Characterization of different carbon nanotubes for the development of a mucoadhesive drug delivery system for intravesical treatment of bladder cancer.
Rieger Christiane,Kunhardt David,Kaufmann Anika,Schendel Darja,Huebner Doreen,Erdmann Kati,Propping Stefan,Wirth Manfred P,Schwenzer Bernd,Fuessel Susanne,Hampel Silke
International journal of pharmaceutics
In order to increase the effectiveness of therapeutics for bladder carcinoma (BCa) treatment, alternative strategies for intravesical applications are needed. The use of carbon nanotubes (CNTs) as basis for a multifunctional drug transporter is a promising possibility to combine traditional chemotherapeutics with innovative therapeutic agents such as antisense oligodeoxynucleotides or small interfering RNA. In the current study four CNT types varying in length and diameter (CNT-1, CNT-2, CNT-3, CNT-4) were synthesized and then characterized with different spectroscopic techniques. Compared to the pristine CNT-1 and CNT-3, the shortened CNT-2 and CNT-4 exhibited more defects and lower aspect ratios. To analyze their mucoadhesive properties, CNTs were exposed to mouse bladders ex vivo by using Franz diffusion cells. All four tested CNT types were able to adhere to the urothelium with a mean covering area of 5-10%. In vitro studies on UM-UC-3 and EJ28 BCa cells were conducted to evaluate the toxic potential of these CNTs. Viability and cytotoxicity assays revealed that the shortened CNT-2 and CNT-4 induced stronger inhibitory effects on BCa cells than CNT-1 and CNT-3. In conclusion, CNT-1 and CNT-3 showed the most promising properties for further optimization of a multifunctional drug transporter.
Advances in intravesical drug delivery systems to treat bladder cancer.
Kolawole Oluwadamilola M,Lau Wing Man,Mostafid Hugh,Khutoryanskiy Vitaliy V
International journal of pharmaceutics
Chemotherapeutic agents administered intravesically to treat bladder cancer have limited efficacy due to periodic dilution and wash-out during urine formation and elimination. This review describes the pathophysiology, prevalence and staging of bladder cancer, and discusses several formulation strategies used to improve drug residence within the bladder. These include the use of amphiphilic copolymers, mucoadhesive formulations, hydrogels, floating systems, and liposomes. Various in vitro and in vivo models recently employed for intravesical drug delivery studies are discussed. Some of the challenges that have prevented the clinical use of some promising formulations are identified.
Polydopamine and peptide decorated doxorubicin-loaded mesoporous silica nanoparticles as a targeted drug delivery system for bladder cancer therapy.
Wei Yi,Gao Li,Wang Lu,Shi Lin,Wei Erdong,Zhou Baotong,Zhou Li,Ge Bo
We reported a simple polydopamine (PDA)-based surface modification method to prepare novel targeted doxorubicin-loaded mesoporous silica nanoparticles and peptide CSNRDARRC conjugation (DOX-loaded MSNs@PDA-PEP) for enhancing the therapeutic effects on bladder cancer. Drug-loaded NPs were characterized in terms of size, size distribution, zeta potential, transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) surface area and drug loading content. In vitro drug release indicated that DOX-loaded MSNs@PDA and MSNs@PDA-PEP had similar release kinetic profiles of DOX. The PDA coating well controlled DOX release and was highly sensitive to pH value. Confocal laser scanning microscopy (CLSM) showed that drug-loaded MSNs could be internalized by human bladder cancer cell line HT-1376, and DOX-loaded MSNs@PDA-PEP had the highest cellular uptake efficiency due to ligand-receptor recognition. The antitumor effects of DOX-loaded nanoparticles were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted nanocarriers DOX-loaded MSNs@PDA-PEP were significantly superior to free DOX and DOX-loaded MSNs@PDA. The novel DOX-loaded MSNs@PDA-PEP, which specifically recognized HT-1376 cells, can be used as a potential targeted drug delivery system for bladder cancer therapy.
Temperature-responsive silk-elastinlike protein polymer enhancement of intravesical drug delivery of a therapeutic glycosaminoglycan for treatment of interstitial cystitis/painful bladder syndrome.
Jensen M Martin,Jia Wanjian,Schults Austin J,Isaacson Kyle J,Steinhauff Douglas,Green Bryant,Zachary B,Cappello Joseph,Ghandehari Hamidreza,Oottamasathien Siam
Interstitial cystitis (IC), also known as painful bladder syndrome, is a debilitating chronic condition with many patients failing to respond to current treatment options. Rapid clearance, mucosal coating, and tight epithelium create strong natural barriers that reduce the effectiveness of many pharmacological interventions in the bladder. Intravesical drug delivery (IDD) is the administration of therapeutic compounds or devices to the urinary bladder via a urethral catheter. Previous work in improving IDD for IC has focused on the sustained delivery of analgesics within the bladder and other small molecule drugs which do not address underlying inflammation and bladder damage. Therapeutic glycosaminoglycans (GAG) function by restoring the mucosal barrier within the bladder, promoting healing responses, and preventing irritating solutes from reaching the bladder wall. There is an unmet medical need for a therapy that provides both acute relief of symptoms while alleviating underlying physiological sources of inflammation and promoting healing within the urothelium. Semi-synthetic glycosaminoglycan ethers (SAGE) are an emerging class of therapeutic GAG with intrinsic anti-inflammatory and analgesic properties. To reduce SAGE clearance and enhance its accumulation in the bladder, we developed a silk-elastinlike protein polymer (SELP) based system to enhance SAGE IDD. We evaluated in vitro release kinetics, rheological properties, impact on bladder function, pain response, and bladder inflammation and compared their effectiveness to other temperature-responsive polymers including Poloxamer 407 and poly(lactic-co-glycolic acid)-poly(ethylene glycol). SAGE delivered via SELP-enhanced intravesical delivery substantially improved SAGE accumulation in the urothelium, provided a sustained analgesic effect 24 h after administration, and reduced inflammation.
Poly(amidoamine)-modified mesoporous silica nanoparticles as a mucoadhesive drug delivery system for potential bladder cancer therapy.
Wang Beilei,Zhang Kebiao,Wang Jiadong,Zhao Ruibo,Zhang Quan,Kong Xiangdong
Colloids and surfaces. B, Biointerfaces
Bladder cancer, with the highest recurrence rate in all malignancy, is a common urologic cancer that arises on the bladder mucosa. Currently, tumor resection followed by intravesical chemotherapy is the primary treatment of bladder cancer, which has limited effectiveness ascribe to short dwell-time of intravesical drugs in bladder. Therefore, there is a need to develop mucoadhesive and sustained drug delivery systems to increase drug residence time for intravesical chemotherapy. In this study, poly(amidoamine) (PAMAM) dendrimers were modified onto the surface of mesoporous silica nanoparticles (MSNPs) through a layer-by-layer grafting method. A series of PAMAM-modified MSNPs were prepared and compared for their mucoadhesive capabilities on pig bladder wall and controlled drug release properties. Results demonstrated an increase in the mucoadhesive capacity of PAMAM-modified MSNPs upon an increase in the number of PAMAM amino groups, and the maximum nanoparticle mucoadhesivity was observed after two-generation PAMAM were grafted on the surface of MSNPs. An antineoplastic, doxorubicin, was encapsulated in the mesopores of PAMAM-modified MSNPs, and the drug-loaded nanoparticles can provide a sustained drug release triggered by acidic pH. The present study demonstrates that the mucoadhesive and drug release properties of MSNPs can be controlled by the layer number of PAMAM dendrimers on the nanoparticle surface, holding significant potential for the development of mucoadhesive drug delivery systems for bladder cancer therapy.
Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer.
Guo Hui,Li Faping,Qiu Heping,Xu Weiguo,Li Pengqiang,Hou Yuchuan,Ding Jianxun,Chen Xuesi
Research (Washington, D.C.)
Intravesical chemotherapy has been recommended after the gold standard of transurethral resection of the bladder tumor to prevent bladder cancer (BC) from local recurrence in the clinic. However, due to rapid urine excretion and barrier protection of the bladder wall, the clinical performances of chemotherapeutic drugs are severely compromised. In the present work, a smart positively charged disulfide-crosslinked nanogel of oligoarginine-poly(ethylene glycol)-poly(L-phenylalanine--L-cystine) (R-PEG-P(LP--LC)) was prepared to prolong the retention period and enhance the penetration capability of chemotherapeutic agent toward the bladder wall. PEG significantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R-PEG-P(LP--LC) (, RNG/HCPT) and enhanced the mucoadhesive capability by the nonspecific interaction between PEG chain and the bladder mucosa accompanied with the electrostatic interaction between the cationic R and negatively charged bladder mucosa. Besides, R, as a cell-penetrating peptide, efficiently penetrated through the cell membrane and delivered carried cargo. The disulfide bond endowed the selective release behavior of HCPT triggered by the intracellular reductive microenvironment. As an advanced chemotherapeutic nanoformulation, the smart RNG/HCPT demonstrated superior cytotoxicity against human BC 5637 cells and remarkably enhanced tumor suppression activity toward orthotopic BC models of mouse and rat , indicating its great potential in the clinical intravesical BC chemotherapy.
Current status of the development of intravesical drug delivery systems for the treatment of bladder cancer.
Yoon Ho Yub,Yang Hee Mang,Kim Chang Hyun,Goo Yoon Tae,Kang Myung Joo,Lee Sangkil,Choi Young Wook
Expert opinion on drug delivery
INTRODUCTION:Intravesical instillation is preferred over the systemic route of administration, as an efficient route of drug administration to treat bladder cancer. However, the periodic voiding of urine washes out the instilled drugs, eventually resulting in reduced drug exposure. Moreover, the presence of the bladder permeability barrier limits drug permeation into tumor tissues. It is therefore important to develop a novel delivery system that not only promotes prolonged retention of drugs in the bladder but also enables drugs to penetrate the barrier. AREAS COVERED:This review addresses the limitations of conventional therapeutic regimens and reports the use of polymeric hydrogels and nano/microcarriers for enhanced intravesical drug delivery in bladder cancer. Strategies to prolong residence time in the bladder and enhance cell penetration and target-cell specificity are discussed. EXPERT OPINION:Although promising results have been obtained in the field of intravesical drug delivery, numerous questions remain unanswered in terms of therapeutic efficacy. Specialized function covering extended drug exposure and/or enhanced drug uptake should be considered. Assessment protocols that adequately mimic the human bladder environment in vitro and in vivo experiments are needed to expedite formulation development.
Biomaterial-assisted drug delivery for interstitial cystitis/bladder pain syndrome treatment.
Lin Zhijun,Hu Hanze,Liu Bolong,Chen Yanyan,Tao Yu,Zhou Xiangfu,Li Mingqiang
Journal of materials chemistry. B
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and painful bladder condition afflicting patients with increased urinary urgency and frequency as well as incontinence. Owing to the elusive pathogenesis of IC/BPS, obtaining effective therapeutic outcomes remains challenging. Current administrational routes such as intravesical-bladder injection improve the treatment efficacy and reduce systemic side effects. However, the bladder permeability barrier hinders drug penetration into the bladder wall to meet the desired therapeutic expectation. These issues can be addressed by encapsulating drugs into biomaterials. When appropriately exploited, they would increase the drug dwelling time in the bladder, enhance the penetration of mucosa and improve the therapeutic response of IC/BPS. In this review, we first elucidate the pathogenesis and animal models of IC/BPS. Then, we highlight recent representative biomaterial-assisted drug delivery systems for IC/BPS treatment. Finally, we discuss the challenges and outlook for further developing biomaterial-based delivery systems for IC/BPS management.
Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery.
Xu Xiaoyan,Goyanes Alvaro,Trenfield Sarah J,Diaz-Gomez Luis,Alvarez-Lorenzo Carmen,Gaisford Simon,Basit Abdul W
Materials science & engineering. C, Materials for biological applications
Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery.
DPPG-based thermosensitive liposomes as drug delivery system for effective muscle-invasive bladder cancer treatment .
Brummelhuis Iris S G,Simons Michiel,Lindner Lars H,Kort Simone,de Jong Sytse,Hossann Martin,Witjes J Alfred,Oosterwijk Egbert
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
PURPOSE:Recommended treatments for muscle-invasive bladder cancer (MIBC) come with considerable morbidity. Hyperthermia (HT) triggered drug release from phosphatidylglycerol-based thermosensitive liposomes (DPPG-TSL) might prevent surgical bladder removal and toxicity from systemic chemotherapy. We aimed to assess the efficacy of DPPG-TSL with HT in a syngeneic orthotopic rat urothelial carcinoma model. METHODS:A total of 191 female Fischer F344 rats were used. Bladder tumors were initiated by inoculation of AY-27 cells and tumor-bearing rats were selected with cystoscopy and semi-randomized over treatment groups. On days 5 and 8, animals were treated with DOX in different treatment modalities: intravenous (iv) DPPG-TSL-DOX with HT, iv free DOX without HT, intravesical DOX without HT, intravesical DOX with HT or no treatment (control group), respectively. Animals were euthanized on day 14 and complete tumor response was assessed by histopathological evaluation. RESULTS:Iv DPPG-TSL-DOX + HT resulted in a favorable rate of animals with complete tumor response (70%), compared to iv free DOX (18%, = .02), no treatment (0%, = .001), and intravesical DOX with (43%, = .35) or without HT (50%, = .41). All rats receiving intravesical DOX with HT and 24% of rats treated with DPPG-TSL-DOX containing the same DOX dose with HT had to be euthanized before day 14 because of substantial bodyweight loss, which was associated with dilated ureters urine retention in a few rats. CONCLUSION:Treatment with DPPG-TSL-DOX combined with intravesical HT outperformed systemic and intravesical DOX . There might be a role for DPPGTSL encapsulating chemotherapeutics in the treatment of MIBC in the future.
Mouse Model to Explore the Therapeutic Effect of Nano-Doxorubicin Drug Delivery System on Bladder Cancer.
Liu Bing,Gao Xiaosong,Han Bing,Chen Guohong,Song Shuqi,Bo Hai
Journal of nanoscience and nanotechnology
To study the therapeutic effect of nano-dosin-loaded drug system in mouse bladder cancer, a luciferase-labeled mouse bladder cancer cell line and a mouse bladder cancer model were constructed. imaging monitors tumor growth and uses a combination of photothermal, immune, and chemotherapy to treat the mouse model. With doxorubicin as an antitumor drug carrier, the drug loading, drug release, cytotoxicity and behavior in cells of mesoporous nano particle-targeted drug delivery system were studied. The cells were injected into the bladder through the urethra, and the mouse bladder cancer subcutaneous model was treated with gelatin-coated single-walled carbon nanotube-encapsulated mouse granulocytes-macrophage colony-stimulating factor and doxorubicin. In the process of using, the use of near-infrared light for irradiation, thereby achieving the combined effect of photothermal, immune and chemotherapy. The experimental results show that the prepared doxorubicin prodrug delivery system can enhance the targeted therapeutic effect and reduce the toxicity and side effects of the drug. Especially for those cancer cells or tissues with overexpression of folate receptors, it has a better therapeutic effect and provides reference for the treatment of subsequent bladder cancer.
Intravesical drug delivery approaches for improved therapy of urinary bladder diseases.
Palugan Luca,Cerea Matteo,Cirilli Micol,Moutaharrik Saliha,Maroni Alessandra,Zema Lucia,Melocchi Alice,Uboldi Marco,Filippin Ilaria,Foppoli Anastasia,Gazzaniga Andrea
International journal of pharmaceutics: X
Diseases of the urinary bladder have high incidence rates and burden healthcare costs. Their pharmacological treatment involves systemic and local drug administration. The latter is generally accomplished through instillation of liquid formulations and requires repeated or long-term catheterization that is associated with discomfort, inflammation and bacterial infections. Consequently, compliance issues and dropouts are frequently reported. Moreover, instilled drugs are progressively diluted as the urine volume increases and rapidly excreted. When penetration of drugs into the bladder wall is needed, the poor permeability of the urothelium has also to be accounted for. Therefore, much research effort is spent to overcome these hurdles, thereby improving the efficacy of available therapies. Particularly, indwelling delivery systems suited for insertion into the bladder through the urethra, intra-organ retention and prolonged release for the desired time lapse, final elimination, either spontaneous or by manual removal, have been proposed to reduce the number of catheterization procedures and reach higher drug levels at the target site. Vesical retention of such devices is allowed by the relevant expansion that can either be triggered from the outside or achieved exploiting elastic and purposely 4D printed shape memory materials. In this article, the main rationales and strategies for improved intravesical delivery are reviewed.
A Bio-Hygromorph Fabricated with Fish Swim Bladder Hydrogel and Wood Flour-Filled Polylactic Acid Scaffold by 3D Printing.
