【作者】 李俊；

【导师】 鄢俊安；

【作者基本信息】 广西大学 ， 物理学， 2024， 博士

【摘要】 排尿是通过下尿路将尿液排出的过程,承担着排除体内废物、维持体液平衡等重要生理功能。正常的排尿过程需要在中枢神经系统的精细调控下,由膀胱逼尿肌和尿道外括约肌(External urethral sphincter,EUS)协调配合共同完成。然而,中枢神经系统的各种病变,例如多系统萎缩、多发性硬化、帕金森病、脑卒中等神经退行性疾病,以及脊髓损伤,常会导致神经源性下尿路功能障碍(Neurogenic lower urinary tract dysfunction,NLUTD)。NLUTD的临床表现包括尿频、尿急、尿失禁和排尿困难等症状,严重影响患者的生活质量和身心健康。尽管现有的药物和手术干预方法在一定程度上能够缓解NLUTD的症状,但这些治疗手段往往具有不可逆性、侵入性高,且在个性化治疗方面效果有限,而开发可逆性好、侵入性低的干预策略在技术方法上面临着重大挑战。本研究旨在探索针对NLUTD的创新治疗方法,主要分为两部分展开。在第一部分中,本研究提出并验证了一种高度个性化的电刺激疗法,该疗法通过数字信号模拟生理排尿特征,并将其转换为模拟电信号,用于双部位有线电刺激,进而实现对膀胱逼尿肌和尿道外括约肌的人工协同控制。在脊髓损伤小鼠模型中,该疗法的有效性得到了验证。首先,本研究通过对小鼠膀胱压力和EUS肌电数据的深入分析,捕捉到正常反射性排尿时膀胱收缩和EUS活动的特征;接着,基于Lab VIEW软件平台,开发了一种电刺激控制程序,该程序通过数据采集卡将预设的EUS活动特征的数字控制信号转化为模拟电刺激信号。该信号传递至阴部神经,成功实现了EUS的活动控制,并伴随膀胱压力瞬时降低。基于上述结果,本文进一步开发了一种联合控制膀胱逼尿肌和EUS活动的双部位电刺激方案。通过Lab VIEW平台,本研究构建了控制双部位活动的程序,并通过数据采集卡将联合刺激信号传递至阴部神经和主要的盆神经节,实现了对膀胱逼尿肌和EUS的人工协同控制排尿。为进一步验证该方法对NLUTD的干预效果,本研究构建了小鼠完全性脊髓损伤(Spinal cord injury,SCI)模型。结果表明,SCI小鼠的排尿次数显著增多,尿斑直径显著减小,表现出典型的NLUTD症状。在该模型中,双部位电刺激法显著提高了SCI小鼠的排尿量,证明了其对NLUTD的有效干预。第二部分研究针对现有有线电刺激治疗NLUTD中存在的电极栓系和设备位移风险问题,本研究设计并制造了多款微型、无线、无电池的柔性光电刺激植入装置,并在双侧阴部神经离断小鼠中验证了其调控膀胱收缩并有效控制排尿功能的能力。首先,本研究设计并制造了多款无线光电植入装置,同时搭建并集成了三代无线功率传输系统,针对第三代系统开发了基于Lab VIEW平台的调制程序。随后,详细表征了一款无线电刺激装置的物理特征,并在小鼠模型中验证该装置的生物安全性。此外,通过该无线装置对主要盆神经节实施电刺激,成功调控了膀胱收缩。最终,在双侧阴部神经离断小鼠中,进一步验证了该无线植入装置在调控膀胱收缩和排尿控制方面的效果。综上所述,本研究针对NLUTD治疗中的关键问题,提出了基于生理排尿特征的电刺激干预策略,并通过软件开发、硬件构建和生物实验多方验证了其有效性。此外,本研究开发了多款无线光电植入装置,并集成了第三代无线功率传输系统,验证了其中一款柔性、微型、无线、无电池的植入装置能够有效调控膀胱收缩及排尿控制。基于阴部神经的数模转换电刺激方法在减少膀胱压力、保护上尿路方面对神经源性出口梗阻患者具有重要临床意义;而双部位人工协同控制膀胱逼尿肌和EUS的电刺激方法则对SCI患者的NLUTD干预具有较高的应用价值。此外,基于本研究开发的有线电刺激系统和无线功率传输系统,具备潜在的商业化前景。总之,本研究为NLUTD的治疗提供了新的思路与方法。双部位同步电刺激策略及无线无电池电刺激装置展现了电刺激技术在排尿控制领域的巨大潜力,而无线无电池电刺激装置的研发为未来下尿路-脑机接口的研究奠定了坚实基础。更多还原

