Tissue-engineered therapies for the treatment of urinary incontinence and vesicoureteral reflux.
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Biocompatible Materials↗
Biomedical subjects
A Atala
Publications and source records attributed to A Atala.
Bladder augmentation techniques in women.
Augmentation cystoplasty is performed in women for a variety of indications, including neurogenic bladder dysfunction, inflammatory diseases, small fibrosed bladders, idiopathic urge incontinence and enuresis. The preoperative evaluation, surgical techniques and postoperative management are reviewed. Complications of stone formation, urinary tract infections, mucus production, metabolic disturbances, hematuria and dysuria syndrome, tumors and perforations are addressed. In addition, alternative techniques such as ureterocystoplasty, autoaugmentation, seromuscular cystoplasty and the future of augmentation of the bladder utilizing techniques of tissue engineering are discussed. The management of pregnancy in women who have previously undergone augmentation cystoplasty is also reviewed.
Cecum↗
Tissue engineering for bladder substitution.
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Biomedical Engineering↗
Biomaterials for tissue engineering.
Biomaterials play a critical role in the engineering of new functional genitourinary tissues for the replacement of lost or malfunctioning tissues. They provide a temporary scaffolding to guide new tissue growth and organization and may provide bioactive signals (e.g., cell-adhesion peptides and growth factors) required for the retention of tissue-specific gene expression. A variety of biomaterials, which can be classified into three types--naturally derived materials (e.g., collagen and alginate), acellular tissue matrices (e.g., bladder submucosa and small-intestinal submucosa), and synthetic polymers [e.g., polyglycolic acid, polylactic acid, and poly(lactic-co-glycolic acid)]--have proved to be useful in the reconstruction of a number of genitourinary tissues in animal models. Some of these materials are currently being used clinically for genitourinary applications. Ultimately, the development or selection of appropriate biomaterials may allow the engineering of multiple types of functional genitourinary tissues.
Biocompatible Materials↗
Tissue engineering of the bladder.
When gastrointestinal tissue is used for bladder augmentation or replacement, multiple complications may ensue, such as infection, metabolic disturbances, urolithiasis, perforation, increased mucous production, and malignancy. Therefore, alternative methods are being sought for cystoplasty. There has been a resurgence of interest in the use of acellular collagen-based matrices as scaffolds for bladder regeneration. Experimental work involving several collagen matrices, such as allogenic bladder and intestinal tissues, is currently being conducted in several academic centers. Recently, functional bladder tissue has been engineered using selective cell transplantation. The approach that has been followed for bioengineering of bladder tissue involves the use of autologous cells, thus avoiding rejection, whereby a biopsy of tissue is obtained from the host, after which the cells are dissociated and expanded in vitro, reattached to a matrix, and implanted into the same host.
Biocompatible Materials↗
Tissue-engineering applications for phallic reconstruction.
Pathologic penile conditions often require reconstructive surgery. Due to the limited amount of autologous tissues available for reconstruction, other tissue substitutes have been used. Phallic reconstruction using engineered autologous genital tissue, i.e., tissue derived from the patient's own cells, may be preferable. In this article we describe tissue-engineering approaches that may be applicable to genital reconstruction.
Biocompatible Materials↗
Experimental and clinical experience using tissue regeneration for urethral reconstruction.
Various urethral conditions often require additional tissue for reconstruction. Although several innovative tissues have been proposed for possible use as free grafts for urethral repair, all have specific advantages and disadvantages. The use of these tissues may be associated with additional procedures for graft retrieval, prolonged hospitalization, and donor-site morbidity. For these reasons, alternate materials have been sought for urethral repair. Our laboratory has developed an acellular collagen matrix that has shown adequate urothelial-cell epithelialization and urethral-tissue regeneration both experimentally and clinically. After a 3-year follow-up period, all patients who have had their urethras reconstructed with the acellular matrix are doing well, showing no clinical change from their immediate postoperative results. Other acellular materials may soon be tried clinically. Long-term studies need to be conducted before any of these materials can be accepted for routine use in urethral reconstructive procedures.
Animals↗
Renal therapy using tissue-engineered constructs and gene delivery.
Currently available renal replacement therapies are not optimal for most patients. In addition to the inherent shortage of transplant organs, significant complications are associated with renal transplantation and immunosuppressive therapy. Dialysis neglects the resorptive, homeostatic, metabolic, and endocrinologic functions of the kidney and only partially replaces its filtration properties, resulting in morbidity and mortality. Application of tissue-engineering techniques may improve many aspects of renal function replacement. Identification of the growth factors capable of directing tissue development and of the technique to be used for their delivery would aid in the engineering of human tissue. The combination of tissue-engineering strategies with gene therapy might allow the transfection of diseased tissues with designated cDNA to eliminate inherent or acquired defects. Devices that have been targeted at replacing a single aspect of renal function, in addition to three-dimensional renal units that are capable of excreting urine-like solutes, have been used experimentally. Combination of these strategies may allow the formation of tissue-engineered kidneys in the future.
