BladderCell | bladder regeneration | bioelectric stimulation



AUGUST 23, 2020Bioelectrical Stimulation for the Treatment of Incontinence:A Randomized Controlled Trial Cristiane Carboni, MSC, PhD Porto Alegre, Brazil Introduction:Dysfunction of the lower urinary tract, including incontinence is a very common clinical problem effecting millions of men and women of all ages. Regenerative medicine has a potential to provide a hope for the recovery of lost bladder and sphincter control. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1757-5672.2010.00066.x","ISBN":"1757-5664","ISSN":"17575664","PMID":"26676212","abstract":"Regenerative medicine offers great hope for lower urinary tract dysfunctions due to irreversibly damaged urinary bladders and urethras. Our aim is the utilization of bone marrow-derived cells to reconstruct smooth muscle layers for the treatments of irreversibly damaged lower urinary tracts. In our mouse model system for urinary bladder regeneration, the majority of smooth muscle layers in about one-third of the bladder are destroyed by brief freezing. Three days after wounding, we implant cultured cells derived from bone marrow. The implanted bone marrow-derived cells survive and differentiate into layered smooth muscle structures that remediate urinary dysfunction. However, bone marrow-derived cells implanted into the intact normal urinary bladders do not exhibit these behaviors. The presence of large pores in the walls of the freeze-injured urinary bladders is likely to be helpful for a high rate of survival of the implanted cells. The pores could also serve as scaffolding for the reconstruction of tissue structures. The surviving host cells upregulate several growth factor mRNAs that, if translated, can promote differentiation of smooth muscle and other cell types. We conclude that the multipotency of the bone marrow-derived cells and the provision of scaffolding and suitable growth factors by the microenvironment enable successful tissue engineering in our model system for urinary bladder regeneration. In this review, we suggest that the development of regenerative medicine needs not only a greater understanding of the requirements for undifferentiated cell proliferation and targeted differentiation, but also further knowledge of each unique microenvironment within recipient tissues.","author":[{"dropping-particle":"","family":"Imamura","given":"Tetsuya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ishizuka","given":"Osamu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamamoto","given":"Tokunori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gotoh","given":"Momokazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishizawa","given":"Osamu","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"LUTS: Lower Urinary Tract Symptoms","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2010"]]},"page":"1-10","title":"Bone marrow-derived cells implanted into freeze-injured urinary bladders reconstruct functional smooth muscle layers","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"(1)","plainTextFormattedCitation":"(1)","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}(1) Incontinence can be caused by several diseases or anatomical alterations the effect the normal cellular and extracellular matrix (ECM) compartments which accomplish the role of storage and control of voiding. The inner lining of the bladder, which is called the urothelium, is necessary to prevent the passage of hypertonic urine to the blood and the exchange of toxic metabolites. In a state of homeostasis, adult urothelial cells are quiescent, however, if the urothelium is damaged by an acute lesion or a exposure to toxins, a rapid process of exfoliation and regeneration is induced ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/apha.12009","ISBN":"1748-1708","ISSN":"17481708","PMID":"23034074","abstract":"The field of bladder research has been energized by the study of novel interstitial cells (IC) over the last decade. Several subgroups of IC are located within the bladder wall and make structural interactions with nerves and smooth muscle, indicating integration with intercellular communication and key physiological functions. Significant progress has been made in the study of bladder ICs' cellular markers, ion channels and receptor expression, electrical and calcium signalling, yet their specific functions in normal bladder filling and emptying remain elusive. There is increasing evidence that the distribution of IC is altered in bladder pathophysiologies suggesting that changes in IC may be linked with the development of bladder dysfunction. This article summarizes the current state of the art of our knowledge of IC in normal bladder and reviews the literature on IC in dysfunctional bladder.","author":[{"dropping-particle":"","family":"McCloskey","given":"K. D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Acta Physiologica","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"7-15","title":"Bladder interstitial cells: An updated review of current knowledge","type":"article-journal","volume":"207"},"uris":[""]}],"mendeley":{"formattedCitation":"(2)","plainTextFormattedCitation":"(2)","previouslyFormattedCitation":"²"},"properties":{"noteIndex":0},"schema":""}(2).The normal functioning urinary bladder is composed of two main parts: a compliant muscular wall and a highly specialized urothelium. It is well know that the pelvic floor muscles (PFM) play an important roll in the management of lower urinary tract symptoms as well (LUTS), including incontinence ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-018-25705-0","ISBN":"2045-2322 (Electronic)\r2045-2322 (Linking)","ISSN":"20452322","PMID":"29740105","abstract":"Human motor cortex can activate pelvic floor muscles (PFM), but the motor cortical representation of the PFM is not well characterized. PFM representation is thought to be focused in the supplementary motor area (SMA). Here we examine the degree to which PFM representation is distributed between SMA and the primary motor cortex (M1), and how this representation is utilized to activate the PFM in different coordination patterns. We show that two types of coordination patterns involving PFM can be voluntarily accessed: one activates PFM independently of synergists and a second activates PFM prior to and in proportion with synergists (in this study, the gluteus maximus muscle – GMM). Functional magnetic resonance imaging (fMRI) showed that both coordination patterns involve overlapping activation in SMA and M1, suggesting the presence of intermingled but independent neural populations that access the different patterns. Transcranial magnetic stimulation (TMS) confirmed SMA and M1 representation for the PFM. TMS also showed that, equally for SMA and M1, PFM can be activated during rest but GMM can only be activated after voluntary drive to GMM, suggesting that these populations are distinguished by activation threshold. We conclude that PFM representation is broadly distributed in SMA and M1 in humans.","author":[{"dropping-particle":"","family":"Yani","given":"Moheb S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wondolowski","given":"Joyce H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eckel","given":"Sandrah P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kulig","given":"Kornelia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fisher","given":"Beth E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordon","given":"James E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kutch","given":"Jason J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018"]]},"page":"1-16","title":"Distributed representation of pelvic floor muscles in human motor cortex","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"(3)","plainTextFormattedCitation":"(3)","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}(3). When the bladder is damaged, all these properties must be taken into account for a global functional recovery ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3390/ijms19061796","ISSN":"14220067","PMID":"29914213","author":[{"dropping-particle":"","family":"Serrano-Aroca","given":"?ngel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vera-Donoso","given":"César David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moreno-Manzano","given":"Victoria","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Molecular Sciences","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2018"]]},"page":"1-26","title":"Bioengineering approaches for bladder regeneration","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"(4)","plainTextFormattedCitation":"(4)","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}(4).The potential use of bioelectrical stimulation (BES) for lower urinary tract dysfunction was initially investigated in animal models, where it caused bladder relaxation by inhibiting the parasympathetic motor neurons. Exploration at the molecular level in an animal model revealed that stress urinary incontinence (SUI) mice exhibit disordered collagen metabolism and corresponding changes in the TGF-β1-Smad2/3 pathway. After BES therapy, the collagen levels increased and the TGF-β1-Smad2/3 pathway was activated in response to mechanical strain. These results indicate that collagen metabolism and the TGF-β1-Smad2/3 pathway are potentially involved in the pathogenesis of SUI as well as in the response to BES therapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/jsm.12740","ISBN":"0160-8347","ISSN":"17436095","PMID":"432","abstract":"Objective To investigate the therapeutic effect and underlying molecular mechanism of electrical stimulation (ES) in a murine stress urinary incontinence (SUI) model. Materials and Methods Sixty female C57BL/6 mice were divided into 4 groups: CON group, no intervention; VD group, vaginal distension (VD) with an 8-mm dilator for 1 hour; VD + ES 20 group, 20 Hz ES for 0.5 hour for 7 days after VD; and VD + ES 50 group, 50 Hz ES for 7 days after VD. For functional studies, assessments of urodynamics and sneezing test were performed; then, anterior vaginal wall specimens were collected. Pathological changes were validated by Masson's trichrome and Van Gieson staining, and the expressions of collagen, transforming growth factor (TGF)-β1-Smad2/3 pathway components, and T-type calcium channels were detected by Western blotting and reverse transcription polymerase chain reaction. Results ES significantly increased maximum bladder capacity, leak point pressure, and sneezing positive rate in SUI mice. The staining results showed that collagen was disorganized in the VD group but became organized after ES, especially at 50 Hz. The same results were found for collagens I and III. The expression of TGF-β1, p-Smad2 and p-Smad3 significantly decreased in the VD group and significantly increased in the VD + ES groups, especially in the VD + ES 50 group. The expression of 2 T-type calcium channel subtypes (Cav 3.1 and Cav 3.2) decreased in the VD group compared with the CON group, but increased in the VD + ES group compared with the VD group. Conclusion Dysregulation of collagen metabolism is involved in the pathogenesis of SUI. ES can ameliorate the symptoms of SUI by activating collagen regeneration through the TGFβ1-Smad2/3 pathway. T-type calcium channels might be involved in these processes.","author":[{"dropping-particle":"","family":"Vallinga","given":"Marleen S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spoelstra","given":"Symen K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hemel","given":"Inge L.