Li Peng,Pan Ling,Liu Dexi,Tao Yubo,Shi Sheldon Q
Materials (Basel, Switzerland)
Non-powered adaptive systems are attractive in the construction of environment actuators, meteorosensitive architectures, biomedical devices, and soft robotics. Combining hydrophilic materials and anisotropic structures to mimic self-morphing plant structures has been demonstrated as an effective approach to creating artificial hygromorphs. The convenience of 3D printing technologies in shaping programmable complex structures facilitates the imitation of complex anisotropic plant structures. In this research, we constructed a bio-hygromorph using fish swim bladder hydrogel as the hydrophilic material and wood flour-filled polylactic acid (WPLA) scaffold, which was printed with fused deposition modeling (FDM) 3D printing technology (3DP). The environmental benign bio-hygromorph displayed morphing abilities triggered by moisture content changes, as the fish swim bladder hydrogel swelled and shrunk during absorption and desorption cycles. The strain disproportion of the two-layered composite structure in the bio-hygromorph drove the bending deformation. Stress analyses performed with finite element analysis (FEA) also revealed the mechanism behind the moisture content driven morphing of the bio-hygromorph. Notably, the bio-hygromorph exhibited faster response times to moisture absorption than desorption, which may donate actuators' different attributes in distinct moisture conditions.
Bladder Regeneration Using a Polycaprolactone Scaffold with a Gradient Structure and Growth Factors in a Partially Cystectomized Rat Model.
Kim Ho Yong,Chun So Young,Lee Eun Hye,Kim Bomi,Ha Yun Sok,Chung Jae Wook,Lee Jun Nyung,Kim Bum Soo,Oh Se Heang,Kwon Tae Gyun
Journal of Korean medical science
BACKGROUND:Tissue engineering can be used for bladder augmentation. However, conventional scaffolds result in fibrosis and graft shrinkage. This study applied an alternative polycaprolactone (PCL)-based scaffold (diameter = 5 mm) with a noble gradient structure and growth factors (GFs) (epidermal growth factor, vascular endothelial growth factor, and basic fibroblast growth factor) to enhance bladder tissue regeneration in a rat model. METHODS:Partially excised urinary bladders of 5-week-old male Slc:SD rats were reconstructed with the scaffold (scaffold group) or the scaffold combined with GFs (GF group) and compared with sham-operated (control group) and untreated rats (partial cystectomy group). Evaluations of bladder volume, histology, immunohistochemistry (IHC), and molecular markers were performed at 4, 8, and 12 weeks after operation. RESULTS:The bladder volumes of the scaffold and GF group recovered to the normal range, and those of the GF group showed more enhanced augmentation. Histological evaluations revealed that the GF group showed more organized urothelial lining, dense extracellular matrix, frequent angiogenesis, and enhanced smooth muscle bundle regeneration than the scaffold group. IHC for α-smooth muscle actin, pan-cytokeratin, α-bungarotoxin, and CD8 revealed that the GF group showed high formation of smooth muscle, blood vessel, urothelium, neuromuscular junction and low immunogenicity. Concordantly, real-time polymerase chain reaction experiments revealed that the GF group showed a higher expression of transcripts associated with smooth muscle and urothelial differentiation. In a 6-month in vivo safety analysis, the GF group showed normal histology. CONCLUSION:This study showed that a PCL scaffold with a gradient structure incorporating GFs improved bladder regeneration functionally and histologically.
Polylactic-co-glycolic acid mesh coated with fibrin or collagen and biological adhesive substance as a prefabricated, degradable, biocompatible, and functional scaffold for regeneration of the urinary bladder wall.
Salem Salah Abood,Hwei Ng Min,Bin Saim Aminuddin,Ho Christopher C K,Sagap Ismail,Singh Rajesh,Yusof Mohd Reusmaazran,Md Zainuddin Zulkifili,Idrus Ruszymah Bt Hj
Journal of biomedical materials research. Part A
The chief obstacle for reconstructing the bladder is the absence of a biomaterial, either permanent or biodegradable, that will function as a suitable scaffold for the natural process of regeneration. In this study, polylactic-co-glycolic acid (PLGA) plus collagen or fibrin was evaluated for its suitability as a scaffold for urinary bladder construct. Human adipose-derived stem cells (HADSCs) were cultured, followed by incubation in smooth muscle cells differentiation media. Differentiated HADSCs were then seeded onto PLGA mesh supported with collagen or fibrin. Evaluation of cell-seeded PLGA composite immersed in culture medium was performed under a light and scanning microscope. To determine if the composite is compatible with the urodynamic properties of urinary bladder, porosity and leaking test was performed. The PLGA samples were subjected to tensile testing was pulled until PLGA fibers break. The results showed that the PLGA composite is biocompatible to differentiated HADSCs. PLGA-collagen mesh appeared to be optimal as a cell carrier while the three-layered PLGA-fibrin composite is better in relation to its leaking/ porosity property. A biomechanical test was also performed for three-layered PLGA with biological adhesive and three-layered PLGA alone. The tensile stress at failure was 30.82 ± 3.80 (MPa) and 34.36 ± 2.57 (MPa), respectively. Maximum tensile strain at failure was 19.42 ± 2.24 (mm) and 23.06 ± 2.47 (mm), respectively. Young's modulus was 0.035 ± 0.0083 and 0.043 ± 0.012, respectively. The maximum load at break was 58.55 ± 7.90 (N) and 65.29 ± 4.89 (N), respectively. In conclusion, PLGA-Fibrin fulfils the criteria as a scaffold for urinary bladder reconstruction.
VEGF-Loaded Nanoparticle-Modified BAMAs Enhance Angiogenesis and Inhibit Graft Shrinkage in Tissue-Engineered Bladder.
Jiang Xincheng,Xiong Qianwei,Xu Guofeng,Lin Houwei,Fang Xiaoliang,Cui Daxiang,Xu Maosheng,Chen Fang,Geng Hongquan
Annals of biomedical engineering
Insufficient angiogenesis is a common problem in bladder tissue engineering and is believed to be a major factor responsible for graft shrinkage. In this study, we investigated the use of bladder acellular matrix allografts (BAMAs) modified with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for the long-term sustained release of VEGF to enhance blood supply and inhibit graft shrinkage in a rabbit model of bladder reconstruction. Rabbits underwent partial bladder cystectomy using a 2 × 3 cm BAMA modified with VEGF-loaded PLGA NPs in the experimental group, while no modification was used in the control. Histology and immunohistochemical analyses showed that urothelium, smooth muscle fibers and blood vessels were formed in both groups at 4 and 12 weeks postoperatively. The microvessel density in the experiment group was significantly higher than that in control and the contracture rate declined to 27%. In vitro functional experiments indicated that the characteristics of regenerated bladders were similar to native bladders. The VEGF release from BAMA in vivo was almost 83% within 3 months. Our data demonstrated the effectiveness of VEGF-loaded PLGA NPs-modified BAMAs to enhance neovascularization and solve the problems of insufficient angiogenesis and graft shrinkage associated with bladder tissue engineering.
Incorporation of Smooth Muscle Cells Derived from Human Adipose Stem Cells on Poly(Lactic-co-Glycolic Acid) Scaffold for the Reconstruction of Subtotally Resected Urinary Bladder in Athymic Rats.
Salem Salah Abood,Rashidbenam Zahra,Jasman Mohd Hafidzul,Ho Christopher Chee Kong,Sagap Ismail,Singh Rajesh,Yusof Mohd Reusmaazran,Md Zainuddin Zulkifli,Haji Idrus Ruszymah Bt,Ng Min Hwei
Tissue engineering and regenerative medicine
BACKGROUND:The urinary tract can be affected by both congenital abnormalities as well as acquired disorders, such as cancer, trauma, infection, inflammation, and iatrogenic injuries, all of which may lead to organ damage requiring eventual reconstruction. As a gold standard, gastrointestinal segment is used for urinary bladder reconstruction. However, one major problem is that while bladder tissue prevents reabsorption of specific solutes, gastrointestinal tissue actually absorbs them. Therefore, tissue engineering approach had been attempted to provide an alternative tissue graft for urinary bladder reconstruction. METHODS:Human adipose-derived stem cells isolated from fat tissues were differentiated into smooth muscle cells and then seeded onto a triple-layered PLGA sheet to form a bladder construct. Adult athymic rats underwent subtotal urinary bladder resection and were divided into three treatment groups (n = 3): Group 1 ("sham") underwent anastomosis of the remaining basal region, Group 2 underwent reconstruction with the cell-free scaffold, and Group 3 underwent reconstruction with the tissue-engineered bladder construct. Animals were monitored on a daily basis and euthanisation was performed whenever a decline in animal health was detected. RESULTS:All animals in Groups 1, 2 and 3 survived for at least 7 days and were followed up to a maximum of 12 weeks post-operation. It was found that by Day 14, substantial ingrowth of smooth muscle and urothelial cells had occurred in Group 2 and 3. In the long-term follow up of group 3 (tissue-engineered bladder construct group), it was found that the urinary bladder wall was completely regenerated and bladder function was fully restored. Urodynamic and radiological evaluations of the reconstructed bladder showed a return to normal bladder volume and function.Histological analysis revealed the presence of three muscular layers and a urothelium similar to that of a normal bladder. Immunohistochemical staining using human-specific myocyte markers (myosin heavy chain and smoothelin) confirmed the incorporation of the seeded cells in the newly regenerated muscular layers. CONCLUSION:Implantation of PLGA construct seeded with smooth muscle cells derived from human adipose stem cells can lead to regeneration of the muscular layers and urothelial ingrowth, leading to formation of a completely functional urinary bladder.
Transplantation of human adipose-derived mesenchymal stem cells on a bladder acellular matrix for bladder regeneration in a canine model.
Hou Xianglin,Shi Chunying,Chen Wei,Chen Bing,Jia Weisheng,Guo Yu,Ma Chao,Ye Gang,Kang Jiuhong,Dai Jianwu
Biomedical materials (Bristol, England)
Tissue engineering brings new hope for the reconstruction of injured bladders. The aim of the present study was to evaluate human adipose-derived mesenchymal stem cells (hADSCs) combined with a bladder acellular matrix (BAM) for bladder regeneration. A BAM or BAM loaded with hADSCs (BAM/hADSCs) was used to repair partial cystectomy of the bladder in a canine model. 6 months after implantation, calculi and urine leakage were not found in either the BAM or BAM/hADSCs group by cystography. And compared to the BAM group, a significant increase of maximum bladder volume and bladder compliance was observed in the BAM/hADSCs group by urodynamics evaluation. Moreover, histological analysis showed that the BAM/hADSCs group could more effectively promote the regeneration of bladder smooth muscle and vascularization than the BAM group. These results demonstrated that a BAM/hADSCs could be an effective approach to promote bladder reconstruction with potential clinical applications.
Urothelium with barrier function differentiated from human urine-derived stem cells for potential use in urinary tract reconstruction.
Wan Qian,Xiong Geng,Liu Guihua,Shupe Thomas D,Wei Guanghui,Zhang Deying,Liang Dan,Lu Xiongbing,Atala Anthony,Zhang Yuanyuan
Stem cell research & therapy
BACKGROUND:Autologous urothelial cells are often obtained via bladder biopsy to generate the bio-engineered urethra or bladder, while urine-derived stem cells (USC) can be obtained by a non-invasive approach. The objective of this study is to develop an optimal strategy for urothelium with permeability barrier properties using human USC which could be used for tissue repair in the urinary tract system. METHODS:USC were harvested from six healthy adult individuals. To optimize urothelial differentiation, five different differentiation methods were studied. The induced cells were assessed for gene and protein expression markers of urothelial cells via RT-PCR, Western blotting, and immunofluorescent staining. Barrier function and ultrastructure of the tight junction were assessed with permeability assays and transmission electron microscopy (TEM). Induced cells were both cultured on trans-well membranes and small intestinal submucosa, then investigated under histology analysis. RESULTS:Differentiated USC expressed significantly higher levels of urothelial-specific transcripts and proteins (Uroplakin III and Ia), epithelial cell markers (CK20 and AE1/AE3), and tight junction markers (ZO-1, ZO-2, E-cadherin, and Cingulin) in a time-dependent manner, compared to non-induced USC. In vitro assays using fluorescent dye demonstrated a significant reduction in permeability of differentiated USC. In addition, transmission electron microscopy confirmed appropriate ultrastructure of urothelium differentiated from USC, including tight junction formation between neighboring cells, which was similar to positive controls. Furthermore, multilayered urothelial tissues formed 2 weeks after USC were differentiated on intestine submucosal matrix. CONCLUSION:The present study illustrates an optimal strategy for the generation of differentiated urothelium from stem cells isolated from the urine. The induced urothelium is phenotypically and functionally like native urothelium and has proposed uses in in vivo urological tissue repair or in vitro urethra or bladder modeling.
Understanding roles of porcine small intestinal submucosa in urinary bladder regeneration: identification of variable regenerative characteristics of small intestinal submucosa.
Lin Hsueh-Kung,Godiwalla Shirley Yezdi,Palmer Blake,Frimberger Dominic,Yang Qing,Madihally Sundar V,Fung Kar-Ming,Kropp Bradley P
Tissue engineering. Part B, Reviews
Neuropathic bladders are the result from damages to the central or peripheral nervous system, and ultimately may require surgical reconstruction to increase bladder volumes and to reduce the risk of damages to the kidneys. Surgical reconstruction through bladder augmentation has traditionally been practiced using a segment of the ileum, colon, or stomach from the patient through enterocystoplasty. However, the use of gastrointestinal segments can lead to serious adverse consequences. Porcine small intestinal submucosa (SIS), a xenogeneic, acellular, biocompatable, biodegradable, and collagen-based bioscaffold is best known to encourage bladder regeneration without ex vivo cell seeding before implantation in various experimental and preclinical animal models. Although it has been demonstrated that SIS supports bladder cell growth in vitro, and SIS-regenerated bladders are histologically and functionally indistinguishable from normal functional tissues, clinical utilization of SIS for bladder augmentation has been hampered by inconsistent preclinical results. Several variables in SIS, such as the age of pigs, the region of the small intestine, and method of sterilization, can have different physical properties, biochemical characteristics, inflammatory cell infiltration, and regenerative capacity due to cellular responses in vitro and in vivo. These parameters are particularly important for bladder regeneration due to its specific biological function in urine storage. Clinical application of SIS for surgical bladder reconstruction may require graft materials to be prepared from a specific region of the small intestine, or to be further formulated or processed to provide uniform physical and biochemical properties for consistent, complete, and functional bladder regeneration.
Surface modification of small intestine submucosa in tissue engineering.
Zhao Pan,Li Xiang,Fang Qin,Wang Fanglin,Ao Qiang,Wang Xiaohong,Tian Xiaohong,Tong Hao,Bai Shuling,Fan Jun
With the development of tissue engineering, the required biomaterials need to have the ability to promote cell adhesion and proliferation and . Especially, surface modification of the scaffold material has a great influence on biocompatibility and functionality of materials. The small intestine submucosa (SIS) is an extracellular matrix isolated from the submucosal layer of porcine jejunum, which has good tissue mechanical properties and regenerative activity, and is suitable for cell adhesion, proliferation and differentiation. In recent years, SIS is widely used in different areas of tissue reconstruction, such as blood vessels, bone, cartilage, bladder and ureter, etc. This paper discusses the main methods for surface modification of SIS to improve and optimize the performance of SIS bioscaffolds, including functional group bonding, protein adsorption, mineral coating, topography and formatting modification and drug combination. In addition, the reasonable combination of these methods also offers great improvement on SIS surface modification. This article makes a shallow review of the surface modification of SIS and its application in tissue engineering.
Application of bladder acellular matrix in urinary bladder regeneration: the state of the art and future directions.
Pokrywczynska Marta,Gubanska Iga,Drewa Gerard,Drewa Tomasz
BioMed research international
Construction of the urinary bladder de novo using tissue engineering technologies is the "holy grail" of reconstructive urology. The search for the ideal biomaterial for urinary bladder reconstruction has been ongoing for decades. One of the most promising biomaterials for this purpose seems to be bladder acellular matrix (BAM). In this review we determine the most important factors, which may affect biological and physical properties of BAM and its regeneration potential in tissue engineered urinary bladder. We also point out the directions in modification of BAM, which include incorporation of exogenous growth factors into the BAM structure. Finally, we discuss the results of the urinary bladder regeneration with cell seeded BAM.
Bi-layer silk fibroin skeleton and bladder acellular matrix hydrogel encapsulating adipose-derived stem cells for bladder reconstruction.
