Muscle derived stem cell therapy for stress urinary incontinence

AIM: The aim of this article is to discuss the potential of muscle-derived stem cells (MDSCs) for rhabdosphincter regeneration and to review the early clinical experiences with its application in patients with stress urinary incontinence. RESULTS: In anatomical and functional studies of the human and animal urethra, the middle urethral contained rhabdosphincter is critical for maintaining continence. Transplanted stem cells have the ability to undergo self-renewal and multipotent differentiation, leading to sphincter regeneration. In addition, such cells may release, or be engineered to release, neurotrophins with subsequent paracrine recruitment of endogenous host cells to concomitantly promote a regenerative response of nerve-integrated muscle. CONCLUSION: Cell-based therapies are most often associated with the use of autologous multipotent stem cells, such as bone marrow stromal cells. However, harvesting bone marrow stromal stem cells requires a general anesthetic, can be painful, and has variable yield of stem cells upon processing. In contrast, with appropriate experience, alternative autologous adult stem cells such as muscle-derived stem cells and adipose-derived stem cells can be obtained in large quantities and with minimal discomfort.     

The promise of stem cell therapy to restore urethral sphincter function

The promise of stem cell therapy for the treatment of stress urinary incontinence is that transplanted stem cells may undergo self-renewal and potential multipotent differentiation, leading to urethral sphincter regeneration. Cell-based therapies are most often associated with the use of autologous multipotent stem cells, such as bone marrow cells. However, harvesting bone marrow stromal stem cells is difficult, painful, and may yield low numbers of stem cells. Alternatively, autologous adult stem cells, such as muscle-derived stem cells, can be obtained in large quantities and with minimal discomfort. Not all cells and cellular therapies are the same, however, and proper placement of cells into target structures may be critical to eventual treatment success. In particular, restoration and repair of the damaged urethral sphincter is crucial to maintain urinary continence because active urethral closure is largely mediated by pudendal nerves that innervate the striated muscles and rhabdosphincter of the middle urethra.     

Stem cell therapy for stress urinary incontinence

The rhabdosphincter at the mid urethra is critical for maintaining urinary continence. In a setting of stress urinary incontinence stem cells transplanted into the site of the rhabdosphincter may augment sphincter regeneration and also release trophic factors promoting muscle and nerve integration of this muscle. We hereby review the use of cellular therapy for SUI and our experience with the development of muscle‐derived stem cells (MDSCs). Neurourol. Urodynam. 29:S36–S41, 2010. © 2010 Wiley‐Liss, Inc.     

Adult stem cell therapy of female stress urinary incontinence

OBJECTIVES: To investigate the efficacy of transurethral ultrasound (TUUS)-guided injections of autologous myoblasts and fibroblasts in women with incontinence. METHODS: Between January and June 2005, 20 female patients suffering from stress urinary incontinence (SUI) were included. Skeletal muscle biopsies were taken from the left arm to obtain cultures from autologous fibroblasts and myoblasts. By TUUS guidance the fibroblasts were injected into the urethral submucosa and the myoblasts were injected into the rhabdosphincter. A defined incontinence score, quality-of-life score and urodynamic, electromyographic, and laboratory parameters, as well as morphology and function of urethra and rhabdosphincter were evaluated before and up to 2 yr after therapy. RESULTS: Eighteen of 20 patients were cured 1 yr after injection of autologous stem cells and in 2 patients SUI was improved. Two years after therapy 16 of the 18 patients presented as cured, 2 others were improved, and 2 were lost to follow-up. Incontinence and quality-of-life scores were significantly improved postoperatively. The thickness of urethra and rhabdosphincter as well as activity and contractility of the rhabdosphincter were also statistically significantly increased after therapy. CONCLUSIONS: Clinical results demonstrate that SUI can be treated effectively with autologous stem cells. The present data support the conclusion that this therapeutic concept represents an elegant and minimally invasive treatment modality to treat SUI.     