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wiel","given":"Harry B.M.","non-dropping-particle":"van de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weijmar Schultz","given":"Willibrord C.M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Sexual Medicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1"]]},"page":"228-237","title":"Transcutaneous Electrical Nerve Stimulation as an Additional Treatment for Women Suffering from Therapy‐Resistant Provoked Vestibulodynia: A Feasibility Study","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"(5)","plainTextFormattedCitation":"(5)","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}(5). Other studies showed that BES causes contractions of the pelvic floor, increasing the number of muscle fibers with rapid contraction ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0094-0143","PMID":"2017820","abstract":"Appropriate management of patients with urinary incontinence requires access to a variety of methods. Electrical stimulation, although so far proportionally small in the armamentarium of methods, is founded on physiologic principles and has the advantage of being curative without significant side effects.","author":[{"dropping-particle":"","family":"Fall","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindstr?m","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Urologic clinics of North America","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1991","5"]]},"page":"393-407","title":"Electrical stimulation. A physiologic approach to the treatment of urinary incontinence.","type":"article-journal","volume":"18"},"uris":[""]}],"mendeley":{"formattedCitation":"(6)","plainTextFormattedCitation":"(6)","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}(6). The BES also increases the blood flow to the urethra and PFM, improving the neuromuscular connections, muscular fiber function, genital atrophy improving the mechanism of urethral closure ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejogrb.2013.11.023","ISBN":"0301-2115\\r1872-7654","ISSN":"03012115","PMID":"24382548","abstract":"Objective To evaluate the effects of surface electrical stimulation (SES) and to compare them with the effects of the intravaginal electrical stimulation (IVES) in women with stress urinary incontinence (SUI). Study design This randomized controlled study included 48 women aged over 50 years, who complained of SUI evaluated according to two structured questions of King's Health Questionnaire (KHQ) and who had not previously undergone physical therapy for SUI. The calculation of the sample size estimated a sample of 45 volunteers with a significance level of 5% and statistical power of 90%. The women were randomized to: Surface Electrical Stimulation Group (SESG) (n = 15), Intravaginal Electrical Stimulation Group (IVESG) (n = 15) and Control Group (CG) (n = 15). Subjects in the intervention groups were treated with the same parameters of electrical stimulation for 12 sessions. The SESG had four silicone electrodes fixed in the suprapubic and ischial tuberosity regions. The IVES group used an intravaginal electrode. The CG did not receive any treatment during the corresponding time. They were evaluated before and after treatment by a physical therapist who was blind to group allocation. The primary outcomes were urinary leakage, pressure and strength of pelvic floor muscle (PFM) contraction. The secondary outcome was quality of life (QOL) evaluated by KHQ. Forty-five women completed the study and were included in the analysis. Statistical analysis was performed using the Wilcoxon test for intragroup analysis and Kruskal-Wallis and Mann-Whitney tests for intergroup analysis (p < 0.05). Results There was significant improvement in urinary loss and pressure of contraction in the SESG and IVESG. PFM strength increased only in the IVESG. Intergroup analysis found differences after the treatment in: urinary leakage between the SESG and CG (p < 0.001) and the IVESG and CG (p < 0.001). Regarding QOL, there was significant reduction in the incontinence impact, limitations of daily activities, physical limitation, emotion, sleep and disposition and severity domains in the SESG (all p < 0.02) and IVESG (all p < 0.04) after the treatments. Conclusion SES and IVES are important treatments to improve the SUI. Both improved the QOL, urinary leakage, and strength and pressure of PFM contraction. ? 2013 Elsevier Ireland Ltd.","author":[{"dropping-particle":"","family":"Correia","given":"Grasiéla N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pereira","given":"Vanessa S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirakawa","given":"Humberto S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Driusso","given":"Patricia","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Obstetrics Gynecology and Reproductive Biology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"113-118","title":"Effects of surface and intravaginal electrical stimulation in the treatment of women with stress urinary incontinence: Randomized controlled trial","type":"article-journal","volume":"173"},"uris":[""]}],"mendeley":{"formattedCitation":"(7)","plainTextFormattedCitation":"(7)","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}(7),ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1034/j.1600-0412.2003.00130.x","ISBN":"0001-6349 (Print)\\r0001-6349","ISSN":"00016349","PMID":"14616279","abstract":"To evaluate the effectiveness of intravaginal electrical stimulation (ES) of the pelvic floor for urinary incontinence in elderly women, and to determine whether ES of the pelvic floor is a preferable treatment for urinary incontinence in elderly women.","author":[{"dropping-particle":"","family":"Spruijt","given":"Johan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vierhout","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verstraeten","given":"Rob","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janssens","given":"Jannes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burger","given":"Curt","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Acta Obstetricia et Gynecologica Scandinavica","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2003"]]},"page":"1043-1048","title":"Vaginal electrical stimulation of the pelvic floor: A randomized feasibility study in urinary incontinent elderly women","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"(8)","plainTextFormattedCitation":"(8)","previouslyFormattedCitation":"⁸"},"properties":{"noteIndex":0},"schema":""}(8) and also induces epithelial cell migration, macrophages, mast inhibition, fibroblasts proliferation and motor axonal regeneration ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1109/ICEEE.2009.5393357","ISBN":"9781424446896","abstract":"We stimulated electrically (In-Vitro) Vagina muscle cells and Rabbit bladder muscle and Epithelial cells, in order to see the effects on growth rate in the cultures. In two medium cultures \"A\" (control) and \"B\" (stimulated) we obtained a significant difference cell growth stimulating with a bipolar wavelet with 400 mVpp and 200 Hz of frequency applied on vagina muscle cells in passing 3, and a 150 mVpp wavelet (with 3.33 Hz, and 10 Hz) on rabbit bladder muscle and epithelial cells for primary culture, passing 2 and 3 [A][B]. We present the results generated by stimulating on muscle and epithelial cells cultures to obtain different viability and proliferation in comparison to control cells. These results (and future ones) will be used to find an optimal wavelet to control the growth factor in cells to improve the quality of neo-tissues in human bladder.","author":[{"dropping-particle":"","family":"Martínez","given":"Ernesto Paredes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiménez","given":"Raquel Vargas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rivera","given":"Atlántida Raya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ni?o-de-Rivera","given":"Luís","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"2009 6th International Conference on Electrical Engineering, Computing Science and Automatic Control, CCE 2009","id":"ITEM-1","issued":{"date-parts":[["2009"]]},"page":"1-6","title":"Electrical stimulation to vagina muscle cells and rabbit bladder muscle and epithelial cells in-vitro to change growth factor","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(9)","plainTextFormattedCitation":"(9)","previouslyFormattedCitation":"⁹"},"properties":{"noteIndex":0},"schema":""}(9).BES is widely used for overactive bladder syndrome (OAB). The effect of BES in afferent pathways provides a preganglionic central inhibition of bladder’s motor neuron influencing the detrusor activity, but the effects of this therapy in the sacral region are better known. In animal models have demonstrated that bladder relaxation can also be induced by the inhibition of parasympathetic motor neurons ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1039/c4dt02697g","ISSN":"1477-9234","PMID":"25375839","abstract":"The new complexes tetra-platinum(II)-thiopyridylporphyrin 3 and tetra-platinum(II)-thiopyridylporphyrinato Zn(II) 4 were obtained by coordination of the peripheral thiopyridyl units of the free-base 5,10,15,20-tetrakis[2,3,5,6-tetrafluoro-4-(4-pyridylsulfanyl)phenyl]porphyrin 1 or their corresponding zinc complex 2, respectively, with four chloro(2,2'-bipyridine)platinum(II) [Pt(bpy)Cl](+) units. Both compounds were characterized by several spectroscopic techniques demonstrating a particular behaviour in the emission spectra due to the absence or presence of zinc. The tetra-platinum(II)-thiopyridylporphyrins exhibited an increase in the emission quantum yield when compared with the starting thiopyridylporphyrins 1 and 2. Spectroscopic studies of both platinum derivatives reveal their ability to interact unequivocally with DNA from calf thymus and DNA of low molecular weight from salmon sperms, and also with the most abundant protein in human blood plasma, human serum albumin (HSA). Herein, both tetra-platinum(II)-thiopyridylporphyrins 3 and 4 exhibit electrostatic surface binding with the negative phosphate groups of DNA. Similar to cationic-anionic binding with DNA, tetra-platinum(II)-thiopyridylporphyrinato zinc(II) demonstrates a particular binding intercalation mode with DNA. Photophysical studies demonstrated that both porphyrins are photostable and able to generate singlet oxygen ((1)O2) after light irradiation. Exposure of pMT123 plasmid DNA to tetra-platinum(II)-thiopyridylporphyrins and irradiation with light lead to single-strand breakage as determined by the conversion of the supercoiled form of the plasmid (form I) into the nicked circular form (form II). The tetra-platinum(II)-thiopyridylporphyrinato Zn(II) demonstrates a particular intercalation binding mode with DNA and an ability to cleave DNA after