Margot S. Damaser

Effects of pudendal nerve injury in the female rat

To test a neurogenic hypothesis for external urethral sphincter (EUS) dysfunction associated with urinary incontinence, the proximal pudendal nerve was crushed in anesthetized retired breeder female rats (n = 5) and compared with a sham lesion group (n = 4). Outcome measures included concentric needle electromyograms (EMGs) from the target EUS, voiding patterns during a 2‐hour dark period, and micturition data over a 24‐hour period. Fast Blue (FB) was introduced to the crush site at the time of injury and Diamidino Yellow (DY) to the EUS at the time the rats were killed (3 months post‐operative), when histological analysis of the nerve and urethra was also performed. EMG records indicated the EUS motor units undergo typical denervation changes followed by regeneration and recovery. Voiding patterns from the crush group show a significant increase of small urine marks in the front third of the cage. At 1–2 weeks post‐op, the frequency of voids was significantly increased in the crush group compared to pre‐op and late post‐op time periods. The mean volume voided in the light phase at the early post‐op time was significantly increased in the sham group. Light and electron microscopic patterns seen in nerve and muscle suggest the regenerating motor units maintain a structural integrity. Motoneurons in the lower lumbar cord were labeled with either DY (14.5 ± 6.8), FB (31.7 ± 23.7), or both (35.0 ± 17.5) tracers, indicating ∼54% of the crushed pudendal neurons regenerated to the EUS. In conclusion, several measures suggest this reversible crush lesion induces mild urinary incontinence. This animal model is promising for further development of hypotheses regarding neural injury, the pathogenesis of incontinence, and strategies aimed at prevention and treatment. Neurourol. Urodynam. 19:53–69, 2000.

Quantity and distribution of levator ani stretch during simulated vaginal childbirth.

OBJECTIVE The objective of the study was to develop a model of the female pelvic floor to study levator stretch during simulated childbirth. STUDY DESIGN Magnetic resonance data from an asymptomatic nulligravida were segmented into pelvic muscles and bones to create a simulation model. Stiffness estimates of lateral and anteroposterior levator attachments were varied to estimate the impact on levator stretch. A 9 cm sphere was passed through the pelvis, along the path of the vagina, simulating childbirth. Levator response was interpreted at 4 positions of the sphere, simulating fetal head descent. The levator was color mapped to display the stretch experienced. RESULTS A maximum stretch ratio of 3.5 to 1 was seen in the posteriomedial puborectalis. Maximum stretch increased with increasing stiffness of lateral levator attachments. CONCLUSION Although preliminary, this work may help explain epidemiologic data regarding the pelvic floor impact of a first delivery. The models and simulation technique need refinement, but they may help study the effect of labor parameters on the pelvic floor.

Animal Models of Female Stress Urinary Incontinence

PURPOSE Urinary incontinence affects 40% of women in the United States and stress urinary incontinence accounts for a large portion of affected patients. As defined by the International Continence Society, stress urinary incontinence is the involuntary leakage of urine upon effort, exertion, sneezing or coughing. Since the ultimate success of long-term management for any condition is based on an understanding of its pathophysiology, and because the pathophysiology of stress urinary incontinence is incompletely defined, animal models have recently been developed to better understand stress urinary incontinence and develop novel treatment alternatives. MATERIALS AND METHODS Several animal models for urethral dysfunction have emerged in the last few years, including those based on pathophysiological theories of urethral sphincter dysfunction that were designed to simulate maternal birth trauma. Other models have focused on the creation of a durable model of dysfunction for investigating novel treatments. RESULTS Since animals cannot express intent, these animal models have focused on measuring decreased urethral resistance. The most widely used methods are the sneeze test, the tilt table technique and the leak point pressure test. Newer techniques include abdominal leak point pressure, urethral pressure measurement and retrograde urethral perfusion pressure. In addition to the advantages and disadvantages of each technique, all methods measure the composite contribution to urethral resistance from smooth and striated muscle, urethral closure and connective tissue, although none measures intent. CONCLUSIONS We critically reviewed the different models of stress urinary incontinence and urethral dysfunction as well as the different methods of measuring urethral resistance.

International continence society guidelines on urodynamic equipment performance

These guidelines provide benchmarks for the performance of urodynamic equipment, and have been developed by the International Continence Society to assist purchasing decisions, design requirements, and performance checks. The guidelines suggest ranges of specification for uroflowmetry, volume, pressure, and EMG measurement, along with recommendations for user interfaces and performance tests. Factors affecting measurement relating to the different technologies used are also described. Summary tables of essential and desirable features are included for ease of reference. It is emphasized that these guidelines can only contribute to good urodynamics if equipment is used properly, in accordance with good practice. Neurourol. Urodynam. 33:370–379, 2014.

