Toward wearable ultrasonic neurostimulation for daily at-home treatment of urinary urge incontinence

用于日常家庭治疗急迫性尿失禁的可穿戴超声神经刺激

• 批准号: 10363621
• 负责人: Steve Majerus
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363621
• 关键词: Acoustics; Action Potentials; Address; Adult; Affect; Age; Aging; Amputees; Anatomy; Animal Model; Automobile Driving; Award; Bathing; Behavior; Biological; Bladder; Computer Simulation; Data; Devices; Diabetes Mellitus; Diagnostic Imaging; Drug Targeting; Economic Burden; Elderly; Electric Stimulation; Elements; Ensure; Equipment; Extravasation; Female; Filler; Frequencies; Functional disorder; Funding; Future; Gastrocnemius Muscle; Geometry; Goals; Health Services Accessibility; Home; Human; Implant; Income; Incontinence; Independent Living; Investigation; Laboratories; Lead; Limb structure; Locales; Location; Long-Term Effects; Major Depressive Disorder; Measurement; Measures; Mechanics; Menopause; Mental Depression; Modeling; Nerve; Nerve Fibers; Neuropathy; Nursing Homes; Obesity; Operative Surgical Procedures; Organ; Outcome; Overactive Bladder; Pain; Painless; Patients; Pattern; Peripheral; Peripheral Nerve Stimulation; Pharmaceutical Preparations; Physiologic pulse; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prostate; Pulse Rates; Rattus; Readiness; Reflex action; Refractory; Rehabilitation therapy; Research; Risk; Risk Factors; Rural; Safety; Sepsis; Skin; Social isolation; Structure of tibial nerve; Surface; Synapses; Technology; Testing; Thinness; Transducers; Translating; Translations; Ultrasonic Transducer; Ultrasonics; Ultrasonography; Urge Incontinence; Urinary Incontinence; Urinary tract infection; Urine; Veterans; Water; Woman; Work; compliance behavior; cost; decubitus ulcer; design; experience; fall risk; flexibility; functional decline; implantation; indexing; innovation; lens; male; micturition urgency; migration; military service; military veteran; nerve threshold; neuroregulation; new technology; novel; painful neuropathy; pressure; primary outcome; relating to nervous system; research clinical testing; response; sciatic nerve; sensor; urinary; wearable device

Urinary incontinence (UI) significantly impacts approximately 30% of the world’s population. The most prevalent condition, overactive bladder (OAB), affects 15% of adults and often manifests with other urinary dysfunctions causing urine leakage. OAB has an enormous US economic burden of $83 billion, in part from increased nursing home use due to UI. Incontinence profoundly impacts dignified, independent living, contributes to urinary tract infections, pressure ulcer sepsis and fall risk, and is a leading factor in functional decline among the elderly. As a result, UI is a major factor in clinical depression and contributes to social isolation . The risk factors for OAB (aging, obesity, diabetes, menopause, enlarged prostate) are disproportionately experienced by Veterans, and UI associates with military service and post-traumatic stress disorder in both male and female Veterans. Therefore UI (and OAB in particular) will continue to affect older Veterans disproportionately. Of the limited treatments for refractory OAB, percutaneous tibial nerve stimulation (PTNS) is likely the cheapest and safest. This project will demonstrate the feasibility of using ultrasonic nerve stimulation (UNS) as a novel alternative to PTNS. The rapidly decreasing cost for ultrasonic equipment is driving investigation of UNS to deliver targeted energy to the nerve without breaking the skin or causing discomfort from surface stimulation. UNS has many potential rehabilitation uses, i.e. for the treatment of neuropathic or amputee pain, or for locations that are difficult to access surgically. These treatments are all opportunities for future research. However, beginning with OAB is an excellent option for initial translation because the tibial nerve is superficial, PTNS is an established therapy, and because there are designated safe limits for ultrasound exposure. At this stage of research, our first goal is to generate the needed evidence to compete for funding to translate UNS to Veterans with OAB. Wearable tibial neurostimulation that is easy to use in the home would greatly expand access to these rehabilitation treatments for Veterans who have limited mobility, income, or live in rural locales. Critically, prior studies have demonstrated that low-intensity tibial UNS modulates bladder function and that peripheral UNS occurs with ultrasonic intensities below FDA safety limits. However, the UNS energy thresholds to produce compound action potentials (CAP) in the tibial and sciatic nerves have not been determined in the context of UI. Further, all prior UNS research has used bulky transducers which are not usable outside of laboratory settings. This work will address two feasibility challenges for future funding and translation: 1) identifying the minimum UNS intensity needed to noninvasively modulate CAPs and inhibit bladder contractions and 2) showing that thin, flexible, beam-formed arrays can produce ultrasonic intensities up to FDA safety limits at human anatomical scales. These data will be generated in two Specific Aims (SA). SA1 will determine the nerve activation and bladder inhibition power thresholds using ultrasonic nerve stimulation in an established rat model of bladder reflex contractions. Commercial fixed-focus transducers and an anesthetized animal model must be used in this aim because wearable devices for UNS are not yet available. Primary outcomes in this aim are i) sciatic CAP amplitude, ii) gastrocnemius electromyogram (EMG) amplitudes, and iii) bladder contraction rates. Outcomes from variable-intensity low-frequency UNS and high-frequency UNS will be compared to conventional electrical tibial nerve stimulation. SA2 will develop a wearable flexible ultrasonic neuromodulation array and demonstrate that flexible ultrasound arrays can generate mechanical index (MI) in the estimated neuromodulation range. In SA2a we will design array geometries and acoustic lens profiles using computer simulations and validate pressure levels with a water bath hydrophone. In SA2b we will fabricate flexible arrays with direct-printed acoustic fillers and lenses, and substrate-printed curvature sensors. Beam steering patterns will be iterated to produce a focal region smaller than 0.1 cm3 and MI between 0.5–1.9, within the estimated neuromodulation range and below FDA safety limits.