Xiao Shuwei,Wang Pengchao,Zhao Jian,Ling Zhengyun,An Ziyan,Fu Zhouyang,Fu Weijun,Zhang Xu
A scaffold, constructed from a bi-layer silk fibroin skeleton (BSFS) and a bladder acellular matrix hydrogel (BAMH) encapsulated with adipose-derived stem cells (ASCs), was developed for bladder augmentation in a rat model. The BSFS, prepared from silk fibroin (SF), had good mechanical properties that allowed it to maintain the scaffold shape and be used for stitching. The prepared BAM was digested by pepsin and the pH was adjusted to harvest the BAMH that provided an extracellular environment for the ASCs. The constructed BSFS-BAMH-ASCs and BSFS-BAMH scaffolds were wrapped in the omentum to promote neovascularization and then used for bladder augmentation; at the same time, a cystotomy was used as the condition for the control group. Histological staining and immunohistochemical analysis confirmed that the omentum incubation could promote scaffold vascularization. Hematoxylin and eosin and Masson's trichrome staining indicated that the BSFS-BAMH-ASCs scaffold regenerated the bladder wall structure. In addition, immunofluorescence analyses confirmed that the ASCs could promote the regeneration of smooth muscle, neurons and blood vessels and the restoration of physiological function. These results demonstrated that the BSFS-BAMH-ASCs may be a promising scaffold for promoting bladder wall regeneration and the restoration of physiological function of the bladder in a rat bladder augmentation model.
Clinical therapies and nano drug delivery systems for urinary bladder cancer.
Jain Pooja,Kathuria Himanshu,Momin Munira
Pharmacology & therapeutics
Bladder cancer is the 10 most commonly occurring malignancy worldwide with a 75% of 5-year survival rate, while it ranks 13 among the deaths occurring due to cancer. The majority of bladder cancer cases are diagnosed at an early stage and 70% are of non-invasive grade. However, 70% of these cases develop chemoresistance and progress to the muscle invasive stage. Conventional chemotherapy treatments are unsuccessful in curbing chemoresistance, bladder cancer progression while having an adverse side effect, which is mainly due to off-target drug distribution. Therefore, new drug delivery strategies, new therapeutics and therapies or their combination are being explored to develop better treatments. In this regard, nanotechnology has shown promise in the targeted delivery of therapeutics to bladder cancer cells. This review discusses the recent discovery of new therapeutics (chemotherapeutics, immunotherapeutic, and gene therapies), recent developments in the delivery of therapeutics using nano drug delivery systems, and the combination treatments with FDA-approved therapies, i.e., hyperthermia and photodynamic therapy. We also discussed the potential of other novel drug delivery systems that are minimally explored in bladder cancer. Lastly, we discussed the clinical status of therapeutics and therapies for bladder cancer. Overall, this review can provide a summary of available treatments for bladder cancer, and also provide opportunities for further development of drug delivery systems for better management of bladder cancer.
Biomaterials assisted reconstructive urology: The pursuit of an implantable bioengineered neo-urinary bladder.
Urinary bladder is a dynamic organ performing complex physiological activities. Together with ureters and urethra, it forms the lower urinary tract that facilitates urine collection, low-pressure storage, and volitional voiding. However, pathological disorders are often liable to cause irreversible damage and compromise the normal functionality of the bladder, necessitating surgical intervention for a reconstructive procedure. Non-urinary autologous grafts, primarily derived from gastrointestinal tract, have long been the gold standard in clinics to augment or to replace the diseased bladder tissue. Unfortunately, such treatment strategy is commonly associated with several clinical complications. In absence of an optimal autologous therapy, a biomaterial based bioengineered platform is an attractive prospect revolutionizing the modern urology. Predictably, extensive investigative research has been carried out in pursuit of better urological biomaterials, that overcome the limitations of conventional gastrointestinal graft. Against the above backdrop, this review aims to provide a comprehensive and one-stop update on different biomaterial-based strategies that have been proposed and explored over the past 60 years to restore the dynamic function of the otherwise dysfunctional bladder tissue. Broadly, two unique perspectives of bladder tissue engineering and total alloplastic bladder replacement are critically discussed in terms of their status and progress. While the former is pivoted on scaffold mediated regenerative medicine; in contrast, the latter is directed towards the development of a biostable bladder prosthesis. Together, these routes share a common aspiration of designing and creating a functional equivalent of the bladder wall, albeit, using fundamentally different aspects of biocompatibility and clinical needs. Therefore, an attempt has been made to systematically analyze and summarize the evolution of various classes as well as generations of polymeric biomaterials in urology. Considerable emphasis has been laid on explaining the bioengineering methodologies, pre-clinical and clinical outcomes. Some of the unaddressed challenges, including vascularization, innervation, hollow 3D prototype fabrication and urinary encrustation, have been highlighted that currently delay the successful commercial translation. More importantly, the rapidly evolving and expanding concepts of bioelectronic medicine are discussed to inspire future research efforts towards the further advancement of the field. At the closure, crucial insights are provided to forge the biomaterial assisted reconstruction as a long-term therapeutic strategy in urological practice for patients' care.
[Female urinary incontinence: diagnosis and treatment].
Therapeutische Umschau. Revue therapeutique
Female urinary incontinence: diagnosis and treatment Urinary incontinence (UI) is a common condition that may affect women of all ages, with a wide range of severity and nature. Although rarely life threatening, UI may seriously influence the physical, psychological and social wellbeing of affected individuals. The two main types are Stress and Urge Urinary Incontinence. A new and important term is used, the overactive bladder syndrome (OAB), which is defined as urgency that occurs with or without urge UI and usually with frequency and nocturia. Stress Urinary Incontinence (SUI) is the result of weak urethral muscle and support. Urge Urinary Incontinence (UUI) is the result of over active bladder muscle. History and physical examination, including vaginal exam and measuring postvoidal residual volume establish the diagnosis, and a urinary tract infection should be ruled out. Therapy consists of behavioral modification. For SUI pelvic floor physiotherapy (Kegel exercises with or without aid of physical therapist) is important, also, devices such as a pessary or urethral insert can be used. When symptoms persist, surgery (typically a synthetic mesh sling) is indicated. In selected cases, transurethral bulking agent injections can be discussed. For OAB or UUI also physiotherapy as well as medications such as antimuscarinics or the recently released beta-3-adrenoreceptor-agonist Mirabegron are well established. In case of failure intravesical botox application is a good option.
Therapeutic potential of intravesical injections of platelet-rich plasma in the treatment of lower urinary tract disorders due to regenerative deficiency.
Ke Qian-Sheng,Jhang Jia-Fong,Lin Teng-Yi,Ho Han-Chen,Jiang Yuan-Hong,Hsu Yuan-Hsiang,Kuo Hann-Chorng
Ci ji yi xue za zhi = Tzu-chi medical journal
The bladder urothelium plays an important role of barrier function to prevent influx of urinary toxic substance and bacteria. When there is insult to the urinary bladder, the urothelium will start to regenerate on injury. However, several factors might affect the regenerative function of bladder urothelium, including aging, chronic inflammation, and system diseases such as diabetes and chronic kidney diseases (CKDs). Impairment of bladder mucosal regenerative function might result in defective urothelial cell differentiation as well as barrier function, which might be the underlying pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) and recurrent bacterial cystitis. Our previous immunohistochemistry (IHC) study and electron microscopic study revealed that the loss of normal umbrella cells and defective junction proteins in IC/BPS and recurrent cystitis. Platelet-rich plasma (PRP) has been previously used in many medical aspects as regenerative medicine therapy. PRP is rich in many growth factors and cytokines which modulate the process of inflammation and regeneration in the wound healing process. Recent pilot studies have shown that intravesical PRP injections improve IC symptoms and yield a success rate of 70% at 3 months after treatment. The results highly suggest that PRP injection could improve urothelial regenerative function and reduce chronic inflammation in IC patients. This article reviews recently published researches on the urothelial dysfunction biomarkers, urothelial cell differentiation, and urinary regenerative and inflammatory proteins in patients with IC/BPS or recurrent bacterial cystitis. The pathophysiology of the insufficient urothelial regeneration and differentiation; and chronic inflammation may induce urothelial dysfunction and further affect the regenerative ability of the diseased bladder urothelium in IC/BPS and recurrent bacterial cystitis are discussed.
Preclinical Animal Studies of Intravesical Recombinant Human Proteoglycan 4 as a Novel Potential Therapy for Diseases Resulting From Increased Bladder Permeability.
Greenwood-Van Meerveld Beverley,Mohammadi Ehsan,Latorre Rocco,Truitt Edward R,Jay Gregory D,Sullivan Benjamin D,Schmidt Tannin A,Smith Nataliya,Saunders Debra,Ziegler Jadith,Lerner Megan,Hurst Robert,Towner Rheal A
OBJECTIVE:To test in an animal model the hypothesis that recombinant human proteoglycan 4 (rhPRG4; lubricin), a highly O-glycosylated mucin-like glycoprotein, may be a novel surface-active therapeutic for treating bladder permeability with comorbid bowel permeability. Previously we showed that inducing bladder permeability in rats with dilute protamine sulfate (PS) produced colonic permeability and visceral hypersensitivity, suggesting increased bladder permeability could represent an etiologic factor in both interstitial cystitis-bladder pain syndrome and irritable bowel syndrome. METHODS:We used an animal model of catheterized ovariectomized female rats instilled intravesically with 1 mg/mL PS for 10 minutes that after 24 hours were treated with 1.2 mg/mL lubricin or with vehicle alone. After 24 hours the bladder and colon were removed and permeability assessed electrophysiologically with the Ussing chamber to measure the transepithelial electrical resistance. A second set of rats was treated identically, except permeability was assessed on day 3 and on day 5 using contrast-enhanced magnetic resonance imaging with gadolinium diethylenetriamine penta-acetic acid instilled into the bladder. RESULTS:Intravesical lubricin reversed bladder permeability induced by PS and prevented the concomitant increase in permeability induced in the bowel (organ crosstalk). The protective effect was confirmed with magnetic resonance imaging, and because individual rats could be followed over time, the impermeability of the bladder restored by rhPRG4 remained for 5 days. CONCLUSION:These data indicate that instillation of rhPRG4 into a permeable bladder can restore its normally impermeable state, and that the effect lasts for 5 days and also prevents bowel symptoms often comorbid with interstitial cystitis-bladder pain syndrome.
Intravesical electrical stimulation treatment for overactive bladder: An observational study.
Yune J Joshua,Shen Jim K,Pierce Matthew A,Hardesty Jeffrey S,Kim Joo,Siddighi Sam
Investigative and clinical urology
Purpose:Intravesical electrical stimulation treatment (IVES) has been successfully used to treat neurogenic bladder. We report the results of an observational study regarding the use of IVES for women with overactive bladder syndrome (OAB) and/or urgency urinary incontinence (UUI). Materials and Methods:IVES was performed in women with OAB (defined by frequency ≥8/day, nocturia ≥2/night, or ≥3 episodes of UUI on 3-day voiding diary) who failed prior medical therapy. Subjects underwent 4 weeks of treatment with an 8-Fr Detruset™ IVES catheter. Primary outcome was Patient Global Impression of Improvement (PGI-I) at 3 months. Secondary outcomes included Visual Analog Scale (VAS), Short Form OAB Questionnaire (OAB-q SF), Pelvic Floor Distress Inventory (PFDI), Pelvic Floor Impact Questionnaire (PFIQ), reduction in frequency and UUI on voiding diary, and adverse effects. Analysis was done with paired t-tests and Wilcoxon signed rank tests. Results:Seventeen subjects completed the study. At 4 weeks post-treatment, 15 improved on PGI-I (11 subjects: 'a little better', 2: 'much better', 2: 'very much better'). There were significant improvements in symptom bother and health-related quality of life as measured by OAB-q SF and pelvic organ prolapse and urinary distress as measured by PFDI. Frequency decreased from 10.3±4.3 at baseline to 8.9±2.3 (p=0.04) at 3 months. No pain was reported during treatment. There was one urinary tract infection during the study period. No other adverse events were reported. Conclusions:IVES appears to be a safe and effective novel treatment for OAB. Larger comparative studies are needed to investigate its potential for long-term treatment.
A doxorubicin loaded colloidal delivery system for the intravesical therapy of non-muscle invasive bladder cancer using wheat germ agglutinin as targeter.
Apfelthaler Christina,Skoll Katharina,Ciola Raphaela,Gabor Franz,Wirth Michael
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
Non-muscle invasive bladder cancer is one of the most frequent forms of cancer. Commonly, the superficial tumor is removed by a minimal invasive surgery, mostly followed by the intravesical instillation of cytostatic agents. Although the initial treatment is usually successful, the recurrence rate is extraordinary high, which might be grounded in limiting factors during instillation, such as the high resistance of the bladder wall and the constant dilution with the permanently produced urine reducing the probability of interaction between the drug and the target cell. To overcome these limitations, we introduce a lectin-mediated drug delivery system consisting of wheat germ agglutinin as targeter, poly-l-glutamic acid as backbone and the active pharmaceutical ingredient (API) doxorubicin that should prolong the residence time in the bladder cavity. The optimized WGA-PGA-Doxo conjugate revealed an API load of 81 molecules per mole backbone and convinced in urothelial cell monolayer studies with an up to 56-fold higher cell-binding potential than pure doxorubicin. Additionally, the highly substituted drug delivery system not only internalized into urothelial cells, but also inhibited cell viability up to 99%. The combination of the high drug load with the promising cell-associative properties, which also revealed a higher affinity to malignant than to healthy urothelial cells, and the proven cytotoxic potential might lead to an improved efficacy of intravesical chemotherapy.
Methacrylated chitosan as a polymer with enhanced mucoadhesive properties for transmucosal drug delivery.
Kolawole Oluwadamilola M,Lau Wing Man,Khutoryanskiy Vitaliy V
International journal of pharmaceutics
Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties which allow it to adhere to mucosal tissues. In this work, we explored chemical modification of chitosan through its reaction with methacrylic anhydride to synthesise methacrylated derivative with the aim to improve its mucoadhesive properties. The reaction products were characterised using H NMR, FTIR and UV-Vis spectroscopy. H NMR and ninhydrin test were used to quantify the degree of methacrylation of chitosan. Turbidimetric analysis of the effect of pH on aqueous solubility of the polymers revealed that the highly methacrylated derivative remained turbid and its turbidity did not change from pH 3 to 9. However, solutions of native chitosan and its derivative with low methacrylation remained transparent at pH 6.5 and exhibited a rapid increase in turbidity at pH > 6.5. The mucoadhesive properties of chitosan and its methacrylated derivatives were evaluated using flow-through method combined with fluorescent microscopy with fluorescein sodium as a model drug. The retention of these polymers was evaluated on porcine bladder mucosa in vitro. The methacrylated derivatives exhibited greater ability to retain fluorescein sodium on the bladder mucosa compared to the parent chitosan. Toxicological studies using MTT assay with UMUC3 bladder cells show no significant differences in toxicity between chitosan and its methacrylated derivatives suggesting good biocompatibility of these novel mucoadhesive polymers.
Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation, overactivity, and nociception in a chemically induced interstitial cystitis-like rat model.
Furuta Akira,Yamamoto Tokunori,Igarashi Taro,Suzuki Yasuyuki,Egawa Shin,Yoshimura Naoki
International urogynecology journal
INTRODUCTION AND HYPOTHESIS:We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model. METHODS:Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl + MSCs) or phosphate-buffered saline (HCl + PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS). RESULTS:The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2-4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-β, and collagen fibers were observed in HCl + PBS compared with sham + PBS, whereas these changes were significantly decreased in HCl + MSCs compared with HCl + PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl + PBS but not in HCl + MSCs compared with sham + PBS. CONCLUSIONS:The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.
Onabotulinumtoxin-A improves health status and urinary symptoms in subjects with refractory overactive bladder: Real-life experience.
