Pudendal neuromodulation for incontinence and sphincter dyssynergia after spinal injury

阴部神经调节治疗脊髓损伤后失禁和括约肌协同失调

• 批准号: 9900511
• 负责人: KARL B THOR
• 金额: $ 26.94万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900511
• 关键词: Action Potentials; Adult Diapers; Anal canal; Animals; Anus; Ataxia; Bilateral; Bladder; Bladder Control; Caregivers; Catheterization; Catheters; Characteristics; Chronic; Clinical; Conscious; Consumption; Contracts; Defecation; Devices; Effectiveness; Electric Stimulation; Electrodes; Extravasation; Fecal Impaction; Fecal Incontinence; Feces; Fiber; Frequencies; Functional disorder; Genitourinary system; Implant; Incontinence; Individual; Infection; Intestines; Kidney Failure; Lead; Life; Mediating; Monitor; Nerve; Neural Conduction; Overactive Bladder; Persons; Phase; Physiologic pulse; Physiological; Relaxation; Skin; Source; Sphincter; Spinal; Spinal Injuries; Spinal cord injury; Stigmatization; Stimulus; Testing; Therapeutic; Time; Urethra; Urethral sphincter; Urinary Incontinence; Urinary Retention; Urinary tract infection; Urination; Urine; Urodynamics; Walking; afferent nerve; behavioral study; digital; experience; improved; nerve supply; neuroregulation; phase 2 study; pre-clinical; pressure; prevent; programs; response; social; standard of care; translational model; urinary

Spinal cord injury (SCI) frequently produces severe, life-long bladder and bowel dysfunction that result in urinary and fecal incontinence, as well as sphincter dyssynergia that causes urinary retention and fecal impaction. Current standard of care for incontinence consists of adult diapers, while bladder and bowel voiding require multiple-times-daily catheterization of the bladder and regular digital extraction of feces. 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. In this application, we propose that currently available, programmable, implantable pulse generators (IPGs), interfaced with electrodes placed bilaterally on the pudendal nerves, can offer people with SCI a remedy for both incontinence and sphincter dyssynergia. The pudendal nerve provides efferent innervation to the urethral and anal rhabdosphincters that produces contractions and prevents the leakage of urine and feces through the urethra and anal canal, respectively. In this application, we focus on improving urinary function and propose that stimulation of the pudendal nerve at low frequencies (LFS) will produce urethral sphincter contractions that resist flow of urine and prevent urinary incontinence. We further propose that LFS will also activate pudendal afferent fibers to suppress bladder overactivity through spinal mechanisms. When voiding is desired, we propose that brief (2-5 min), intermittent (4-5/day), pudendal nerve stimulation at high (kHz) frequencies (KHFS) will occlude pudendal nerve action potentials and prevent sphincter dyssynergia to allow voiding. Unilateral stimulation of the pudendal nerve was found clinically safe and efficacious for treating various urogenital dysfunctions, but bilateral stimulation, which is necessary to fully contract the sphincter, has not been attempted. Specific Aim 1 will establish the most efficient LFS pulse characteristics needed to provide maintained urethral sphincter contractions to prevent leakage of urine during periods of elevated bladder pressure (Storage Mode). Specific Aim 2 will explore whether the LFS pulse characteristics that activate efferent fibers, to contract the sphincter, can also provide effective stimulation of the afferent fibers, to inhibit bladder overactivity. Specific Aim 3 will establish if the same electrodes used for LFS can also deliver KHFS to block pudendal nerve activity, relax the sphincter, and facilitate voiding (Voiding Mode). Phase 2 studies using implanted IPGs for long-term behavioral studies of urinary function in a preclinical, translational model of chronic SCI will also establish if the device simultaneously improves bowel function.

脊髓损伤（SCI）经常产生严重的，终身的膀胱和肠功能障碍，导致 尿失禁和大便失禁，以及括约肌协同失调，导致尿潴留和粪便 嵌塞目前的标准护理失禁包括成人尿布，而膀胱和肠道排尿 需要每天多次插入膀胱导管和定期用手指抽取粪便。尿布是 有气味的导尿管会引起频繁的尿路感染，而数字排便程序也很耗时 并对个人和/或他们的照顾者造成耻辱。对于大多数SCI患者，膀胱和肠道 功能障碍对他们的职业和社会生活的影响大于他们无法行走。 在本申请中，我们建议使用目前可用的可编程植入式脉冲发生器（IPG）， 与放置在阴部神经两侧的电极连接，可以为SCI患者提供治疗， 失禁和括约肌协同失调阴部神经为尿道提供传出神经支配 和肛门横纹括约肌，其产生收缩并防止尿液和粪便通过肛门渗漏。 尿道和肛管。在本申请中，我们专注于改善泌尿功能，并提出 以低频（LFS）刺激阴部神经将产生尿道括约肌收缩， 阻止尿流，防止尿失禁。我们进一步提出，LFS也将激活阴部 传入纤维通过脊髓机制抑制膀胱过度活动。当我们需要排尿时， 建议在高频率（kHz）下进行短暂（2-5分钟）、间歇（4-5次/天）的阴部神经刺激 （KHFS）将阻断阴部神经动作电位，并防止括约肌协同失调，以允许排尿。 单侧阴部神经刺激在临床上被发现是安全和有效的，用于治疗各种 泌尿生殖功能障碍，但双边刺激，这是必要的，以充分收缩括约肌， 被尝试。 具体目标1将建立最有效的LFS脉冲特征，以提供维持尿道 括约肌收缩，以防止在膀胱压力升高期间尿液泄漏（存储模式）。 具体目标2将探讨是否LFS脉冲特性，激活传出纤维，以收缩 括约肌，也可以提供有效的刺激传入纤维，以抑制膀胱过度活动。具体 目标3将确定用于LFS的相同电极是否也可以输送KHFS以阻断阴部神经 活动，放松括约肌，促进排尿（排尿模式）。使用植入式IPG进行的II期研究 在慢性SCI的临床前转化模型中对泌尿功能的长期行为研究也将 确定该器械是否同时改善肠功能。