Novel modalities for assessing the cortical tissue-electrode interface

评估皮质组织-电极界面的新方法

• 批准号: 8003184
• 负责人: Jeffrey R Capadona
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003184
• 关键词: Ablation; Acute; Allergic Reaction; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Apoptosis; Arthritis; Astrocytes; Atherosclerosis; Attenuated; Binding; Biochemical; Biochemical Pathway; Biocompatible Materials; Blood - brain barrier anatomy; Brain; Cell Death; Cells; Chemicals; Chronic; Cicatrix; Clinical; Complex; Coupled; Data; Detection; Devices; Diffusion; Disease; Electric Stimulation; Electrodes; Engineering; Ensure; Equipment Malfunction; Event; Failure; Foreign Bodies; Foreign-Body Reaction; Future; Gene Transfer; Genetic Engineering; Genetic Materials; Goals; Growth; Homeostasis; Human; Image; Imaging Techniques; Immunohistochemistry; Implant; Implanted Electrodes; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Lead; Lentivirus Infections; Lentivirus Vector; Life; Literature; Longevity; Malignant Neoplasms; Measurement; Measures; Mediating; Methods; Microelectrodes; Microglia; Modality; Modification; Molecular; Molecular Probes; Morbidity - disease rate; Motor; Mus; Nerve Degeneration; Neurologic; Neurons; Neurosciences; Noise; Oligodendroglia; Patients; Peptide Hydrolases; Play; Population; Prosthesis; Qualifying; Rattus; Reaction; Reactive Oxygen Species; Research; Research Project Grants; Role; Secondary to; Signal Transduction; Slice; Solutions; Spinal cord injury; Staging; Staining method; Stains; Stroke; Subfamily lentivirinae; Surface; Surface Properties; System; Techniques; Technology; Testing; Therapeutic Intervention; Thinking; Time; Tissues; Topical application; Translating; Validation; Veterans; Viral Vector; Virus; Virus Diseases; Work; abstracting; attenuation; base; cancer imaging; caspase-9; cell type; clinical application; cytokine; density; design; electric impedance; functional restoration; imaging modality; imaging probe; implantation; improved; macrophage; method development; molecular imaging; novel; promoter; public health relevance; relating to nervous system; repaired; response; suicide gene; time use

DESCRIPTION (provided by applicant): Project Summary / Abstract Our long-term goal is to develop advanced materials for neural interfaces which will seamlessly assimilate within the neural tissue to facilitate sustained molecular level connections with individual neurons. To accomplish this goal, the materials must mediate the inflammatory response and interact with the normal cellular machinery. In order to quench the neurodegenerative inflammatory response to cortical electrodes, the objective of this project is to first develop an improved understanding of the inflammatory cascade, in order to later engineer more specific interventions. The primary hypothesis of this proposal is that selective ablation of microglia/macrophage cells at the cortical tissue - electrode interface will attenuate the neurodegenerative effects of the chronic inflammatory response. Furthermore, it is also hypothesized that inflammation at the cortical tissue-electrode interface can be imaged in real-time using protease selective Near Infrared Fluorescent (NIRF) imaging probes to assess the cortical tissue-electrode interface, for the first time in living animals. This research project is divided into three distinct aims. The first will engineer a viral vector to specifically cause the programmed cell death of microglial cells, a key contributor in the inflammatory response to this class of electrode. A unique attribute of the design of our virus, is that a chemical initiator must be provided, secondary to the genetic material, to initiate cell ablation. This allows the research team to investigate various stages of the inflammatory cascade with one concise modality. Further, chemical modifications to traditional penetrating intracortical microelectrodes will also be explored, with the focus of promoting biomaterial-mediated gene transfer of the new virus to microglial cells at the electrode-tissue interface. The completion of this aim will provide a comprehensive strategy to selectively ablate microglial cells only at the electrode-tissue interface, allowing for as much unaffected tissue as possible, to maintain tissue homeostasis and repair. The second aim to this project will be in the validation of extending the application of molecular imaging techniques to the investigation of inflammation at the cortical tissue-electrode interface. Such "molecular probes" have been readily employed to study cancer growth and inflammatory disease due to their ability to detect precise biochemical events in the inflammatory cascade. Specifically, reactive microglial and macrophages over express a class of proteases. The probes used here bind exclusively to these proteases and fluoresce to allow for quantification of the protease - thus an indirect measurement of inflammation. The technique will first be validated through topical administration to excised brains having previously received an implanted electrode. Then, the molecular probes will be delivered intravenously to live animals to ensure the ability of the molecules to pass the blood-brain-barrier and localize at the electrode-tissue interface. The final aim of this project will be to demonstrate that both techniques can be applied to living animals (mice) to gain a real-time, molecular-level understanding of the complex biochemical pathways which are at play at the cortical tissue-electrode interface. This research team will, for the first time, be able to investigate such interactions in real-time, thus developing a responsive system for the investigation of future therapeutic interventions; while at the same time gaining an understanding for the role microglial cells play in device failure. Once the primary objectives of this proposal have been accomplished, we will then begin to investigate the effects of microglia ablation on the ability to maintain chronic neural recordings. PUBLIC HEALTH RELEVANCE: Project Narrative: It has become a reality for prosthetic devices to be controlled by intracortical electrodes which record one's 'thoughts.' Such devices could restore function to patients with motor deficiencies including individuals who have suffered from spinal cord injuries (~15,000/yr in the US) or stroke (750,000/yr in the US); of which a significant population are veterans. Unfortunately, this technology is not readily available to our veterans due to the lack of reliability of the recordings, regardless of the type of electrode used. While several methods have been investigated to increase the longevity of electrodes implanted in the brain, this technology has rarely applied to human patients due to an incomplete understanding of the mechanisms that lead to the device failure, largely attributed to the inflammatory response. Therefore a more robust understanding of the inflammatory response at the device-tissue interface promises to expedite the development of methods to attenuate the response, and translate the powerful technology into clinical solutions for our veterans.