Tamburro Fabiola R,Castellan Pietro,Neri Fabio,Berardinelli Francesco,Bada Maida,Sountoulides Petros,Giuliani Nicola,Finazzi Agrò Enrico,Schips Luigi,Cindolo Luca
OBJECTIVE::Onabotulinumtoxin-A has been approved for wet overactive bladder refractory to anticholinergics in randomised controlled trials; however, data from real-life practice are scarce. This study was designed to assess the efficacy of intravesical onabotulinumtoxin-A injections, focusing on health status, urinary symptoms and subjective satisfaction. METHODS::Data from consecutive patients with overactive bladder-refractory to anticholinergics treated with onabotulinumtoxin-A were prospectively collected and analysed. Standard doses (100-150 U) were used, followed by repeat sessions when clinical benefits diminished. Efficacy and safety of repeat onabotulinumtoxin-A administrations were assessed at 12-week post-injection. Clinical parameters evaluated were: change in the magnitude and frequency of incontinence, urgency and nocturia episodes, change in the number of pads used and procedural complications. Quality of life was evaluated using the 36-Item Short-Form Health Survey, Overactive Bladder Screener and Treatment Benefit Scale questionnaires. RESULTS::Consecutive overactive bladder-refractory to anticholinergics patients ( n = 22) (median duration of oral therapy: 10 months) were enrolled. No intraoperative complications occurred, but two urinary retention cases were recorded. Forty-five percent of patients (10/22) were re-treated (median duration of perceived benefits: 18 months, range: 8-55 months). The number of urinary incontinence, frequency and nocturia episodes, and pads used went from 3.6, 11.3, 2.7 and 2.4 preoperatively to 1.0, 5.8, 0.7 and 0.7 postoperatively ( p < 0.005). Quality of life (36-Item Short-Form Health Survey) was significantly improved and symptom scores (Overactive Bladder Screener) were reduced, from 34.5 to 17.1 at week 12 ( p < 0.05). Eighty-seven percent of patients indicated improvement/great improvement in their condition (Treatment Benefit Scale). CONCLUSION::Intradetrusor injections of onabotulinumtoxin-A in patients with overactive bladder-refractory to anticholinergics significantly improved health status and urinary symptoms, with high subjective satisfaction.
ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk "BCG failure" non muscle invasive bladder cancer: 3 years follow-up outcomes.
Racioppi Marco,Di Gianfrancesco Luca,Ragonese Mauro,Palermo Giuseppe,Sacco Emilio,Bassi Pier Francesco
BACKGROUND:In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the "gold" standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG. METHODS:We carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with "BCG refractory" HGNMIBC on a 3 years follow-up. EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current. EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations. Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract. We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival. RESULTS:At the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease. At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05). Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%). CONCLUSIONS:In the field of alternative strategies to radical cystectomy, the EMDA®-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a "bladder sparing" therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results. TRIAL REGISTRATION:EudraCT2017-002585-43. 17 June 2017 (retrospectively registered).
Paclitaxel/Chitosan Nanosupensions Provide Enhanced Intravesical Bladder Cancer Therapy with Sustained and Prolonged Delivery of Paclitaxel.
Liu Yongjia,Wang Ruibin,Hou Jingwen,Sun Binbin,Zhu Bangshang,Qiao Zhiguang,Su Yue,Zhu Xinyuan
ACS applied bio materials
Bladder cancer (BC) is a very common cancer. Nonmuscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. After postoperative tumor resection, chemotherapy intravesical instillation is recommended as a standard treatment to significantly reduce recurrences. Nanomedicine-mediated delivery of a chemotherapeutic agent targeting cancer could provide a solution to obtain longer residence time and high bioavailability of an anticancer drug. The approach described here provides a nanomedicine with sustained and prolonged delivery of paclitaxel and enhanced therapy of intravesical bladder cancer, which is paclitaxel/chitosan (PTX/CS) nanosupensions (NSs). The positively charged PTX/CS NSs exhibited a rod-shaped morphology with a mean diameter about 200 nm. They have good dispersivity in water without any protective agents, and the positively charged properties make them easy to be adsorbed on the inner mucosa of the bladder through electrostatic adsorption. PTX/CS NSs also had a high drug loading capacity and can maintain sustained release of paclitaxel which could be prolonged over 10 days. Cell experiments demonstrated that PTX/CS NSs had good biocompatibility and effective bladder cancer cell proliferation inhibition. The significant anticancer efficacy against intravesical bladder cancer was verified by an bladder cancer model. The paclitaxel/chitosan nanosupensions could provide sustained delivery of chemotherapeutic agents with significant anticancer efficacy against intravesical bladder cancer.
Mucoadhesive maleimide-functionalised liposomes for drug delivery to urinary bladder.
Kaldybekov Daulet B,Tonglairoum Prasopchai,Opanasopit Praneet,Khutoryanskiy Vitaliy V
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
Intravesical drug administration is used to deliver chemotherapeutic agents via a catheter to treat bladder cancer. The major limitation of this treatment is poor retention of the drug in the bladder due to periodic urine voiding. In this work, maleimide-functionalised PEGylated liposomes (PEG-Mal) were explored as mucoadhesive vehicles for drug delivery to the urinary bladder. The retention of these liposomes on freshly excised porcine bladder mucosa in vitro was compared with conventional liposomes, PEGylated liposomes, two controls (dextran and chitosan), and evaluated through Wash Out (WO) values. PEG-Mal liposomes exhibited greater retention on mucosal surfaces compared to other liposomes. The penetration abilities of conventional, PEG-Mal-functionalised and PEGylated liposomal dispersions with encapsulated fluorescein sodium into the bladder mucosa ex vivo were assessed using a fluorescence microscopy technique. PEGylated liposomes were found to be more mucosa-penetrating compared to other liposomes. All liposomes were loaded with fluorescein sodium salt as a model drug and the in vitro release kinetics was evaluated. Longer drug release was observed from PEG-Mal liposomes.
A lectin mediated delivery system for the intravesical treatment of bladder diseases using poly-(L)-glutamic acid as polymeric backbone.
Apfelthaler Christina,Gassenbauer Patrick,Weisse Sandra,Gabor Franz,Wirth Michael
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
In this study, we present a targeted drug delivery system to improve intravesical therapy of bladder diseases. The drug delivery system consists of wheat germ agglutinin (WGA) to facilitate specific interaction with the surface of bladder cells and α-poly-(L)-glutamic acid (PGA) as polymeric backbone to increase the number of drug molecules per targeting moiety. Additionally, fluorescein cadaverine was coupled to PGA to visualise and track the delivery system. Using 5637 single cells and cell monolayers, the optimised F-PGA-WGA delivery system, with an approximate molecular weight of 670kDa, could convince with its promising cytoadhesive as well as cytoinvasive potential. Using the competitive inhibitor N, N', N″-triacetylchitotriose a specificity of the carbohydrate-mediated interaction between the cell and the delivery system of up to 98% was determined. F-PGA alone did not show any interaction with the cells. Moreover, a high drug loading of 77 molecules of the model drug Dansylcadaverine per backbone was achieved. Microscopic analysis further confirmed binding and uptake of the cytoadhesive polymer even after additional loading with the model drug. Combining the auspicious targeting properties of WGA with the high drug loading possibilities of the backbone might finally lead to an enhanced efficacy when used for intravesical therapy.
Early experimental results of using a novel delivery carrier, hyaluronan-phosphatidylethanolamine (HA-PE), which may allow simple bladder instillation of botulinum toxin A as effectively as direct detrusor muscle injection.
El Shatoury Mohamed Galal,DeYoung Ling,Turley Eva,Yazdani Arjang,Dave Sumit
Journal of pediatric urology
INTRODUCTION:Botulinum toxin A (BTX-A) is a neurotoxin that inhibits acetylcholine release by cleaving cytosolic synaptosome-associated protein 25 (SNAP-25) and results in bladder relaxation. A BTX-A intravesical injection has been established as an effective option for treating detrusor overactivity. STUDY DESIGN:Sixty female Sprague Dawley rats were equally divided into control and experimental groups. Control Groups 1 to 3 received: BTX-A 10 units + saline instillation; hyaluronan-phosphatidylethanolamine (HA-PE) 0.5 g + saline instillation; and BTX-A 5 Uintra-detrusor injections, respectively. Treatment Groups 4 to 6 received: Alexa594-labeled BTX-A 10 U + HA-PE 0.5 g + saline instillation; BTX-A 5 U + HA-PE 0.2-0.5 g instilled for 60 min; and BTX-A 10 U + HA-PE 0.2-0.5 g instilled for 30 min, respectively. All procedures were performed under isoflurane general anesthesia. The primary outcome of this study was the degree of SNAP-25 staining in control and experimental groups compared to Group 3 (detrusor muscle injection). Urodynamic studies were performed at baseline and at day 14 after 1% acetic acid (AA) instillation, to evaluate the maximum pressure during filling (MP) and inter-contraction intervals (ICI). Group 4 rats were examined for Alexa594 fluorescence to demonstrate physical translocation of BTX-A-HA-PE complex. Standard histology was performed to assess the effect of HA-PE on bladder mucosa and detrusor muscle. RESULTS:Group 3 showed the least SNAP-25 staining (7.3 ± 5.0%) compared with all groups except Group 5A (12.4 ± 12.27%, P = 1.0). Group 6A, which had high HA-PE dose but a shorter instillation time, showed fairly extensive SNAP-25 staining (22.9 ± 10%). Confocal microscopy of Group 4 confirmed the presence of Alexa594 fluorescence across the urothelium. Urodynamic parameters were not significantly different at baseline (P = 1.0). After acetic acid instillation, Group 5A showed minimal change in ICI, which was comparable to ICI in Group 3 rats. DISCUSSION:SNAP-25 staining in Group 5A was comparable to Group 3, suggesting that adequate HA-PE and instillation time allows the efficacy of this carrier mechanism to be comparable to standard intra-detrusor injections. All other groups showed significantly higher SNAP-25 staining compared to Group 3. A dose response effect was demonstrated; higher dose of HA-PE (Group 5A vs Group 5B) and longer instillation time (Group 5 vs Group 6) led to lower SNAP-25 staining. CONCLUSION:This novel method of BTX-A delivery to the bladder using a carrier (HA-PE) is promising and requires further investigation. Using a larger animal model, identifying an optimal dose of HA-PE and instillation time, and reproducing the current results are further required to validate this carrier.
Intravesical Electromotive Botulinum Toxin Type "A" Administration for Management of Urinary Incontinence Secondary to Neuropathic Detrusor Overactivity in Children: Long-term Follow-up.
Ladi-Seyedian Seyedeh-Sanam,Sharifi-Rad Lida,Kajbafzadeh Abdol-Mohammad
OBJECTIVE:To investigate the long-term efficacy and success rate of intravesical electromotive botulinum toxin type A (BoNTA) "Dysport" administration in patients with myelomeningocele who had urinary incontinence due to neuropathic detrusor overactivity (NDO). MATERIALS AND METHODS:Twenty-four patients with myelomeningocele (mean age: 9 ± 3.6 years, range: 3-16) were included in the study and followed up for 6 years. Using an electrode bladder catheter, 10 IU/kg of Dysport (BoNTA) was inserted into the bladder for electromotive drug administration (EMDA) without anesthesia on outpatient basis. The EMDA equipment was connected to the electrode of an indwelling catheter and 2 dispersive electrodes, and a pulsed current generator delivered 10 mA for 20 minutes. The preliminary assessments were voiding diary, urodynamic study, kidney and bladder ultrasounds which were also performed annually. RESULTS:Prior to the treatment, all patients had NDO and urinary incontinence. During the follow-up, 18 of 24 (75%), 11 of 24 (45.5%), 9 of 24 (37.5%), 8 of 24 (33%), and 7 of 24 (29.1%) of the patients were completely dry between 2 consecutive clean intermittent catheterizations after once BoNTA-EMDA treatment at 1, 2, 3, 5, and 6 years of follow-up, respectively. The mean maximum detrusor pressure significantly decreased and mean maximal cystometric capacity significantly increased at follow-ups (P <.05). CONCLUSION:The results of the present study have shown that BoNTA-EMDA is a feasible, safe, reproducible, cost-effective, long-lasting, and pain free method on an outpatient basis, with long-term duration of effects without anesthesia or cystoscopy procedure. This novel delivery system resulted in considerable improvement in urinary incontinence and urodynamic study parameters in patients with refractory NDO.
Novel in-situ gel for intravesical administration of ketorolac.
Sherif Abdelrahman Y,Mahrous Gamal Mohamed,Alanazi Fars Kaed
Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society
The urinary bladder stores urine until the time of urination. Systemic administration of drugs to treat bladder diseases faces several limitations. Therefore, intravesical drug delivery is a promising alternative route of administration. An in-situ gel is used to form a gel inside the bladder cavity and ensure continuous release of the drug even after urination. The objective of the present study was to optimize an in-situ gel formulation of poloxamer and chitosan for intravesical delivery of ketorolac tromethamine. The gelling temperature of the prepared combinations ranged from 20.67 to 25.8 °C. In-vitro release of KT was sustained for up to 7 h using a poloxamer concentration ranging from 17% to 19% and a chitosan concentration ranging from 1% to 2%. Design-Expert® 10 was used to select the optimized formulation (poloxamer/chitosan 17/1.589% w/w) which significantly ( < 0.05) extended the drug release more than each polymer alone. An study showed the ability of the optimized formulation to sustain drug release after emptying two times to mimic urination. Furthermore, the formed gel adhered to the bladder tissue throughout the time period of the experiment. Intravesical administration of the optimized formulation to rabbits via catheter showed no obstruction of urine flow and continuous release of the drug for 12 h.
Intravesical electro-osmotic administration of mitomycin C.
Di Stasi Savino M,Verri Cristian,Celestino Francesco,De Carlo Francesco,Pagliarulo Vincenzo
Bladder cancer is very common and most cases are diagnosed as nonmuscle invasive disease, which is characterized by its propensity to recur and progress. Intravesical therapy is used to delay recurrence and progression, while cystectomy is reserved for patients who are refractory to transurethral resection and intravesical therapy. There is an increasing interest in methods to enhance the delivery of intravesical chemotherapeutic agents to improve efficacy. In vitro and in vivo studies demonstrated that electro-osmosis of mitomycin C (MMC) is more effective in delivering this drug into the urothelium, lamina propria, and superficial muscle layers of the bladder wall than is passive transport. Higher MMC tissue concentrations might have a clinical impact in the treatment of nonmuscle invasive bladder cancer (NMIBC). In randomized trials, intravesical electro-osmotic MMC was associated with superior response rate in high-risk NMIBC cancer, compared with passive diffusion MMC transport. New strategies such as intravesical Bacillus Calmette-Guerin (BCG) combined with electro-osmotic MMC as well as intravesical pre-operative electro-osmotic MMC provided promising results in terms of higher remission rates and longer remission times.Device-assisted intravesical chemotherapy may be a useful ancillary procedure in the treatment of NMIBC. Its evaluation must be planned with respect to the technical functioning of equipment and their use for a clear purpose to avoid the financial and human costs associated with incorrect therapies.
Therapeutic Potential of Human Chorionic Gonadotropin Against Painful Bladder Syndrome/Interstitial Cystitis.
Rao C V
Reproductive sciences (Thousand Oaks, Calif.)
Painful bladder syndrome/interstitial cystitis is a debilitating chronic bladder disease that primarily affects women. The disease is due to a damage of urothelial cell lining. As a result, potassium particles and other toxic substances in urine can leak into bladder mucosa, causing the symptoms of lower abdominal/pelvic discomfort, pain, increased urination frequency, urgency, nocturia, and so on, all of which can substantially reduce the quality of daily life. There are multiple symptom reliving therapies. Among them, only pentosan polysulfate sodium, sold under the brand name of Elmiron, has been approved for oral use by US Food and Drug Administration. It provides the relief after several months of use. Based on the scientific leads presented in this article, we propose that human chorionic gonadotropin has a therapeutic potential that is worth investigating for the treatment of this disease.
Implantable Devices for Sustained, Intravesical Drug Delivery.
Lee Seung Ho,Choy Young Bin
International neurourology journal
In clinical settings, intravesical instillation of a drug bolus is often performed for the treatment of bladder diseases. However, it requires repeated instillations to extend drug efficacy, which may result in poor patient compliance. To alleviate this challenge, implantable devices have been developed for the purpose of sustained, intravesical drug delivery. In this review, we briefly summarize the current trend in the development of intravesical drug-delivery devices. We also introduce the most recently developed devices with strong potential for intravesical drug-delivery applications.
Expected Next-Generation Drugs Under Development in Relation to Voiding Symptoms.
Chung Kyung Jin,Chung Benjamin I
International neurourology journal
New drug development is a high-risk venture, but if successful, will bring great revenues to those willing to accept the risk. In the field of urology, in particular for lower urinary tract symptoms (LUTS), the recent successful landing of drugs (e.g., mirabegron, botulinum toxin A, and tadalafil) has resulted in increased interest in new drug development. Benign prostatic hyperplasia and overactive bladder syndrome, representative LUTS diseases, are attractive targets because of their prevalence and market size in the field of urology. Additionally, the awareness about new stream of research is very important not only because of the market size and economic factors, but also because to keep steady attention to these research for the researcher's. We have reviewed a selection of new drugs currently under development for the treatment of the two aforementioned diseases and hope to offer urologists an overview of the current situation and future directions in the field of urology.
The Use of Polymer Chitosan in Intravesical Treatment of Urinary Bladder Cancer and Infections.
