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Topoliova, K.; Harsanyi, S.; Danisovic, L.; Ziaran, S. SC and TE Treatment of Neurogenic Bladder Dysfunction. Encyclopedia. Available online: https://encyclopedia.pub/entry/47784 (accessed on 24 June 2024).
Topoliova K, Harsanyi S, Danisovic L, Ziaran S. SC and TE Treatment of Neurogenic Bladder Dysfunction. Encyclopedia. Available at: https://encyclopedia.pub/entry/47784. Accessed June 24, 2024.
Topoliova, Katarina, Stefan Harsanyi, Lubos Danisovic, Stanislav Ziaran. "SC and TE Treatment of Neurogenic Bladder Dysfunction" Encyclopedia, https://encyclopedia.pub/entry/47784 (accessed June 24, 2024).
Topoliova, K., Harsanyi, S., Danisovic, L., & Ziaran, S. (2023, August 08). SC and TE Treatment of Neurogenic Bladder Dysfunction. In Encyclopedia. https://encyclopedia.pub/entry/47784
Topoliova, Katarina, et al. "SC and TE Treatment of Neurogenic Bladder Dysfunction." Encyclopedia. Web. 08 August, 2023.
SC and TE Treatment of Neurogenic Bladder Dysfunction
Edit

Tissue engineering (TE) is a rapidly evolving biomedical discipline that can play an important role in treating neurogenic bladder dysfunction and compensating for conventional options’ shortcomings. 

stem cell tissue engineering neurogenic bladder bladder dysfunction

1. Introduction

The possibility of artificially creating organs has fascinated humans for a long time. Although the use of stem cells in modern medicine probably began with the treatment of myeloproliferative disorders with bone marrow transplantation in 1959, the interest has sparked significantly in the last 25 years, with the main reason being the first successful cloning of the sheep, Dolly, using a somatic cell nuclear transfer technique [1][2]. The related interest in stem cells (SC) and tissue engineering (TE) research allowed for improved and more stable access to funding. SC therapy can potentially revolutionize conventional medicine as we practice it today. TE is an interdisciplinary field that combines stem cells, scaffolds with suitable growth factors, cytokines, and chemokines to improve, replace, or regenerate organs. The self-renewal and differentiation potential of SCs can repair and regenerate damaged tissue in certain conditions.
There are four categories of SCs [3]. Embryonic SCs are undifferentiated SCs that originate from the pre-implantation blastocyst derived from 4–5-day-old human embryos. They have high proliferative capability, but since their harvesting requires human embryo destruction, their use has raised ethical concerns.
Somatic (adult) SCs are undifferentiated SCs in differentiated tissue/organs with limited capacity for differentiation.
Mesenchymal SCs are non-blood adult SCs that can differentiate into different connective tissue cells. They also include cells from, but not limited to, adipose tissue and bone marrow.
Induced pluripotent SCs are adult SCs that are reverted to pluripotent SCs by the introduction of certain transcription factors (Oct4, Sox2, Klf4, and Myc). They turn into patient-specific SCs [4].
In recent decades, there has been relevant research aiming at SC therapy in several chronic urological conditions for which conventional therapy is unsatisfactory.
Although the ability of SCs to repair diseased tissue has been proven in other fields, such as ophthalmology, the biological complexity of human organs was initially underestimated, and the clinical translation of SC therapy to human disease was only successful after more than 2 decades of intense research [5]. As of today, the main challenge of SC therapy and TE remains their questionable competitiveness in relation to conventional therapy when it comes to effectiveness, cost-effectiveness, and potential adverse effects.
Because the urinary tract is easily accessible via endoscopy, and due to relatively low rates of morbidity, urology remains at the top of the fields of technological innovation in medicine.
The main breakthroughs come from the application of SC therapy in animal models of bladder dysfunction, stress urinary incontinence (SUI), erectile dysfunction, and urethral injury [6][7][8][9][10][11][12].

