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 2 超过 25% 的成年人患有高血压，而在高血压患者中， 3 估计 20% 至 30% 的人对标准药物治疗有耐药性。 4 射血分数降低的功能性 III 级心力衰竭患者的死亡率为 30%。 通过颈动脉窦球电刺激产生的压力反射 5 最近已获得市场批准 6 美国食品和药物管理局通过诱导大系统治疗来治疗高血压和心力衰竭 与多次失败的迷走神经刺激 (VNS) 不同的是，交感/副交感神经张力发生了 7 种变化。 8 项双盲、随机和假对照 III 期研究 (RCT)，刺激颈动脉窦球部 9 已证明，与假手术相比，随机对照试验中血压大幅下降。VNS 的失败可能是由于以下原因造成的。 10 运动神经传出神经的激活导致治疗在参与前限制颈部肌肉的激活 11 条通往心脏的副交感传出神经或通往孤独触觉核 (NTS) 的感觉传入通路 12 尽管压力感受反射激活疗法 (BAT) 在临床试验中取得了成功，但它是仅使用的最后手段 13 药物治疗失败后。 14 导致最佳可行技术未能广泛采用的主要原因有四个：1) 15 手术植入对于大部分无症状且不受控制的高血压患者没有吸引力，2) 16 当前植入系统的复杂性会导致长期且严重的多点故障 17 增加了供应链的复杂性，导致 VNS 中备受瞩目的设备召回，3) 的一般成本 18 植入系统是令人望而却步的，并且 4) 颈部肌肉的并发激活仍然是治疗极限 19 对许多患者的疗效 为了克服这些问题，我们开发了一种新型电极，称为“ 20 Injectrode®，一种注射器可注射的柔性电极材料，可适应神经丛等复杂结构 21 或孔一旦注射，我们最近展示了通过简单的连接在深部神经上注射的能力。 22 线连接到注射到皮下的 Injectrode“收集器”，并使用 23 标准廉价非侵入式 TENS 装置，无需任何跨越皮肤的电线连接。 24 只需一个无源元件即可创建从皮下到复杂神经的传导导管 颈内动脉/球部的颈动脉窦神经形成的神经丛等25个结构，大大减少了 26 导致不良事件的慢性故障点的数量。 27 在第一阶段 SBIR 中，我们将优化、验证和完善 Injectrode 概念，以实现侵入性较小、 28个更强大、更隔离的BAT。 29