In a typical high-throughput drug screening (HTS) process, up to millions of chemical compounds are applied to cells cultured in well plates, aiming to find molecules that exhibit a robust dose-response, as evidenced for example by a fluorescence signal. In high-content screening (HCS), one goes a step further by linking the tested compounds to phenotypic information, obtained, for instance, from microscopic cell images, thereby creating richer data sets that also require more advanced analysis methods. The nematode Caenorhabditis elegans came into the screening picture due to the wide availability of its mutants and human disease models, its relatively easy culture and short life cycle. Being a whole-organism model, it allows drug testing under physiological conditions at multi-tissue levels and provides additional observable phenotypes with respect to cell models, related, for instance, to development, aging, behavior or motility. Worm-based HTS studies in liquid environments on microwell plates have been demonstrated, while microfluidic devices allowed surpassing the performance of plates by enabling more versatile and accurate assays, precise and dynamic dosing of compounds, and readouts down to single-animal resolution. In this review, we discuss microfluidic devices for C. elegans analysis and related studies, published in the period from 2012 to 2017. After an introduction to the different screening approaches, we first focus on microfluidic systems with potential for screening applications. Various enabling technologies, e.g. electrophysiological on-chip recordings or laser axotomy, have been implemented, as well as techniques for reversible worm immobilization and high-resolution imaging, combined with algorithms for automated experimentation and analysis. Several devices for developmental or behavioral assays, and worm sorting based on different phenotypes, have been proposed too. In a subsequent section, we review the application of microfluidic-based systems for medium- and high-throughput screens, including neurobiology and neurodegeneration studies, aging and developmental assays, toxicity and pathogenesis screens, as well as behavioral and motility assays. A thorough analysis of this work reveals a trend towards microfluidic systems more and more capable of offering high-quality analyses of large worm populations, based on multi-phenotypic and/or longitudinal readouts, with clear potential for their application in larger HTS/HCS contexts.

中文翻译：

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使用线虫秀丽隐杆线虫进行高通量和高含量筛选的微流控系统

在典型的高通量药物筛选（HTS）过程中，将多达数百万种化合物应用于孔板中培养的细胞，目的是寻找表现出强大剂量反应的分子，例如荧光信号所证明的那样。在高含量筛选（HCS）中，通过将被测化合物与表型信息（例如从微观细胞图像中获得的信息）联系起来，又向前迈进了一步，从而创建了更丰富的数据集，而这些数据集也需要更高级的分析方法。线虫秀丽隐杆线虫由于其突变体和人类疾病模型的广泛可用性，其相对容易的培养和较短的生命周期而成为筛选图片。作为一种全生物模型，它可以在多种组织水平的生理条件下进行药物测试，并提供与细胞模型有关的其他可观察到的表型，例如与发育，衰老，行为或运动有关的表型。已经证明了在微孔板上的液体环境中基于蠕虫的HTS研究，而微流体设备通过实现更通用，更准确的测定，化合物的精确和动态配量以及低至单动物分辨率的读数，可以超越板的性能。在这篇综述中，我们讨论了秀丽隐杆线虫的微流控设备分析和相关研究，于2012年至2017年期间发表。在介绍了不同的筛选方法之后，我们首先关注具有筛选应用潜力的微流体系统。各种启用技术，例如已经实现了电生理芯片记录或激光轴切术，以及用于可逆蠕虫固定和高分辨率成像的技术，并结合了用于自动实验和分析的算法。还已经提出了几种用于发育或行为测定以及基于不同表型的蠕虫分选的装置。在随后的部分中，我们将回顾基于微流体的系统在中，高通量筛选中的应用，包括神经生物学和神经退行性研究，衰老和发育测定，毒性和致病机理筛查以及行为和运动测定。对这项工作的透彻分析揭示了一种朝着微流控系统发展的趋势，该系统越来越有能力为大型蠕虫种群提供高质量的分析，