Regenerative Medicine in Bladder Reconstructive Surgery

https://doi.org/10.1016/j.eursup.2016.10.005Get rights and content

Abstract

This article explores the options for bladder reconstructive surgery and the role of regenerative medicine and tissue engineering. The indications for bladder reconstructive surgery are explored to complement medical management, which remains the first line for bladder dysfunction. Different strategies for research in tissue engineering of the bladder are discussed.

Patient summary

Options for bladder reconstructive surgery are discussed, including regenerative medicine and tissue engineering.

Introduction

The bladder is a complex organ with specialised functions of storage and volitional voiding of urine mediated by spinal reflex mechanisms involving sympathetic and parasympathetic neural pathways, respectively [1], [2], [3].

Storage of urine delivered by the kidneys is combined with maintaining its electrolyte composition via passive permeability and active ion transport [4]. The urothelium separates the bladder muscle from the urine and has mechanosensory attributes, and thus responds via endocytosis and exocytosis to physical and chemical changes such as intravesical pressure and urinary electrolytes [5], [6].

Section snippets

Bladder dysfunction and its consequences

The pattern of normal reflex voiding can be disturbed by bladder and/or sphincter dysfunction. Any structural, neurogenic, or functional abnormality of the bladder, structural or functional outflow obstruction, or abnormal uroflow dynamics, as in severe vesicoureteric reflux, can have significant consequences along the entire urinary tract [7], [8], [9]. Some of these anomalies, such as posterior urethral valves [10], [11], myelodysplasia, sacral agenesis, spinal tumours, and exstrophy of the

Bladder augmentation

Urothelial-based strategies for augmentation include ureterocystoplasty (UC) and detrusorotomy with or without a seromuscular colonic patch (autoaugmentation, AA). UC is only appropriate in selected clinical scenarios and is not an option in most circumstances [27], [28], [29], [30]. AA needs to be performed early to be effective and concerns regarding failure with limited success have been reported in isolated series, so AA is not an universally accepted option [31], [32], [33], [34].

Regenerative medicine and the bladder

Regenerative medicine involves diverse areas of tissue engineering, stem cells, and cloning with the common goals of “replacing or regenerating human cells, tissues or organs, to restore or establish normal function” [42]. It offers the possibility to replace old and damaged cells with genetically compatible young and functional cells [43].

Tissue engineering is multidisciplinary and combines the principles of cell transplantation, materials science, and engineering to construct functional

Urothelial tissue engineering

Native urothelium is a quiescent tissue for which the turnover of cells is extremely slow, with few cells if at all in cycle. However, in response to injury, the urothelium adopts a proliferative wound-healing phenotype with high regenerative capacity in attempting to re-establish an effective urinary barrier [46]. This characteristic of the urothelium has been exploited in regenerative medicine laboratories, where urothelium can be freely grown via passaging.

For tissue culture to be considered

Bladder tissue engineering strategies

Most strategies involve the use of a scaffold or matrix to support the development of new tissues. Scaffolds can be natural or synthetic. Natural materials can be in their original form, such as amniotic membrane [48]; in a processed form, such as bladder acellular matrix [49], [50]; or in elemental form, such as collagen [51]. Synthetic scaffolds are typically made of poly-glycolic acid (PGA) or poly-lactic glycolic acid (PLGA) as materials approved by the US Food and Drug Administration [45].

Bioreactor

Urothelial cells in culture are immature, although altering the environment can influence their terminal differentiation. The physical environment is just as important as the chemical conditioning [45]. To improve the biomimetic properties of bladder tissue generated in vitro, the physical environment of the bladder must be simulated [54]. In functional tissue engineering, scaffolds seeded with cells are conditioned in an external bioreactor. The bioreactor manages the physical environment by

Reseeding scaffolds

Oberpenning et al [58] used tissue engineering to create a functional canine de novo bladder. Autologous urothelial cells and SMCs were passaged in vitro and then seeded on either side of a polymer in the shape of a bladder and transplanted over an area above the trigone. The authors claimed that the capacity, compliance, and histology of their neobladder were similar to those of native tissue.

This reseeding approach with engineered urothelial cells and SMC was translated into humans,

Composite cystoplasty

Composite cystoplasty is a different strategy that our group has been working on for a considerable number of years. The idea is to propagate autologous urothelial cells in vitro and then transfer them onto a vascular smooth muscle substrate that has been de-epithelialised. The main difference is that only the urothelium needs to be engineered; the smooth muscle tissue is borrowed from an existing preformed vascularised tissue in vivo. In clinical practice, the smooth muscle component of an

Tissue engineering potential for diseased bladders

In common with all experimental models, tissue engineering methodology is first attempted in animals with normal bladders to establish proof of the principle. Therefore, before any of this work is translated into humans, we need to evaluate the growth potential of urothelium harvested from diseased human bladders and the differentiation capacity of the cells.

Despite considerable progress in the development of robust techniques to culture and differentiate urothelium from surgical samples of

Alternative cell sources

Researchers in tissue engineering continue to search for cell sources with regenerative potential. Those working on the urinary tract have considered, besides the urologic organs, candidate cells from non-urologic tissue and stem cells.

