Search

Current drug treatment of lower urinary tract disorders, for example, overactive bladder syndrome and lower urinary tract symptoms associated with benign prostatic hyperplasia, is moderately effective, has a low treatment persistence and some short- and long-term adverse events. Even if combination therapy with approved drugs may offer advantages in some patients, there is still a need for new agents.New bNew potential alternatives to currently used drugs/drug principles are emerging, but further clinical testing is required before they can be evaluated as therapeutic alternatives. It seems that for the near future individualized treatment with approved drugs and their combinations will be the prevailing therapeutic approach.

A need exists for local (ie, bladder-specific) interventions to treat overactive bladder (OAB) with low risk of unwanted postprocedural outcomes. Gene therapy targeted to leverage endogenous physiology in bladder cells may assist in restoring normal cell and organ function. Herein, we review the potential promise of gene therapy for treating OAB, focusing on gene transfer of URO-902, a non-viral naked plasmid DNA expressing the big potassium (BK) channel. We searched PubMed for articles concerning functional aspects of the BK channel and its potential use for gene transfer as local OAB treatment. Results from preclinical, phase 1, and phase 2 studies of URO-902 for erectile dysfunction and phase 1 studies of URO-902 for OAB are included. The BK channel has been extensively studied; however, URO-902 is the first gene therapy used in clinical trials directed toward treating OAB via the BK channel. In both URO-902 studies, there were no serious adverse events considered treatment related and no adverse events leading to early withdrawal. Both studies included secondary efficacy endpoints with promising results suggesting improvement in OAB symptoms, and quality of life, with use of URO-902 versus placebo. Gene therapy involving the BK channel, such as gene transfer with URO-902, has demonstrated promising safety and efficacy results in women with OAB. Findings warrant further investigation of the use of URO-902 for OAB treatment.

Aims: Rodent cystometry has provided valuable insights into the impact of the disease, injury, and aging on the cellular and molecular pathways, neurologic processes, and biomechanics of lower urinary tract function. The purpose of this white paper is to highlight the benefits and shortcomings of different experimental methods and strategies and to provide guidance on the proper interpretation of results. Methods: Literature search, selection of articles, and conclusions based on discussions among a panel of workers in the field. Results: A range of cystometric tests and techniques used to explore biological phenomena relevant to the lower urinary tract are described, the advantages and disadvantages of various experimental conditions are discussed, and guidance on the practical aspects of experimental execution and proper interpretation of results are provided. Conclusions: Cystometric evaluation of rodents comprises an extensive collection of functional tests that can be performed under a variety of experimental conditions. Decisions regarding which approaches to choose should be determined by the specific questions to be addressed and implementation of the test should follow standardized procedures. (Less)

Aims Two phase 1 trials were performed in healthy women with the overactive bladder (OAB) syndrome and urodynamically demonstrated detrusor overactivity (DO), with the aim to demonstrate the safety and potential efficacy of URO‐902, which comprises a gene therapy plasmid vector expressing the human big potassium channel α subunit. Methods ION‐02 (intravesical instillation) and ION‐03 (direct injection) were double‐blind, placebo‐controlled, multicenter studies without overlap in enrollment between studies. Active doses were administered and evaluated sequentially (lowest dose first) for safety. ION‐02 participants received either 5000 µg or 10 000 µg URO‐902, or placebo. ION‐03 participants received either 16 000 or 24 000 µg URO‐902, or placebo, injected directly into the bladder wall using cystoscopy. Primary outcome variables were safety parameters occurring subsequent to URO‐902 administration; secondary efficacy variables also were evaluated. Results Among the safety outcomes, there were no dose‐limiting toxicities or significant adverse events (AEs) preventing dose escalation during either trial, and no participants withdrew due to AEs. For efficacy, in ION‐02 (N = 21), involuntary detrusor contractions on urodynamics at 24 weeks in patients receiving URO‐902 (P

Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I), tadalafil, is also approved to treat BPH and LUTS suggesting a role for nitric oxide (NO•), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO• production, or inflammation-related oxidation of the sGC haem group, normally maintained in a reduced state by the cofactor, cytochrome-b5-reductase 3 (CYB5R3). sGC activators, such as cinaciguat (BAY 58-2667), have been developed to enhance sGC activity in the absence of NO• or when sGC is oxidised. Accordingly, their effects on the prostate and LUT function of aged mice were evaluated. Aged mice (≥24 months) demonstrated a functional BPH/BOO phenotype, compared to adult animals (2-12 months), with low, delayed voiding responses and elevated intravesical pressures as measured by telemetric cystometry. This was consistent with outflow tract histological and molecular data that showed urethral constriction, increased prostate weight, greater collagen deposition and cellular hyperplasia. All changes in aged animals were attenuated by daily oral treatment with cinaciguat for two weeks, without effect on serum testosterone levels. Cinaciguat had only transient (1 h) cardiovascular effects with oral gavage suggesting a positive safety profile. The benefit of cinaciguat was suggested by its reversal of an overactive cystometric profile in CYB5R3 smooth muscle knock-out mice that mirrors a profile of oxidative dysfunction where PDE5I may not be effective. Thus, the aged male mouse is a suitable model for BPH-induced BOO and cinaciguat has a demonstrated ability to reduce prostate-induced obstruction and consequent effects on bladder function. This article is protected by copyright. All rights reserved.

Purpose of review Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD). Recent findings In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model. Summary As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.

Lower urinary tract (LUT) dysfunction is the most common complication of diabetes mellitus (DM). An involvement of the 5-HT2A receptor in spinal micturition control has been demonstrated in urethane anaesthetized DM rats in which i.v. administration of the 5-HT2A/2C receptor agonist 2,5-methoxy-4-iodoamphetamine (DOI), stimulated high frequency oscillations (HFOs) and improved micturition. However, the mechanisms involved in these effects are not completely understood. The present work showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons, and the number of serotonergic paraneurons were downregulated in the urethra in DM group. The importance of the downregulation of urethral paraneurons in DM remains to be elucidated but may be related to the reduced urethral sensation caused by the disease. We suggest that targets of 5-HT receptor agonists for improvement of voiding function may be found both in the LUT and lumbosacral spinal cord.

Objective: To perform a descriptive microscopic study of prostatectomy specimens from 19 patients which anatomically characterizes the distributions of periprostatic nerve qualities, and to visualize these using diffusion tensor imaging (DTI). Materials and Methods: Serial whole-mounted sections were stained for cholinergic (neuronal nitric oxide synthase), adrenergic (tyrosine hydroxylase) and sensory (calcitonin gene-related peptide) nerves. Extracapsular stained nerves were counted by prostate surface sector, and classified by diameter. Stain-related relative density was calculated, and distribution patterns were evaluated. To better visualize the reported neuronal structures and independently confirm our findings, nerve concordance in five male volunteers was investigated using a 3-Tesla magnetic resonance imaging-DTI system. Results: At the base, cholinergic nerves were distributed from the anterolateral to posterior sectors, continuing posterolaterally (mid-section) into the posterolateral-posterior sector toward the apex. Adrenergic nerves were distributed across the anterolateral-posterior sectors at the base, with the course narrowing to the posterolateral-posterior sectors at the mid- and apical levels. Sensory fibres were found posterolaterally posteriorly at the base, continuing posterolaterally over the mid- and apical levels. Although it was not possible to determine the different nerve qualities, DTI confirmed histological findings from the base to the apex. Conclusions: Different types of nerve fibres were found to vary in distribution. When linked to possible functional aspects of the different nerve types, this morphological evidence may be of importance to further protect function after radical prostatectomy (RP). To our knowledge, this is the first time that DTI has confirmed reported histological findings in nerve-sparing RPs. DTI could be an important tool with which to correlate nerves to tumour for better preoperative planning and to incorporate imaging into treatment.