Células madre derivadas de músculo para la incontinencia urinaria de esfuerzo

The knowledge of the urinary effort incontinence (UEI) has increased, giving like result an ample range of different therapeutic options available. The middle urethra and external urethral sphincter are the focus in management of UEI. Stem cells therapy for the regenerative repair of the deficient sphincter has been the leading research of incontinence. Obtaining autologous myoblasts and fibroblasts of skeletal muscle-biopsies, cultivating them and transplanting them after its differentiation, into the external urethral sphincter it warns a new concept in the treatment of the incontinence. Instead of using heterologous materials such as synthetic mesh (slings) or bulking agents (collagen, silicone, etc); we now have the potential to restore function with the use of autologous stem cells.     

Cell-Based Therapy for the Deficient Urinary Sphincter

When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.     

Applicability of regenerative medicine and tissue engineering for the treatment of stress urinary incontinence in female patients

Stress urinary incontinence (SUI) is an age health‐related issue that generates interest due to its considerable public health burden and the controversies surrounding treatment. It is highly prevalent affecting 30–40% of all women during their lifetime. Midurethral slings are the standard of gold standard treatment for female patients with SUI. They have excellent short‐term cure rates; however, their efficacy tends to decrease over time and patients often report urinary incontinence recurrence. This paper addresses the applicability of regenerative medicine and tissue engineering for the treatment of SUI in female patients. Cell‐based treatment with periurethral injection of autologous adipose or muscle‐derived stem cells have been used for SUI; however, the cure rates and SUI recurrence at 1 year were 40% and 70%, respectively. Novel minimally invasive approaches, such as low‐intensity extracorporeal shock wave therapies have shown promising results in SUI animal models. In addition, local injection of growth factors, chemokines, and specific antibodies have shown histological evidence of neoangiogenesis, nerve, and sphincter regeneration in rodents and nonhuman primates with SUI. The use of bioactive factors and proteins secreted by cells, which is called secretomes, have been recognized as key regulators of various mechanisms, such as immunomodulation, angiogenesis, inflammation, apoptosis, and tissue repair. Emerging therapies aiming to replace or restore tissues and organ functionality may improve the long‐term efficacy and in the near future may represent the standard of care for the treatment of SUI.     

Development of cellular therapy for the treatment of stress urinary incontinence

Stress urinary incontinence (SUI) is highly prevalent and associated with a reduced quality of life. An intact rhabdosphincter at the mid-urethra is mandatory to maintain urinary continence. Adult stem cell injection therapy for the regenerative repair of an impaired sphincter is currently at the forefront of incontinence research. The implanted cells will fuse with muscle and release trophic factors promoting nerve and muscle integration. Hereby, we review the use of mesenchymal stem cell therapy for SUI and the experience with the development of muscle-derived stem cells.     

Innovations in pharmacotherapy for stress urinary incontinence

The purpose of this review article is to highlight new pharmacotherapies on the horizon for the treatment of stress urinary incontinence (SUI). Although behavioral and surgical therapies are currently the mainstay of treating SUI, we believe that medications will take center stage and possibly become first-line therapy. Currently, there are no FDA medications indicated for SUI. However, results are becoming available about an oral medication, duloxetine, which appears to be clinically safe and efficacious for the treatment of SUI. In addition to discussing medications currently under development, we will also discuss exciting pharmacological targets that could be suitable to treat SUI.Abbreviations EUS External urethral sphincter - SPN Sacral parasympathetic nucleus - SUI Stress urinary incontinence     

Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence

This review discusses the control of the urethra by the central nervous system, emphasizing the importance of nervous system control and the role of serotonin and noradrenaline in storage, micturition and sphincter reflexes. The concept of pharmacological neuromodulation and the use of pharmacological therapy as first-line therapy for stress urinary incontinence (SUI) is presented. Coordination between the urinary bladder and urethra is mediated by many reflex pathways organized in the brain and spinal cord. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes depend on interneuronal circuitry in the spinal cord and are modulated by descending pathways. It would therefore seem that neurotransmission in the central nervous system and periphery may be important in SUI, and moreover that pharmacological agents affecting these neurotransmitter pathways may be used to treat SUI. The central and peripheral mechanisms of action of duloxetine affect serotonin and noradrenaline neurotransmission in ways that may ameliorate the symptoms of SUI.     

