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

项目摘要/摘要 压力性尿失禁(SUI)是许多女性阴道后常见的尿路状况 送货。据报道，约55%的孕妇有尿失禁症状。而~20%-45%的 这一人群在阴道分娩后经历了持续性SUI，其余人群仍有发展的风险 晚年大小便失禁，尽管是自然恢复。阴道术后对阴部神经的损害 分娩导致再生细胞因子和神经营养因子(即脑源性)表达减少 神经营养因子(BDNF)，随后去神经的外道括约肌(EUS)。它有 已经证明，使用直接电刺激(ES)的PN的特定靶点可以提供PN再生 通过损伤神经元和内源性雪旺细胞(SC)分泌神经营养因子(即BDNF)，并可 被认为是SUI治疗的潜在替代方案。然而，这种方法的临床翻译可能是 具有挑战性的原因如下：(1)PN因其解剖过程而难于定位 固定电极的困难。(2)ES只能在术中应用(仅限一次 ~1小时)。(3)由于电极的侵入性和盲穿性，术后多个ES难以应用。 缺乏精确的、准确的和局部的治疗。(4)通过金属电极进行ES需要专业人员和 不允许按需自我治疗。在本项目中，一种基于压电材料的可生物降解和 植入式平台是实现无线、本地和按需机制的替代方法 电刺激PN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，柔性袖套电极集成压电平台将 设计、制造和表征。产生的压电响应和体外降解曲线 将下决心控制MES条件。在目标2中，压电平台的体外性能将 从生物相容性、安全性和治疗效果方面进行评估。一项试验性的体内研究也将是 对手术过程和平台植入进行评估，并在体内进行 生物相容性和生物降解性。在目标3中，通过植入产生的MES的治疗性能 平台将在RAT SUI模型上进行验证。亚阈值MES值将被确定，体内 压电平台的治疗效果将通过跑轮练习进行评估，并详细 组织化学和功能恢复试验。这些目标的成功实现将带来一个 创新设计的压电式平台，可实现本地、无线和术后的PN MES。在漫长的岁月里 长期而言，这种压电平台可以与Kegel Exercise协同结合，为当地提供MES 康复凯格尔运动促进PN再生和再神经支配，一种开创性和创新性 能够在泌尿外科领域为SUI治疗带来范式转变的战略。

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.