Erman Andreja,Veranič Peter
The most frequent diseases of the urinary bladder are bacterial infections and bladder cancers. For both diseases, very high recurrence rates are characteristic: 50⁻80% for bladder cancer and more than 50% for bladder infections, causing loss of millions of dollars per year for medical treatment and sick leave. Despite years of searching for better treatment, the prevalence of bladder infections and bladder cancer remains unchanged and is even increasing in recent years. Very encouraging results in treatment of both diseases recently culminated from studies combining biopolymer chitosan with immunotherapy, and chitosan with antibiotics for treatment of bladder cancer and cystitis, respectably. In both pathways of research, the discoveries involving chitosan reached a successful long-lasting cure. The property of chitosan that boosted the effectivity of illness-specific drugs is its ability to enhance the accessibility of these drugs to the very sources of both pathologies that individual treatments without chitosan failed to achieve. Chitosan can thus be recognised as a very promising co-player in treatment of bladder cancer and bacterial cystitis.
Nanotechnology in Urology.
Indian journal of urology : IJU : journal of the Urological Society of India
INTRODUCTION:Nanotechnology has revolutionized our approach to medical diagnostics as well as therapeutics and has spanned an entirely new branch of research. This review addresses the potential applications of Nanotechnology in Urology. This article is based on the Dr. Sitharaman Best Essay award of the Urological Society of India for 2016. METHODS:A PubMed search was performed for all relevant articles using the terms, "nanotechnology, nanoparticles, nanoshells, nanoscaffolds, and nanofibers." RESULTS:The developments in diagnostics include novel techniques of imaging of genitourinary malignancies, prostate-specific antigen measurement, early detection of mutations that are diagnostic for polycystic kidney disease. The potential applications of nanotechnology are in the targeted therapy of genitourinary malignancies, erectile dysfunction, overactive bladder, bladder reconstruction, construction of artificial kidneys and biodegradable stents as well as in robotic surgery. CONCLUSIONS:Nanotechnology is a rapidly emerging branch of research in urology with diverse and clinically significant applications in diagnostics as well as therapeutics.
Bladder augmentation in children: current problems and experimental strategies for reconstruction.
Langer Sophie,Radtke Christine,Györi Eva,Springer Alexander,Metzelder Martin L
Wiener medizinische Wochenschrift (1946)
Bladder augmentation is a demanding surgical procedure and exclusively offered for selected children and has only a small spectrum of indications. Paediatric bladder voiding dysfunction occurs either on a basis of neurological dysfunction caused by congenital neural tube defects or on a basis of rare congenital anatomic malformations. Neurogenic bladder dysfunction often responds well to a combination of specific drugs and/or intermittent self-catheterization. However, selected patients with spinal dysraphism and children with congenital malformations like bladder exstrophy and resulting small bladder capacity might require bladder augmentation. Ileocystoplasty is the preferred method of bladder augmentation to date. Because of the substantial long-and short-term morbidity of augmentation cystoplasty, recent studies have tried to incorporate new techniques and technologies, such as the use of biomaterials to overcome or reduce the adverse effects. In this regard, homografts and allografts have been implemented in bladder augmentation with varying results, but recent studies have shown promising data in terms of proliferation of urothelium and muscle cells by using biological silk grafts.
Management of vesicoureteral reflux in neurogenic bladder.
Wu Charlotte Q,Franco Israel
Investigative and clinical urology
Vesicoureteral reflux (VUR) is a significant risk factor for pyelonephritis and renal scarring. VUR can occur through a defective ureterovesical junction (UVJ) or an overwhelmed normal UVJ mechanism such as in bladder dysfunction of congenital, acquired, or behavioral etiology. There are numerous causes for the development of a neurogenic bladder from spinal dysraphisms to spinal cord trauma and even centrally based abnormalities in children with apparently normal motor function (inappropriately termed nonneurogenic neurogenic bladder). The foundation of managing reflux in these neurogenic bladders is to maintain low bladder pressures which will commonly mean that compliance will be normal as well. There have been several publications that have shown that if bladder pressures are lowered simply with clean intermittent catheterization and medications that the reflux can resolve spontaneously. Alternatively, the patients that are in need of bladder augmentation can have spontaneous resolution of their reflux with the resulting increase in capacity. Surgical intervention is called for when bladder capacity is adequate and the reflux persists or if it is part of a larger operation to increase capacity and to manage outlet resistance. In some instances, reimplantation is necessary because the ureters interfere with the bladder neck procedure. Aside from open and robotic surgical intervention the use of endoscopic injectable agents is beginning to become more popular especially when combined with intravesical botulinum toxin A injections. Great strides are being made in the management of patients with neurogenic bladders and we are seeing more choices for the urologist to be able to manage these patients.
Co-delivery of VEGF and bFGF via a PLGA nanoparticle-modified BAM for effective contracture inhibition of regenerated bladder tissue in rabbits.
Jiang Xincheng,Lin Houwei,Jiang Dapeng,Xu Guofeng,Fang Xiaoliang,He Lei,Xu Maosheng,Tang Bingqiang,Wang Zhiyong,Cui Daxiang,Chen Fang,Geng Hongquan
Graft contracture is a common problem associated with the regeneration processes of tissue-engineered bladders. Currently, most strategies used for incorporating bioactive molecules into biomaterial designs do not work during all phases of tissue regeneration. In this study, we used a growth factor-PLGA nanoparticle thermo-sensitive gel system (i.e., BAM with incorporated VEGF and bFGF-loaded PLGA nanoparticles and mixed with a hydrophilic gel) to promote bladder tissue regeneration in a rabbit model. At 4 and 12 weeks after surgery, contracture rate assessment and histological examination were conducted to evaluate bladder tissue regeneration. The results indicated that the functional composite scaffold continuously and effectively released VEGF and bFGF and promoted bladder reconstruction with a significant decrease in graft contracture. In addition, the number and arrangement of regenerated urothelial cells and smooth muscle cells as well as microvascular density and maturity were improved in the VEGF/bFGF nanoparticle group compared with the single factor VEGF or bFGF nanoparticle group and BAM alone. The nanoparticle thermo-sensitive gel system, which exhibited favourable performance, may effectively inhibit graft contracture and promote bladder tissue regeneration in rabbits.
The potential role of polymethyl methacrylate as a new packaging material for the implantable medical device in the bladder.
Kim Su Jin,Choi Bumkyoo,Kim Kang Sup,Bae Woong Jin,Hong Sung Hoo,Lee Ji Youl,Hwang Tae-Kon,Kim Sae Woong
BioMed research international
Polydimethylsiloxane (PDMS) is used in implantable medical devices; however, PDMS is not a completely biocompatible material for electronic medical devices in the bladder. To identify novel biocompatible materials for intravesical implanted medical devices, we evaluated the biocompatibility of polymethyl methacrylate (PMMA) by analyzing changes in the levels of macrophages, macrophage migratory inhibitory factor (MIF), and inflammatory cytokines in the bladder. A ball-shaped metal coated with PMMA or PDMS was implanted into the bladders of rats, and after intravesical implantation, the inflammatory changes induced by the foreign body reaction were evaluated. In the early period after implantation, increased macrophage activity and MIF in the urothelium of the bladder were observed. However, significantly decreased macrophage activity and MIF in the bladder were observed after implantation with PMMA- or PDMS-coated metal in the later period. In addition, significantly decreased inflammatory cytokines such as IL-1β, IL-6, and TNF-α were observed with time. Based on these results, we suggest that MIF plays a role in the foreign body reaction and in the biocompatible packaging with PMMA for the implanted medical devices in the bladder.
Comparison of laparoscopic closure of the bladder with barbed polyglyconate versus polyglactin suture material in the pig bladder model: an experimental in vitro study.
Gözen Ali Serdar,Arslan Murat,Schulze Michael,Rassweiler Jens
Journal of endourology
PURPOSE:The objective of this randomized in-vitro study was to compare the suturation time, integrity, and quality of the bladder closure in fresh cadaver pig bladders performed with barbed polyglyconate sutures vs polyglactin 910 sutures in running and interrupted fashion. MATERIALS AND METHODS:Forty-eight pig bladders, each weighing from 120 to 150 g, were randomly divided into three groups: Group 1 (interrupted polyglactin 910 suture group), group 2 (running polyglactin 910 suture group), and group 3 (running barbed polyglyconate suture group). The bladder defects were closed laparoscopically, and the suturation times were noted. Two surgeons evaluated the integrity of each bladder closure. A cystometry was performed, and the filling and leak pressures were noted. A Kruskal-Wallis variance analysis test was used to compare the results of the three groups, and P<0.05 was considered significant. RESULTS:There was a statistically significant difference between the mean suturation times of three groups: Group 1, 15.2 minutes; group 2, 9.14 minutes; and group 3, 7.13 minutes (P<0.05). Mean bladder capacity at the time of leakage was 276.2, 353.8, and 419.7 mL for groups 1, 2, and 3, respectively, and the difference was statistically significant (P<0.05). CONCLUSION:For the first time, we demonstrated laparoscopic knotless closure of bladder defects using the barbed polyglyconate suture material in an experimental in-vitro model. Closing the pig bladder with running knotless barbed suture provides a more effective and faster watertight bladder closure than traditional polyglactin 910 suture material.
Review of clinical experience on biomaterials and tissue engineering of urinary bladder.
Chua Michael E,Farhat Walid A,Ming Jessica M,McCammon Kurt A
World journal of urology
PURPOSE:In recent pre-clinical studies, biomaterials and bladder tissue engineering have shown promising outcomes when addressing the need for bladder tissue replacement. To date, multiple clinical experiences have been reported. Herein, we aim to review and summarize the reported clinical experience of biomaterial usage and tissue engineering of the urinary bladder. METHODS:A systematic literature search was performed on Feb 2019 to identify clinical reports on biomaterials for urinary bladder replacement or augmentation and clinical experiences with bladder tissue engineering. We identified and reviewed human studies using biomaterials and tissue-engineered bladder as bladder substitutes or augmentation implants. The studies were then summarized for each respective procedure indication, technique, follow-up period, outcome, and important findings of the studies. RESULTS:An extensive literature search identified 25 studies of case reports and case series with a cumulative clinical experience of 222 patients. Various biomaterials and tissue-engineered bladder were used, including plastic/polyethylene mold, preserved dog bladder, gelatine sponge, Japanese paper with Nobecutane, lypholized human dura, bovine pericardium, amniotic membrane, small intestinal mucosa, and bladder tissue engineering with autologous cell-seeded biodegradable scaffolds. However, overall clinical experiences including the outcomes and safety reports were not satisfactory enough to replace enterocystoplasty. CONCLUSION:To date, several clinical experiences of biomaterials and tissue-engineered bladder have been reported; however, various studies have reported non-satisfactory outcomes. Further technological advancements and a better understanding is needed to advance bladder tissue engineering as a future promising management option for patients requiring bladder drainage.
Stem Cells in Functional Bladder Engineering.
Smolar Jakub,Salemi Souzan,Horst Maya,Sulser Tullio,Eberli Daniel
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie
Conditions impairing bladder function in children and adults, such as myelomeningocele, posterior urethral valves, bladder exstrophy or spinal cord injury, often need urinary diversion or augmentation cystoplasty as when untreated they may cause severe bladder dysfunction and kidney failure. Currently, the gold standard therapy of end-stage bladder disease refractory to conservative management is enterocystoplasty, a surgical enlargement of the bladder with intestinal tissue. Despite providing functional improvement, enterocystoplasty is associated with significant long-term complications, such as recurrent urinary tract infections, metabolic abnormalities, stone formation, and malignancies. Therefore, there is a strong clinical need for alternative therapies for these reconstructive procedures, of which stem cell-based tissue engineering (TE) is considered to be the most promising future strategy. This review is focused on the recent progress in bladder stem cell research and therapy and the challenges that remain for the development of a functional bladder wall.
Current status of tissue engineering applied to bladder reconstruction in humans.
Actas urologicas espanolas
CONTEXT AND OBJECTIVE:Bladder reconstruction is performed to replace or expand the bladder. The intestine is used in standard clinical practice for tissue in this procedure. The complications of bladder reconstruction range from those of intestinal resection to those resulting from the continuous contact of urine with tissue not prepared for this contact. In this article, we describe and classify the various biomaterials and cell cultures used in bladder tissue engineering and reviews the studies performed with humans. ACQUISITION OF EVIDENCE:We conducted a review of literature published in the PubMed database between 1950 and 2017, following the principles of the PRISM declaration. SYNTHESIS OF THE EVIDENCE:Numerous in vitro and animal model studies have been conducted, but only 18 experiments have been performed with humans, with a total of 169 patients. The current evidence suggests that an acellular matrix, a synthetic polymer with urothelial and autologous smooth muscle cells attached in vitro or stem cells would be the most practical approach for experimental bladder reconstruction. CONCLUSIONS:Bladder replacement or expansion without using intestinal tissue is still a challenge, despite progress in the manufacture of biomaterials and the development of cell therapy. Well-designed studies with large numbers of patients and long follow-up times are needed to establish an effective clinical translation and standardisation of the check-up functional tests.
Biomimetic scaffold containing PVDF nanofibers with sustained TGF-β release in combination with AT-MSCs for bladder tissue engineering.
Ardeshirylajimi Abdolreza,Ghaderian Sayyed Mohammad-Hossein,Omrani Mir Davood,Moradi Sadegh Lotfalah
Since the functional recovery of the reconstructed bladder is related to the bladder wall contraction and existing therapies do not respond to this, tissue engineering could be worth considered promising candidates for developing of conventional treatments in these kinds of ailments. Due to the low mechanical properties of natural scaffolds, biocompatible synthetic scaffolds can play a key role in the stem cells proliferation and differentiation and apply for many tissue-engineering applications. On the other hand, considering the low shelf life of TGFβ, encapsulating this growth factor can help maintain its functionality throughout the study period. In this study, poly (vinylidene fluoride) (PVDF) nanofibrous scaffolds were fabricated through electrospinning method with or without chitosan nanoparticles loaded TGFβ. All scaffolds characterized morphologically by using SEM, TGFβ release profiling as well as biocompatibility by using SEM and MTT assays. Adipose tissue derived mesenchymal stem cells (AT-MSCs) was isolated and characterized immediately and the differentiation of SMC was investigated when cultured on the surface of the scaffolds and tissue culture polystyrene (TCPS) as a control of gene and protein expression levels. Fabricated scaffold possess smooth structure with nanoscale size and long time releasing of sustained profiles. MTT, qRT-PCR and immunocytochemistry results demonstrated that AT-MSCs proliferation rate and SMC differentiation potential were significantly increased when cultured on the PVDF-TGFβ scaffold in comparison with PVDF and TCPS. According to the results, PVDF-TGFβ as a bio-functional scaffold can provide greater treatment possibilities in bladder tissue engineering applications.
Tetronic(®)-based composite hydrogel scaffolds seeded with rat bladder smooth muscle cells for urinary bladder tissue engineering applications.
Sivaraman Srikanth,Ostendorff Rachel,Fleishman Benjamin,Nagatomi Jiro
Journal of biomaterials science. Polymer edition
Natural hydrogels such as collagen offer desirable properties for tissue engineering, including cell adhesion sites, but their low mechanical strength is not suitable for bladder tissue regeneration. In contrast, synthetic hydrogels such as poly (ethylene glycol) allow tuning of mechanical properties, but do not elicit protein adsorption or cell adhesion. For this reason, we explored the use of composite hydrogel blends composed of Tetronic (BASF) 1107-acrylate (T1107A) in combination with extracellular matrix moieties collagen and hyaluronic acid seeded with bladder smooth muscle cells (BSMC). This composite hydrogel supported BSMC growth and distribution throughout the construct. When compared to the control (acellular) hydrogels, mechanical properties (peak stress, peak strain, and elastic modulus) of the cellular hydrogels were significantly greater. When compared to the 7-day time point after BSMC seeding, results of mechanical testing at the 14-day time point indicated a significant increase in both ultimate tensile stress (4.1-11.6 kPa) and elastic modulus (11.8-42.7 kPa) in cellular hydrogels. The time-dependent improvement in stiffness and strength of the cellular constructs can be attributed to the continuous collagen deposition and reconstruction by BSMC seeded in the matrix. The composite hydrogel provided a biocompatible scaffold for BSMC to thrive and strengthen the matrix; further, this trend could lead to strengthening the construct to match the mechanical properties of the bladder.
Bladder tissue engineering: a literature review.
Lam Van Ba Ornella,Aharony Shachar,Loutochin Oleg,Corcos Jacques
Advanced drug delivery reviews
PURPOSE OF REVIEW:In bladder cancer and neuro-bladder, reconstruction of the bladder requires bowel segment grafting for augmentation cystoplasty or neo-bladder creation. However, even if currently considered as the gold standard, it is associated with potentially severe short- and long-term adverse effects. Thus, bladder tissue engineering is a promising approach to bladder reconstruction. RECENT FINDINGS:In the last few years, progress has been made with the development of new biomaterials for bladder tissue replacement and in deciphering the role of stem cells as well as their contribution to bladder scaffold integration and tissue regeneration. SUMMARY:This review of recently published articles allows us to forecast the characteristics of efficient and safe bladder biomaterials. However, several factors, such as native bladder traits, the specific involvement of urine, and bladder tissue replacement indications, have to be assessed with caution before including bladder tissue engineering in clinical trials. Many authors agree that these challenging techniques could deliver significant benefits with clinical application, reducing morbidity and global long-term costs.
