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)严重影响大约30%的世界人口。最多的 流行的疾病是膀胱过度活动(OAB)，影响15%的成年人，通常表现为其他尿路 功能障碍导致尿液渗漏。OAB给美国带来了830亿美元的巨大经济负担，部分原因是 由于用户界面，增加了疗养院的使用量。大小便失禁深刻影响有尊严、独立的生活，有助于 尿路感染、压疮败血症和跌倒的风险，是导致以下人群功能下降的主要因素 老年人。因此，UI是临床抑郁的一个主要因素，并有助于社交隔离。风险 OAB的因素(衰老、肥胖、糖尿病、更年期、前列腺肥大)不成比例地由以下因素经历 退伍军人和UI与男性和女性的服兵役和创伤后应激障碍有关 退伍军人。因此，UI(特别是OAB)将继续不成比例地影响年长的退伍军人。 在难治性OAB的有限治疗中，经皮胫神经刺激(PTNS)可能是 最便宜、最安全的。本项目将演示使用超声神经刺激(UNS)作为 一种替代PTNS的新方法。超声设备成本的快速下降推动了对UNS的研究 在不破坏皮肤或表面刺激引起不适的情况下，将目标能量传递到神经。 UNS有许多潜在的康复用途，即用于治疗神经病理性或截肢者的疼痛，或用于局部 很难通过手术接触到。这些治疗方法都是未来研究的机会。然而， 从OAB开始是一个很好的初始平移选择，因为胫神经很浅，PTNS是一种 因为超声波照射有指定的安全限度。在这个阶段 研究，我们的第一个目标是产生所需的证据，以竞争资金，将UNS翻译为退伍军人 与OAB合作。易于在家中使用的可穿戴式胫骨神经刺激将极大地扩大获得这些刺激的途径 为行动不便、收入有限或生活在农村地区的退伍军人提供康复治疗。 重要的是，先前的研究已经证明，低强度的胫骨UNS可以调节膀胱功能，并且 外周UNS发生时，超声强度低于FDA安全限值。然而，联合国系统的能源门槛 在胫神经和坐骨神经中产生复合动作电位(CAP)的方法尚未在 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换能器，这些换能器在外部无法使用 实验室环境。这项工作将解决未来资金和翻译面临的两个可行性挑战：1) 确定非侵入性调节膀胱帽和抑制膀胱收缩所需的最小UNS强度 2)展示了薄的、灵活的、波束形成的阵列可以产生高达FDA安全限度的超声强度 在人体解剖尺度上。这些数据将在两个特定目标(SA)中生成。 SA1将利用超声神经测定神经激活和膀胱抑制功率阈值 在已建立的大鼠膀胱反射收缩模型中进行刺激。商用定焦换能器和 为了达到这个目的，必须使用麻醉的动物模型，因为目前还没有用于UNS的可穿戴设备。 该目的的主要结果是：i)坐骨神经CAP幅度，ii)腓肠肌肌电(EMG)幅度， 和iii)膀胱收缩速度。可变强度低频UNS和高频UNS的结果 将其与传统的电刺激胫神经进行比较。 SA2将开发一种可穿戴的柔性超声神经调制阵列，并展示 超声阵列可以在估计的神经调节范围内产生机械指数(MI)。在SA2a，我们将 使用计算机模拟设计阵列几何形状和声透镜轮廓，并使用 水浴式水听器。在SA2B中，我们将用直接印制的声学填充物和透镜来制造柔性阵列， 以及基板印制的曲率传感器。波束方向图将被迭代以产生更小的焦域 超过0.1cm3，MI在0.5-1.9之间，在估计的神经调节范围内，低于FDA的安全限度。