Combined external urethral bulking and artificial urinary sphincter for urethral atrophy and stress urinary incontinence

OBJECTIVE: To describe a technique of externally bulking the urethra with a soft-tissue graft before placing another artificial urinary sphincter (AUS), as when placing another AUS for recurrent male stress urinary incontinence (SUI) other manoeuvres, e.g. placing a tandem cuff or transcorporal cuff, must be used to obtain urinary continence in an atrophic urethra, and each is associated with morbidity. PATIENTS AND METHODS: From January 2003 to July 2004, five patients (mean age 74 years, range 62-84) treated by radical prostatectomy were referred for recurrent SUI after placing an AUS (four, including one with urethral erosion) or a male sling (one, with a resulting atrophic urethra). Each patient was treated with an external urethral bulking agent (Surgisis) ES, Cook Urological, Spencer, Indiana) and had an AUS placed. RESULTS: In each patient the greatest urethral circumference was <4 cm. To place a functional 4 cm cuff, the diameter of the urethra was enhanced by wrapping it with Surgisis ES. Continence was significantly improved in all patients except one 84-year-old man who had the replanted artificial sphincter removed because of erosion 14 months after surgery. CONCLUSION: In cases of severe recurrent SUI from urethral atrophy after placing an AUS, externally bulking the urethra with Surgisis ES before placing another AUS is well tolerated, and gives satisfactory results.     

The UCLA surgical approach to sphincteric incontinence in women

Stress urinary incontinence (SUI) in the female may be treated by a variety of non-surgical and surgical therapies. However, once the patient has chosen to undergo operative repair the ideal procedure is based on three considerations: the degree of anterior vaginal wall prolapse, the degree of incontinence and associated anatomic abnormalities requiring surgical repair. In the vast majority of cases vaginal wall sling is our procedure of choice for the surgical treatment of SUI in the female. Vaginal wall sling is based on sound anatomic principles, may be performed as an outpatient procedure and is equally efficacious for the treatment of SUI due to anatomic incontinence (urethral hypermobility) and intrinsic sphincter deficiency. Since vaginal wall sling is performed through a transvaginal approach, other associated manifestations of pelvic floor prolapse such as rectocele can be addressed and repaired simultaneously. When necessary the vaginal wall sling can be easily modified to repair large grade cystoceles.     

Surgery insight: management of failed sling surgery for female stress urinary incontinence

Sling surgery has replaced Burch colposuspension as the most common surgery for women with stress urinary incontinence (SUI). While incontinence surgery has become a routine part of urologic care, the management of surgical complications and recurrent incontinence can be quite difficult. It is important that the urologic surgeon is well informed about the most common complications that are associated with sling surgery, and how to best manage them. In addition, the management of recurrent incontinence following sling surgery should follow a stepwise approach, with appropriate diagnostic studies, conservative treatment if possible, and surgery if necessary. While sling surgery in the patient with urethral hypermobility is often straightforward, reoperation for recurrent incontinence can be more technically challenging. In the patient with a fixed and incompetent urethra, periurethral bulking agents, pubovaginal sling, spiral sling, or artificial urinary sphincter placement may be indicated.     

Autologous myoblasts and fibroblasts for female stress incontinence: a 1-year follow-up in 123 patients

OBJECTIVE: To assess the efficacy and safety of the application of autologous myoblasts and fibroblasts for treating female stress urinary incontinence (SUI) after a follow-up of >/=1 year. PATIENTS AND METHODS: In all, 123 women with SUI (aged 36-84 years) were treated with transurethral ultrasonography-guided injections with autologous myoblasts and fibroblasts obtained from skeletal muscle biopsies. The fibroblasts were suspended in a small amount of collagen as carrier material and injected into the urethral submucosa, while the myoblasts were implanted into the rhabdosphincter. All patients were evaluated before and 12 months after the injection using the Incontinence and Quality of Life Instrument (I-QOL) scores, urodynamic variables, and morphology and function of the urethra and rhabdosphincter. RESULTS: At 1 year after implanting the cells, 94 of the 119 women (79%) were completely continent, 16 (13%) had a substantial improvement and nine (8%) a slight improvement. Four patients were lost to follow-up.The incontinence and I-QOL scores, and the thickness, contractility and electromyographic activity of the rhabdosphincter were significantly improved after treatment. CONCLUSIONS: These results show the efficacy and safety of transferring autologous myoblasts and fibroblasts in the treatment of female SUI, after a follow-up of 1 year.     