Biocompatible Materials↗
Controlled release of therapeutic agents: slow delivery and cell encapsulation.
Some of the most promising systems for the controlled release of bioactive agents, i.e., peptides or hormones, involve the encapsulation or entrapment of hormones or peptides in biocompatible polymeric devices that enable their continuous release over prolonged periods. In urology, two major pathologic conditions, androgen deficiency and prostate cancer, currently benefit from treatments based on controlled delivery. Leuprolide acetate depot (Lupron-depot) was one of the first controlled-delivery systems used for the treatment of prostate cancer. Clinical studies indicate that patients with prostate cancer who undergo therapy with leuprolide acetate depot can benefit from this treatment. Currently available androgen-replacement therapies include the oral administration of testosterone tablets or capsules, depot injections, sublingual treatment, and skin patches. However, side effects such as metabolic inactivation of testosterone on oral administration; fluctuations in levels of the hormone; and burning, rash, and skin necrosis during the use of skin patches may occur. These side effects may be avoided through the application of encapsulated Leydig cells, which produce testosterone. Studies in our laboratory have shown that Leydig cells encapsulated in alginate/poly-L-lysine/alginate microspheres are capable of secreting testosterone in culture and in vivo. Microencapsulated Leydig cells delivered intraperitoneally into castrated rats maintained a testosterone level of 0.51 ng/ml for more than 3 months without any human chorionic gonadotropin stimulation. Similar studies are also being conducted in our laboratory on encapsulation of ovarian cells for the secretion of progesterone and estrogen in culture and in vivo using microencapsulation techniques.
Animals↗
Tissue engineering of artificial organs.
Tissue engineering efforts are currently being undertaken for every type of tissue and organ within the urinary system. Most of the effort expended to engineer genitourinary tissues has occurred within the last decade. Tissue engineering techniques require expertise in growth factor biology, a cell culture facility designed for human application, and personnel who have mastered the techniques of cell harvest, culture, and expansion. Polymer scaffold design and manufacturing resources are essential for the successful application of this technology. In order to apply these engineering techniques to humans, further studies need to be performed with many of the tissues described. The first human application of cell-based tissue engineering technology for urologic applications took place at our institution, with the injection of autologous cells for the correction of vesicoureteral reflux in children. The same technology has been expanded to treat adult patients with urinary incontinence. Trials of urethral tissue replacement with processed collagen matrices are in progress, and bladder replacement using tissue engineering techniques are currently being arranged. Recent progress suggests that engineered urologic tissues may have clinical applicability in the future.
Artificial Organs↗
Ketorolac suppresses postoperative bladder spasms after pediatric ureteral reimplantation.
UNLABELLED: We evaluated the efficacy of ketorolac in suppressing postoperative bladder spasms after ureteroneocystostomy (ureteral reimplantation). Twenty-four pediatric patients undergoing intravesical ureteroneocystostomy were enrolled prospectively to receive either ketorolac or placebo via double-blinded randomization. Twelve patients in each group shared similar preoperative characteristics. All were maintained on an epidural infusion of bupivacaine (0.1%) with fentanyl (2 microg/mL) throughout the study. Patients were given either ketorolac (0.5 mg. kg(-1). dose(-1)) or placebo (equivalent volume saline) IV after surgery and every 6 h thereafter for 48 h. Parents were instructed to record bladder spasm episodes prospectively by using a standardized time-flow diary. Three patients (25%) in the ketorolac group experienced bladder spasms, compared with 10 patients (83%) in the placebo group (two-sided P < 0.05). The median severity score for the ketorolac group was 1.2 (mild = 1.0, severe = 3.0), compared with 2.6 for the placebo group (P = 0.003). We conclude that IV ketorolac reduces the frequency and severity of postoperative bladder spasms after intravesical ureteroneocystostomy. IMPLICATIONS: We studied the efficacy of ketorolac, a prostaglandin synthesis inhibitor, in the treatment of bladder spasm after ureteroneocystostomy (antireflux operation). Patients were randomized in a double-blinded manner to receive either ketorolac or placebo after the surgery. We demonstrate that ketorolac reduces the frequency and severity of postoperative bladder spasm.
