Microfluidic-multiple electrode array platform for scalable analysis of epilepsy

描述(由申请人提供)：目前可用的抗癫痫药物(AED)是需要持续给药以抑制癫痫发作的抗惊厥药物，并且不能防止癫痫的发展。此外，大约30%的患者出现药物难治性癫痫。因此，发现可以预防或治疗癫痫的药物，分别被定义为抗癫痫药物和疾病修饰药物，已被确定为癫痫研究的主要目标。这类药物的开发因长时间的癫痫发生和癫痫进展而变得复杂。潜伏期、发作间隔和频率的变化需要使用连续的周到月长的电记录，以敏感地、定量地评估抗癫痫或改善疾病的效果。这项建议旨在通过显著改善癫痫活动的长期电监测的可扩展性来提高药物开发的速度。混合微流控多电极阵列(Upsilon Flow-MEA)芯片将被开发用于癫痫的器官型海马区培养模型。培养物将被放置在微孔中，并通过入口和出口微通道灌流培养基来保持培养。这种方法将显著减少每种培养所需的面积。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。微通道网络将把培养物连接到试验组，以促进药物、抑制剂或其他分子的应用。然后，该平台将被放大，以进行具有小分子抑制物库的中试筛选。该筛查的目标是展示Upsilon Flow-MEA平台在可扩展性和实验吞吐量方面的增长，并发现抗癫痫或疾病修改药物的新靶点。

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.