Pudendal neuromodulation for urinary and fecal incontinence and sphincter dyssynergia

摘要/摘要 脊髓损伤(SCI)经常导致严重的、终生的膀胱和肠道功能障碍，导致 尿失禁(UI)和大便失禁(FI)，以及括约肌协同失调，导致尿潴留和 粪便嵌塞。目前治疗大小便失禁的标准包括适度有效的药物，复杂的 手术，或者成人尿布。膀胱和肠道排尿需要每天多次的膀胱插管 以及对大多数SCI患者定期进行数字粪便提取。尿布不育，导尿管诱导 频繁的尿路感染，数字肠道程序是耗时和耻辱的 个人和/或其照顾者。对于大多数脊髓损伤患者来说，膀胱和肠道功能障碍会影响他们的 更多的是他们的职业和社交生活，而不是他们无法行走。 在麻醉制剂中，我们的第一阶段STTR应用确定了电脉冲特征 (例如，3T，100微秒，10-30赫兹)，当应用于阴部(PUD)神经时，刺激传出和 分别产生尿道和肛门括约肌持续收缩(1小时)的传入纤维 随着膀胱容量的增加，膀胱活动受到抑制。膀胱漏气点压力也是 明显增加。这些生理效应在复制时应会显著减少UI和FI 病人。此外，用于刺激PUD神经的相同电极和刺激器也被 能够通过从低频切换到KHZ高频(恒定占空比)来阻断PUD神经 防止括约肌收缩的脉冲。 在此第二阶段SBIR应用的目标1中，首先测试慢性脊髓损伤准备以确认它们 对上述脉冲特征的反应类似于我们在脊柱完整研究中的第一阶段研究。对于目标2，a 在可植入脉冲发生器(IPG)与电极接口的情况下进行平移研究 双侧放置于慢性脊髓损伤模型的阴部神经上2个月。在此期间，IPG 当需要储存尿液和粪便时，用来刺激PUD神经，然后切换到阻断 当需要排出尿液和粪便时，便会出现神经。IPG使用遥控器在 存储模式和作废模式。通过比较来评估控制UI和FI剧集的有效性 测试日的剧集数量和体积/重量，激活存储模式与不激活存储模式的对比。 通过测量药物诱导的排尿效率来评估控制括约肌协同障碍的有效性 在有无排尿模式激活的情况下，对考试日的信用难度进行主观评分。在 研究结束时，对括约肌进行评估，看是否有括约肌肥大和疲劳增加的迹象。 抵抗性肌肉纤维。最后，为了准备FDA的讨论，我们将评估不同的制剂 考虑GLP安全研究。

SUMMARY / ABSTRACT Spinal cord injury (SCI) frequently produces severe, life-long bladder and bowel dysfunction that results in urinary (UI) and fecal incontinence (FI), as well as sphincter dyssynergia that results in urinary retention and fecal impaction. Current standard of care for incontinence consists of modestly effective drugs, complicated surgery, or adult diapers. Bladder and bowel voiding require multiple-times-daily catheterization of the bladder and regular digital extraction of feces for most SCI individuals. Diapers are odiferous, catheters induce frequent urinary tract infections, and digital bowel programs are time-consuming and stigmatizing for the individual and/or their caregiver. For most people with SCI, bladder and bowel dysfunction impacts their professional and social lives more than their inability to walk. Our Phase 1 STTR application, in anesthetized preparations, determined electrical pulse characteristics (e.g. 3T, 100 usec, 10-30 Hz), which when applied to the pudendal (PUD) nerve, stimulated efferent and afferent fibers to produce, respectively, sustained contractions (>1 hour) of the urethral and anal sphincters and inhibition of bladder activity with increased bladder capacity. Bladder leak point pressures were also markedly increased. These physiological effects should significantly reduce UI and FI when replicated in patients. In addition, the same electrodes and stimulator that were used to stimulate the PUD nerve were also able to block the PUD nerve by switching from low frequency to kHz high frequency (constant duty cycle) pulses that prevented sphincter contractions. In Aim 1 of this Phase 2 SBIR application, chronic SCI preparations are first tested to confirm that they respond to the above pulse characteristics similarly to our Phase 1 study in spinal intact studies. For Aim 2, a translational study is performed in which an implantable pulse generator (IPG), is interfaced with electrodes placed bilaterally on the pudendal nerves of chronic SCI preparations for 2 months. During this time, the IPG is used to stimulate the PUD nerve when “Storage” of urine and feces is desired and then switched to block the PUD nerve when “Voiding” of urine and feces is desired. The IPG uses a remote control to switch between Storage Mode and Voiding Mode. Effectiveness in controlling UI and FI episodes is assessed by comparing the number and volume/weight of episodes on test days, with versus without, activation of Storage Mode. Effectiveness for controlling sphincter dyssynergia is assessed by measuring drug-induced voiding efficiency and subjective ratings of Credé difficulty on test days, with versus without, activation of Voiding Mode. At the end of the study sphincters are evaluated for signs of sphincter muscle hypertrophy and increases in fatigue- resistant muscle fibers. Finally, in preparation for FDA discussions, we will assess different preparations in consideration of GLP safety studies.