Stefanovic V. Tissue engineering of the urinary bladder: current concepts and future perspectives

There are many conditions that can affect the normal structure of the urinary bladder wall and lead to the inadequate evacuation of urine or even disable urine excretion. In these cases, the essential task is to restore the function of the urinary bladder, most often through surgical intervention. Some of the disorders, such as bladder acontractility, bladder cancer, and inflammatory disease, represent a great challenge in practice due to the number of complications that can occur after the intervention and due to frequent relapses. The use of tissue engineering strategies that include the use of stem cells and artificially created scaffolds could give solutions for treatment of many disorders of the urinary bladder and transplantation therapies in the future. Although the research in this field is still in its infancy, there are some promising results that raise hope that the tissue engineering approach could offer long-term solutions for many issues in regenerative urology. This review summarizes the current achievements and perspectives in the use of stem cells and tissue engineering techniques in the field of urinary bladder regeneration. KEYWORDS: urinary bladder, tissue engineering, stem cells INTRODUCTION The increasing need for organ regeneration/replacement imposes the development of new techniques that would be introduced in clinical practice. Tissue engineering and regenerative medicine could contribute to the treatment of many disorders in urology. Although there is an increased number of published studies in animals and a few studies in humans, with very promising results, many of these novel techniques are still being investigated. The field of regenerative medicine is advancing rapidly, so the use of tissue engineering strategies that include the use of stem cells and artificially created scaffolds represent the most probable solution for treatment of many urological disorders and transplantation therapies in the future. METHODS IN BLADDER REGENERATION Today, the most common approach for bladder replacement or repair comprises the use of gastrointestinal segments. However, due to differences in the functions of these two tissues, numerous complications may Petrovic et al.: Tissue Engineering of the Urinary Bladder TheScientificWorldJOURNAL (2011) 11, 1479-1488 1480 occur as a result of such a treatment, including hematuria and dysuria syndrome, metabolic abnormalities, infection, urolithiasis, perforation, and even malignancy The application of tissue engineering strategies by using the appropriate scaffolds and methods for cell culturing was seen by investigators as a possible solution for these problems. So far, the proposed methods for bladder replacement or repair are tissue expansion for bladder augmentation, use of seromuscular grafts and de-epithelialized bowel segments, as well as the use of tissue engineering strategies Augmentation of the Bladder The treatment of the small-capacity, high-intravesical storage pressure urinary bladder remains a major challenge in urology. Many techniques have been proposed to increase bladder capacity and decrease intravesical pressure. Some of them, such as gastrocystoplasty, colocystoplasty, and ileocystoplasty, are routinely performed in clinical practice, but are related with various complications that may occur postoperatively Some experiments performed on animals where augmentation cystoplasty was performed with dilated ureteral segments or by causing progressive expansion of native bladder tissue showed promising results. The subsequent urodynamic, histological, and immunocytochemical studies showed that the compliance, structure, and normal phenotypic characteristics of the cells were maintained, while the bladder capacity was significantly increased Seromuscular Grafts and De-Epithelialized Bowel Segments The use of seromuscular grafts and de-epithelialized bowel segments has also been the subject of investigation, bearing in mind that this approach avoids the use of intestinal mucosa, and, therefore, keeps the urothelium intact. In that way, the complications associated with the use of the bowel in continuity with the urinary tract could be avoided González et al. reported that seromuscular colocystoplasty lined with urothelium has proved to be an effective method to augment the bladder in patients who have an artificial urinary sphincter or who undergo simultaneous artificial urinary sphincter implantation The benefit of gastric seromuscular flaps was also investigated in a rat model. A gastric seromuscular flap based on an omentum pedicle was transferred to the rat bladder. The results showed that the use of the gastric seromuscular flap in the bladder of a rat resulted in the complete re-epithelialization of the flap and sufficient bladder capacity. However, squamous metaplasia was detected in 30% of the 1-month rats and in 55% of the 4-month rats, as well as the formation of gross calculi in 20% of the 1-month rats and Petrovic et al.: Tissue Engineering of the Urinary Bladder TheScientificWorldJOURNAL (2011) 11, 1479-1488 1481 in 34% of the 4-month rats Tissue Engineering and the Urinary Bladder Tissue engineering is a multidisciplinary field involving biology, medicine, and engineering, with the main goal to restore, maintain, or enhance the function of tissues and organs There are two approaches in tissue engineering. The acellular approach involves the use of natural or synthetic matrices (scaffolds) to enhance the body's natural ability to repair itself and help in the determination of new tissue growth direction. The cellular approach principle is to use donor cells that are either seeded into the scaffold (cell-seeded scaffold approach) or used alone (the stem cell approach). The source of cells in cell-seeded scaffolds can be from an autologous, allogeneic, or heterologous (xenogeneic) source. The best option is to use autologous cells in order to eliminate the risk of rejection There are many conditions that can affect the normal structure of the urinary bladder wall and lead to the inadequate evacuation of urine or even disable urine excretion. In these cases, the essential task is to restore the function of the urinary bladder, most often through surgical interventions. Some of the disorders, such as bladder acontractility, bladder cancer, and inflammatory disease, represent a great challenge in practice due to the number of complications that can occur after the intervention and due to frequent relapses. The need to find stable and long-term therapeutic strategies that would resolve these problems incited the increased interest in the field of tissue engineering. The current therapies cannot give the desired results because of their limitations. Patients with acontractile bladders that can occur as a complication from lower motor neuropathies, severe diabetes, or chronic obstruction often require intermittent catheterizations. Bladder cancer as well as inflammatory diseases of the urinary bladder lead to extensive cell damage, so in these patients, autologous cell harvesting is not possible