduce the cost burden for the NHS of lifelong management of such complex patients and their complications. Once validated, the proposed surgical approach to composite cystoplasty will be easily and quickly translated into clinical application. We also envisage that this research may have, in the long term, a wider economic impact. This is based on the fact that our results could be of interest not only for the cure of congenital anomalies, but also for the treatment of acquired diseases in children, as well as in adults of all ages. Moreover tissue engineering is linked to advances in technology and is likely to generate commercial interests. If our approach would prove to be correct, possible patents could be generated for commercially exploitable results. It is not our primary interest to develop a patent, but we believe that this could help acquiring future grants and fostering of future research.

Publications

10 25 50
 
Description B Braun-Synthetic Mesh 
Organisation B.Braun Melsungen AG
Country Germany 
Sector Private 
PI Contribution We have been testing mesh products to identify the most suitable mesh for the growth of epithelial cells for tissue engineering.
Collaborator Contribution They have provided different samples of meshes to test
Impact Collaboration has recently started, analysis of the data is not yet available
Start Year 2017
 
Description Bladder Augmentation with bladder conformer 
Organisation GC Aesthetics
Country Ireland 
Sector Private 
PI Contribution We have been testing various conformers for identifying the most appropriate
Collaborator Contribution They have provided different samples
Impact Collaboration recently started
Start Year 2017
 
Description J& J Improvement on cell lifting with synthetic mesh 
Organisation Johnson & Johnson
Country United States 
Sector Private 
PI Contribution We have been testing various materials for identifying the most suitable mesh
Collaborator Contribution They have provided different samples of meshes to test
Impact Collaboration has recently started, analysis of the data is not yet available
Start Year 2016
 
Description 27th ESPU Congress Harrogate 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to give a lecture.
Year(s) Of Engagement Activity 2016
 
Description GOSH Charity visit 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact Around 10 employees of the GOSH Charity -fundraise section- visited our laboratory to learn about the ongoing projects. The information they gathered were then conveyed to donors through the Charity's communication channels in order to keep donors' updated and possibly attract new benefactors.
Year(s) Of Engagement Activity 2019
 
Description Invited talk at conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact "A new regenerative medicine approach for urinary incontinence" presented at Incontinence: the Engineering Challenge XI Conference, Institution of Mechanical Engineers, London.
Year(s) Of Engagement Activity 2017
URL http://events.imeche.org/ViewEvent?code=CON6475
 
Description Plenary speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact presentation to a national multidisciplinary network for incontinence research working to showcase the difficulties of dealing with this condition as a way of drawing together scientific experts, facilitating new research collaborations and inspiring novel ideas for next generation treatments.
Year(s) Of Engagement Activity 2016
 
Description Presentation at World Stem Cell Summit, Miami 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The 2018 World Stem Cell Summit is the global, super-ecosystem event, trans-disciplinary in scope. The Summit is designed to breakdown silos, expand your knowledge and forge collaborations, with the overarching collective goal to improve health and deliver cures. I was invited to deliver a talk on tissue engineering oesophagus in front of other scientists, patients and representative of major industry partners.
Year(s) Of Engagement Activity 2018
URL http://www.worldstemcellsummit.com/
 
Description Presentation to BAPS-IPEG Conference 2017 (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation was made in an international conference with attendees coming from various parts of the world. There have been questions at the end of the presentation and comments were made about the importance of the topic presented.
Year(s) Of Engagement Activity 2017
URL http://congress.baps.org.uk/news/whats-new/baps-ipeg-in-london-2017/
 
Description Presentation to ESPU Conference 2016 (Harrogate) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We presented part of the results achieved during the awarded grant in an international medical conference (European Society for Paediatric Urologist)
Year(s) Of Engagement Activity 2016
URL https://www.espu.org/events/calendar/eventdetail/6/-/
 
Description Presentation to ESPU Conference 2019 (Lyon) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact We presented part of results achieved during the awarded grant to an international conference (European Society for Pediatric Urology)
Year(s) Of Engagement Activity 2019
URL https://congress2019.espu.org/
 
Description Presentation to EUPSA Conference 2016 (Milan) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We presented part of results achieved during the awarded grant to an international conference (European Pediatric Surgery Association)
Year(s) Of Engagement Activity 2016
 
Description Presentation to EUPSA Conference 2018 (Paris) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We presented part of results achieved during the awarded grant to an international conference (European Pediatric Surgery Association)
Year(s) Of Engagement Activity 2018
URL https://www.chirpediatric.fr/upload/documents/congres_2018/EUPSA_2018/SCIENTIFIC-PROGRAM-EUPSA-PARIS...
 
Description Presentation to HYMS MedTech Society & York Surgical Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact "Fit-for-purpose Tissue Engineering of the Urinary Bladder" invited presentation to HYMS MedTech Society & York Surgical Society (recorded).
Year(s) Of Engagement Activity 2018
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public lecture to University of Huddersfield.
Year(s) Of Engagement Activity 2017
URL http://www-old.hud.ac.uk/events/?view=fulltext&month=11&day=1&year=2017&id=d.en.224960×tamp=151...
 
Description Regenerative Biology and Applications: Cell Differentiation, Tissue Organization and Biomedical Engineering (T3) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This four-day Keystone Symposia conference focuses on three important aspects of the rapidly developing area of regenerative biology: 1) The biology of the stem cell, with a focus on single-cell transcriptomics, deduction of cell lineage, pluripotency control and epigenetic regulation; 2) The tissue level, including the stem cell niche, organ generation, organoids and dysregulation of these processes in disease; and 3) Biomedical engineering and various types of disease modeling. Focusing on these three particular areas I have provided insights into research fields where progress currently occurs in regenerative medicine.
Year(s) Of Engagement Activity 2017
URL http://www.keystonesymposia.org/18T3
 
Description Talk and visit to laboratories 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact York Festival of Ideas. Talk and lab tour of the Jack Birch Unit enabling the public to find out more about 'how science works'.
Year(s) Of Engagement Activity 2018
 
Description Talk at PICU - Renal study day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presentation to postgraduate student as part of a teaching day
Year(s) Of Engagement Activity 2017,2018
 
Description Talk to Medical School Student Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Talk to medical school students - recorded and made available via the web.
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/HYMSMedTech/photos/d41d8cd9/2259640517696484/
 
Description Talk to Surgical Sixty Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk to Surgical Sixty Club
Year(s) Of Engagement Activity 2016
 
Description Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Workshop on basic science to a trainee clinical audience at the European Society for Paediatric Urology, Harrogate.
Year(s) Of Engagement Activity 2016
 
Description ZCR donor stewardship event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact The purpose of this event is to showcase to a wide panel of charitable donors the scientific activities that takes place at the ZCR. An overview of the project currently ongoing in the laboratory, as well as the main achievements obtained so far, will be given. This will possibly make the audience realise the importance of their contribution, maintain them engaged and gain some new donor.
Year(s) Of Engagement Activity 2020
 
Description public engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Civic visit to the laboratory by Lord Mayor of York and Sheriff plus their partners, with reporter.
Year(s) Of Engagement Activity 2016
 
Description public engagement talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk to York Vikings Rotary Club
Year(s) Of Engagement Activity 2016