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

项目总结/摘要 压力性尿失禁（SUI）是一种常见的泌尿系统疾病，许多妇女在阴道手术后都会遇到这种情况。 交付.据报道，约55%的孕妇有尿失禁的症状。而约20 - 45%的 这一人群在阴道分娩后经历持续性SUI，其余人群仍有发展的风险。 在以后的生活中失禁，尽管自发恢复。经阴道手术后阴部神经（PN）的损伤 递送导致再生细胞因子和神经营养因子的表达降低（即，脑源 神经营养因子（BDNF）），随后去神经支配外尿道括约肌（EUS）。它有 已经表明，使用直接电刺激（ES）的PN的特异性靶向可以提供PN再生 通过神经营养素分泌（即，BDNF）对损伤的神经元和内源性雪旺细胞（SC）的作用，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 具有挑战性，原因如下：（1）由于其解剖过程导致PN难以定位， 固定电极的困难。(2)ES只能在术中应用（仅一次用于 ~1小时）。(3)由于电极的侵入性和盲目穿透，术后多次ES难以应用 缺乏精确、准确和局部治疗。(4)通过金属电极的ES需要专业人员， 不允许按需自我治疗。在这个项目中，一种基于压电材料的可生物降解和 植入式平台被提出作为一种替代方法，使无线，本地和按需机械， PN电刺激（MES）用于术后SUI治疗。为此目的，将追求三个目标 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 将被确定为控制MES条件。在目标2中，压电平台的体外性能将 在生物相容性、安全性和治疗有效性方面进行评价。还将进行一项初步体内研究， 用于评价手术程序和平台植入沿着以及体内 生物相容性和生物降解性。在目标3中，通过植入的微囊化装置产生的MES的治疗性能被评估。 将在大鼠SUI模型上验证平台。将确定亚阈值MES值，并且将在体内测定MES值。 通过跑轮运动评价压电平台的治疗效果， 组织化学和功能恢复测试。这些目标的成功实现将使 创新设计的压电平台可实现PN的本地、无线和术后MES。从长远 总之，该压电平台可以与凯格尔运动协同地组合，以提供局部MES， 康复凯格尔运动，以促进PN再生和神经再支配，一个开创性和创新的 这是一种可以在SUI治疗的泌尿学领域产生范式转变的策略。

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.