Rethinking the artificial urinary sphincter : from current knowledge to the development of a new smart device

Background: Urinary incontinence (UI) plagues millions of women and men worldwide, leading to social stigma, low self-esteem, poor quality of life, and affects their loved ones. In women, frequent causes include childbirth, and in men prostate surgery for benign or malignant disease. In both genders congenital anomalies, neurological diseases, pelvic surgery, and radiation therapy are incriminating factors. Many patients struggle daily with pads and/or diapers, often unaware of the existence of a surgical cure. Since the seventies, the AMS 800Ô (Boston Scientific - Marlborough, Massachusetts, USA) artificial urinary sphincter (AUS) has been the reference to treat severe male stress UI (SUI) secondary to intrinsic sphincter deficiency (ISD). In women, it constitutes a second-line option, the mid-urethral sling (MUS) being recommended as first-line surgical therapy in moderate to severe cases. However, although efficient, it has several drawbacks, namely poor ergonomics, untailored status to patients’ physical activities, high revision and explantation rates. Aims: To solve the above issues, a novel electronic AUS was incepted in France in 2007. This thesis tells the modern developmental journey of this device for severe SUI treatment. The objective is three- fold: to conduct a review of the current AMSÔ in both genders to identify potential literature gaps to identify and analyze data resulting from bench tests and clinical studies, and to conduct pre-clinical feasibility, performance and safety studies on human cadavers and animals prior to FIM studies. The 6 constituent papers present the results of the process rethinking the current AMS 800Ô known today, from State of the Art (papers I-III) to the design stages (paper IV) and subsequent pre-clinical implantation phases (papers V and VI) prior to the First in Man study, which eventually leads to the obtention of CE marking. Material, Methods, and Results: In Paper I, a systematic literature review of AMS 800Ô implantation in women with non-neurogenic severe SUI, non-extant to date, was performed. The 12 articles included showed a very low level of evidence, result heterogeneity in performance and safety outcomes and highlighted the need for post- market studies. Paper II addressed the absence of standardized continence outcome measurement tool, essential to homogenize functional reported outcomes data, but also crucial for defining the primary outcomes of the FIM study. We retrospectively assessed the 24- hour pad weight test in 180 men treated with primary AUS for PPUI. Secondarily, its correlation to quality-of-life was analyzed. Thirdly (Paper III), we retrospectively evaluated long-term continence and safety results of transscrotal versus transperineal (TP) primary AUS implantation in 183 men with PPUI in a single center. No statistical difference in performance outcomes was seen; however, the TP technique appeared to present worse long-term safety results. In Paper IV, we dimensioned the novel AUS by prospectively measuring the exact in vivo volume taken by the AMS 800Ô occlusive cuff after its pressurization at implantation. We found that the larger the cuff, the greater the accommodated volume, which did not surpass 1 cc. Therefore, the final prototype could be designed, an essential developmental milestone. In paper V the usability and performance of the novel AUS was established, in accordance with current FDA and European regulations on AIMDs in development. The device’s usability and performance were shown in 8 anatomical subjects, using randomly obtained urodynamic maximum urethral closure pressure ranges, equivalent to those of the AMS 800Ô. In Paper VI, we ascertained the novel device’s feasibility of implantation and histopathological safety in an animal pilot study using two wether models. The study showed the suitability of the models, the device’s ease of implantation and the absence of peri-or postoperative, and histopathological adverse events. We could therefore safely consider a Pivot study. Conclusion: Developing a novel AUS is a lengthy, expensive, and regulatory challenging process. In the ‘State of the Art’, essential to assess the ‘Gold standard’, we identified three literature gaps relevant for the risk analysis and evaluated similar competing devices. We showed a fine example of the application of ‘in vivo’ clinical study to the design of the smart AUS device. These initiated the required pre- clinical studies prior to FIM trials, demonstrating device feasibility, performance, and safety. the importance of post-market studies was also highlighted, and we strive to soon deliver a safe and efficient electronic device, tailored to the patient’s needs, whilst abiding to current regulations

The development and testing of an artificial anal sphincter

The physiological mechanisms for achieving fecal continence and the results of the surgical methods to correct incontinence are reviewed. The devices hitherto designed to attempt to achieve continence artificially are discussed and an analysis of 4130 reported complications of a successful device for the control of urinary incontinence (the AMS 800) are presented. Based on these reviews, the need to design and evaluate a prosthetic anal sphincter is identified and such a device is presented in this thesis.The effect of circumferential occlusive pressure on the blood flow of porcine colon was assessed by a Laser Doppler flow meter. It was demonstrated that distal blood flow is reduced by 50% at 52 mmHg. The occlusion pressure required to achieve continence to semi-solids was shown to be reduced by the introduction of angulation both in a theoretical model and experimentally, using a specifically designed fecal substitute.The Neosphincter was, therefore, designed to simulate the normal physiology of the anorectum by closing and angulating the bowel without causing crenation and ischaemia.The design parameters of the device were evaluated in an in-vitro model and its placement assessed in a series of acute animal experiments in a porcine model. The effects of the prosthesis set at an operating occlusion pressure of 33-45 mmHg were then evaluated in survival animal experiments by implantation in Yucatan minipigs for up to 20 weeks. The device produced fecal continence in 85% of the activation times without causing ischaemic injury. Mechanical complications associated with the control pump were encountered and design faults were identified. A new pump was designed by the author.The effect of Neosphincter function on blood flow distribution in the human colon was studied during colectomy using a prototype Laser Doppler flow scanner. Blood flow remained greater than 50% at 60 mmHg occlusion pressure.d flow remained greater than 50% at 60 mmHg occlusion pressure. The data presented show that the Neosphincter achieves continence in the mini-pig model and further suggest that continence would be achieved in the human without producing intestinal ischaemia. Ethical approval has been obtained to proceed to trials in human patients