【Abstract】 Urination is a vital physiological process that eliminates bodily waste and maintains fluid balance.Normal urination involves the coordinated action of the bladder detrusor muscle and the external urethral sphincter(EUS),finely regulated by the central nervous system(CNS).However,various CNS disorders,such as multiple system atrophy,multiple sclerosis,Parkinson’s disease,stroke,and spinal cord injury(SCI),often result in neurogenic lower urinary tract dysfunction(NLUTD).NLUTD manifests with symptoms such as urinary frequency,urgency,incontinence,and difficulty voiding,which severely impair patients’ quality of life and mental well-being.While existing pharmacological and surgical interventions can alleviate NLUTD symptoms to some extent,these treatments are often irreversible,highly invasive,and limited in their capacity to provide personalized solutions.Thus,there is an urgent need to develop innovative interventions that are reversible,minimally invasive,and tailored to individual patient needs for more effective NLUTD management.This study explores innovative strategies for NLUTD treatment in two main parts.In the first part,we propose a personalized electrical stimulation strategy that mimics physiological voiding by converting digital signals into analog stimulation.This strategy enables artificial coordination of bladder detrusor and EUS activity,and its efficacy was validated in a SCI mouse model.To generate reliable digital signals,we analyzed bladder pressure and EUS electromyogram data in mice during normal reflex voiding to capture unique features of bladder contractions and EUS activity.We then developed an electrical stimulation program based on Lab VIEW,which converts predefined digital signals mimicking reflex voiding into analog stimulation signals.These signals were transmitted to the pudendal nerve,controlling EUS activity and causing a rapid decrease in bladder pressure.Building on these results,we developed a dual-site electrical stimulation program to coordinate the activity of the EUS and bladder detrusor,achieving artificial voiding control.This dual-site stimulation was delivered to the pudendal and post-ganglionic pelvic nerves to mimic physiological voiding.The strategy was further validated in a SCI mouse model,where it significantly increased urine output by restoring coordinated bladder and EUS activity.In the second part,to address the risks of tethering and displacement associated with wired stimulation devices,we designed and fabricated several miniature,wireless,battery-free optoelectronic implants.These devices were tested in a bilateral pudendal nerve transection mouse model,where they successfully regulated bladder contractions and controlled voiding.We developed and integrated three generations of wireless power transmission systems,including modulation software for the third-generation system.After characterizing the physical properties of one wireless stimulation device,we confirmed its biocompatibility and validated its ability to control bladder contractions via stimulation of the pelvic nerves.In bilateral pudendal nerve transected mice,the device effectively restored voiding function.In summary,this study addresses critical challenges in NLUTD treatment by proposing a dual-site electrical stimulation strategy that mimics physiological voiding.This approach was validated across multiple platforms,including software,hardware,and biological evaluations.Additionally,we developed and tested wireless,battery-free optoelectronic implants integrated with a third-generation wireless power system.This research presents significant clinical implications for reducing bladder pressure and protecting the upper urinary tract in patients with neurogenic outlet obstruction.Moreover,the coordinated dual-site stimulation of bladder and EUS activity offers great potential for treating NLUTD in SCI patients,while the wireless and wired systems developed hold strong commercial value.In conclusion,this study provides new perspectives and methods for NLUTD treatment.The dual-site electrical stimulation strategy and wireless,battery-free implants highlight the enormous potential of electrical stimulation for voiding control and lay a solid foundation for future research on lower urinary tract-brain interfaces.更多还原