2. SC and TE Treatment of Neurogenic Bladder Dysfunction (NBD)

Neurogenic bladder is a collective term for disorders of the storage or excretory functions of the bladder that have neurological etiologies. These disorders can result in incontinence, urine retention, or their combination. The clinical manifestation depends on the lesion’s location and relationship to the CNS’s urinary centers. The most common causes of NBD are spinal cord injury (SCI), multiple sclerosis (MS), Parkinson’s disease (PD), and stroke.
NBD can lead to various health conditions that may greatly affect the quality of life for the patient as a source of embarrassment, discomfort, and social isolation. Aside from the inability to control urination, the NBD can lead to other severe consequences connected to urinary retention like urinary tract infections (UTIs—the inability to empty the bladder fully can cause stagnant urine to accumulate, which increases the risk of UTIs); kidney damage (if the urine backs up into the kidneys, it can cause damage to the delicate kidney tissue, leading to chronic kidney disease and even kidney failure (hydronephrosis); and bladder stones (stagnant urine in the bladder can lead to the formation of bladder stones, which can cause pain, discomfort, and urinary tract infections). Apart from issues related to urinary incontinence and retention, a neurogenic bladder may also lead to autonomic dysreflexia (a sudden and severe increase in blood pressure, which is a potentially life-threatening condition that can occur in people with spinal cord injuries) [13].
Management strategies for NBD include conservative methods (lifestyle changes, bladder retraining, and pelvic floor muscle training), pharmacological (anticholinergics and β-adrenoceptor agonists), and nonpharmacological approaches (electrical stimulation, clean intermittent catheterization, and indwelling catheters), and surgical interventions (augmentation cystoplasty) [14][15].
Despite the existing conventional therapies, improvement in voiding dysfunction has not been fully achieved and is accompanied by several side effects [16][17][18][19]. Due to the known side effects, there is a demand for alternative therapy treatments, such as SC therapy and TE. The potential of self-renewal, multilineage differentiation, site-specific migration, and tissue regeneration made SC a beneficial therapeutic tool in the treatment of several types of complications such as degenerative diseases [20]. Based on the results from previous experiments, SC transplantation is used in the management of neuro-urological diseases and is accompanied by promising outcomes [21].
As of today, there are several SC and TE approaches being investigated for bladder repair and regeneration:
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Scaffold-based approaches: These approaches involve the use of biodegradable scaffolds to support the growth and differentiation of cells [22][23][24]. Scaffold-based approaches may be further differentiated based on whether the approach uses a scaffold seeded with cells (seeded scaffold approaches) or a scaffold not seeded with cells (scaffold alone approaches). Furthermore, the seeded scaffold approaches may be generally divided into scaffolds seeded with the patient’s cells (autologous cells, such as urothelial cells and smooth muscle cells, which are implanted into the bladder to promote tissue regeneration) and scaffolds seeded with other cells (allogeneic cells, which are obtained from a donor who is genetically different from the patient but which are from the same species or xenogeneic cells obtained from a donor of a different species). Seeding a scaffold refers to the process of introducing cells onto or into the porous structure of the scaffold, with the scaffold acting as a framework or support structure for the cells to become the desired tissue type.
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Cell-based approaches: These approaches involve the use of SCs or other cell types to either generate new bladder tissue (using SCs in scaffold-based approaches as mentioned above via seeding). Alternatively, SCs may be used without a scaffold by directly transplanting them via an injection to enhance regeneration. Researchers are exploring the use of different types of stem cells, including mesenchymal stem cells, induced pluripotent stem cells (iPSCs), and bladder progenitor cells, for bladder repair and regeneration [21][25][26].
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Gene therapy approaches: These approaches involve the use of gene therapy to promote bladder regeneration. Researchers are investigating the use of growth factors and other genes that can stimulate the growth and differentiation of bladder cells [27][28].
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3D printing approaches: These approaches involve the use of 3D printing technology to create custom-made bladder scaffolds that can support the growth and differentiation of cells [29][30].
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Neural stem cell transplantation: Neural stem cells can be transplanted into the bladder to generate new nerve cells. These cells can be obtained from the patient’s own body or from a donor. The transplanted cells can differentiate into new nerve cells and integrate into the existing neural network in the bladder, restoring bladder function [31].
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iPSC therapy: iPSCs can be differentiated into various cell types, including nerve cells. These cells can then be transplanted into the bladder to replace the damaged nerves [32].

