Regenerative Medicine in Bladder Reconstructive Surgery☆
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.
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Cited by (1)
Use of an acellular collagen-elastin matrix to support bladder regeneration in a porcine model of peritoneocystoplasty
2018, Central European Journal of Urology
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