Optimizing Delivery of a Known Therapeutic Agent, Dexamethasone, to Improve Microelectrode Recording Performance

优化已知治疗剂地塞米松的输送，以提高微电极记录性能

• 批准号: 10217285
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217285
• 关键词: 3-Dimensional; Address; Amputation; Anterior; Anti-Inflammatory Agents; Antibiotics; Behavior; Behavioral; Bilateral; Biological; Blood; Blood Chemical Analysis; Blood Platelets; Blood Vessels; Body Weight; Brain; Cerebrospinal fluid shunts procedure; Chronic; Cicatrix; Data; Devices; Dexamethasone; Dose; Drug Delivery Systems; Drug Targeting; Drug usage; Electrodes; Engineering; FDA approved; Failure; Frequencies; Future; Gender; Gene Expression; Glucocorticoids; Goals; Health; Hemorrhage; Hemostatic function; High Pressure Liquid Chromatography; Human; Implant; Inflammation; Inflammatory Response; Kidney; Kinetics; Label; Left; Limb Prosthesis; Liver; Local Therapy; Longevity; Lung; Measurement; Measures; Mechanics; Mediating; Medical Device; Medical Research; Metabolic Clearance Rate; Methods; Microelectrodes; Motor; Motor Cortex; Nerve Degeneration; Neuraxis; Neurons; Organ; Outcome; Pain; Paralysed; Parkinson Disease; Patients; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Prevalence; Prosthesis; Quality of life; Randomized; Rattus; Rehabilitation therapy; Research; Research Personnel; Rodent; Rodent Model; Safety; Saline; Side; Signal Transduction; Silicon; Site; Spinal cord injury; Spleen; Steroids; Stroke; System; Technology; Therapeutic Agents; Thinking; Time; Tissues; Touch sensation; Trauma; Treatment Efficacy; Tremor; Veterans; animal imaging; base; behavior test; blood-brain barrier permeabilization; brain computer interface; chronic pain; cohort; commercialization; dosage; fluorescence imaging; imaging modality; implantable device; implantation; improved; limb movement; medical implant; nanoparticle; neuroinflammation; neuromuscular; pharmacokinetics and pharmacodynamics; prevent; relating to nervous system; response; sensor; side effect; tissue processing; treatment comparison

The overall goal of this proposal is to improve the chronic performance of intracortical recording microelectrodes using a targeted drug-delivery approach. Microelectrode-based devices have the potential to resolve many challenges in rehabilitation for Veterans with paralysis and/or amputation. Notably, brain-computer interface (BCI) endeavors within the VA have provided patients the ability to control electromechanical or neuromuscular prostheses using ‘thoughts’ or signals from their motor cortex. BCIs are further being extended by researchers at the VA to restore the sensation of touch by integrating sensors and stimulators into mechanical prosthetic limbs.3-5 While the promises of intracortical microelectrode interfaces are significant, the devices suffer from a key challenge: long term stability and functionality. The failure modes are multifaceted, but a substantial component is attributed to vascular trauma from implantation that initiates bleeding and a prolonged biological response, including inflammation which leads to significant reduction in healthy neurons near recording contacts. Several FDA-approved drugs have demonstrated the ability to reduce the biological inflammatory response and augment microelectrode recording performance in rodents. However, due to limitations of pharmacokinetics and pharmacodynamics, most of the agents reach the implant site in relatively low concentrations, limiting the magnitude of effect and/or requiring frequent dosages to attain meaningful results. Additionally, in the case of steroids and antibiotics, long-term systemic administration is contraindicated due to side effects on peripheral systems. Leveraging a platelet-inspired drug delivery platform currently undergoing commercialization, we have engineered a method for targeting drugs specifically to the microelectrode implantation site. Localizing the drug to the microelectrode site will reduce the systemically administered dose, while minimizing the payload delivered to peripheral organs, e.g., liver and kidneys. During this study, we will focus on delivering the drug, dexamethasone (Dex), which is a potent glucocorticoid steroidal anti-inflammatory drug. While we have demonstrated the ability to target the microelectrode with drug-loaded nanoparticles, further optimization of dosing with Dex and characterization of chronic recordings are needed. Our objective is to establish a safe and effective drug-delivery platform for localized therapy to improve chronic BCI performance. We hypothesize that administration of targeted dexamethasone-loaded nanoparticles (Dex-NPs) will prevent chronic scarring and neurodegeneration associated with improved chronic recording quality of intracortical microelectrodes and associated motor-behavioral function. If proven effective, the platform may be further developed and characterized to release other pharmaceutical payloads that have unique or complementary effects on the system. Additionally since the delivery platform is being commercialized, there is increased potential for scaling the technology to human application.

本提案的总体目标是改善皮质内记录微电极的慢性性能