Stem Cells for the Treatment of Urinary Incontinence

Stress urinary incontinence (SUI) is highly prevalent. As of now, there is no minimally invasive long-term treatment available. Adult stem cells are nonimmunogenic and have the ability to self-renew and to differentiate into multiple cell types. Over the past decade, in vivo studies have described periurethral injections of adult-derived stem cells for the treatment of SUI. The ultimate goal has been to achieve a permanent cure for SUI by restoration of the intrinsic and extrinsic urethral sphincter and the surrounding connective tissue, including peripheral nerves and blood vessels. For this purpose, future studies need to focus on delivery systems, cell survival, and functional improvement of the urethral closure mechanism, including improvement of innervation and vascularization.     

干细胞治疗女性压力性尿失禁的研究进展

压力性尿失禁(SUI)是成年女性常见的泌尿系统疾病,给患者生活、工作和社会活动带来极大的影响。目前悬吊带术治疗SUI较成熟,微创简便,疗效确切,但可能出现并发症或者疾病复发。尿道周围注射填充剂,如牛胶原蛋白,远期效果不理想。干细胞是近年来研究的热点,有学者已尝试用其治疗SUI,特别是在大鼠SUI模型中研究较多,经尿道周围注射干细胞,如骨髓来源干细胞,肌肉来源干细胞和脂肪来源干细胞等,其可分化为平滑肌细胞等,提高大鼠尿道括约肌单位的功能,并促进神经细胞再生;注射的干细胞还可旁分泌多种因子,促进尿道组织再生,多种机制共同作用恢复尿道生理性的尿流控制能力。该治疗方法在临床开展较少,但仅有的数据也表明,在超声引导下经尿道周围注射干细胞能明显提高SUI患者的预后,改善排尿状况。     

Therapieoptionen der rezidivierenden oder persistierenden Belastungsharninkontinenz

After synthetic sling procedures, up to 16?% of women and 45.5?% of men complain about a persistent or recurrent stress urinary incontinence (SUI). Currently, randomized studies comparing the different treatment modalities of persistent or recurrent SUI are lacking. There are data of retrospective studies investigating the efficiency of synthetic slings and the artificial urinary sphincter AMS 800® in men. Synthetic slings can be applied in patients with mild SUI and without prior radiation of the pelvic region. The AMS 800® is the treatment of choice in patients with severe SUI or previous radiation. In women with persistent and recurrent SUI, the efficiency of colposuspensions, autologous and synthetic slings as well as the AMS 800® has been investigated in retrospective studies. Due to comparable cure rates and a faster postoperative recovery, synthetic slings are now superseding colposuspensions and autologous slings. Excellent success rates after AMS 800® implantation have been described for both genders; nonetheless, postoperative complications and revisions as well as the requirement of dexterity of the patients should be taken into account. Data about the efficiency of adjustable slings, the ACT® and newer artificial urinary sphincter devices like Flow-Secure® and Zephyr® ZSI 375 in the treatment of persistent and recurrent SUI is lacking.     

Periurethral injection of autologous adipose-derived stem cells for the treatment of stress urinary incontinence in patients undergoing radical prostatectomy: Report of two initial cases