Buccal mucosa is a non-urologic source that has been cultured successfully for use in urethroplasty in particular [69], [70], [71], [72]. Keratinocytes from various sources, including the back of minipigs, foreskin in a rabbit model, and oral mucosa, have been

Conclusions

The treatment options for end-stage bladder disease include bladder augmentation and substitution with alternatives such as bowel. However, the bowel is not structurally or functionally suited to exposure to urine; therefore, it is not surprising that there is a higher risk of infection and of calculi due to mucus production, along with metabolic and cellular changes.

Regenerative medicine offers hope via tissue engineering to develop alternative urothelium-based solutions with or without the

Conflicts of interest

The author has nothing to disclose.

Funding support

None.

References (83)

  • S.V. Perovic et al.

    Augmentation ureterocystoplasty could be performed more frequently

    J Urol

    (2000)
  • E.H. Landau et al.

    Bladder augmentation: ureterocystoplasty versus ileocystoplasty

    J Urol

    (1994)
  • A.E. MacNeily et al.

    Autoaugmentation by detrusor myotomy: its lack of effectiveness in the management of congenital neuropathic bladder

    J Urol

    (2003)
  • P.C. Cartwright et al.

    Bladder autoaugmentation: early clinical experience

    J Urol

    (1989)
  • A.R. Mundy

    Metabolic complications of urinary diversion

    Lancet

    (1999)
  • F. Bolland et al.

    Development and characterisation of a full-thickness acellular porcine bladder matrix for tissue engineering

    Biomaterials

    (2007)
  • C. Akbal et al.

    Bladder augmentation with acellular dermal biomatrix in a diseased animal model

    J Urol

    (2006)
  • H. Baumert et al.

    Terminal urothelium differentiation of engineered neoureter after in vivo maturation in the “omental bioreactor”

    Eur Urol

    (2007)
  • A. Atala et al.

    Tissue-engineered autologous bladders for patients needing cystoplasty

    Lancet

    (2006)
  • R. Subramaniam et al.

    Seromuscular grafts for bladder reconstruction: extra-luminal demucosalisation of the bowel

    Urology

    (2012)
  • R. Subramaniam et al.

    Tissue engineering potential of urothelial cells from diseased bladders

    J Urol

    (2011)
  • S. Bhargava et al.

    Tissue-engineered buccal mucosa urethroplasty — clinical outcomes

    Eur Urol

    (2008)
  • C. Li et al.

    Urethral reconstruction using oral keratinocyte seeded bladder acellular matrix grafts

    J Urol

    (2008)
  • R.N. Yu et al.

    Stem cells: a review and implications for urology

    Urology

    (2010)
  • W.K. Ong et al.

    Adipose-derived stem cells: fatty potentials for therapy

    Int J Biochem Cell Biol

    (2013)
  • Y. Zhang et al.

    Urine derived cells are a potential source for urological tissue reconstruction

    J Urol

    (2008)
  • W.C. De Groat

    Anatomy of the central neural pathways controlling the lower urinary tract

    Eur Urol

    (1998)
  • K.-E. Andersson et al.

    Urinary bladder contraction and relaxation: physiology and pathophysiology

    Physiol Rev

    (2004)
  • C.J. Fowler et al.

    The neural control of micturition

    Nat Rev Neurosci

    (2008)
  • S.A. Lewis

    Everything you wanted to know about the bladder epithelium but were afraid to ask

    Am J Physiol Renal Physiol

    (2000)
  • L.A. Birder et al.

    Is the urothelium intelligent?

    Neurourol Urodyn

    (2010)
  • S.T. Truschel et al.

    Stretch-regulated exocytosis/endocytosis in bladder umbrella cells

    Mol Biol Cell

    (2002)
  • A. Springer et al.

    Relevance of current guidelines in the management of VUR

    Eur J Pediatr

    (2014)
  • M.A. Sargent

    What is the normal prevalence of vesicoureteral reflux?

    Pediatr Radiol

    (2000)
  • H.F. Parkhouse et al.

    Long-term outcome of boys with posterior urethral valves

    Br J Urol

    (1988)
  • C.R. Woodhouse et al.

    Late failure of the reconstructed exstrophy bladder

    Br J Urol

    (1996)
  • C. Verpoorten et al.

    The neurogenic bladder: medical treatment

    Pediatr Nephrol

    (2008)
  • J.-J. Wyndaele et al.

    Clean intermittent catheterization and urinary tract infection: review and guide for future research

    BJU Int

    (2012)
  • L.L. Dyer et al.

    Botulinum toxin-A therapy in pediatric urology: indications for the neurogenic and non-neurogenic neurogenic bladder

    Sci World J

    (2009)
  • S.B. Bauer

    Neurogenic bladder: etiology and assessment

    Pediatr Nephrol

    (2008)
  • P. Mitrofanoff

    Trans-appendicular continent cystostomy in the management of the neurogenic bladder

    Chir Pédiatr

    (1980)
  • Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.

    View full text