Some promising results in the research and use of stem cells and biomaterials in the regeneration of urinary tissues raised a lot of hope, but also a lot of questions that need to be resolved before their widespread use. The current efforts are oriented in two directions. The first is to find the most appropriate stem cells for bladder regeneration and to master their manipulation and control. The second is to design implantable tissue-engineered grafts that display characteristics consistent with the physiology and function of the equivalent healthy native tissue BIOMATERIALS Scaffolds are constructs that are designed to support cell growth and to provide the accurate tissue architectonic regeneration during the process of healing. Also, the scaffolds can be used as carriers for different growth factors that could enhance the regenerative process. The scaffolds used in bladder tissue regeneration are decellularized natural matrices and synthetic scaffolds. The decellularized natural matrices can be harvested from autologous, allogeneic, or xenogeneic tissues, and are processed by chemical and mechanical means in order to remove cellular components for eventual implantation Petrovic et al.: Tissue Engineering of the Urinary Bladder TheScientificWorldJOURNAL (2011) 11, 1479-1488 1482 as a matrix in bladder tissue regeneration There have been attempts to use many different materials as synthetic scaffolds for urinary bladder regeneration. The most used of these materials in experiments and clinical trials were polyvinyl sponges, Teflon, collagen matrices, Vicryl (PGA, polyglycolic acid) matrices, and silicone. However, these materials failed to successfully regenerate the bladder tissue due to mechanical, structural, functional, or biocompatibility problems Use of Unseeded Matrices in Bladder Tissue Engineering The matrices serve as vehicles for partial bladder regeneration, and one of their major advantages is that they do not display relevant antigenicity. The matrices are prepared by mechanically and chemically removing all cellular components from tissue A successful regeneration of a mouse bladder by implanting a decellularized bladder matrix scaffold impregnated with fibroblast growth factor was obtained In one study, a heterologous and homologous bladder acellular matrix graft and the influence of collagen ratio on the regeneration of function in a dog model was compared. The homologous graft led to more complete regeneration, whereas collagen seemed not to be replaced in the heterologous model, but changed over time. It is possible that the ratio of collagen types seemed to influence smooth muscle regeneration The normal regeneration of the urothelial layer was observed in many studies where the unseeded grafts were used for cystoplasty, while the muscle layer never fully developed 1483 Use of Cell-Seeded Matrices in Bladder Tissue Engineering The use of cell-seeded allogeneic bladder matrices has also shown some positive results in bladder regeneration. The study performed on beagle dogs compared the effects of the use of allogeneic acellular matrices obtained from bladder submucosa that were seeded with urothelial and muscle cells obtained from the cystotomy material of five beagle dogs with the unseeded matrices of the same origin. Fluoroscopic and urodynamic tests performed after 2-3 months showed normal bladders and adequate compliance in all cases. Bladders treated with seeded matrices showed a 99% increase in capacity compared to those treated with the acellular matrix, which showed only a 30% increase in capacity. All bladders showed a normal histological structure; however, a larger muscle layer and more nervous fibers were found in the bladders of beagle dogs treated with cell-seeded matrices Eweida et al. showed positive effects of a urinary bladder matrix (UBM) seeded with keratinocytes in wound healing in the urinary bladder In another study, PGA acellular matrices seeded with urothelial and smooth muscle cells harvested from a suprapubic transmural bladder biopsy were used in beagle dogs after subtotal cystectomy, preserving only the trigone. The control groups consisted of dogs that underwent simple closure of the bladder or bladder reconstruction with a cell-free matrix. The bladders of the dogs treated with PGA acellular matrices seeded with urothelial and smooth muscle cells showed a mean bladder capacity of 95% of the preoperative capacity, compared to the other two groups that showed 20% (treated with simple closure of bladder) and 46% (treated with cell-free matrix). The compliance of the cell-seeded, tissue-engineered bladders was almost no different from preoperative values (106%), compared to the two other groups (10 and 42% total compliance, respectively). The histological and immunohistochemical studies showed a normal three-layer bladder histology in groups of the cell-seeded, tissue-engineered bladders and bladders that underwent simple closure, while there was pronounced fibrosis in bladders treated with the cell-free matrix A small clinical trial with seven patients suffering from neurogenic bladder was reported. The patients underwent augmentation cystoplasty with acellular matrices seeded with in vitro-expanded urothelial and smooth muscle cells. The patients received acellular bladder submucosa matrices or collagen-PGA composite matrices, some with full omental coverage and some without. The use of collagen-PGA cellseeded scaffolds with omental coverage showed beneficial effects on patients. The most important of these effects were increased compliance and capacity, decreased end-filling pressures, as well as longer dry periods. Biopsies revealed a normal histological structure. The complications related to enterocystoplasty did not appear. This study demonstrated the possibility of using engineered tissue substitutes for partial hollow organ replacement in humans, thus avoiding the need for intestinal substitutio

Tissue Engineering of the Urinary Bladder: Current Concepts and Future Perspectives

There are many conditions that can affect the normal structure of the urinary bladder wall and lead to the inadequate evacuation of urine or even disable urine excretion. In these cases, the essential task is to restore the function of the urinary bladder, most often through surgical intervention. Some of the disorders, such as bladder acontractility, bladder cancer, and inflammatory disease, represent a great challenge in practice due to the number of complications that can occur after the intervention and due to frequent relapses. The use of tissue engineering strategies that include the use of stem cells and artificially created scaffolds could give solutions for treatment of many disorders of the urinary bladder and transplantation therapies in the future. Although the research in this field is still in its infancy, there are some promising results that raise hope that the tissue engineering approach could offer long-term solutions for many issues in regenerative urology. This review summarizes the current achievements and perspectives in the use of stem cells and tissue engineering techniques in the field of urinary bladder regeneration