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高血压影响25％以上的成年人，而在那些患有高血压的人中， 3估计20％至30％在标准药物治疗中具有抵抗力。同样，三年 4功能性III类心力衰竭患者的死亡率减少为30％。激活 5通过对颈动脉窦灯泡的电刺激的降压力反射，最近已获得市场批准 6食品和药物管理局通过诱导的大型全身性治疗高血压和心力衰竭 7交感/副交感神经语调的变化。与迷走神经刺激（VNS）不同，该刺激失败了 8双盲，随机和假控制期III期研究（RCT），刺激颈动脉鼻窦鳞茎 9显示了RCT与假手术的血压下降。 VNS的故障被推理在 10激活运动神经效率，导致治疗限制颈部肌肉激活，然后参与 11副交感效率对孤立触觉（NTS）核的心脏或感觉传入途径 12尽管在临床试验中取得了成功 13药物疗法失败后。 14驱动蝙蝠缺乏宽度的主要原因有四个主要原因：1） 15手术植入对大大不对称的高血压患者没有吸引力，2） 16当前植入系统的复杂性长期和巨大的失败点导致多个失败点 17增加了供应链的复杂性，导致VNS中的备受瞩目的设备召回，3） 18禁止植入系统，4）颈部肌肉的同时激活仍限制治疗 许多患者的效率19。为了克服这些问题，我们开发了一种名为 20Injextrode®，一种注射的注射柔性电极材料，符合复杂的结构，例如丛 注射一旦注射21或孔。我们最近显示了在深神上注入的能力，通过简单的 22导入皮肤下注射的“收集器”，并可靠地刺激深神经 23标准廉价的非侵入型单元，没有任何电线连接跨越皮肤。该系统具有 24只有一个被动组件来创建从皮肤下方到复杂神经元的导电导管 25种结构，例如颈动脉/鳞茎上颈动脉神经形成的丛，大大降低 26导致不良事件的慢性故障点的数量。 27在这个阶段I SBIR中，我们将优化，验证和完善注射概念，以减少侵入性， 28更强大，更孤立的蝙蝠。 29