Objectives:   To report a novel cell therapy using autologous adipose tissue-derived stem cells (ADSC) for stress urinary incontinence caused by urethral sphincteric deficiency and the outcomes in two initial cases undergoing periurethral injection of stem cells for the treatment of urinary incontinence after radical prostatectomy.
Methods:   Two patients with moderate stress incontinence after radical prostatectomy were enrolled. After liposuction of 250 mL of adipose tissue from the abdomen, we isolated ADSC from this tissue by using the Celution system. Subsequently, the isolated ADSC and a mixture of stem cells and adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Short-term outcomes during a 12-week follow-up were assessed by a 24-h pad test, a validated patient questionnaire, urethral pressure profile, transrectal ultrasonography, and magnetic resonance imaging.
Results:   Urinary incontinence progressively improved after 2 weeks of injection up to 12 weeks in terms of decreased leakage volume in a 24-h pad test, decreased frequency and amount of incontinence, and improved quality of life as per the questionnaire. In urethral pressure profile, both maximum urethral closing pressure and functional profile length increased. Ultrasonography and magnetic resonance imaging showed sustained presence of the injected adipose tissue. Enhanced ultrasonography showed a progressive increase in the blood flow to the injected area. No significant adverse events were observed peri- and postoperatively.
Conclusion:   This preliminary study showed that periurethral injection of the autologous ADSC is a safe and feasible treatment modality for stress urinary incontinence.     

Transurethral delivery of radiofrequency energy for tissue micro-remodeling in the treatment of stress urinary incontinence

This initial human study was performed to determine the safety and quality of life impact of transurethral radiofrequency energy (RFe) tissue micro-remodeling of the proximal urethra and bladder outlet in patients with stress urinary incontinence (SUI). Forty-one patients with SUI were sequentially enrolled into four treatment groups and then underwent rapid outpatient treatment under conscious sedation using an investigational RFe delivery device. The device is passed through the urethra and palpably positioned by the anchoring of a balloon within the bladder outlet. Four small needle electrodes are deployed into the proximal urethra and/or bladder outlet submucosa, and RFe is delivered. No patient has suffered a serious adverse event in 6 months of follow-up. At 6 months, 75%–80% of patients in all four groups have demonstrated an improvement in quality of life. Two groups demonstrated statistical significance in both mean quality of life improvement and incontinence frequency reduction at 6 months.Abbreviations MCE Minor clinical event - SAE Serious adverse events - SUI Stress urinary incontinence - VAS Visual analog scaleEditorial Comment: Treatment of stress urinary incontinence via transurethral delivery of radiofrequency energy appears to be effective and safe in this small study with 6 months' follow-up. Treatment resulted in significantly improved quality of life scores and up to 75% of patients were cured 3–6 months after treatment. Although the simplicity of this minimally invasive procedure is appealing, the long-term efficacy and safety of transurethral delivery of radiofrequency energy for the treatment of stress urinary incontinence should be carefully evaluated in larger prospective studies.     

中老年人行前列腺癌根治术后发生尿失禁的高危因素分析

目的 分析中老年人行前列腺癌根治术后发生尿失禁的高危险因素。方法 选取2014年至2020年福建省内5家综合性医院泌尿外科行前列腺癌根治术的626例中老年人患者作为研究对象,根据入组患者术后是否发生尿失禁将患者分为对照组（术后未发生尿失禁者,526例）和观察组（术后并发尿失禁者,100例）。分析两组患者的一般资料、临床资料、手术治疗、护理资料的各指标间差异,采用多因素logistic分析前列腺癌根治术后发生尿失禁的高危因素。结果 共100例患者术后发生尿失禁,尿失禁发生率为15.97%。中老年人行前列腺癌根治术患者术后发生尿失禁与年龄、体重指数（BMI）、术前前列腺增生、术前膀胱功能、前列腺癌病理分期、既往尿道前列腺手术史、放疗史、手术者的手术台数、手术损伤括约肌、术中神经损伤、术后康复锻炼依从性均有相关性（均P<0.05）。多因素logistic结果分析显示,年龄≥75岁、前列腺增生、术前膀胱失代偿、手术损伤括约肌、术中神经损伤、既往有尿道前列腺手术史、术后康复锻炼依从性低均为中老年人行前列腺癌根治术患者术后发生尿失禁的独立危险因素（均P<0.05）。结论 中老年人行前列腺癌根治术后发生尿失禁的概率高,影响术后尿失禁危险因素主要是患者病情、手术质量,临床制定围手术期治疗和护理方案应充分考虑其危险因素,制定针对性措施预防尿失禁,提高患者术后病情康复及生活质量水平。