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) 严重影响着世界上约 30% 的人口。最 膀胱过度活动症 (OAB) 是一种常见病症，影响 15% 的成年人，并且经常与其他泌尿系统疾病一起出现。 功能障碍导致漏尿。 OAB 给美国带来了 830 亿美元的巨大经济负担，其中一部分来自 由于 UI，疗养院的使用量增加。失禁严重影响有尊严、独立的生活，有助于 尿路感染、压疮败血症和跌倒风险，并且是功能衰退的主要因素 老年人。因此，UI 是临床抑郁症的一个主要因素，并导致社会孤立。风险 OAB 的因素（衰老、肥胖、糖尿病、更年期、前列腺肥大）不成比例地经历过 退伍军人和 UI 相关人员服兵役并患有创伤后应激障碍（男性和女性） 退伍军人。因此，UI（特别是OAB）将继续对老年退伍军人产生不成比例的影响。 在难治性 OAB 的有限治疗方法中，经皮胫神经刺激 (PTNS) 可能是最有效的治疗方法。 最便宜、最安全。该项目将展示使用超声神经刺激（UNS）作为治疗手段的可行性 PTNS 的新颖替代品。超声波设备成本的迅速下降正在推动 UNS 的调查 向神经输送有针对性的能量，而不会破坏皮肤或因表面刺激而引起不适。 UNS 有许多潜在的康复用途，即用于治疗神经性疼痛或截肢疼痛，或用于定位 是很难通过手术接近的。这些治疗方法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，因为胫神经是浅表的，PTNS 是 既定疗法，并且因为超声暴露有指定的安全限度。现阶段的 研究，我们的首要目标是生成所需的证据来竞争资金，将 UNS 转化为退伍军人 与OAB。易于在家中使用的可穿戴胫骨神经刺激器将极大地扩大这些设备的使用范围 为行动不便、收入有限或居住在农村地区的退伍军人提供康复治疗。 重要的是，先前的研究表明低强度胫骨 UNS 可以调节膀胱功能，并且 当超声强度低于 FDA 安全限值时，会发生外周 UNS。然而，UNS 能源阈值 在胫骨和坐骨神经中产生复合动作电位（CAP）的机制尚未确定 用户界面的上下文。此外，所有先前的 UNS 研究都使用了笨重的传感器，这些传感器在外部无法使用 实验室设置。这项工作将解决未来资助和翻译的两个可行性挑战：1) 确定无创调节 CAP 和抑制膀胱收缩所需的最小 UNS 强度 2) 表明薄而灵活的波束形成阵列可以产生高达 FDA 安全限值的超声波强度 在人体解剖学尺度上。这些数据将在两个特定目标 (SA) 中生成。 SA1 将使用超声波神经确定神经激活和膀胱抑制功率阈值 对已建立的膀胱反射性收缩大鼠模型进行刺激。商业定焦传感器和 为此必须使用麻醉动物模型，因为目前还没有用于 UNS 的可穿戴设备。 该目标的主要结果是 i) 坐骨 CAP 振幅，ii) 腓肠肌电图 (EMG) 振幅， iii) 膀胱收缩率。可变强度低频 UNS 和高频 UNS 的结果 将与传统的胫神经电刺激进行比较。 SA2将开发可穿戴式柔性超声神经调节阵列，并证明柔性 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几何形状和声学透镜轮廓，并验证压力水平 水浴水听器。在 SA2b 中，我们将使用直接印刷的声学填料和透镜制造柔性阵列， 和基板印刷曲率传感器。光束转向模式将被迭代以产生更小的焦点区域 低于 0.1 cm3，MI 介于 0.5-1.9 之间，在估计的神经调节范围内且低于 FDA 安全限值。