Purpose A major question remaining in approaches to tissue engineering and organ replacement is the role of native mobilized native cells in the regeneration process of damaged tissues and organs. The goal of this study was to compare the cell mobilizing effects of the chemokine CXCL12 and cell therapy on the urinary sphincter of nonhuman primates (NHP) with chronic intrinsic urinary sphincter dysfunction. Methods Either autologous lenti-M-cherry labeled skeletal muscle precursor cells (skMPCs) or CXCL12 were injected directly into the sphincter complex of female NHPs with or without surgery-induced chronic urinary sphincter dysfunction (n=4/treatment condition). All monkeys had partial bone marrow transplantation with autologous lenti-green fluorescent protein (GFP) bone marrow cells prior to treatment. Labeled cells were identified, characterized and quantified using computer-assisted immunohistochemistry 6 months posttreatment. Results GFP-labeled bone marrow cells (BMCs) were identified in the bone marrow and both BMCs and skMPCs were found in the urinary sphincter at 6-month postinjection. BMCs and skMPCs were present in the striated muscle, smooth muscle, and lamina propria/urothelium of the sphincter tissue. Sphincter injury increased the sphincter content of BMCs when analyzed 6-month postinjection. CXCL12 treatment, but not skMPCs, increased the number of BMCs in all layers of the sphincter complex (P

During the late 19th and the early 20th century there was an unprecedented development in medical research. Tissue and cell culture rapidly developed into areas with many contributing scientists. The same is true for tissue transplantation. When these achievements are described afterwards in a historical context and a mainline development is constructed, there are researchers whose pioneering work is forgotten. The present paper attempts to correct this and to present a correct description of the start of tissue preservation and transplantation. We have traced relevant original publications in international journals between 1870 and 1920. The traditional view is that Alexis Carrel was the first He received a Nobel Prize 1912 for his work on vascular suture and the transplantation of blood vessels and organs. The same year he published an article on human skin storage and transplantation. This was more than a decade later than Carl August Ljunggren (1860–1934) who 1898 published his pioneering but long forgotten work on human skin preservation and transplantation, and with a vision of tissue banks. Our article contains a brief biography of Ljunggren, and further reconstructs the processes that resulted in the lack of awareness today of his achievements. Conclusion: Carl August Ljunggren was the first to preserve human skin in vitro for prolonged periods, followed by transplantation of the specimens to other patients. He was also the first to propose the use of tissue banks.

Aim: To discuss animal models of lower urinary tract disorders (LUTD) and their translational impact. Methods: Report of discussions based on presented literature-search based reviews relevant for the purpose. Results: Animal models can be used to investigate fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of disease and to provide early evidence of any safety risk. Several different models may be required to obtain information that can have a translational impact. The term “translational research” covers not only the process of directly transferring knowledge from basic sciences to human trials to produce new drugs, devices, and treatment options for patients (T1 type translation) but also the implementation of early clinical research findings (phases I-III) into practice to improve care for patients (T2 type). Direct transfer of animal data to T2 is rarely possible, and the process often does not continue after the first trials in humans (phase I). It should be emphasized that many preclinical observations do not have (and do not need to have) immediate translational impact. Conclusions: No single animal model can mimic the complexity of the human disease. Still, animal models can be useful for gaining information on LUT function in humans, for elucidating pathophysiological mechanisms, and for the definition of targets for future drugs to treat LUT disorders. (Less)

Several studies indicate that pelvic ischemia and oxidative stress may play a significant role in lower urinary tract dysfunction (LUTD), including detrusor overactivity (DO)/overactive bladder (OAB) and detrusor underactivity (DU)/underactive bladder (UAB). The present article addresses proposal 1: "Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?" from the 2019 International Consultation on Incontinence-Research Society (ICI-RS) meeting. Bladder ischemia in animals and humans is briefly described, along with the proposed progression from ischemia to LUTD. Bladder ischemia is compared with ischemia of other organs, and the ongoing development of pelvic ischemia animal models is discussed. In addition, the distribution of blood within the bladder during filling and voiding and the challenges of quantification of blood flow in vivo are described. Furthermore, oxidative stress, including potential biomarkers and treatments, and challenges regarding antioxidant therapy for the treatment of LUTD are discussed. Finally, seven critical research questions and proposed studies to answer those questions were identified as priorities that would lead to major advances in the understanding and treatment of lower urinary tract symptoms (LUTS)/LUTD associated with pelvic ischemia and oxidative stress.

The bladder and urethra constitute a functional unit controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. Peripherally, lower urinary tract function is dependent on the coordinated action of the smooth and striated muscles of the urinary bladder, urethra, and periurethral region. Various neurotransmitters, including acetylcholine, noradrenaline, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in this neural regulation, which in the adult is controlled by a spinobulbospinal reflex, which is under suprapontine control. In the present review the relevant anatomy, innervation and receptor functions in the bladder and urethra are discussed.