PDMS and DLC-coated unidirectional valves for artificial urinary sphincters: Opening performance after 126 days of immersion in urine

In this work, unidirectional valves made of bare polydimethylsiloxane (PDMS) and PDMS provided with a micrometric diamond-like carbon (DLC) coating were fabricated and characterized, in terms of surface properties and opening pressure. The valve performance was also tested over 1250 repeated cycles of opening/closure in water, finding a slight decrease in the opening pressure after such cycles (10%) for the PDMS valves, while almost no variation for the PDMS + DLC ones. The valves were then immersed in urine for 126 days, evaluating the formation of encrustations and the trend of the opening pressure over time. Results showed that PDMS valves were featured by a thin layer of encrustations after 126 days, but the overall encrustation level was much smaller than the one shown by PDMS in static conditions. Furthermore, the opening pressure was almost not affected by such a thin layer of crystals. DLC-coated valves showed even less encrustations at the same time-point, with no significant loss of performance over time, although they were featured by a higher variability. These results suggest that most encrustations can be removed by the mechanical action of the valve during daily openings/closures. Such a self-cleaning behavior with respect to a static condition opens exciting scenarios for the long-term functionality of mobile devices operating in the urinary environment

Sphincter artificiel contrôlé et alimenté en énergie sans fil

RÉSUMÉ L’incontinence urinaire est un trouble qui touche aussi bien les hommes que les femmes, les personnes âgées aussi bien que les jeunes. N’ayant pas une définition universellement admise, son incidence varie considérablement. Être incontinent implique l’impossibilité pour la personne de se retenir. Cela la place dans des situations très inconfortables. Appelée aussi « La maladie de la honte », elle a des répercussions psychologiques et sociales très importantes. Elle peut limiter les activités physiques et perturber la vie sexuelle et professionnelle. Grâce à la médecine moderne l’incontinence est soignable. Elle est initialement traitée avec la médication, l’hygiène de vie, ou la rééducation. Mais si ces mesures sont insuffisantes, l’urologue fait le plus souvent appel aux dispositifs implantables tels que l’AMS 800™. En l’état actuel des connaissances, l’implantation du sphincter urétral artificiel AMS 800™ est en effet le traitement standard pour l’incontinence urinaire sévère (Gold standard) due à une insuffisance sphinctérienne. Le dispositif en question est un implant hydromécanique mimant le comportement d’un sphincter urétéral sain. Il exerce une pression constante sur l’urètre du patient pour fermer sa lumière et garder l’urine dans la vessie. Pour uriner, le patient contrôle l’ouverture de son urètre en pressant sur une pompe manuelle située dans le scrotum ou la Labia Majora. Malgré le principe simple et l’efficacité de cet implant, les études cliniques lui attribuent certaines limitations. Certains patients à dextérité réduite (Parkinsoniens, âgés, obèses, etc.) ont des difficultés à localiser et actionner la pompe manuelle. Par ailleurs et bien que faisable chez les femmes, l’implantation de l’AMS 800 est compliquée. La pression constante appliquée sur l’urètre provoque l’atrophie et l’érosion. La pompe est sujette à des pannes mécaniques. Ces évènements peuvent engendrer le retour de l’incontinence, affecter la qualité de vie du patient, et nécessiter une chirurgie de révision. L’objectif de nos recherches est de développer une nouvelle génération de sphincters artificiels intelligents, dans le but de corriger ces limitations, et développer les capacités des sphincters actuels dont la conception est âgée de plus de 30 ans.---------- ABSTRACT Urinary incontinence is a complication that affects both men and women, the elderly as well as young people. Without a universally accepted definition, its incidence varies widely. Being incontinent implies the impossibility for the patient to control his micturition, which makes him very uncomfortable. Also called "the shameful disease", urinary incontinence has negative psychological and social impacts. It may limit physical activities and disrupt sexual and professional life. Thanks to modern medicine, urinary incontinence is treatable. It is initially treated with medication, lifestyle changes, or rehabilitation. If these measures are insufficient, the urologist recommends the use of implantable devices such as the AMS 800 ™. In the current state of knowledge, the implantation of the artificial urinary sphincter AMS 800 ™ is the gold standard treatment for severe urinary incontinence due to intrinsic sphincter deficiency. This device is a hydro-mechanical implant imitating the behavior of a healthy urethral sphincter. It exerts a constant pressure on the patient's urethra to close it, and keeps urine in the bladder. To urinate, the patient opens his urethra by pressing a manual pump located in the scrotum or Labia Majora. Despite the simple mechanism and the effectiveness of this implant, clinical studies report certain limitations. Some patients with limited dexterity (Parkinson, aged, obese, etc.) have difficulties to locate and operate the manual pump. Furthermore and although it is feasible in women, the implantation of the AMS 800 is complicated. The constant pressure applied on the urethra causes atrophy and erosion. The pump is subject to mechanical failure. These events can cause the return of incontinence, affect the patient's quality of life, and may require revision surgery. The aim of our research is to develop a new generation of intelligent artificial sphincters, in order to correct the limitations and extend the capabilities of current sphincters that are over 30 years old. Our hypothesis assumes that, an artificial urinary sphincter equipped with embedded electronics and precise micro-actuators allows the remote control of the implant and the variation of the pressure exerted on the urethra