photo-excitation.","author":[{"dropping-particle":"","family":"Rodrigues","given":"Rafaela Fintelman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"da","family":"Silva","given":"Elirez Bezerra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodrigues","given":"Rafaela Fintelman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"da","family":"Silva","given":"Elirez Bezerra","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Fisioterapia em Movimento","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016"]]},"page":"813-820","title":"Intracavitary electrical stimulation as treatment for overactive bladder: systematic review","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"(10)","plainTextFormattedCitation":"(10)","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}(10). Other factors involved in OAB usually includes weakness of the pelvic floor muscles as wellADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00192-011-1651-5","ISBN":"1433-3023 (Electronic)\\n0937-3462 (Linking)","ISSN":"14333023","PMID":"22246576","abstract":"The objective of this study is to evaluate the effectiveness of existing\\nphysiotherapy modalities for the treatment of urge urinary incontinence\\n(UUI). A systematic review was performed for primary studies of\\nphysiotherapy techniques for UUI published in English between 1996 and\\nAugust 2010 in major electronic databases. Only randomized clinical\\ntrials that reported outcomes separately for women with UUI were\\nincluded. Outcomes assessed were reduction in UUI, urinary frequency,\\nand nocturia. Data from 13 full-text trials including the modalities of\\npelvic floor muscles exercises with or without biofeedback, vaginal\\nelectrical stimulation, magnetic stimulation, and vaginal cones were\\nanalyzed. The methodologic quality of these trials was fair. Significant\\nimprovement in UUI was reported for all physiotherapy techniques except\\nvaginal cone therapy. There are insufficient data to determine if pelvic\\nphysiotherapy improves urinary frequency or nocturia. Evidence suggests\\nthat physiotherapy techniques may be beneficial for the treatment of\\nUUI.","author":[{"dropping-particle":"","family":"Greer","given":"Joy A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Ariana L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arya","given":"Lily A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Urogynecology Journal","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012"]]},"page":"687-697","title":"Pelvic floor muscle training for urgency urinary incontinence in women: A systematic review","type":"article-journal","volume":"23"},"uris":[""]}],"mendeley":{"formattedCitation":"(11)","plainTextFormattedCitation":"(11)","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}(11). Previous work by this investigator using BES for bladder incontinence in a randomized prospective controlled study of stimulation of the sacral or tibial nerves via acupuncture needles demonstrated that sacral nerve stimulation was superior to tibial nerve and that both were significantly superior to the patient’s prs-study assessment of the frequency of incontinence.The hypothesis of this study is that BES will be a novel and effective, science-based non-invasive method to treat bladder dysfunction manifest as incontinence, by regenerating bladder tissue engineered by significant upregulation local expression of several stem cell homing and regenerative proteins to enhance bladder muscle tone. We propose to study this concept by using two different routes of micro-current bioelectric stimulation on bladder function and LTUS using patch surface electrodes. The two treatment arms will include sacral nerve stimulation alone compared to a sequential stimulation of the sacral and tibial nerves to evaluate a possible additive effect superior to either alone. In addition, we will separately evaluate the benefit provided by standard pelvic floor stimulation exercises alone, as well as in combination with the Sacral nerve, and Sacral plus Tibial nerve combination. There will be no separate Control group, as each patient will serve as their own control with a carefully documented record of the frequency of incontinence/day and the number of pads used daily for the two weeks prior to study entry.Study Name: Bioelectric Stimulation for treatment of Bladder IncontinenceStudy Sponsor: BladderCell, a subsidiary of Leonhardt Ventures, LLCPrinciple Investigator: Cristiane Carboni, MSC, PhD, Director Pelvic Floor World ClinicNumber of Study Sites: 1-3Study Locations: Pelvic Floor Dysfunction Clinic, Porte Allegre, BrazilStudy Design: Prospective, Randomized, 4 Arm, Open Label, Pilot TrialTreatment Arms: Gp 1: Pelvic floor stimulation/exercises Gp 2: Sacral Nerve stimulation with patch electrodes alone Gp 3: Sacral Nerve stimulation plus pelvic floor exercises GP 4: Sacral and Tibal nerve plus pelvic floor exercisesNumber of Subjects: 40Duration of Each Treatment: 30 minutesFrequency of Treatments: 2 x’s/week for two monthsNumber of Treatments: 16Stimulator to be Used: CE Mark and FDA 510K approved Mettler model 240General objectives The present study aims to evaluate the benefit of BES at two different nerve stimulation locations versus pelvic floor stimulation alone and in combination with the nerve stimulation on improving bladder function and LTUS including frequency of incontinence and absorbent pad use using questionaires and clinical patient assessment as study end points.Primary End Point:Change in frequency of incontinence from baseline to end of study and scores of the internationally accepted questionaires, and change in the