3. Examining the Potential of TE and SC Treatment of Neurogenic Bladder (NGB)

One of the main challenges in the TE of bladder tissue is creating functional urothelial and smooth muscle layers. In this regard, SCs, including neural SCs and mesenchymal SCs, have shown potential for the regeneration of bladder tissues. Neural SCs can differentiate into multiple cell types, including smooth muscle cells and urothelial cells, while mesenchymal stem cells can differentiate into smooth muscle cells and provide trophic support to promote tissue repair and regeneration. Scaffold-based approaches are also being investigated for the TE of bladder tissues. These approaches involve the use of porous biomaterials as a scaffold to support the growth and differentiation of cells into functional bladder tissues. Additionally, advances in 3D printing technology have allowed for the creation of patient-specific bladder constructs, which can be tailored to the specific needs of each patient.
TE has been explored in pediatric urology as an alternative to enterocystoplasty for the management of NBD by utilizing biodegradable scaffolds, either unseeded or seeded with primary cells, in both animal models and clinical trials [33][34][35][36][37]. Synthetic materials that have been tested in experimental and clinical settings include polyvinyl sponges, Teflon, collagen matrices, Vycryl (PGA) matrices, and silicone; however, most of them failed because of mechanical, structural, functional, and biocompatibility issues. It was soon clear that non-biodegradable synthetic scaffolds used for bladder reconstruction are usually prone to mechanical failure and urinary stone formation, while biodegradable ones can lead to fibroblast deposition, scarring, graft contracture, and reduced reservoir volume over time, especially in a non-seeded configuration. Consequently, studies were then mainly focused on biodegradable scaffolds (bladder submucosa, collagen and polyglycolic acid, small intestinal submucosa, bladder acellular matrix, amniotic membrane, etc.) for urinary bladder reconstruction, eventually involving the use of seeded cells to enhance tissue regeneration. To date, several types of scaffolds and cells have been evaluated to reconstruct the urinary bladder, but various animal models and surgical repairs have also been investigated [38].
Although the ideal solution is yet to be found, biodegradability seems to be a crucial feature, especially in the pediatric field. Additionally, if urothelial regeneration can be more easily obtained, muscle, nerve, and vascular regeneration cannot be achieved without the pre-seeding of a scaffold, eventually combining the use of specific growth factors. Consequently, it became clear that scaffolds working well in healthy urinary tissues could not necessarily be as effective in a diseased model in which the cells that would populate the graft were generally abnormal. Therefore, the main measure of success for the scaffold should be to demonstrate not only tissue layer regeneration but also its ability to improve the capacity and compliance of the bladder. Minimizing the effects of congenital malformations of the urinary tract remains a challenge [39].
Despite the progress made in urological TE, several issues still have to be faced in order to improve the results in terms of muscle regeneration, the limitation of complications, and the functional restoration of the urethra and urinary bladder, especially in the case of pediatric patients [22]. Future challenges lie in resolving several factors including the mechanical properties of the graft (with the intention to mimic the structure, biomechanics, and physiology of a natural bladder), the size of the graft (the consistency of reporting graft sizes in research is lacking, and extensive cell regeneration tends to occur in the peripheral area of the graft, while the regeneration in the center is not necessarily sufficient), the vascularization of the graft (difficulties in the neovascularization of larger grafts), the fibrotic reaction of the graft (the implantation of bladder scaffolds typically triggers a fibrotic reaction), and the innervation of bioengineered bladders (although patients with neurogenic bladder undergo bladder augmentation, in order to expand urinary bladder capacity and decrease bladder pressure) [40].

References

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