描述（由申请人提供）： 项目摘要 /摘要我们的长期目标是为神经界面开发高级材料，这些材料将无缝地吸收神经组织中，以促进与单个神经元的持续分子水平连接。为了实现这一目标，材料必须介导炎症反应并与正常的细胞机械相互作用。为了消除对皮质电极的神经退行性炎症反应，该项目的目的是首先对炎症性级联反应有了改进的了解，以便后来设计更具体的干预措施。该提议的主要假设是，在皮质组织 - 电极界面的小胶质细胞/巨噬细胞的选择性消融将减轻慢性炎症反应的神经退行性作用。此外，还假设可以使用蛋白酶选择性近红外荧光（NIRF）成像探针实时成像皮质组织 - 电极界面处的炎症，以评估活动物中首次评估皮质组织 - 电极界面。 该研究项目分为三个不同的目标。第一个将设计病毒载体，以特别引起小胶质细胞的编程细胞死亡，这是对该类电极的炎症反应的关键因素。我们的病毒设计的独特属性是，必须为遗传材料提供化学引发剂以启动细胞消融。这使研究团队可以以一种简洁的方式研究炎症级联的各个阶段。此外，还将探索对传统穿透性内部微电极的化学修饰，重点是促进新病毒的生物材料介导的基因转移，将新病毒转移到电极组织界面处的小胶质细胞向小胶质细胞。此目标的完成将提供一项全面的策略，仅在电极组织界面上有选择性地烧掉小胶质细胞，从而使尽可能多的没有影响的组织保持组织稳态和修复。 该项目的第二个目的是验证分子成像技术在皮质组织 - 电极界面的炎症研究中的应用。这种“分子探针”由于能够检测炎症性级联反应精确的生化事件的能力，因此很容易地用于研究癌症的生长和炎症性疾病。具体而言，反应性的小胶质细胞和巨噬细胞表达一类蛋白酶。这里使用的探针专门与这些蛋白酶结合，荧光以允许定量蛋白酶 - 因此间接测量了炎症。该技术将首先通过局部给药验证，以先前收到植入电极的切除大脑。然后，分子探针将静脉内输送到活动物，以确保分子通过血脑屏障并定位在电极组织界面。 该项目的最终目的是证明这两种技术都可以应用于活动物（小鼠），以获得对在皮质组织 - 电极界面处于起作用的复杂生化途径的实时，分子级的理解。该研究团队将首次能够实时调查此类相互作用，从而开发一个响应系统来调查未来的治疗干预措施；同时，了解小胶质细胞在设备故障中起着作用的理解。一旦完成了该提案的主要目标，我们将开始研究小胶质细胞消融对维持慢性神经记录能力的影响。 公共卫生相关性： 项目叙述：假肢设备由录制“思想”的物质内电极控制已成为现实。这种设备可以恢复运动缺陷患者的功能，包括患有脊髓损伤的人（美国约15,000/年）或中风（美国750,000/年）；其中大量人口是退伍军人。不幸的是，由于录音的可靠性缺乏，无论使用的电极类型如何，因此我们的退伍军人不容易获得这项技术。虽然已经研究了几种方法以增加大脑中植入的电极的寿命，但由于对导致设备失效的机制的不完全了解，该技术很少应用于人类患者，这主要归因于炎症反应。因此，对设备组织界面上炎症反应的更加强烈的理解有望加快减轻反应的方法的发展，并将强大的技术转化为退伍军人的临床解决方案。