Anti-Inflammatory Agents, Non-Steroidal↗
Initial experience with the transurethral self-detachable balloon system for urinary incontinence in pediatric patients.
PURPOSE: A new endoscopic technique to treat urinary incontinence in children using a self-detachable balloon device was studied. MATERIALS AND METHODS: The study includes 11 patients with a mean age of 14.6 years and all of whom had intrinsic sphincter deficiency due to myelomeningocele in 9, spinal artery bleed in 1 and cloacal exstrophy in 1. All patients were on clean intermittent catheterization preoperatively and postoperatively. Endoscopic balloon treatment was performed on an outpatient basis. A mean of 5 balloons (range 2 to 8) were placed per patient. All patients underwent formal urodynamic study preoperatively and at 6 weeks and 6 months following balloon placement. RESULTS: Of the 9 patients without prior bladder neck surgery 7 had improvement in urodynamic parameters, including urethral pressure profile in all 7 and functional bladder capacity in 6, 4 were markedly improved clinically and 2 were dry. Two patients with prior bladder neck surgery were clinically unchanged following balloon placement, although 1 had urodynamic improvement. CONCLUSIONS: Our initial experience with the transurethral self-detachable balloon system as a minimally invasive outpatient procedure to treat urinary incontinence in children has been encouraging. To date this procedure appears most applicable to the patient who has not undergone surgery and has a neurogenic etiology for urinary incontinence.
Adolescent↗
Defunctionalized bladders: effects before and after refunctionalization in an animal model.
PURPOSE: Bladder behavior after refunctionalization is usually unpredictable. We comparatively analyze various aspects of bladder defunctionalization and subsequent refunctionalization using an animal model. MATERIALS AND METHODS: A total of 18 rabbits were divided equally into 3 groups. Animals in group 1 underwent 2 successive surgical procedures, including bladder division and reattachment. Bladder division was performed by hemisecting the bladder from dome to trigone into a functioning and nonfunctioning chamber. Bladder reattachment was achieved by reanastomosing both hemibladders. Group 2 animals underwent sham operations, and group 3 animals were age matched normal controls. Serial urodynamic studies and fluoroscopic cystograms were performed in all animals. Gross, histochemical (hematoxylin and eosin, Masson's trichrome and Sirius red) and immunocytochemical (alpha-actin, collagen I and III) analyses, collagen content determination and organ bath studies were performed. RESULTS: The defunctionalized hemibladders demonstrated lower wet weight, capacity and compliance compared to the functional contralateral and normal control bladders. Refunctionalization of the bladders resulted in a progressive recovery of capacity and compliance with time. The bladder contractile response and connective tissue-to-muscle ratio were abnormal in the defunctionalized segments but normalized after bladder refunctionalization. CONCLUSIONS: Defunctionalization results in remarkable alterations in bladder growth, capacity, compliance and distribution of connective tissue. However, these bladders demonstrate an innate capacity to recover from these alterations following refunctionalization.
Animals↗
Comparative assessment of pediatric testicular volume: orchidometer versus ultrasound.
PURPOSE: Testicular volume measurements obtained with the Prader and Rochester orchidometers were compared to those obtained using scrotal ultrasound. The ability of each orchidometer versus ultrasound in detecting volume differential between 2 testes and the accuracy of orchidometer measurement by a less experienced examiner to that of a urologist were compared. MATERIALS AND METHODS: A total of 65 males were examined by the attending urologist and urology nurse using the Prader and Rochester orchidometers, and scrotal ultrasound was subsequently performed by an attending radiologist. Statistical analysis of the results was performed to determine the correlation of orchidometer measurements between examiners, as well as with ultrasound, and sensitivity and specificity of orchidometer and ultrasound in detecting defined volume differentials between testes of 10%, 15%, 20% and 25%. RESULTS: There was a strong linear relationship between testicular volume measurements using either orchidometer and ultrasound. To detect a defined volume differential as determined by ultrasound orchidometer sensitivity was weak, whereas orchidometer specificity was better. There was a strong correlation between orchidometer measurements of the urology nurse and attending urologist. CONCLUSIONS: Although the orchidometer remains valuable in assessing size of the individual testis, it is too insensitive to volume differentials relative to ultrasound to be used routinely to determine growth impairment. For this reason observation of an adolescent with varicocele should include an annual ultrasound assessment of testicular volume.
Adolescent↗
New methods of bladder augmentation.