Co-culturing porcine normal urothelial cells, urinary bladder fibroblasts and smooth muscle cells for tissue engineering research.
Zupančič Daša,Mrak Poljšak Katjuša,Kreft Mateja Erdani
Cell biology international
New strategies for culturing and co-culturing of the main types of urinary bladder cells are essential for successful establishment of biomimetic in vitro models, which could be applied for research into, and management of, diverse urological disorders. Porcine normal urothelial cells are available in nearly unlimited amounts and have many properties equivalent to human urothelial cells. In the present study, we established normal differentiated porcine urothelial cells in co-cultures with porcine urinary bladder normal fibroblasts and/or smooth muscle cells. The optimal culture medium for establishment of differentiated urothelial cells, demonstrated by positive immunofluorescence of uroplakins, cytokeratins (CK 7, CK 20), zonula occludens 1 (ZO-1), claudin 4, claudin 8, and E-cadherin, was the medium composed of equal parts of Advanced Dulbecco's modified Eagle's medium (A-DMEM) and MCDB 153 medium with physiological calcium concentration of 2.5 mM and without fetal bovine serum, named UroM (+Ca - S). This medium was also proven to be suitable for culturing of bladder fibroblasts and smooth muscle cells and co-culturing of urothelial cells with these mesenchymal cells. Urothelial cell differentiation was optimal in UroM (+Ca - S) medium in all co-culture conditions and when compared to all conditioned-media combinations. To summarize, these strategies for culturing and co-culturing of urinary bladder urothelial cells with mesenchymal cells could be used as new in vitro models for future basic and applicable research of the urinary bladder and thus potentially also for translational tissue engineering studies.
Polyesterurethane and acellular matrix based hybrid biomaterial for bladder engineering.
Horst Maya,Milleret Vincent,Noetzli Sarah,Gobet Rita,Sulser Tullio,Eberli Daniel
Journal of biomedical materials research. Part B, Applied biomaterials
Poly(lactic-co-glycolic acid) (PLGA) based biomaterials for soft tissue engineering have inherent disadvantages, such as a relative rigidity and a limited variability in the mechanical properties and degradation rates. In this study, a novel electrospun biomaterial based on degradable polyesterurethane (PEU) (DegraPol ) was investigated for potential use for bladder engineering in vitro and in vivo. Hybrid microfibrous PEU and PLGA scaffolds were produced by direct electrospinning of the polymer onto a bladder acellular matrix. The scaffold morphology of the scaffold was analyzed, and the biological performance was tested in vitro and in vivo using a rat cystoplasty model. Anatomical and functional outcomes after implantation were analyzed macroscopically, histologically and by cystometry, respectively. Scanning electron microscopy analysis showed that PEU samples had a lower porosity (p < 0.001) and were slightly thinner (p = 0.009) than the PGLA samples. Proliferation and survival of the seeded smooth muscle cells in vitro were comparable on PEU and PLGA scaffolds. After 8 weeks in vivo, the PEU scaffolds exhibited no shrinkage. However, cystometry of the reconstructed bladders exhibited a slightly greater functional bladder capacity in the PLGA group. Morphometric analyses revealed significantly better tissue healing (p < 0.05) and, in particular, better smooth muscle regeneration, as well as a lower rate of inflammatory responses at 8 weeks in the PEU group. Collectively, the results indicated that PEU-hybrid scaffolds promote bladder tissue formation with excellent tissue integration and a low inflammatory reaction in vivo. PEU is a promising biomaterial, particularly with regard to functional tissue engineering of the bladder and other hollow organs. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 658-667, 2017.
Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device.
Nickel J Curtis,Jain Pankaj,Shore Neal,Anderson Jessica,Giesing Dennis,Lee Heejin,Kim Grace,Daniel Karen,White Suellen,Larrivee-Elkins Cheryl,Lekstrom-Himes Julie,Cima Michael
Science translational medicine
Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because their concentrations in the bladder are low. A previous attempt to develop a drug delivery device for use in the bladder was unsuccessful, likely as a result of poor tolerability. A continuous lidocaine-releasing intravesical system (LiRIS) was designed to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. The 16 women with IC/BPS who were enrolled in the study met the National Institute of Diabetes and Digestive and Kidney Diseases criteria for bladder hemorrhages or Hunner's lesions. Subjects received either LiRIS 200 mg or LiRIS 650 mg for 2 weeks. Safety, efficacy, cystoscopic appearance of the bladder, and limited pharmacokinetic data were collected. Both doses were well tolerated, and clinically meaningful reductions were seen in pain, urgency, voiding frequency, and disease questionnaires. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner's lesions in five of six subjects with baseline lesions. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed.
[New perspectives of treatment with fesoterodine fumarate in patients with overactive bladder].
García-Baquero R,Madurga B,García M V,Fernández M A,Rosety J M,Álvarez-Ossorio J L
Actas urologicas espanolas
OBJECTIVE:Evaluate the effect of the treatment with fesoterodine fumarate in patients with overactive bladder, as an alternative in case of failure of the usual anticholinergic treatment, due to either lack of therapeutic efficacy or due to intolerance to side effects. MATERIAL AND METHOD:A retrospective review of 158 patients with overactive bladder was carried out. The patients were divided into two groups; the first group; 56 patients where the anticholinergic treatment showed to be ineffective, and the second group; 102 patients who presented intolerance to anticholinergic side effects. RESULTS:For the first group where fesoterodine fumarate was used to improve effectiveness of the anticholinergics, improvement in the components of urinary urgency (p=0.001), insufficient emptying (p=0.001), incontinence (p=0.009), and in the number of pads/day (p<0.001) was detected. As to the second group where fesoterodine fumarate was used as an alternative to anticholinergics to avoid side effects, a high reduction in the incidence of dry mouth (p<0.001) and constipation (p=0.015) was seen, as well as a significant clinical improvement. CONCLUSION:Fesoterodine fumarate is an optimal treatment option when the clinical response to anticholinergics has not been satisfactory, either by the lack of therapeutic action or by intolerance to side effects, and especially when the treatment is expected to be long.
UC-VEGF-SMC Three Dimensional (3D) Nano Scaffolds Exhibits Good Repair Function in Bladder Damage.
Ling Qing,Wang Tao,Yu Xiao,Wang Shao-Gang,Ye Zhang-Qun,Liu Ji-Hong,Yang Sen-Wu,Zhu Xiong-Bo,Yu Jin
Journal of biomedical nanotechnology
We constructed a UC-VEGF-SMC three dimensional (3D) scaffold to explore its effect on blood vessel regeneration and bladder repair function in a rabbit model with bladder injury. Rabbit adipose tissue-derived stem cells (ADSCs) were cultured to construct pluripotent stem cell systems that can be induced to differentiate into urothelial cells (UCs) and smooth muscle cells (SMCs). Reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, MTT assay and HE staining were used in our study. Rabbit models were divided into an experimental group, control group and sham group. The bladder histology, urodynamics, smooth muscle function, stent degradation rate, urothelial permeability and biomechanical determination of rabbits were detected after grafting the scaffold. Correct stem cells based on the ADSC surface marker and found that CD90 and CD105 were positive and that CD34 and CD45 were negative. RT-PCR showed that ADSC-iPS cells expressed the marker gene of embryonic stem cells (ESCs), which indicated that Sox2, Klf4, Oct4 and c-Myc were inserted into the iPS nucleus and that the ADSC-iPS system was constructed successfully. Immunofluorescence and MTT assays indicated that iPS differentiated into mature SMCs and UCs. ELISA and HEMC culturing methods revealed that vascular endothelia growth factor (VEGF) could promote the growth of HMECs. Rabbit bladder repair function (urodynamics, smooth muscle function, urothelial permeability and biomechanical determination) was stronger in the experimental group than in the control group. UC-VEGF-SMC 3D nano scaffold exhibits good repair function for bladder damage, which may helpful for treatment of damaged bladders.
Novel Delivery of Mitoxantrone with Hydrophobically Modified Pullulan Nanoparticles to Inhibit Bladder Cancer Cell and the Effect of Nano-drug Size on Inhibition Efficiency.
Tao Xiaojun,Tao Ting,Wen Yi,Yi Jiajin,He Lihua,Huang Zixuan,Nie Yu,Yao Xiaoyan,Wang Yingying,He Chunlian,Yang Xiaoping
Nanoscale research letters
Reducing the dosage of chemotherapeutic drugs via enhancing the delivery efficiency using novel nanoparticles has great potential for cancer treatment. Here, we focused on improving mitoxantrone delivery by using cholesterol-substituted pullulan polymers (CHPs) and selected a suitable nano-drug size to inhibit the growth of bladder cancer cells. We synthesized three kinds of CHPs, named CHP-1, CHP-2, CHP-3. Their chemical structures were identified by NMR, and the degree of cholesterol substitution was 6.82%, 5.78%, and 2.74%, respectively. Their diameters were 86.4, 162.30, and 222.28 nm. We tested the release rate of mitoxantrone in phosphate-buffered saline for 48 h: the release rate was 38.73%, 42.35%, and 58.89% for the three CHPs. The hydrophobic substitution degree in the polymer was associated with the self-assembly process of the nanoparticles, which affected their size and therefore drug release rate. The release of the three drug-loaded nanoparticles was significantly accelerated in acid release media. The larger the nanoparticle, the greater the drug release velocity. At 24 h, the IC value was 0.25 M, for the best inhibition of mitoxantrone on bladder cancer cells.3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) experiments demonstrated that drug-loaded CHP-3 nanoparticles with the largest size were the most toxic to bladder cancer cells. Immunofluorescence and flow cytometry revealed that drug-loaded CHP-3 nanoparticles with the largest size had the strongest effect on promoting apoptosis of bladder cancer cells. Also, the three drug-loaded nanoparticles could all inhibit the migration of MB49 cells, with large-size CHP-3 nanoparticles having the most powerful inhibition.
Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer.
Buss Julieti Huch,Begnini Karine Rech,Bender Camila Bonemann,Pohlmann Adriana R,Guterres Silvia S,Collares Tiago,Seixas Fabiana Kömmling
Frontiers in pharmacology
bacillus Calmette-Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.
Compressed collagen gel: a novel scaffold for human bladder cells.
Engelhardt E-M,Stegberg E,Brown R A,Hubbell J A,Wurm F M,Adam M,Frey P
Journal of tissue engineering and regenerative medicine
Collagen is highly conserved across species and has been used extensively for tissue regeneration; however, its mechanical properties are limited. A recent advance using plastic compression of collagen gels to achieve much higher concentrations significantly increases its mechanical properties at the neo-tissue level. This controlled, cell-independent process allows the engineering of biomimetic scaffolds. We have evaluated plastic compressed collagen scaffolds seeded with human bladder smooth muscle cells inside and urothelial cells on the gel surface for potential urological applications. Bladder smooth muscle and urothelial cells were visualized using scanning electron microscopy, conventional histology and immunohistochemistry; cell viability and proliferation were also quantified for 14 days in vitro. Both cell types tested proliferated on the construct surface, forming dense cell layers after 2 weeks. However, smooth muscle cells seeded within the construct, assessed with the Alamar blue assay, showed lower proliferation. Cellular distribution within the construct was also evaluated, using confocal microscopy. After 14 days of in vitro culture, 30% of the smooth muscle cells were found on the construct surface compared to 0% at day 1. Our results provide some evidence that cell-seeded plastic compressed collagen has significant potential for bladder tissue regeneration, as these materials allow efficient cell seeding inside the construct as well as cell proliferation.
Evaluation of gel spun silk-based biomaterials in a murine model of bladder augmentation.
Mauney Joshua R,Cannon Glenn M,Lovett Michael L,Gong Edward M,Di Vizio Dolores,Gomez Pablo,Kaplan David L,Adam Rosalyn M,Estrada Carlos R
Currently, gastrointestinal segments are considered the gold standard for bladder reconstructive procedures. However, significant complications including chronic urinary tract infection, metabolic abnormalities, urinary stone formation, bowel dysfunction, and secondary malignancies are associated with this approach. Biomaterials derived from silk fibroin may represent a superior alternative due their robust mechanical properties, biodegradable features, and processing plasticity. In the present study, we evaluated the efficacy of a gel spun silk-based matrix for bladder augmentation in a murine model. Over the course of 70 d implantation period, H&E and Masson's trichrome (MTS) analysis revealed that silk matrices were capable of supporting both urothelial and smooth muscle regeneration at the defect site. Prominent uroplakin and contractile protein expression (α-actin, calponin, and SM22α) was evident by immunohistochemical analysis demonstrating maturation of the reconstituted bladder wall compartments. Gel spun silk matrices also elicited a minimal acute inflammatory reaction following 70 d of bladder integration, in contrast to parallel assessments of small intestinal submucosa (SIS) and poly-glycolic acid (PGA) matrices which routinely promoted evidence of fibrosis and chronic inflammatory responses. Voided stain on paper analysis revealed that silk augmented animals displayed similar voiding patterns in comparison to non surgical controls by 42 d of implantation. In addition, cystometric evaluations of augmented bladders at 70 d post-op demonstrated that silk scaffolds supported significant increases in bladder capacity and voided volume while maintaining similar degrees of compliance relative to the control group. These results provide evidence for the utility of gel spun silk-based matrices for functional bladder tissue engineering applications.
Tolterodine Tartrate Proniosomal Gel Transdermal Delivery for Overactive Bladder.
Rajabalaya Rajan,Leen Guok,Chellian Jestin,Chakravarthi Srikumar,David Sheba R
The goal of this study was to formulate and evaluate side effects of transdermal delivery of proniosomal gel compared to oral tolterodine tartrate (TT) for the treatment of overactive bladder (OAB). Proniosomal gels are surfactants, lipids and soy lecithin, prepared by coacervation phase separation. Formulations were analyzed for drug entrapment efficiency (EE), vesicle size, surface morphology, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, and in vivo effects. The EE was 44.87%-91.68% and vesicle size was 253-845 nm for Span formulations and morphology showed a loose structure. The stability and skin irritancy test were also carried out for the optimized formulations. Span formulations with cholesterol-containing formulation S1 and glyceryl distearate as well as lecithin containing S3 formulation showed higher cumulative percent of permeation such as 42% and 35%, respectively. In the in vivo salivary secretion model, S1 proniosomal gel had faster recovery, less cholinergic side effect on the salivary gland compared with that of oral TT. Histologically, bladder of rats treated with the proniosomal gel formulation S1 showed morphological improvements greater than those treated with S3. This study demonstrates the potential of proniosomal vesicles for transdermal delivery of TT to treat OAB.
A gel system for single instillation of non-muscle-invasive bladder Cancer: A "divide-and-rule" strategy.
Guo Pengyu,Shang Wenting,Peng Li,Wang Lu,Wang Hongzhi,Han Ziyu,Jiang Hongmei,Tian Jie,Wang Kun,Xu Wanhai
Journal of controlled release : official journal of the Controlled Release Society
Single instillation (SI) reduces recurrence of non-muscle-invasive bladder cancer by chemoresecting floating tumor cells and residual tumor lesions (RTLs) after transurethral resection of the bladder, but with limited efficacy. Current studies improved this by prolonging retention time and increasing penetration to bladder wall, ignoring that the two separate factors should be treated in different ways. Here, we introduced a smart gel system-based SI to prevent re-implantation of tumor cells (RTCs) and ablate RTLs in a "divide-and-rule" approach. The gel system was synthesized by PEG-PAMAM and dextran aldehyde and composed of gold nanorods and gemcitabine for photothermal therapy and chemotherapy, respectively. It was developed to provide dextran aldehyde-selective adhesion with tissue amines. Since tumor surface expressed high levels of collagen, the exposed amines could act as adhesion points for the gel system. Thus, the gel presented more affinity to tumor tissues. When being instilled, it could form a protective layer on the inner face of the entire bladder wall immediately, preventing RTCs in early time. And it persisted long at the tumor site, ablating RTLs. Our data proved the gel system improved intravesical treatment efficacy in a "divide-and-rule" approach and might be a promising treatment strategy for SI.
Single center experience with oxybutynin transdermal system (patch) for management of symptoms related to non-neuropathic overactive bladder in children: an attractive, well tolerated alternative form of administration.