Low-Power Wireless Micromanometer System for Acute and Chronic Bladder-Pressure Monitoring

This letter describes the design, fabrication, and testing of a wireless bladder-pressure-sensing system for chronic, point-of-care applications, such as urodynamics or closed-loop neuromodulation. The system consists of a miniature implantable device and an external RF receiver and wireless battery charger. The implant is small enough to be cystoscopically implanted within the bladder wall, where it is securely held and shielded from the urine stream. The implant consists of a custom application-specific integrated circuit (ASIC), a pressure transducer, a rechargeable battery, and wireless telemetry and recharging antennas. The ASIC includes instrumentation, wireless transmission, and power-management circuitry, and on an average draws less than 9 μA from the 3.6-V battery. The battery charge can be wirelessly replenished with daily 6-h recharge periods that can occur during the periods of sleep. Acute in vivo evaluation of the pressure-sensing system in canine models has demonstrated that the system can accurately capture lumen pressure from a submucosal implant location.

Animal Models of Stress Urinary Incontinence

Stress urinary incontinence (SUI) is a common health problem significantly affecting the quality of life of women worldwide. Animal models that simulate SUI enable the assessment of the mechanism of risk factors for SUI in a controlled fashion, including childbirth injuries, and enable preclinical testing of new treatments and therapies for SUI. Animal models that simulate childbirth are presently being utilized to determine the mechanisms of the maternal injuries of childbirth that lead to SUI with the goal of developing prophylactic treatments. Methods of assessing SUI in animals that mimic diagnostic methods used clinically have been developed to evaluate the animal models. Use of these animal models to test innovative treatment strategies has the potential to improve clinical management of SUI. This chapter provides a review of the available animal models of SUI, as well as a review of the methods of assessing SUI in animal models, and potential treatments that have been tested on these models.

WHOLE BLADDER MECHANICS DURING FILLING

In addition to molecular and cellular properties, elemental and whole bladder properties are important to the function of the bladder during filling. The bladder pressure volume filling relation is dependent on all aspects of bladder tissue. Elemental mechanics properties include elasticity, viscoelasticity, and plastic deformation of bladder tissue. Whole bladder properties include bladder shape, mass, and distension. This paper reviews work on mathematical model aimed at determining the effect of whole bladder properties on bladder filling mechanics and outlines directions for the future.

Pelvic organ distribution of mesenchymal stem cells injected intravenously after simulated childbirth injury in female rats.

The local route of stem cell administration utilized presently in clinical trials for stress incontinence may not take full advantage of the capabilities of these cells. The goal of this study was to evaluate if intravenously injected mesenchymal stem cells (MSCs) home to pelvic organs after simulated childbirth injury in a rat model. Female rats underwent either vaginal distension (VD) or sham VD. All rats received 2 million GFP-labeled MSCs intravenously 1 hour after injury. Four or 10 days later pelvic organs and muscles were imaged for visualization of GFP-positive cells. Significantly more MSCs home to the urethra, vagina, rectum, and levator ani muscle 4 days after VD than after sham VD. MSCs were present 10 days after injection but GFP intensity had decreased. This study provides basic science evidence that intravenous administration of MSCs could provide an effective route for cell-based therapy to facilitate repair after injury and treat stress incontinence.

The effect of urinary bladder shape on its mechanics during filling

Despite the normal variation in the shape of the urinary bladder, it has always been modeled as a sphere. We have investigated whether its steady-state pressure-volume relation would be significantly different if it were a spheroid. From pressure-volume curves of anesthetized dogs, we deduced stress-strain constitutive relationships for the bladder wall material. We then solved the equilibrium equations for prolate and oblate spheroids with these constitutive relationships and predicted stress, strain, and volume at 120 different transmural pressures and eight different eccentricities of both types of spheroids. The pressure-volume relation of the prolate spheroid never differed very much from that of a sphere. However, an oblate spheroid made of urinary bladder material is significantly more compliant than either a prolate spheroid or a sphere made of the same material. Applications include identification of the position of highest stress in the bladder wall, estimation of material properties of urinary bladders, and determination of the physiological signal indicating bladder fullness.

Neuroregeneration and voiding behavior patterns after pudendal nerve crush in female rats.

Since the pudendal nerve innervates the external urethral sphincter, pudendal nerve injury and resultant neuroregeneration should affect voiding behavior. In this study, neuroregenerative activity of pudendal nerve was correlated to the changes in urinary behavior in female rats. Eighteen female rats underwent bilateral pudendal nerve crush, and 17 to 21 age‐matched rats were used as unoperated controls. Urinary volume and frequency were recorded 6 and 13 days post‐operatively (dpo). Initiation of pudendal nerve regeneration was indicated by an upregulation of βII tubulin mRNA in the dorsolateral motoneurons (DLM), as measured at 7 and 14 dpo by in situ hybridization with radio‐labeled βII tubulin cDNA. At 6 dpo, mean volume voided by the crush group was significantly decreased compared to the control group during the light cycle (P < 0.05). At 7 dpo, the DLM mRNA level was significantly increased in the nerve crush group compared to the control group (P < 0.05). At 13 dpo, there were no differences in volume or frequency between the two groups, suggesting a return to normal voiding behavior. At 14 dpo, there was no significant difference in DLM mRNA levels between crush and control groups. Initiation of nerve regeneration occurs before normalization of voiding behavior after pudendal nerve crush. This data suggest that treatments to accelerate nerve regeneration would improve functional recovery of neurologically based incontinence. Neurourol. Urodynam. 19:311–321, 2000.