Advances in Assistive Electronic Device Solutions for Urology

Recent technology advances have led urology to become one of the leading specialities to utilise novel electronic systems to manage urological ailments. Contemporary bladder management strategies such as urinary catheters can provide a solution but leave the user mentally and physically debilitated. The unique properties of modern electronic devices, i.e., flexibility, stretchability, and biocompatibility, have allowed a plethora of new technologies to emerge. Many novel electronic device solutions in urology have been developed for treating impaired bladder disorders. These disorders include overactive bladder (OAB), underactive bladder (UAB) and other-urinary-affecting disorders (OUAD). This paper reviews common causes and conservative treatment strategies for OAB, UAB and OUAD, discussing the challenges and drawbacks of such treatments. Subsequently, this paper gives insight into clinically approved and research-based electronic advances in urology. Advances in this area cover bladder-stimulation and -monitoring devices, robot-assistive surgery, and bladder and sphincter prosthesis. This study aims to introduce the latest advances in electronic solutions for urology, comparing their advantages and disadvantages, and concluding with open problems for future urological device solutions

Novel Artificial Urinary Sphincter for Stress Urinary Incontinence Treatment

University of Minnesota M.S.E.E. thesis. September 2017. Major: Electrical Engineering. Advisor: Gerald Timm. 1 computer file (PDF); xiv, 129 pages.The American Medical System’s AMS 800TM has been the gold standard for over 40 years with over 150,000 patients treated for Urinary Incontinence and is the leading treatment for male stress urinary incontinence (SUI) following prostate surgery. Type III SUI, or intrinsic sphincter deficiency, is the inability of the urethra to maintain closure pressure sufficient to keep the patient clinically dry at rest and during periods of heightened activity (~120 cmH2O; coughs, sneezes, posture changes, and exercises). The current AMS 800TM is not personalized to a patient’s needs and compromises with an in between pressure- as high (61-70 cmH2O) as it can be without exceeding safety threshold levels. As such many men still leak when they are active. The market is hungry for a device that can adapt to the patient’s level of activity, reducing pressure most of the day to protect the urethra and then briefly increasing the pressure when he is more active. We are developing a novel implantable pump (henceforth called “add-on device”) which will be an add-on to the AMS 800TM and it includes a solenoid coil-cum-plunger and a fluid reservoir within the pump body. The add-on device will be small, light-weight and battery powered, and maintain compatibility with the AMS 800TM device. The device idea is in its proof-of-concept stage. This add-on device can be a possible solution to reducing the risks including urethral atrophy (leading to return of incontinence) and erosion (leading to infection of the implant) resulting from the constant pressure

Magnetic Actuation of Smooth Muscle Cells Loaded with Superparamagnetic Iron Oxide Nanoparticles

Faecal incontinence (FI) is a debilitating disorder that affects a significant portion of the population. The research included in this thesis aimed to test the hypothesis that magnetic actuating of smooth muscle cells loaded with superparamagnetic iron oxide nanoparticles (SPION) can modify the cell phenotype, which could be used with as a future therapy. The research focused on exploring a novel method of magnetic actuation and assessing its effects on the phenotype and biocompatibility of human rectal smooth muscle cells (HRSMC). A 2D model was used to demonstrate the effects of SPION on HRSMC. Initially, the effect of incubating HRSMC with different concentrations of SPION (0, 31.25, 250 and 1000 μg/ml) for 24 hours was investigated. Transmission electron microscopy revealed that SPION were endocytosed by cells and became concentrated inside endosomes. Superconducting quantum interference device (SQUID) measurements showed that SPION loading was concentration dependent and also that saturation occurred for concentrations above 250 μg/ml. SPION loading of HRSMC led to inhibition of the gene expression of actin and calponin when incubated in differentiation medium, with or without magnetic actuation, suggesting SPION caused the cells to shift towards a more proliferative phenotype. Live cell imaging revealed actuation of SPION-loaded HRSMC with stronger magnets led to an observable movement of internalized SPION and the plasma membrane. The findings from this research indicate SPION is biocompatible and may alter the phenotype of HRSMC. Therefore, SPION may offer novel benefits for regenerating damaged muscle in the treatment of FI. Further investigation is needed to assess the effects of magnetic actuation on SPION loaded cells