Gleason Joseph M,Daniels Catherine,Williams Katharine,Varghese Abby,Koyle Martin A,Bägli Darius J,Pippi Salle Joao L,Lorenzo Armando J
Journal of pediatric urology
OBJECTIVE:Oxybutynin is the current gold standard drug for management of overactive bladder (OAB) in children, but can have significant side effects or be difficult to administer in multiple daily doses. Herein, we report our experience with transdermal oxybutynin patch (TOP) as an alternative in a selected patient population without neuropathic compromise. MATERIALS AND METHODS:Consecutive patients assessed in a pediatric urology clinic over a 1-year period, diagnosed with OAB with minimum follow-up of 3 months, were included. TOP starting dose was 3.9 mg/day based on product design (Oxytrol). Demographics and outcomes data were retrospectively collected. Symptomatic response was defined as improvement or resolution of lower urinary tract symptoms. RESULTS:35 children met inclusion criteria (mean age 8 years, range 4-16). Overall, 97% reported good symptom response. The main side effect was skin irritation at TOP site (35%), leading to discontinuation in 20%. There were no reports of other significant side effects. Mean bladder capacity increased from 104 ml to 148 ml at follow-up. CONCLUSIONS:Our data suggest that TOP is a viable alternative for children with non-neuropathic OAB who do not tolerate other formulations of oxybutynin. These findings highlight the potential benefit of transdermal drug delivery in the pediatric setting.
Overactive bladder: OTC oxybutynin transdermal patch for women.
Molnar Christin,Fusco Julie
The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists
The prevalence and burden of overactive bladder (OAB) in the population is remarkable. An estimated 20 million adult women in the United States have symptoms of OAB. Despite the negative impact on their health-related quality of life, many do not seek treatment. Antimuscarinic agents for OAB have long been available only with a prescription. However, the Food and Drug Administration approved an over-the-counter (OTC) oxybutynin transdermal patch for use in women in 2013, and the product recently came to market. The availability of an OTC antimuscarinic medication for OAB introduces the opportunity for females to self-treat the condition. Prior to the prescription-to-OTC switch, the efficacy and safety data for the prescription product were evaluated. Consumer research studies guided the development of the drug label.
[Maintenance of the efficacy of the oxybutynin patch for the treatment of overactive bladder syndrome despite the change in the area of application: study of four cases.]
Merino Salas Sergio
Archivos espanoles de urologia
The transdermal route for administration of anticholinergic drugs can provide efficacy with less systemic adverse effects. The transdermal oxybutynin patch (OXYTDS) offers advantages over oral administration for patients treated for Overactive bladder (OAB) syndrome. The limited evidence on the OXY-TDS patch application areas of the skin, makes difficult counseling patients who require a change to skin zones other than those recommended by the manufacturer. The preliminary experience of four patients included in this case report suggests that changing the application area for the OXY-TDS patch outside those skin areas recommended by the manufacturer, seems effective and safe in the treatment of OAB syndrome, regardless of the characteristics of the patients.
Bladder augmentation in anuric/defunctioned microbladders and a novel antireflux mechanism for Mitrofanoff anastomosis to the ileal patch.
Lopes Joana,Robb Andy,McCarthy Liam
Journal of pediatric surgery
BACKGROUND/PURPOSE:Reconstruction of microbladders is a difficult surgical challenge: How can a neobladder be recreated when >90% of the new bladder is augmented patch, and how can a Mitrofanoff conduit be anastomosed when the native bladder is so tiny? This series describes microbladders secondary to anuria and/or diversion that required augmentation. This was done using a de-tubularized ileal segment, and because of the small size of the native bladder, Mitrofanoff anastomosis was performed to the bowel patch (using a novel "Keel Procedure"). METHODS:Our surgical experience in reconstruction of microbladders was reviewed: pre and post augmentation capacity, compliance and maximum detrusor pressure were compared. The success of the Mitrofanoff anti-reflux technique is described. Data are given as median (interquartile range) and compared by Wilcoxon paired rank test. RESULTS:10 patients, median bladder capacity pre-op 10 (9-20) mls were reconstructed. The follow up time is 2.7years (2.2-4.2). Post-op bladder capacity increased 16-fold to 167 (114-281) mls, P<0.01. Compliance significantly improved from 1.7 (0.3-4.8) to 14.3 (4.1-66.3) mls/cmHO, P<0.05. Maximum detrusor over-activity decreased from 27 (7-120) to 12.5 (8-26) cmHO, (N.S. P=0.3). Videourodynamics confirmed a leak in 2 patients, leading to incorporation into the technique of a non-absorbable seromuscular suture to provide long-term robustness to the antireflux procedure. CONCLUSION:Bladder augmentation in microbladders is possible, and a functional Mitrofanoff procedure with a continent anti-reflux procedure can be created using the "Birmingham keel technique" implanting the Mitrofanoff into the augment patch, with 80% success (similar to published results for conventional anastomosis to native bladders). LEVEL OF EVIDENCE:Level IV.
Bladder reconstruction using a collagen patch prefabricated within the omentum.
Hattori Kazunori,Joraku Akira,Miyagawa Tomoaki,Kawai Koji,Oyasu Ryoichi,Akaza Hideyuki
International journal of urology : official journal of the Japanese Urological Association
OBJECTIVE:We present our experience with a novel bladder reconstruction model using a collagen sponge pre-embedded within the omentum. The aim of the study is to evaluate tissue regeneration of the reconstructed bladder and the effect of prefabricating the collagen patch within the omentum. MATERIALS AND METHODS:Twenty pigs were divided into three groups. For the prefabricated patch group (PFP; n=10), collagen sponge was inserted into the omentum. After 1 week, the pigs underwent a hemicystectomy and the sponge with an attached omental flap was brought to close the defect. For the non-prefabricated patch group (NPFP; n=6), pigs received hemicystectomy and closure with a collagen sponge without prefabricating in the omentum. Four other pigs received hemicystectomy alone as a control (C; n=4). All animals in the NPFP and C groups, and 7 of 10 in the PFP group were sacrificed at 4 or 8 weeks. Three other pigs in the PFP group were sacrificed at 12 weeks. Resected bladders were submitted to hematoxylin-eosin, and immunohistochemical staining. RESULTS:All animals except for two in the NPFP group survived. At the time of grafting, the collagen sponge was covered with thick omental methothelial layers, and neo-vascularization from the omentum was observed. At each time point, only slight adhesion was observed around the patch in the PFP group, while severe adhesion between the patch and the bowel was observed in the NPFP group, suggesting that prefabricated collagen sponge within the omentum prevented urine leakage from the bladder. Histologically, the patch was well vascularized, and the luminal surface was covered with urothelium at 4 weeks in both groups. However, in the PFP group, there was mild inflammation in the submucosa and in-growth of smooth muscle derived from the adjacent muscle layers was observed with time, whereas severe inflammation was observed and in-growth of smooth muscle was limited in the NPF group. CONCLUSIONS:Prefabricating of a collagen patch within the omentum stimulated early neo-vascularization before grafting, and this procedure appears to offer an advantage for bladder reconstruction over a non-prefabricated procedure in terms of prevention of urine leakage and inflammation, and favorable tissue regeneration.
Re-epithelialization of demucosalized stomach patch with tissue-engineered urothelial mucosa combined with Botox A in bladder augmentation.
Zhang Yuanyuan,Liu Guihua,Kropp Bradley P
UNLABELLED:Re-epithelialization demucosa stomach patch is important to prevent the patch being exposed to urine that might cause patch shrinkage and fibrosis formation due to urine-derived chemical irritation. Additionally, Botox A acts by blocking the transmission of nerve impulses to smooth muscles and so paralysing the muscles, which is commonly used to relax muscle for treatment of oesophageal achalasia due to overactive smooth muscle and sphincters of gastrointestinal tract. We fabricated in vitro tissue engineered urothelial mucosa with multi-layers of urothelium and smooth muscle layers seeded on SIS scaffold and then used this cell-scaffold construct to cover nuke gastro patch combining with Botox A for gastrocystoplasty in a canine model. OBJECTIVE:To evaluate the demucosalized stomach patch covered with tissue-engineered urothelium for gastrocystoplasty and to determine whether or not injections of Botox A into the re-epithelialized stomach patch can protect the graft from contraction in a canine bladder reconstruction model. MATERIALS AND METHODS:Gastrocystoplasty was performed in 10 adult beagles after hemi-cystectomy using five types of stomach patch (n = 2 per group): entire stomach patches (group I); demucosalized patches (group II); demucosalized patches covered with cell-free small intestinal submucosa (SIS) (group III); demucosalized patches with urothelial and smooth muscle cell-seeded SIS (group IV); and demucosalized patches with the cell-seeded SIS combined with injections of Botox A (group V). The bladder volume/pressure and the graft sizes were measured before surgery and again 10 weeks after bladder augmentation. The graft tissues were examined both histologically and using immunohistochemistry. RESULTS:All dogs survived and their gastric grafts were all vital with a good blood supply. Gastric metaplasia of urothelium appeared on the top of stomach mucosa patches in two animals in group I. There was calcification formation at the centre of the graft in one animal in group II. As compared with urothelium that was partially covered over with stomach patches in groups II and III, stratified urothelium completely covered the demucosalized gastric patches in groups IV and V. There was less shrinkage of the stomach grafts in groups I and V, which shrank to half of their original size, than of the stomach grafts in groups II, III, and IV, which shrank significantly to one-quarter of their original sizes. CONCLUSIONS:Botox A injections appear to protect the graft contraction in the re-epithelialized stomach flaps. The gastrocystoplasty using demucosalized patches covered with tissue-engineered urothelial mucosa combined with an injection of Botox A could have clinical potential for use in bladder reconstruction.
Optimum Dose of Once-Daily Oxybutynin Patch in Japanese Patients with Overactive Bladder: A Randomized Double-Blind Trial Versus Placebo.
Yamaguchi Osamu,Uchida Eiji,Higo Naruhito,Minami Hidenao,Kobayashi Shigeo,Sato Hiroyuki,
Lower urinary tract symptoms
OBJECTIVE:To evaluate the efficacy, safety, and optimum dose of once-daily oxybutynin patch for overactive bladder. METHODS:A randomized double-blind trial was conducted in patients with overactive bladder symptoms for ≥24 weeks, who received an oxybutynin patch (73.5 or 105 mg) or placebo once daily for 8 weeks. The primary endpoint was the change in the daily frequency of micturition from baseline to the end of study. RESULTS:A total of 579 patients were randomized to the placebo group (n = 164), 73.5 mg oxybutynin patch group (n = 166), and 105 mg oxybutynin patch group (n = 165). The frequency of micturition (mean ± standard deviation) decreased by 1.19 ± 1.80 in the placebo group, 1.87 ± 1.93 in the 73.5 mg group, and 1.80 ± 1.76 in the 105 mg group. Compared with the placebo group, micturition decreased significantly in the 73.5 mg and 105 mg groups (t-test: P = 0.0025 and 0.0039, respectively), while the decrease was similar in both oxybutynin groups. The oxybutynin groups showed significant improvement of urgency, urge incontinence, incontinence, nocturia, mean voided volume, and five or six domains of the King's Health Questionnaire. Dry mouth was noted in 12.1% of the 73.5 mg group and 13.3% of the 105 mg group. Constipation was comparable between the oxybutynin groups and the placebo group. Application site reactions were less frequent in the 73.5 mg group than the 105 mg group. CONCLUSION:The efficacy of oxybutynin patch was confirmed, and the optimum dose for Japanese patients with overactive bladder was 73.5 mg.
Procyanidins-crosslinked small intestine submucosa: A bladder patch promotes smooth muscle regeneration and bladder function restoration in a rabbit model.
Zhang Xiu-Zhen,Jiang Yan-Lin,Hu Jun-Gen,Zhao Long-Mei,Chen Qiu-Zhu,Liang Yan,Zhang Yi,Lei Xiong-Xin,Wang Rui,Lei Yi,Zhang Qing-Yi,Li-Ling Jesse,Xie Hui-Qi
Currently the standard surgical treatment for bladder defects is augmentation cystoplasty with autologous tissues, which has many side effects. Biomaterials such as small intestine submucosa (SIS) can provide an alternative scaffold for the repair as bladder patches. Previous studies have shown that SIS could enhance the capacity and compliance of the bladder, but its application is hindered by issues like limited smooth muscle regeneration and stone formation since the fast degradation and poor mechanical properties of the SIS. Procyanidins (PC), a natural bio-crosslinking agent, has shown anti-calcification, anti-inflammatory and anti-oxidation properties. More importantly, PC and SIS can crosslink through hydrogen bonds, which may endow the material with enhanced mechanical property and stabilized functionalities. In this study, various concentrations of PC-crosslinked SIS (PC-SIS) were prepared to repair the full-thickness bladder defects, with an aim to reduce complications and enhance bladder functions. assays showed that the crosslinking has conferred the biomaterial with superior mechanical property and anti-calcification property, ability to promote smooth muscle cell adhesion and upregulate functional genes expression. Using a rabbit model with bladder defects, we demonstrated that the PC-SIS scaffold can rapidly promote tissue regrowth and regeneration, in particular smooth muscle remodeling and improvement of urinary functions. The PC-SIS scaffold has therefore provided a promising material for the reconstruction of a functional bladder.
Efficacy of cinnamon patch treatment for alleviating symptoms of overactive bladder: A double-blind, randomized, placebo-controlled trial.
Chen Lih-Lian,Shen Yuh-Chiang,Ke Chih-Chun,Imtiyaz Zuha,Chen Hui-I,Chang Chin-Hsien,Lee Mei-Hsien
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Current treatments for overactive bladder (OAB) have limited efficacy, low persistence and a high rate of adverse events commonly leading to treatment cessation in clinical practice. Clinicians in Asia commonly use traditional Chinese medicine as an alternative for OAB treatment despite it having uncertain efficacy and safety. To evaluate the efficacy and safety of cinnamon patch (CP) treatment for alleviating symptoms of OAB, a double-blind randomized, placebo-controlled trial was conducted in the present study. MATERIALS AND METHODS:In this 6-week randomized clinical trial conducted in an outpatient setting, 66 subjects diagnosed as having OAB were enrolled and treated with a placebo (n=33) or CP (n=33). The OAB symptom score (OABSS) was selected as the primary end point, and a patient perception of bladder condition (PPBC), an urgency severity scale (USS), and post-voiding residual urine (PVR) volume were selected as secondary end points. Statistical analyses were performed with IBM SPSS Statistics 20. Groups were compared using an independent sample t-test, Fisher exact test, and Chi-squared test. RESULTS:In total, 66 participants (40 women and 26 men), 60.35 ± 12.77 years of age, were included in the intention-to-treat analyses. Baseline characteristics were comparable between the CP (n ==33) and placebo (n ==33) groups. Treatment with a CP showed statistically significant differences in reductions in OABSS scores (9.70 ± 2.20 to 6.33 ± 2.42), PPBC scores (3.36 ± 0.60 to 2.15 ± 0.83), and USS scores (2.67 ± 0.54 to 1.64 ± 0.60). CONCLUSIONS:Compared to a placebo, treatment with CP might be considered an effective and safe complementary therapy for OAB. Further studies employing a positive control, different dosage forms, larger sample sizes, and longer treatment periods are warranted.
Effect of oxybutynin patch versus mirabegron on nocturia-related quality of life in female overactive bladder patients: A multicenter randomized trial.
Suzuki Toshiro,Minagawa Tomonori,Saito Tetsuichi,Nakagawa Tatsuo,Suzuki Tomio,Furuhata Masayuki,Hosaka Kyoko,Ogawa Teruyuki,Ishizuka Osamu
International journal of urology : official journal of the Japanese Urological Association
OBJECTIVES:To investigate the effect of oxybutynin patch versus β3-adrenoceptor agonist mirabegron on nocturia-related quality of life in female overactive bladder patients. METHODS:In the present study, female overactive bladder patients were enrolled. The patients were randomly allocated into two groups: the oxybutynin patch group and the mirabegron group. Each of the drugs was given for 8 weeks. The changes in the total Nocturia Quality of Life Questionnaire score were evaluated. Parameters on a frequency volume chart were also evaluated. RESULTS:In total, 100 patients (51 oxybutynin patch, 49 mirabegron) were treated with oxybutynin patch or mirabegron. The changes in the Nocturia Quality of Life Questionnaire score 4 weeks after administration were 3.8 ± 18.6 and 8.7 ± 13.1 with the oxybutynin patch group and the mirabegron group, respectively, which were significantly higher than those at the baseline. Furthermore, the changes in the Nocturia Quality of Life Questionnaire score 8 weeks after administration were 4.3 ± 16.5 and 7.7 ± 12.3, respectively. A statistical difference was seen only in the mirabegron group. Regarding the Nocturia Quality of Life Questionnaire subscores, oxybutynin patch and mirabegron significantly improved the Nocturia Quality of Life Questionnaire bother/concern subscore 4 and 8 weeks after administration, whereas the Nocturia Quality of Life Questionnaire sleep/energy subscore was not significantly improved in each period. Eight weeks after administration, 24-h frequency, 24-h urinary urgency and mean voided urine volume were improved in both groups statistically. CONCLUSIONS:The oxybutynin patch improves quality of life, focusing mainly on nocturia by improving the bother/concern subscores of the Nocturia Quality of Life Questionnaire in the short term.
