Microfluidic-multiple electrode array platform for scalable analysis of epilepsy

用于癫痫可扩展分析的微流控多电极阵列平台

• 批准号: 8754939
• 负责人: YEVGENY BERDICHEVSKY
• 金额: $ 20.67万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754939
• 关键词: Anticonvulsants; Antiepileptic Agents; Antiepileptogenic; Area; Biological Assay; Chronic; Culture Media; Development; Disease; Drug Targeting; Electrodes; Epilepsy; Epileptogenesis; Frequencies; Goals; Hippocampus (Brain); Hybrids; In Vitro; Libraries; Maintenance; Methods; Microfluidics; Modeling; Monitor; Patients; Perfusion; Pharmaceutical Preparations; Phase; Refractory; Research; Seizures; Technology; Time; Tonic-Clonic Epilepsy; Work; drug development; drug discovery; improved; in vitro Model; in vitro activity; inhibitor/antagonist; kinase inhibitor; prevent; public health relevance; research study; scale up; small molecule

DESCRIPTION (provided by applicant): Currently available antiepileptic drugs (AEDs) are anticonvulsants that require continuous administration for suppression of seizures, and that do not prevent development of epilepsy. Furthermore, approximately 30% of patients develop drug refractory epilepsy. Therefore, discovery of drugs that can prevent or cure epilepsy, defined as antiepileptogenic or disease-modifying drugs, respectively, has been identified as a major epilepsy research goal. Development of these classes of drugs is complicated by the long time course of epileptogenesis and epilepsy progression. Variability in the duration of latent period and seizure intervals and frequency necessitate the use of continuous week-to-month long electrical recordings for sensitive, quantitative assessment of antiepileptogenic or disease-modifying effects. This proposal aims to increase the rate of drug development by significantly improving scalability of long-term electrical monitoring of epileptic activity in vitro. Hybrid microfluidic-multiple electrode array (Upsilon flow-MEA) chips will be developed for use with organotypic hippocampal culture model of epilepsy. Cultures will be placed in microwells, and maintained via perfusion of culture medium through inlet and outlet microchannels. This method will significantly reduce the area required for each culture. Each chip will be capable of monitoring 12-18 cultures simultaneously to quantitatively assess development and progression of epilepsy. Microchannel network will connect cultures into experimental groups to facilitate application of drugs, inhibitors, or other molecules. This platform will then be scaled up to conduct a pilot screen with a small molecule inhibitor library. The goal of the screen is to demonstrate an increase in scalability and experimental throughput achieved with Upsilon flow-MEA platform, and to discover new targets for antiepileptogenic or disease-modifying drugs.

描述（由申请人提供）：目前可用的抗癫痫药物（AED）是抗惊厥药，需要连续给药以抑制癫痫发作，并且不能预防癫痫的发展。此外，大约 30% 的患者患有药物难治性癫痫。因此，发现可以预防或治疗癫痫的药物（分别定义为抗癫痫药物或疾病缓解药物）已被确定为癫痫研究的主要目标。由于癫痫发生和癫痫进展的时间较长，这类药物的开发变得复杂。潜伏期持续时间、癫痫发作间隔和频率的可变性需要使用连续的每周到每月的长时间电记录，以敏感、定量地评估抗癫痫或疾病缓解效果。该提案旨在通过显着提高体外癫痫活动长期电监测的可扩展性来提高药物开发速度。将开发混合微流体-多电极阵列（Upsilon flow-MEA）芯片，用于癫痫的器官型海马培养模型。将培养物置于微孔中，并通过入口和出口微通道灌注培养基来维持。这种方法将显着减少每种培养物所需的面积。每个芯片将能够同时监测 12-18 种培养物，以定量评估癫痫的发展和进展。微通道网络将培养物连接到实验组中，以促进药物、抑制剂或其他分子的应用。然后，该平台将扩大规模，以利用小分子抑制剂库进行试点筛选。该筛选的目的是展示使用 Upsilon flow-MEA 平台实现的可扩展性和实验通量的提高，并发现抗癫痫药物或缓解疾病药物的新靶点。