number of absorbent pSecondary End Points: Adverse Events including local pain or inflammation at the sites of patch electrodes for delivery of BES or pain radiating from the bladder or along the track of the tibial or sacral nerves used before and after the study.RandomizationRandomization will be carried out in two steps: generation of random numbers in each group, using the RANDOM subroutine of the PEPI software suit (computer programs for urologist); and allocation concealment, placing numbers in letter-sized manila envelopes. Participants will be randomly assigned to four groups as the entire study per patient rather than per site to assure complete randomization.Primary End Point: Change in questionaires and self-assessment of severity and frequency of urinary incontinence including number of urinations/day and number of pads used/day.Second End Points:Any device-related or BES related adverse events including local pain, skin irritation, painful urination, urinary track infection, blood in the urine. Treatment Groups: (Each group will have 10 subjects)Gp I: Pelvic Floor exercises aloneGp II: Sacral nerve stimulation alone using patch electrodes Gp III: Sacral nerve plus pelvic floor exercises Gp IV: Simultaneous Sacral nerve and Tibial nerve stimulation using patch surface electrodes plus pelvic floor exercisesInclusion criteria: Women, 18 - 80 age Symptoms of stress, urge, or mixed urinary incontinence of more than 3 month duration. Willing and able to sign the Informed ConsentAble to attend all clinic visits defined in the protocolExclusion criteria: Current urinary tract infection (positive urine culture after antibiotic treatment)History of recurrent urinary tract infection (> 3 within the previous year)Bladder pathology or dysfunction because of fistula, tumor, pelvic irradiation, neurological or otherAny previous surgical or device treatment of incontinence during the previous 12 months Genital prolapse to, or beyond, the introitus,Cardiac pacemaker or internal defibrillatorCognitive impairment or insufficient mental condition/cognitionStudyEligibility:All patients who meet all the Inclusion and none of the Exclusion criteria and signed the Consent Form, and select a current level for stimulator use that is at or above the minimum level for the study, will be enrolled in the study.Pre-Treatment Screening:All enrolled subjects will have an evaluation of pain sensitivity to the current that is comfortable to them and will be used for each treatment during the study. The current will be increased to a level below the motor threshold that does not cause muscle contraction and is at or above the minimum current to be used for the study. Pre-Treatment Questionaires:All subjects will complete validated self-assessment questionaires used to quantitate the severity of incontinence including: PRAFAB-score, OAB-V8, PGI-I, Pelvic Floor Impact Questionnaire-short form 7 and King’s Health Questionnaire. These questionaires will repeated at the end of the study to evaluate potential changes. In addition, they will keep a record of the number of urinations for two weeks before and throughout treatment, as well as a pad study of the amount of moisture and weight of the pad before and at months one an two of therapy.Protocol: ? BES Treatment:Each subject will be randomized to a specific treatment arm and receive treatment for 30 minutes twice a week for 8 weeks to take place only in the clinic of an approved Site Principal Investigator. Those randomized to Gp 1 will have Pelvic Floor Stimulation with electrodes applied to either side of the anus and connected to the Mettler stimulator for the same amount of time as with other arms of the study at each treatment session. INCLUDEPICTURE "cid:58f5f5a0-e189-46ca-b8eb-0c28e9624079" \* MERGEFORMATINET Those randomized to Gp 2, will have Sacral nerve stimulation alone with patch surface electrodes placed 2-3 cm lateral to the edge of sacrum just above the buttock, which will be connected to the stimulator which will be turned on at their comfort level for 30 minutes 2X’s/week for the 8 week duration of the study. Those randomized to Gp 3 will have electrodes placed as described for both Sacral nerve and Tibial Nerve. Stimulation with electrodes for the Tibial nerve placed as shown below along the medial side of lower extremity 2 cm lateral to the ankle for the frequency and duration of all arms of the study.Those randomized to Gp 4 will have one pair of electrodes placed on the Sacral Nerve and a separate pair placed along the Tibial Nerve as shown above and undergo a standard 30 minute treatment. Following completion of this stimulation of both nerves for the standard 30 minutes, subjects randomized to Gp 4 will also have a 30 minute treatment of BES for Pelvic Floor stimulation as shown in the Figure above. All subjects will record the number of episodes of incontinence daily as well as the number of absorbent pads used daily.Stopping Rules:The study of an individual subject will be paused for any subject that develops symptoms of more than moderate severity or adverse events that in the opinion of the PI are directly related to the BES treatment. The study may be restarted at the next scheduled treatment session.The entire study will be paused if 3 subjects develop adverse events of moderate severityuntil an action plan is put in place as a mediation of the adverse events reported.Statistical Analysis: All data will be collated and analyzed by a statistician not involved in the study and unaware of treatment assignment. Simple ANOVA of the difference between and within groups will be performed. Final analysis will be given to the Principal Investigator and study sponsor.