Wireless mechano-electrical stimulation of pudendal nerve using piezoelectric platform for stress urinary incontinence

利用压电平台无线机电刺激阴部神经治疗压力性尿失禁

• 批准号: 10629570
• 负责人: Metin Uz
• 金额: $ 43.52万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629570
• 关键词: Action Potentials; Affect; Anatomy; Anxiety; Brain-Derived Neurotrophic Factor; Cell Survival; Cells; Clinic; Clinical; Cues; Denervation; Deterioration; Discipline; Economic Burden; Economics; Electric Stimulation; Electrodes; Engineering; Exercise; Exposure to; Feasibility Studies; Generations; Health; Home; Hour; Human; Human Resources; Implant; In Vitro; Incontinence; Injury; Kegel exercise; Life; Mechanics; Mental Depression; Metals; Methods; Microfluidics; Modeling; Motor Neurons; Movement; Muscle; Natural regeneration; Nerve; Nerve Entrapment; Nerve Regeneration; Neuronal Injury; Neurons; Operative Surgical Procedures; Patients; Pelvic floor structure; Penetration; Performance; Physical activity; Polymers; Population; Postoperative Period; Pregnant Women; Prevalence Study; Property; Quality of life; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Research; Risk; Running; Safety; Schwann Cells; Site; Social isolation; Sphincter; Stress Urinary Incontinence; Stretching; Symptoms; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Urethral sphincter; Urinary Incontinence; Urology; Vaginal delivery procedure; Woman; biomaterial compatibility; blind; clinical translation; cytokine; design; electric field; exercise rehabilitation; experience; flexibility; implantation; in vivo; injured; innovation; mechanical force; mechanical properties; nerve injury; neurotrophic factor; prototype; regenerative; reinnervation; response; simulation; stem cell therapy; success; technology platform; translational approach; urinary; wireless

PROJECT SUMMARY / ABSTRACT Stress urinary incontinence (SUI) is a common urinary condition that many women experience after vaginal delivery. It is reported that ~55% of pregnant women have symptoms of urinary incontinence. While ~20-45% of this population experience persistent SUI after vaginal delivery, the remaining population is still at risk to develop incontinence later in life despite the spontaneous recovery. The damage to the pudendal nerve (PN) after vaginal delivery causes decreased expression of regenerative cytokines and neurotrophins (i.e., brain-derived neurotrophic factor (BDNF)) followed by subsequent denervation of the external urethral sphincter (EUS). It has been shown that the specific targeting of PN using direct electrical stimulation (ES) can provide PN regeneration via neurotrophin secretion (i.e., BDNF) of injured neurons and endogenous Schwann Cells (SC) and can be considered as a potential alternative for SUI treatment. However, clinical translation of this approach may be challenging due to the following reasons: (1) PN is difficult to locate because of its anatomical course leading to difficulties in fixing the electrodes. (2) ES can only be applied intraoperatively during the surgery (only once for ~1 hour). (3) Postoperative multiple ES is difficult to apply due to invasive and blind penetration of electrodes lacking precise, accurate, and local treatment. (4) ES via metal electrodes requires professional personnel and does not allow on-demand self-treatment. In this project, a piezoelectric material-based biodegradable and implantable platform is proposed as an alternative approach to enable wireless, local, and on-demand mechano- electrical stimulation (MES) of PN for postoperative SUI treatment. For this purpose, three aims will be pursued to complete the feasibility studies. In Aim 1, flexible cuff electrode-integrated piezoelectric platform will be designed, fabricated, and characterized. The generated piezoelectric response and in vitro degradation profile will be determined to control MES conditions. In Aim 2, the in vitro performance of the piezoelectric platform will be evaluated in terms of biocompatibility, safety, and therapeutic efficacy. A pilot in vivo study will also be conducted for evaluating the surgical procedure and implantation of the platform along with the in vivo biocompatibility and biodegradability. In Aim 3, therapeutic performance of generated MES by the implanted platform will be validated on rat SUI model. The subthreshold MES value will be determined, and the in vivo therapeutic efficacy of piezoelectric platform will be evaluated by running wheel exercise and detailed histochemical and functional recovery tests. The successful completion of these aims will introduce an innovatively engineered piezoelectric platform enabling local, wireless, and postoperative MES of PN. In the long term, this piezoelectric platform can be synergistically combined with Kegel exercise to provide local MES upon rehabilitative Kegel movements to promote PN regeneration and reinnervation, a pioneering and innovative strategy that can generate a paradigm shift in the urology field for SUI treatment.

项目概要/摘要 压力性尿失禁（SUI）是一种常见的泌尿系统疾病，许多女性在阴道手术后都会经历这种情况。 送货。据报道，约55%的孕妇有尿失禁的症状。而约 20-45% 的 该人群在阴道分娩后经历持续性 SUI，其余人群仍有发生风险 尽管可自行恢复，但仍会在以后的生活中出现尿失禁。阴道手术后对阴部神经（PN）的损害 递送导致再生细胞因子和神经营养因子（即脑源性细胞因子）表达减少 神经营养因子（BDNF）），随后尿道外括约肌（EUS）去神经支配。它有 研究表明，使用直接电刺激 (ES) 特异性靶向 PN 可以提供 PN 再生 通过受损神经元和内源雪旺细胞 (SC) 的神经营养蛋白分泌（即 BDNF），并且可以 被认为是 SUI 治疗的潜在替代方案。然而，这种方法的临床转化可能是 由于以下原因，该技术具有挑战性：(1) PN 难以定位，因为其解剖路线导致 固定电极的困难。 （2）ES只能在手术过程中术中应用（一次只能应用一次） 〜1小时）。 (3)术后多次ES由于电极的侵入性和盲目刺入而难以应用 缺乏精准、准确、局部的治疗。 (4)金属电极ES需要专业人员和 不允许按需自我治疗。在该项目中，基于压电材料的可生物降解和 植入式平台被提议作为一种替代方法来实现无线、本地和按需机械 PN 电刺激 (MES) 用于术后 SUI 治疗。为此，将实现三个目标 完成可行性研究。在目标 1 中，柔性袖带电极集成压电平台将被 设计、制造和表征。产生的压电响应和体外降解曲线 将确定控制MES条件。在目标 2 中，压电平台的体外性能将 从生物相容性、安全性和治疗效果等方面进行评估。一项体内试点研究也将在 进行评估手术过程和平台植入以及体内 生物相容性和生物降解性。在目标 3 中，植入的 MES 产生的治疗性能 平台将在大鼠 SUI 模型上进行验证。将确定亚阈值 MES 值，并且体内 压电平台的治疗效果将通过跑轮运动进行评估，并详细说明 组织化学和功能恢复测试。这些目标的成功实现将引入 创新设计的压电平台可实现 PN 的本地、无线和术后 MES。在漫长的 从长远来看，该压电平台可以与凯格尔运动协同结合，提供局部 MES 康复凯格尔运动促进PN再生和神经支配，开创性创新 该策略可以在 SUI 治疗的泌尿外科领域产生范式转变。