The Current Use of Stem Cells in Bladder Tissue Regeneration and Bioengineering.
Chan Yvonne Y,Sandlin Samantha K,Kurzrock Eric A,Osborn Stephanie L
Many pathological processes including neurogenic bladder and malignancy necessitate bladder reconstruction, which is currently performed using intestinal tissue. The use of intestinal tissue, however, subjects patients to metabolic abnormalities, bladder stones, and other long-term sequelae, raising the need for a source of safe and reliable bladder tissue. Advancements in stem cell biology have catapulted stem cells to the center of many current tissue regeneration and bioengineering strategies. This review presents the recent advancements in the use of stem cells in bladder tissue bioengineering.
Bioengineering Approaches for Bladder Regeneration.
Serrano-Aroca Ángel,Vera-Donoso César David,Moreno-Manzano Victoria
International journal of molecular sciences
Current clinical strategies for bladder reconstruction or substitution are associated to serious problems. Therefore, new alternative approaches are becoming more and more necessary. The purpose of this work is to review the state of the art of the current bioengineering advances and obstacles reported in bladder regeneration. Tissue bladder engineering requires an ideal engineered bladder scaffold composed of a biocompatible material suitable to sustain the mechanical forces necessary for bladder filling and emptying. In addition, an engineered bladder needs to reconstruct a compliant muscular wall and a highly specialized urothelium, well-orchestrated under control of autonomic and sensory innervations. Bioreactors play a very important role allowing cell growth and specialization into a tissue-engineered vascular construct within a physiological environment. Bioprinting technology is rapidly progressing, achieving the generation of custom-made structural supports using an increasing number of different polymers as ink with a high capacity of reproducibility. Although many promising results have been achieved, few of them have been tested with clinical success. This lack of satisfactory applications is a good reason to discourage researchers in this field and explains, somehow, the limited high-impact scientific production in this area during the last decade, emphasizing that still much more progress is required before bioengineered bladders become a commonplace in the clinical setting.
Current Applications and Future Directions of Bioengineering Approaches for Bladder Augmentation and Reconstruction.
Wang Xuesheng,Zhang Fan,Liao Limin
Frontiers in surgery
End-stage neurogenic bladder usually results in the insufficiency of upper urinary tract, requiring bladder augmentation with intestinal tissue. To avoid complications of augmentation cystoplasty, tissue-engineering technique could offer a new approach to bladder reconstruction. This work reviews the current state of bioengineering progress and barriers in bladder augmentation or reconstruction and proposes an innovative method to address the obstacles of bladder augmentation. The ideal tissue-engineered bladder has the characteristics of high biocompatibility, compliance, and specialized urothelium to protect the upper urinary tract and prevent extravasation of urine. Despite that many reports have demonstrated that bioengineered bladder possessed a similar structure to native bladder, few large animal experiments, and clinical applications have been performed successfully. The lack of satisfactory outcomes over the past decades may have become an important factor hindering the development in this field. More studies should be warranted to promote the use of tissue-engineered bladders in clinical practice.
Efficacy of an additional flap operation in bladder-preserving surgery with radical prostatectomy and cystourethral anastomosis for rectal cancer involving the prostate.
Noguchi Keita,Nishizawa Yuji,Komai Yoshinobu,Sakai Yasuyuki,Kobayasi Akihiro,Ito Masaaki,Saito Norio
PURPOSE:Sphincter-preserving operations performed with bladder-preserving surgery and a cystourethral anastomosis (CUA) do not require a urinary stoma, but leakage from the CUA may develop. The aim of this study was to evaluate the efficacy of performing an additional flap operation. METHODS:The subjects were 39 patients who underwent bladder-preserving surgery for advanced rectal cancer involving the prostate, between 2001 and 2015.32 of whom had a CUA and one of whom had a neobladder. Five of these 32 patients underwent an ileal flap operation, 2 underwent an omental flap operation, and 3 underwent an operation using both flaps. RESULTS:Leakage developed in 3 (30%) of the 10 patients who underwent additional flap operations, but in 14 (60.9%) of the 23 patients who did not undergo a flap operation. The mean periods of catheterization for the patients who suffered leakage were 31 weeks (8-108 weeks) in those without a flap and 16 weeks (8-20 weeks) in those with a flap. Four (33.3%) of the 12 patients with leakage after surgery without a flap had a period of urinary catheterization >30 weeks, and 2 (16.7%) had leakage of CTCAE grade 3. There were no cases of leakage after flap surgery. CONCLUSION:An additional flap operation may decrease the risk of leakage from a CUA.
[Bladder neck sclerosis following prostate surgery : Which therapy when?]
Rassweiler J J,Weiss H,Heinze A,Elmussareh M,Fiedler M,Goezen A S
Der Urologe. Ausg. A
Secondary bladder neck sclerosis represents one of the more frequent complications following endoscopic, open, and other forms of minimally invasive prostate surgery. Therapeutic decisions depend on the type of previous intervention (e.g., radical prostatectomy, TURP, HoLEP, radiotherapy, HIFU) and on associated complications (e.g., incontinence, fistula). Primary treatment in most cases represents an endoscopic bilateral incision. No specific advantages of any type of the applied energy (i.e., mono-/bipolar HF current, cold incision, holmium/thulium YAG laser) could be documented. Adjuvant measures such as injection of corticosteroids or mitomycin C have not been helpful in clinical routine. In case of first recurrence, a transurethral monopolar or bipolar resection can usually be performed. Recently, the ablation of the scared tissue using bipolar vaporization has been recommended providing slightly better long-term results. Thereafter, surgical reconstruction is strongly recommended using an open, laparoscopic, or robot-assisted approach. Depending on the extent of the bladder neck sclerosis and the underlying prostate surgery, a Y-V/T-plasty, urethral reanastomosis, or even a radical prostatectomy with new urethravesical anastomosis should be performed. Stent implantation should be reserved for patients who are not suitable for surgery. The final palliative measure is a cystectomy with urinary diversion or a (continent) cystostomy.
Long-term Follow-up of Intravesical Onabotulinum Toxin-A Injections in Male Patients with Idiopathic Overactive Bladder: Comparing Surgery-naïve Patients and Patients After Prostate Surgery.
European urology focus
BACKGROUND:Evidence regarding long-term results in male idiopathic overactive bladder (iOAB) patients is limited and rarely focuses on the effects of prior prostatic surgery. OBJECTIVE:This study aims to identify the long-term treatment persistency and occurrence of adverse events of intravesical onabotulinum toxin-A (BoNT-A) injections in male iOAB patients after prostatic surgery (ie, transurethral resection of the prostate [TURP] or radical prostatectomy [RP]) compared with surgery-naïve patients. DESIGN, SETTING, AND PARTICIPANTS:In this retrospective, single-centre study, data from 477 patients treated with intravesical BoNT-A injections were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Outcome data of 120 male patients with iOAB, with collectively 207 BoNT-A injections, were analysed and presented in this study. RESULTS AND LIMITATIONS:At the last point of follow-up, 35 patients (29.2%) were still on active treatment. Twenty patients (16.7%) required de novo clean intermittent self-catheterisation (CISC). Three groups were identified: 56 patients without prostate surgery, 40 patients with TURP, and 24 patients with RP prior to treatment. Discontinuation rates and patient-reported outcomes of BoNT-A treatment (none, insufficient, or satisfactory) were similar, but a significant difference was seen in de novo CISC (p=0.004): 28.6% in the group without prior surgery, 7.5% in the TURP subgroup, and 4.2% in the RP subgroup. Odds of de novo CISC was significantly higher for the group without prior surgery than for both the TURP subgroup (odds ratio [OR] 4.9; 95% confidence interval [CI]: 1.33-18.31; p=0.017) and the RP subgroup (OR 9.2; 95% CI: 1.14-73.96; p= 0.037). CONCLUSIONS:The data of this retrospective, single-centre cohort suggest that BoNT-A treatment leads to lower CISC rates in male patients after prior desobstructive surgery than in surgery-naïve patients. PATIENT SUMMARY:This study describes the results of onabotulinum toxin-A (BoNT-A) injections in the bladder of male patients with idiopathic overactive bladder after initial prostate surgery compared with surgery-naïve patients. The results showed that BoNT-A treatment leads to lower catheterisation rates in patients after prior prostate surgery than in men without prior prostate surgery.
Understanding the role of mesenchymal stem cells in urinary bladder regeneration-a preclinical study on a porcine model.
Pokrywczynska Marta,Jundzill Arkadiusz,Rasmus Marta,Adamowicz Jan,Balcerczyk Daria,Buhl Monika,Warda Karolina,Buchholz Lukasz,Gagat Maciej,Grzanka Dariusz,Drewa Tomasz
Stem cell research & therapy
BACKGROUND:The tissue engineering of urinary bladder advances rapidly reflecting clinical need for a new kind of therapeutic solution for patients requiring urinary bladder replacement. Majority of the bladder augmentation studies have been performed in small rodent or rabbit models. Insufficient number of studies examining regenerative capacity of tissue-engineered graft in urinary bladder augmentation in a large animal model does not allow for successful translation of this technology to the clinical setting. The aim of this study was to evaluate the role of adipose-derived stem cells (ADSCs) in regeneration of clinically significant urinary bladder wall defect in a large animal model. METHODS:ADSCs isolated from a superficial abdominal Camper's fascia were labeled with PKH-26 tracking dye and subsequently seeded into bladder acellular matrix (BAM) grafts. Pigs underwent hemicystectomy followed by augmentation cystoplasty with BAM only (n = 10) or BAM seeded with autologous ADSCs (n = 10). Reconstructed bladders were subjected to macroscopic, histological, immunofluoresence, molecular, and radiological evaluations at 3 months post-augmentation. RESULTS:Sixteen animals (n = 8 for each group) survived the 3-month follow-up without serious complications. Tissue-engineered bladder function was normal without any signs of post-voiding urine residual in bladders and in the upper urinary tracts. ADSCs enhanced regeneration of tissue-engineered urinary bladder but the process was incomplete in the central graft region. Only a small percentage of implanted ADSCs survived and differentiated into smooth muscle and endothelial cells. CONCLUSIONS:The data demonstrate that ADSCs support regeneration of large defects of the urinary bladder wall but the process is incomplete in the central graft region. Stem cells enhance urinary bladder regeneration indirectly through paracrine effect.
Evaluation of the bioactivity about anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold for pelvic reconstruction.
Li Jiankui,Chen Xi,Ling Kaijian,Liang Zhiqing,Xu Huicheng
Journal of biomaterials applications
Introduction and hypothesis: Pelvic support structure injury is the major cause of pelvic organ prolapse. At present, polypropylene-based filler material has been suggested as a common method to treat pelvic organ prolapse. However, it cannot functionally rehabilitate the pelvic support structure. In addition to its poor long-term efficiency, the urinary bladder matrix was the most suitable biological scaffold material for pelvic floor repair. Here, we hypothesize that anti-sca-1 monoclonal antibody and basic fibroblast growth factor were cross-linked to urinary bladder matrix to construct a two-factor bioscaffold for pelvic reconstruction. METHODS:Through a bispecific cross-linking reagent, sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-smcc) immobilized anti-sca-1 and basic fibroblast growth factor to urinary bladder matrix. Then scanning electron microscope and plate reader were used to detect whether the anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold was built successfully. After that, the capacity of enriching sca-1 positive cells was measured both in vitro and in vivo. In addition, we evaluated the differentiation capacity and biocompatibility of the scaffold. Finally, western blotting was used to detect the level of fibulin-5 protein. RESULTS:The scanning electron microscope and plate reader revealed that the double-factor biological scaffold was built successfully. The scaffold could significantly enrich a large number of sca-1 positive cells both in vitro and in vivo, and obviously accelerate cells and differentiate functional tissue with good biocompatibility. Moreover, the western blotting showed that the scaffold could improve the expression of fibulin-5 protein. CONCLUSION:The anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold revealed good biological properties and might serve as an ideal scaffold for pelvic reconstruction.
Production and Preparation of Porcine Urinary Bladder Matrix (UBM) for Urinary Bladder Tissue-Engineering Purposes.
Davis N F,Callanan A
Advances in experimental medicine and biology
Surgical repair for the end stage bladder disease utilises vascularised, autogenous and mucus-secreting gastrointestinal tissue to replace the diseased organ or to augment inadequate bladder tissue. Post-operatively, the compliance of the bowel is often enough to restore the basic shape, structure and function of the urinary bladder; however, lifelong post-operative complications are common. Comorbidities that result from interposition of intestinal tissue are metabolic and/or neuromechanical, and their incidence approaches 100%. The debilitating comorbidities and complications associated with such urological procedures may be mitigated by the availability of alternative, tissue-engineered, animal-derived extracellular matrix (ECM) scaffolds such as porcine urinary bladder matrix (UBM). Porcine UBM is a decellularized biocompatible, biodegradable biomaterial derived from the porcine urinary bladder. This chapter aims to describe the production and preparation techniques for porcine UBM for urinary bladder regenerative purposes.
Two differentially structured collagen scaffolds for potential urinary bladder augmentation: proof of concept study in a Göttingen minipig model.
Leonhäuser Dorothea,Stollenwerk Katja,Seifarth Volker,Zraik Isabella M,Vogt Michael,Srinivasan Pramod K,Tolba Rene H,Grosse Joachim O
Journal of translational medicine
BACKGROUND:The repair of urinary bladder tissue is a necessity for tissue loss due to cancer, trauma, or congenital abnormalities. Use of intestinal tissue is still the gold standard in the urological clinic, which leads to new problems and dysfunctions like mucus production, stone formation, and finally malignancies. Therefore, the use of artificial, biologically derived materials is a promising step towards the augmentation of this specialised tissue. The aim of this study was to investigate potential bladder wall repair by two collagen scaffold prototypes, OptiMaix 2D and 3D, naïve and seeded with autologous vesical cells, as potential bladder wall substitute material in a large animal model. METHODS:Six Göttingen minipigs underwent cystoplastic surgery for tissue biopsy and cell isolation followed by implantation of unseeded scaffolds. Six weeks after the first operation, scaffolds seeded with the tissue cultured autologous urothelial and detrusor smooth muscle cells were implanted into the bladder together with additional unseeded scaffolds for comparison. Cystography and bladder ultrasound were performed to demonstrate structural integrity and as leakage test of the implantation sites. Eighteen, 22, and 32 weeks after the first operation, two minipigs respectively were sacrificed and the urinary tract was examined via different (immunohistochemical) staining procedures and the usage of two-photon laser scanning microscopy. RESULTS:Both collagen scaffold prototypes in vivo had good ingrowth capacity into the bladder wall including a quick lining with urothelial cells. The ingrowth of detrusor muscle tissue, along with the degradation of the scaffolds, could also be observed throughout the study period. CONCLUSIONS:We could show that the investigated collagen scaffolds OptiMaix 2D and 3D are a potential material for bladder wall substitution. The material has good biocompatible properties, shows a good cell growth of autologous cells in vitro, and a good integration into the present bladder tissue in vivo.
[Using of cell biocomposite material in tissue engineering of the urinary bladder].
Glybochko P V,Olefir Yu V,Alyaev Yu G,Butnaru D V,Bezrukov E A,Chaplenko A A,Zharikova T M
Urologiia (Moscow, Russia : 1999)
In a systematic review, to present an overview of the current situation in the field of tissue engineering of urinary bladder related to the use of cell lines pre-cultured on matrices. The selection of eligible publications was conducted according to the method described in the article Glybochko P.V. et al. "Tissue engineering of urinary bladder using acellular matrix." At the final stage, studies investigating the application of matrices with human and animal cell lines were analyzed. Contemporary approaches to using cell-based tissue engineering of the bladder were analyzed, including the formation of 3D structures from several types of cells, cell layers and genetic modification of injected cells. The most commonly used cell lines are urothelial cells, mesenchymal stem cells and fibroblasts. The safety and efficacy of any types of composite cell structures used in the cell-based bladder tissue engineering has not been proven sufficiently to warrant clinical studies of their usefulness. The results of cystoplasty of rat bladder are almost impossible to extrapolate to humans; besides, it is difficult to predict possible side effects. For the transition to clinical trials, additional studies on relevant animal models are needed.