A 3D-Printed Nerve Cuff for 1-Photon Optogenetic Vagal Stimulation

用于 1 光子光遗传学迷走神经刺激的 3D 打印神经袖带

• 批准号: 10285881
• 负责人: Arjun K Fontaine
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285881
• 关键词: 3D Print; Acute; Adverse effects; Animal Model; Anti-Cholinergics; Anti-Inflammatory Agents; Attenuated; Autonomic Pathways; Autonomic nervous system; Axon; Beta Cell; Biocompatible Materials; Cardiac; Cells; Cervical; Cholinergic Fibers; Chronic; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Communities; Crohn' s disease; Custom; Cytokine Suppression; Data; Dermal; Development; Devices; Diabetes Mellitus; Disease; EFRAC; Electric Stimulation; Electrodes; Epilepsy; Fiber; Future; Gastrointestinal Diseases; Genetic; Head; Heart Diseases; Heart Rate; Heart failure; IL6 gene; Immune; Implant; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-1; Intervention; Investigation; Islets of Langerhans; Left ventricular structure; Light; Lighting; Lipopolysaccharides; Longevity; Measurement; Measures; Mechanics; Medical Research; Mental Depression; Methods; Modeling; Mus; Nature; Nerve; Nerve Tissue; Nervous system structure; Neural Pathways; Opsin; Optics; Organ; Outcome; Pathology; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Photons; Polyethylene Glycols; Printing; Property; Quality of life; Regulation; Research; Resolution; Rheumatoid Arthritis; Signal Pathway; Signal Transduction; Spleen; Structure; Surgical sutures; System; TNF gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Therapeutic Uses; Time; Tissues; Transgenic Animals; Vagus nerve structure; Validation; Viral; Viscera; Visceral; Work; adeno-associated viral vector; awake; base; biomaterial compatibility; cell type; cholinergic; cytokine; efficacy testing; flexibility; implantable device; implantation; improved; improved outcome; in vivo; interest; islet; mouse model; neural circuit; neuroregulation; novel; optical fiber; optogenetics; pre-clinical; preclinical study; preservation; pressure; relating to nervous system; response; systemic inflammatory response; therapeutic target; tool; vagus nerve stimulation

Project Summary/Abstract Therapeutic interventions using peripheral nerves of the autonomic nervous system are increasingly being considered and applied to modulate organ function for disease treatments. Vagus nerve stimulation (VNS) has been clinically approved for over two decades for its treatment of epileptic seizures and depression. It has also demonstrated positive clinical outcomes in the treatment of inflammatory disorders such as rheumatoid arthritis and Crohn's disease, while clinical and pre-clinical data suggest therapeutic benefit in heart disease and diabetes. Cholinergic (parasympathetic) pathways are believed to be central in the therapeutic effects that are observed. The `cholinergic anti-inflammatory pathway' is an established signaling mechanism by which the expression and release of pro-inflammatory cytokines are reduced in the spleen and in other visceral tissues. Because inflammation is a driver of numerous diseases, the ability to regulate inflammatory mediators is of major interest. While these neural pathways hold promising therapeutic potential, current devices have significant limitations. Electrode- based devices used in existing VNS therapies apply current broadly to the nerve. The non-specific nature of this electrical stimulation activates off-target pathways causing adverse effects to the patient, and furthermore, does not provide an adequate tool to study and understand therapeutically relevant nerve pathways. The proposed research will develop a new device for optogenetic vagus nerve stimulation that can eliminate these off-target complications. With optogenetic tools, light-sensitive actuators can be targeted to cell-types of interest via genetic targeting and tissue-specific viral delivery, thus enabling highly specific activation and investigation of neural circuits. The current study will develop and validate a 3D printed vagus nerve cuff system for optogenetic studies. Novel micro- resolution stereolithographical 3D-printing capabilities will be leveraged to produce a biocompatible, single-component, optical stimulation nerve implant (Aim 1). This approach will enable an easy-to-fabricate and easy-to-implant device that can be applied to study and identify neural circuits across many disease states. The device will be validated in a transgenic animal model (Aim2) in which cholinergic pathways will be optogenetically stimulated in mouse models of acute and chronic systemic inflammation. Modulation of pro-inflammatory mediators will be measured in vivo over a period of two months along with the cholinergic-vagal heart rate response to test efficacy of the system. It is hypothesized that this device will enable a simply-employed system for chronic optogenetic vagus nerve stimulation that will reduce systemic inflammatory mediators in an animal model.

项目摘要/摘要 使用自主神经系统的周围神经进行治疗干预措施正在越来越多地考虑在 应用于调节器官功能进行疾病治疗。迷走神经刺激（VNS）已在临床上批准 二十年来，其治疗癫痫发作和抑郁症。它也表现出阳性临床 治疗炎症性疾病（例如类风湿关节炎和克罗恩病）的结果，而临床和 临床前数据表明对心脏病和糖尿病的治疗益处。胆碱能（副交感神经）途径为 被认为是观察到的治疗作用中的核心。 “胆碱能抗炎途径”是 建立的信号传导机制，通过这种机制，促炎细胞因子的表达和释放降低了 脾脏和其他内脏组织。因为炎症是许多疾病的驱动力，所以调节的能力 炎症介体具有重大关注。 尽管这些神经途径具有有希望的治疗潜力，但当前的设备却有很大的局限性。电极- 现有VNS疗法中使用的基于基于的设备广泛应用于神经。该电气的非特异性性质 刺激会激活靶向途径，从而对患者产生不良影响，此外，不提供 足够的工具来研究和理解与治疗相关的神经途径。拟议的研究将开发新的 光遗传迷走神经刺激的装置，可以消除这些脱靶并发症。使用光遗传学工具， 光敏感的致动器可以通过遗传靶向和组织特异性病毒递送来靶向感兴趣的细胞类型， 从而实现了高度特异性的激活和神经回路的研究。 当前的研究将开发并验证3D打印的迷走神经袖口系统进行光遗传学研究。新型微型 - 分辨率立体印刷3D打印功能将被利用以产生生物相容性的单一组件， 光学刺激神经植入物（AIM 1）。这种方法将启用一种易于制作且易于植入的设备 可以应用于许多疾病状态的神经回路。该设备将在 转基因动物模型（AIM2），其中将在小鼠模型中刺激胆碱能途径 急性和慢性全身炎症。促炎性介质的调节将在体内测量 两个月的周期以及胆碱能 - 气率对系统功效的反应。它是假设的 该设备将启用一个简单地雇用的系统，用于慢性光学迷走神经刺激，以减少 动物模型中的全身炎症介体。