Gastrointestinal segments are commonly used for bladder replacement or repair. However, when gastrointestinal tissue is in contact with the urinary tract, several complications may ensue. Recent surgical approaches have relied on native urological tissue for reconstruction. These are based on sound surgical principles, allowing for the exclusion of tissue that is not urological. De-epithelialized bowel segments, either alone or over native urothelium, have also been used. An experimental system of progressive dilatation for ureters and bladders has been proposed. This appears promising, although it has yet to be attempted clinically. There has been a resurgence of interest in the use of acellular collagen-based matrices as scaffolds for bladder regeneration; experimental work is currently underway. Recently, functional bladder tissue has been engineered using selective cell transplantation. This technique uses autologous cells, so avoiding rejection. Tissue is obtained from the host, the cells then dissociated and expanded in vitro, re-attached to a matrix and implanted into the same host. Clinical trials are currently being arranged. Even though the use of bowel for bladder tissue replacement was first proposed over 100 years ago, it remains the gold standard, despite its associated problems. It is evident that urothelial-urothelial anastomoses are preferable functionally. Experience is currently being gained with the recent clinical and experimental approaches to augmentation cystoplasty. It is hoped that this will result in more technologies and methods for bladder augmentation.
Animals↗
Effect of chronic, low-pressure, sterile vesicoureteral reflux on renal growth and function in a porcine model: a radiologic and pathologic study.
PURPOSE: To study the effects of chronic, low-pressure, sterile vesicoureteral reflux (VUR) on renal growth and function in a porcine model. MATERIALS AND METHODS: Unilateral VUR was created in five pigs, with the contralateral kidney serving as a control. Preoperatively, and 1 year later, ultrasonography, technetium 99m-dimercaptosuccinic acid (DMSA) scintigraphy, contrast material-enhanced computed tomography (CT), and contrast-enhanced magnetic resonance (MR) imaging were performed. Morphologic abnormalities and relative uptake of (99m)Tc-DMSA were recorded. The postcontrast enhancement ratios for parenchymal regions of interest at CT and MR imaging were determined. Ruthenium 103-labeled microspheres were used to determine regional blood flow. After the pigs were sacrificed, the kidneys were excised, weighed, and analyzed pathologically. RESULTS: Two of five refluxing kidneys had less than 45% function at scintigraphy. One of these two kidneys was small at postmortem examination. There were no other imaging or gross pathologic abnormalities. There was no significant difference in regional blood flow between the refluxing and nonrefluxing kidneys. In all of the operated on kidneys, histologic examination showed focal chronic inflammation and fibrosis. CONCLUSION: Low-pressure sterile reflux into previously normal kidneys led to mild, focal, chronic interstitial inflammation and fibrosis after 1 year. Imaging findings were normal apart from a subtle decrease in tubular function in two refluxing kidneys.
Animals↗
Sibling vesicoureteral reflux in multiple gestation births.
BACKGROUND: Vesicoureteral reflux (VUR) is the most commonly inherited disease of the genitourinary tract. Although the majority of evidence supports a genetic cause, the tendency for this condition to spontaneously improve over time has made it difficult to determine the actual mode of transmission. We report the incidence of VUR in siblings of multiple gestation births and for the first time compare the relative incidence of reflux between identical and fraternal twins. METHODS: A database consisting of all radionuclide cystograms and voiding cystourethrograms performed between the years 1986 and 1996 was searched for multiple gestation births. The medical records of each patient were evaluated for age at presentation, zygosity, reflux grade, and time to resolution. Children with secondary causes of VUR (eg, posterior urethral valves) were excluded. Triplets were treated as 2 pairs of twins for statistical analysis. RESULTS: Forty-six pairs met the inclusion criteria (31 dizygotic and 15 monozygotic). Overall, 23 (50%) of 46 siblings of index cases had demonstrable VUR. Comparison of VUR prevalence between identical and nonidentical twins was revealing with 80% (12/15) of identical twins and 35% (11/31) of fraternal twins having VUR. When only the youngest individuals in each group were considered, 100% (7/7) of the monozygotics and 50% (5/10) of the dizygotics demonstrated this trait. CONCLUSIONS: High concordance for VUR in identical twin siblings supports a genetic basis for the transmission of this disease. Results obtained from fraternal twin siblings provides convincing evidence that this trait is transmitted in an autosomal dominant fashion.
Child↗
Tissue engineering applications in the genitourinary tract system.
The concept of cell transplantation using tissue engineering techniques has provided numerous possibilities in the area of urologic tissue reconstruction. Tissue engineering applications in the genitourinary tract system have been investigated in almost every tissue in order to improve, restore and replace existing tissue function. Although most reconstructive efforts still remain in the experimental stage, several technologies have been transferred to the bedside with satisfactory outcome. In this article, we describe tissue engineering approaches attempted in the genitourinary system for reconstruction.
Animals↗