Objectives To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). Materials and methods In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. Results LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 μg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10 μg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. Conclusion A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.

AIMS To explore whether autophagy plays a role in the remodeling of bladder smooth muscle cells (SMCs) in children with neurogenic lower urinary tract dysfunction (NLUTD), we investigated the effect of autophagy in NLUTD in the paediatric population. METHODS Bladder biopsies were taken from children with NLUTD and healthy donors as controls. Samples were labeled with the SMC markers calponin, smoothelin, and the autophagy proteins LC3, ATG5, and Beclin1. The contractile ability of bladder derived SMCs was investigated. RESULTS ATG5 gene and protein was upregulated in NLUTD muscle tissue compared to normal bladder. NLUTD muscle exhibited a punctated immunostaining pattern for LC3 in a subset of the SMCs, confirming the accumulation of autophagosomes. Pronounced elevation of ATG5 in the SMC in NLUTD tissue was associated with a downregulation of the key contractile proteins smoothelin and calponin. Pharmacological blocking of autophagy completely stopped the cells growth in normal bladder SMCs. Inhibition of autophagy in the NLUTD SMCs, with already elevated levels of ATG5, resulted in a reduction of ATG5 protein expression to the basal level found in normal controls. CONCLUSIONS Our study suggests that autophagy is an important factor affecting the remodeling of SMCs and the alteration of functionality in bladder smooth muscle tissue in the NLUTD. Since autophagy can be influenced by oral medication, this finding might lead to novel strategies preventing the deterioration of NLUTD muscle.

The acontractile bladder (AcB) is a urodynamic-based diagnosis wherein the bladder is unable to demonstrate any contraction during a pressure flow study. Although it is often grouped with underactive bladder, it is a unique phenomenon and should be investigated independently. The purpose of the present review was to examine the current literature on AcB regarding its pathology, diagnosis, current management guidelines, and future developments. We performed a review of the PubMed database, classifying the evidence for AcB pathology, diagnosis, treatment, and potential future treatments. Over the 67 years covered in our review period, 42 studies were identified that met our criteria. Studies were largely poor quality and mainly consisted of retrospective review or animal models. The underlying pathology of AcB is variable with both neurological and myogenic aetiologies. Treatment is largely tailored for renal preservation and reduction of infection. Although future developments may allow more functional restorative treatments, current treatments mainly focus on bladder drainage. AcB is a unique and understudied bladder phenomenon. Treatment is largely based on symptoms and presentation. While cellular therapy and neuromodulation may hold promise, further research is needed into the underlying neuro-urological pathophysiology of this disease so that we may better develop future treatments.

The discovery of the nitric oxide/cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of PDE5 have been the first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms, and pulmonary arterial hypertension, which are now approved indications. However, PDE5 inhibitors have also been used in several other disorders not discussed in this review, and the fields of clinical use are increasing. In the present review, the pharmacological basis of the NO/cGMP pathway and the rationale and clinical use of PDE5 inhibitors in different diseases are discussed.

Previous work demonstrated restoration of a bioequivalent bladder within 8 weeks of removing the majority of the bladder (subtotal cystectomy or STC) in rats. The goal of the present study was to extend our investigations of bladder repair to the murine model, to harness the power of mouse genetics to delineate the cellular and molecular mechanisms responsible for the observed robust bladder regrowth. Female C57 black mice underwent STC, and at 4, 8, and 12 weeks post-STC, bladder repair and function were assessed via cystometry, ex vivo pharmacologic organ bath studies, and T2-weighted magnetic resonance imaging (MRI). Histology was also performed to measure bladder wall thickness. We observed a time-dependent increase in bladder capacity (BC) following STC, such that 8 and 12 weeks post-STC, BC and micturition volumes were indistinguishable from those of age-matched non-STC controls and significantly higher than observed at 4 weeks. MRI studies confirmed that bladder volume was indistinguishable within 3 months (11 weeks) post-STC. Additionally, bladders emptied completely at all time points studied (i.e., no increases in residual volume), consistent with functional bladder repair. At 8 and 12 weeks post-STC, there were no significant differences in bladder wall thickness or in the different components (urothelium, lamina propria, or smooth muscle layers) of the bladder wall compared with age-matched control animals. The maximal contractile response to pharmacological activation and electrical field stimulation increased over time in isolated tissue strips from repaired bladders but remained lower at all time points compared with controls. We have established and validated a murine model for the study of de novo organ repair that will allow for further mechanistic studies of this phenomenon after, for example, genetic manipulation.