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Imamura T, Ishizuka O, Yamamoto T, Gotoh M, Nishizawa O. Bone marrow-derived cells implanted into freeze-injured urinary bladders reconstruct functional smooth muscle layers. LUTS Low Urin Tract Symptoms. 2010;2(1):1–10. 2. McCloskey KD. Bladder interstitial cells: An updated review of current knowledge. Acta Physiol. 2013;207(1):7–15. 3. Yani MS, Wondolowski JH, Eckel SP, Kulig K, Fisher BE, Gordon JE, et al. Distributed representation of pelvic floor muscles in human motor cortex. Sci Rep. 2018;8(1):1–16. 4. Serrano-Aroca ?, Vera-Donoso CD, Moreno-Manzano V. Bioengineering approaches for bladder regeneration. Int J Mol Sci. 2018;19(6):1–26. 5. Vallinga MS, Spoelstra SK, Hemel ILM, van de Wiel HBM, Weijmar Schultz WCM. Transcutaneous Electrical Nerve Stimulation as an Additional Treatment for Women Suffering from Therapy‐Resistant Provoked Vestibulodynia: A Feasibility Study. J Sex Med [Internet]. 2015 Jan;12(1):228–37. Available from: . Fall M, Lindstr?m S. Electrical stimulation. A physiologic approach to the treatment of urinary incontinence. Urol Clin North Am [Internet]. 1991 May;18(2):393–407. Available from: . Correia GN, Pereira VS, Hirakawa HS, Driusso P. Effects of surface and intravaginal electrical stimulation in the treatment of women with stress urinary incontinence: Randomized controlled trial. Eur J Obstet Gynecol Reprod Biol. 2014;173(1):113–8. 8. Spruijt J, Vierhout M, Verstraeten R, Janssens J, Burger C. Vaginal electrical stimulation of the pelvic floor: A randomized feasibility study in urinary incontinent elderly women. Acta Obstet Gynecol Scand. 2003;82(11):1043–8. 9. Martínez EP, Jiménez RV, Rivera AR, Ni?o-de-Rivera L. Electrical stimulation to vagina muscle cells and rabbit bladder muscle and epithelial cells in-vitro to change growth factor. 2009 6th Int Conf Electr Eng Comput Sci Autom Control CCE 2009. 2009;1–6. 10. Rodrigues RF, Silva EB da, Rodrigues RF, Silva EB da. Intracavitary electrical stimulation as treatment for overactive bladder: systematic review. Fisioter em Mov [Internet]. 2016;29(4):813–20. Available from: . Greer JA, Smith AL, Arya LA. Pelvic floor muscle training for urgency urinary incontinence in women: A systematic review. Int Urogynecol J. 2012;23(6):687–97. Annexes:Annexes 1 - PRAFAB scorePRAFAB score: The patient was asked to give the most appropriate answer;only one answer per section was possibleProtection1 I never use pads for urinary incontinence2 I occasionally use pads or have to change underwear3 As a rule I use pads or have to change underwear more than once a day4 I always use pads for urinary incontinenceAmount1 My loss of urine is limited to an occasional drop2 My loss of urine can sometimes be as much as a teaspoon3 My loss of urine is enough to really wet my pads and/or clothing4 My loss of urine usually completely soaks my pads and/or clothingFrequency: Involuntary loss of urine occurs1 Once a week or less2 More than once but less than three times a week3 More than three times a week but not every day4 Every dayAdjustment: My urinary incontinence1 Does not inhibit me in my daily activities2 Made me quit some activities like sports or other strenuous exertion3 Made me quit most activities that provoke my urinary incontinence4 Prevents me from leaving the house altogetherBody image1 I am not really bothered by my urinary incontinence2 My urinary incontinence is an inconvenience but not a real problem3 My urinary incontinence makes me feel unclean4 I am disgusted with myself because of my urinary incontinenceAnnexes 2 - OAB-V8Annexes 3 – Patient Global Impression of Improvement Annexes 4 - Pelvic Floor Impact Questionnaire—short form 7 (PFIQ-7)Pelvic Floor Impact Questionnaire—short form 7 (PFIQ-7) Name DATE DOB Instructions: Some women find that bladder, bowel, or vaginal symptoms affect their activities, relationships, and feelings. For each question, check the response that best describes how much your activities, relationships, or feelings have been affected by your bladder, bowel, or vaginal symptoms or conditions over the last 3 months. Please make sure you mark an answer in all 3 columns for each question.How do symptoms or conditions in the followingusually affect yourAbility to do household chores (cooking, laundryhousecleaning)?Bladder or urine□Not at all□Somewhat□Moderately□Quite a bitBowel or rectum□Not at all□Somewhat□Moderately□Quite a bitVagina or pelvis□Not at all□Somewhat□Moderately□Quite a bitAbility to do physical activities such as walking,swimming, or other exercise?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitEntertainment activities such as going to amovie or concert?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitAbility to travel by car or bus for a distancegreater than 30 minutes away from home?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitParticipating in social activities outside yourhome?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitEmotional health (nervousness, depression,etc)?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitFeeling frustrated?