The Injectrode- An injectable, easily removable electrode as a trial lead for baroreceptor activation therapy to treat hypertension and heart failure

Injectrode——一种可注射、易于拆卸的电极，作为压力感受器激活疗法的试验引线，以治疗高血压和心力衰竭

• 批准号: 10697600
• 负责人: Manfred Franke
• 金额: $ 59.66万
• 依托单位: NEURONOFF, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697600
• 关键词: Acute; Adoption; Adult; Adverse event; Affect; Afferent Pathways; Animal Model; Animal Testing; Animals; Automobile Driving; Autopsy; Baroreflex; Blood Pressure; Cardiac; Chronic; Clinical Trials; Complex; Cranial Nerves; Development; Devices; Dissection; Double-Blind Method; EFRAC; Efferent Neurons; Electric Stimulation; Electrodes; Electromyography; Energy Transfer; Equipment Malfunction; Evaluation; Failure; Family suidae; Fluoroscopy; Heart; Heart Rate; Heart failure; Histologic; Human; Hypertension; Implant; Individual; Industry Standard; Injectable; Injections; Internal carotid artery structure; Lead; Marketing; Measurement; Mechanics; Medical; Methodology; Methods; Motor; Muscle; Neck; Nerve; Neuroanatomy; Neurostimulation procedures of spinal cord tissue; Nucleus solitarius; Operative Surgical Procedures; Pain; Pathway interactions; Patients; Periodicals; Pharmacological Treatment; Pharmacotherapy; Phase; Physiologic pulse; Positioning Attribute; Pressoreceptors; Procedures; Process; Publishing; Randomized; Resistance; Sensory; Sinus; Skeletal muscle structure of neck; Skin; Small Business Innovation Research Grant; Structure; Syringes; System; Telemetry; Testing; Therapeutic; Time; Transcutaneous Electric Nerve Stimulation; Treatment Efficacy; United States Food and Drug Administration; Validation; Visualization; abdominal aorta; carotid sinus; cost; design; electric impedance; energy efficiency; experience; flexibility; good laboratory practice; healing; heart rate monitor; hypertension treatment; implantation; instrument; manufacture; migration; minimal risk; minimally invasive; mortality; neural; novel; phase 3 study; porcine model; pressure; prevent; rate of change; response; side effect; success; supply chain; tool; transcutaneous stimulation; ultrasound; vagus nerve stimulation; wireless

1 Abstract 2 Hypertension affects upwards of 25% of adults, and of those individuals with hypertension, it has been 3 estimated that between 20 to 30% are resistant to standard pharmacological treatment. Similarly, the 3-year 4 mortality rate for patients with functional Class III heart failure with reduced ejection fraction is 30%. Activation 5 of the baroreflex through electrical stimulation of the carotid sinus bulb has recently been market approved by 6 the Food and Drug Administration to treat both hypertension and heart failure by inducing large systemic 7 changes in sympathetic/parasympathetic tone. Unlike vagus nerve stimulation (VNS) which has failed multiple 8 double-blinded, randomized and sham controlled Phase III studies (RCT), stimulation of the carotid sinus bulb 9 has demonstrated large decreases in blood pressure in RCT vs sham. The failure of VNS is putatively due to 10 activation of motor nerve efferents causing therapy limiting neck muscle activation prior to engagement of 11 parasympathetic efferents to the heart or sensory afferent pathways to the Nucleus of the Solitary Tact (NTS) 12 Despite its success in clinical trials, baroreflex activation therapy (BAT) is a treatment of last resort used only 13 after drug therapies have failed. 14 There are four primary reasons driving the lack of widespread adoption of BAT: 1) the invasiveness of 15 surgical implantation is unattractive to patients with largely asymptomatic uncontrolled hypertension, 2) the 16 complexity of the present implanted system leads to multiple points of failure chronically and dramatically 17 increases the complexity of the supply chain leading to high-profile device recalls in VNS, 3) the general cost of 18 the implanted system is prohibitive, and 4) concurrent activation of the neck muscles still limits therapeutic 19 efficacy in many patients. To overcome these issues, we have developed a novel electrode called the 20 Injectrode®, a syringe injectable, flexible electrode material that conforms to complex structures like a plexus 21 or foramen once injected. We have recently shown the ability to inject on a deep nerve, connect via a simple 22 wire to an Injectrode ‘collector’ that is injected under the skin, and reliably stimulate the deep nerve using a 23 standard inexpensive non-invasive TENS unit without any wire connection spanning the skin. This system has 24 only one passive component to create a conductive conduit from just under the skin to complex neural 25 structures like the plexus formed by the carotid sinus nerve at the internal carotid artery/bulb, greatly reducing 26 the number of chronic failure points leading to adverse events. 27 In this Phase I SBIR, we will optimize and validate and refine the Injectrode concept for less invasive, 28 more robust, and more isolated BAT. 29

1摘要 超过25%的成年人患有高血压，在那些患有高血压的人中，高血压一直是 3估计有20%至30%的人对标准药物治疗具有抵抗力。同样，3年期 4射血分数降低的III级心力衰竭患者死亡率为30%。激活 5通过电刺激颈动脉窦球部的压力感受性反射最近已经被市场认可。 6食品和药物管理局通过诱导大的系统性高血压和心力衰竭来治疗高血压和心力衰竭 7交感/副交感神经音调变化。与多次失败的迷走神经刺激(VNS)不同 8项双盲、随机和假对照III期研究(RCT)，刺激颈动脉窦球 9与假手术相比，RCT组的血压有较大幅度的下降。据推测，VNS的失败是由于 10运动神经传出神经的激活导致在接合之前限制颈部肌肉活动的治疗 11条到心脏的副交感传出通路或到孤束核的感觉传入通路(NTS) 尽管在临床试验中取得了成功，但压力感受器反射激活疗法(Bat)只是一种最后的治疗手段。 13在药物治疗失败后。 14没有广泛采用BAT的主要原因有四个：1) 15外科植入物对大部分无症状的失控高血压患者没有吸引力，2) 16当前植入系统的复杂性导致长期和戏剧性的多个故障点 17增加了供应链的复杂性，导致在VNS中高调召回设备；3)总体成本 植入的系统令人望而却步，同时颈部肌肉的激活仍然限制了治疗。 19在许多患者中有效。为了克服这些问题，我们开发了一种新型电极，名为 20 Inputrode®，一种注射器可注射的柔性电极材料，符合神经丛等复杂结构 21或一次注射孔洞。我们最近展示了注入深层神经的能力，通过简单的 22电线连接到注射电极的“收集器”，注射到皮下，并可靠地刺激深部神经 23个标准的廉价非侵入性TENS单元，没有任何跨越皮肤的电线连接。这个系统有 24只需一个无源组件即可创建一条从皮肤下到复杂神经的传导管道 25个结构，如颈内动脉/球部的颈动脉窦神经形成的神经丛，大大减少 26导致不良事件的慢性故障点的数量。 27在此第一阶段SBIR中，我们将优化、验证和改进注射器的概念，以降低侵入性， 28只更健壮，更孤立的蝙蝠。 29