Objectives To explore if the mechanism of the voiding dysfunction caused by spinal cord injury in rats can be improved by intravenous administration of the 5-HT2A/2C receptor agonist, DOI, and discuss whether it can be ascribed to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons. Materials and Methods Female Sprague-Dawley rats were used, which were divided into two groups (Spinal cord injury group VS Normal control group). Under urethane anesthesia, cystometry was performed to examine the variation of urodynamic parameters before and after successive intrathecal administration of various doses of DOI into the lumbosacral cord. Additionally, the changes of serotonin 2A and 2C receptors in the lumbosacral cord were investigated by immunohistochemical staining and Western blot. Results Compared to controls, spinal cord injured rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After spinal cord injury, DOI improved voiding efficiency likely via affecting external urethral sphincter activity. Immunohistochemical staining and Western blot analysis showed that serotonin 2A and 2C receptors were up-regulated in lumbosacral cord motoneurons. Conclusion In rats with spinal cord injury, DOI can improve voiding efficiency, and this may be due to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons controlling external urethral sphincter activity. This article is protected by copyright. All rights reserved.

The overactive bladder (OAB) syndrome, characterized by urinary urgency with or without urgency urinary incontinence (UUI) and usually associated with increased daytime frequency and nocturia (1), is a common condition worldwide. Independent of the methodology used (telephone survey, postal survey) several epidemiologic studies in Europe, Canada, the United States, and Japan have shown the OAB syndrome to be present in 8.0% to 16.5% of adults, with similar rates between men and women (2,3).

Half of the female population over age 50 years will experience pelvic organ prolapse. We suggest a new approach based on tissue engineering principles to functionally reconstruct the anatomical structures of the pelvic floor. The aim of this study is to investigate the mechanical performance and effect on collagen and elastin production of a degradable mesh releasing basic fibroblast growth factor (bFGF). Implantation of biodegradable mesh with or without bFGF in their core has been conducted in 40 rats in an abdominal wall defect model. Samples were explanted after 4, 8, and 24 weeks, and tested for mechanical properties and the composition of connective tissue. The study showed an increase in mRNA expression for collagen-I (p = 0.0060) and collagen-III (p = 0.0086) in the 4 weeks group with bFGF. The difference was equalized at 8 and 24 weeks. No difference was found at any time for protein amount for collagen-I, collagen-III, and fibronectin. The amount of collagen decreased from 4 to 24 weeks but the fraction of collagen increased. The maximal load of the newly formed tissue showed no effect of bFGF at any time. Exclusively, histology showed a limited ingrowth of collagen fibers after 4 weeks with bFGF but signs of elastin fibers were seen at 24 weeks. The investigation showed that a biodegradable mesh promotes tissue formation with a promising strength. The mesh with bFGF did not represent any advantage on either long or short term in comparison to the mesh without bFGF. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 680–688, 2018.

The clinical success of mirabegron as the first β3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β3-AR stimulation have still not been established. The recent demonstration of β3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β3-ARs can be found these structures. However, recent studies suggest that the β3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.

Purpose: Mixed efficacy results of autologous skeletal muscle precursor cell therapy in women with chronic intrinsic urinary sphincter deficiency have increased interest in the therapeutic value of alternative regenerative medicine approaches. The goal of this study was to compare the effects of the cell homing chemokine CXCL12 (C-X-C motif chemokine 12) and skeletal muscle precursor cells on chronic urinary sphincter regeneration in chronic intrinsic urinary sphincter deficiency.Materials and Methods: Five million autologous skeletal muscle precursor cells or 100 ng CXCL12 were injected in the urinary sphincter complex of adult female cynomolgus monkeys with chronic (6-month history) intrinsic urinary sphincter deficiency. These treatment groups of 3 monkeys per group were compared to a group of 3 with no intrinsic urinary sphincter deficiency and no injection, and a group of 3 with intrinsic urinary sphincter deficiency plus vehicle injection. Maximal urethral pressure was measured at rest, during stimu...