尿失禁（UI）显着影响世界人口的30％。最多 普遍的状况，过度活跃的膀胱（OAB），会影响15％的成年人，并且经常与其他尿 功能障碍导致尿液泄漏。 OAB拥有830亿美元的美国经济燃烧，部分原因是 增加了护士家庭用户的使用。尿失禁深刻影响确定，独立生活，贡献 引起尿路感染，压溃疡败血症和降低风险，是功能下降的主要因素 较早的。结果，UI是临床抑郁症的主要因素，并有助于社会隔离。风险 OAB（衰老，肥胖，糖尿病，更年期，前列腺肿大的因素）经历了不成比例的 退伍军人和UI与男性和女性的兵役和创伤后应激障碍相关联 退伍军人。因此，UI（尤其是OAB）将继续对老年退伍军人的影响不成比例。 在难治性OAB的有限治疗方法中，经皮胫骨神经刺激（PTN）可能是 最便宜，最安全。该项目将证明使用超声神经刺激（UNS）的可行性 PTN的新颖替代品。超声设备的迅速降低的成本正在推动对UNS的调查 向神经传递靶向能量而不会破坏皮肤或引起表面刺激的不适。 UNS具有许多潜在的康复用途，即用于治疗神经性或截肢者疼痛或位置 很难通过外科手术进入。这些治疗都是未来研究的机会。然而， 从OAB开始是初始翻译的绝佳选择，因为胫骨神经是浅表的，PTN是一个 已建立的治疗，并且因为有超声暴露的指定安全限制。在这个阶段 研究，我们的第一个目标是生成所需的证据，以争夺资金，将UNS转化为退伍军人 与OAB。可穿戴的胫骨神经刺激在家中易于使用，可以大大扩展对这些的访问 在农村地区有限的流动性，收入或居住在农村地区的退伍军人的康复治疗。 至关重要的是，先前的研究表明，低强度的胫骨UNS调节膀胱功能，并且 外围uns发生，超声强度低于FDA安全限制。但是，联合国能源阈值 在胫骨和坐骨神经中产生复合动作电位（CAP）尚未确定 UI的上下文。此外，所有先前的联合国研究都使用了笨重的传感器，这些传感器在 实验室环境。这项工作将解决未来资金和翻译的两个可行性挑战：1） 识别非侵入性调节帽所需的最低强度并抑制膀胱收缩 2）表明薄，柔性，横梁形成的阵列可以产生高达FDA安全极限的超声强度 在人类解剖量表上。这些数据将在两个特定目标（SA）中生成。 SA1将使用超声神经确定神经激活和膀胱抑制功率阈值 在膀胱反射收缩的已建立大鼠模型中刺激。商业固定聚焦传感器和 在此目标中必须使用麻醉的动物模型，因为尚无可穿戴设备。 此目的的主要结果是i）坐骨帽放大器，ii）胃肌电图（EMG）放大器，， 和iii）膀胱收缩率。可变强度低频和高频UNS的结果 将与常规的胫骨神经刺激进行比较。 SA2将发展一个可穿戴的柔性超声神经调节阵列，并证明这种柔性 超声阵列可以在估计的神经调节范围内生成机械指数（MI）。在SA2A中，我们将 使用计算机模拟设计阵列的几何形状和声学镜头轮廓，并验证压力水平 水浴水文。在SA2B中 和底物打印的曲率传感器。横梁转向图案将迭代产生较小的焦点区域 在估计的神经调节范围内，低于FDA安全限制，高于0.1 cm3和0.5–1.9之间。