□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bit□Not at all□Somewhat□Moderately□Quite a bitTotal x 100 x 100 x 100 Scoring the PFIQ-7: =All of the items use the following response scale:0, Not at all; 1, somewhat; 2, moderately; 3, quite a bit PFIQ-7 Score Scales:Urinary Impact Questionnaire (UIQ-7): 7 items under column heading “Bladder or urine”Colorectal-Anal Impact questionnaire (CRAIQ-7): 7 items under column heading “Bowel / rectum”Pelvic Organ Prolapse Impact Questionnaire (POPIQ-7): Items under column “Pelvis / Vagina”Scale Scores: Obtain the mean value for all of the answered items within the corresponding scale (possible value 0 – 3) and then multiply by (100/3) to obtain the scale score (range 0-100).Missing items are dealt with by using the mean from answered items only. PFIQ-7 Summary Score: Add the scores from the 3 scales together to obtain the summary score (range 0-300).Annexes 5 – The King’s Health QuestionnaireTHE KING’S HEALTH QUESTIONNAIRETHE KING’S HEALTH QUESTIONNAIREHow would you describe your health at the present?Please tick one answer38674674764443867467110049Very good Good Fair3867467522643867467509464Poor Very poorHow much do you think your bladder problem affects your life?Please tick one answer39271571640243927157529784Not at all A little3927157630593927157428819Moderately A lotPlease turn the pageBelow are some daily activities that can be affected by bladder problems. How much does your bladder problem affect you?We would like you to answer every question. Simply tick the box that applies to you12343. ROLE LIMITATIONSNot at allSlightlyModeratelyA lotA. Does your bladder problem affect yourhousehold tasks? (cleaning, shopping etc)B. Does your bladder problem affect your job, or your normal daily activities outside the home?433070-8166100012344. PHYSICAL/SOCIAL LIMITATIONNot at allSlightlyModeratelyA lot4384357163008529875716300862645921630087064692163008A Does your bladder problem affect your physical activities (e.g. going for a walk, running, sport, gym etc)?4390072177613530447217761362645921776137064692177613Does your bladder problem affect your ability to travel?4384357123765529875712376562645921237657064692123765Does your bladder problem limit your social life?4384357150816529875715081662645921508167064692150816Does your bladder problem limit your ability to see and visit friends?4330702057405. PERSONAL RELATIONSHIPS0Not Applicable1Not at all23SlightlyModerately4A lotDoes your bladder problem affect your relationship with your partner?Does your bladder problem affect your sex life?Does your bladder problem affect your family life?005. PERSONAL RELATIONSHIPS0Not Applicable1Not at all23SlightlyModerately4A lotDoes your bladder problem affect your relationship with your partner?Does your bladder problem affect your sex life?Does your bladder problem affect your family life?1234EMOTIONSDoes your bladder problem makeNot at allSlightlyModeratelyVery muchyou feel depressed?404717256836500729256836592169256836695039256836Does your bladder problem make you feel anxious or nervous?404717214164500729214164593883735754695039235754Does your bladder problem make you feel bad about yourself?12347.SLEEP/ENERGYNeverSometimesOftenAll the timeA. Does your bladder problemaffect your sleep?B. Does your bladder problem makeyou feel worn out and tired ?8.Do you do any of the following?If so how much?1234NeverSometimesOftenAll the timeA. Wear pads to keep dry?B. Be careful how much3818572-246634847272-246635875972-246636853237-24663fluid you drink ?3818572107636484727210763658759721076366853237107636Change your underclothes because they get wet?3818572-186014847272-414615875972-414616853237-41461Worry in case you smell?We would like to know what your bladder problems are and how much they affect you ? From the list below choose only those problems that you have at present. Leave out those that don’t apply to you.88265026289000How much do they affect you? FREQUENCY: going to the toilet very oftenA little2.Moderately3. A lotNOCTURIA: getting up at night to pass urine1189672239970347567223997061045722399701. A little2.Moderately3. A lot882650444500URGENCY: a strong and difficult to control desire to pass urine1. A little2.Moderately3. A lotURGE INCONTINENCE: urinary leakage associated with a strong desire to pass urine1189672240859347567224085961045722408591. A little2.Moderately3. A lot882650444500STRESS INCONTINENCE: urinary leakage with physical activity eg. coughing, running1. A little2.Moderately3. A lotNOCTURNAL ENURESIS: wetting the bed at night1189672240605347567224060561045722406051. A little2.Moderately3. A lot882650444500INTERCOURSE INCONTINENCE: urinary leakage with sexual intercourse1. A little2.Moderately3. A lotWATERWORKS INFECTIONS1189672237303347567223730361045722373031. A little2.Moderately3. A lot882650127000BLADDER PAINA little2.Moderately3. A lotThank You For Your Time To Calculate ScoresPART 1General Health PerceptionsVery good1Good2Fair3Poor4Very poor5Score = ((Score to Q1 – 1)/4) x 100Incontinence ImpactNot at all1A little2Moderately3A lot4Score =((Score to Q2 – 1)/3) x 100PART 2Individual scores as recorded at the top of each column of possible responsesRole limitationsScore =(((Scores to Q 3A + 3B) – 2)/6) x 100Physical limitationsScore =(((Scores to Q 4A + 4B) – 2)/6) x 100Social limitations[If 5C >/= 1] Score =(((Score to Q 4C + 4D + 5C) – 3)/9) X 100[If 5C = 0]Score =(((Score to Q 4C + 4D) – 2)/6) x 100Personal relationships[If 5A+5B >=2]Score =(((Scores to Q 5A + 5B) – 2)/6) x 100 [If 5A+5B =1] Score =(((Scores to Q 5A + 5B) – 1)/3) x 100 [If 5A+5B =0] Treat as missing valueEmotionsScore =(((Score to Q 6A + 6B + 6C) – 3)/9) X 100Sleep / energyScore =(((Scores to Q 7A + 7B) – 2)/6) x 100Severity measuresScore =(((Scores to Q 8A + 8B + 8C + 8D) – 4)/12) x 100PART 3ScalescoreOmitted0A little1Moderately2A lot3Number of absorbent pads used daily:BASELINE: END OF STUDY< 10/day ___ < 10/day ___10-15/day ___ 10-15/day ___15-20/day ____ 15-20/day ____20-25/day ____ 20-25/day ____ ................
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