Chemical and Biomolecular Engineering, Cornell University, USA.
Lab Chip. 2010 Feb 21;10(4):446-55. doi: 10.1039/b917763a. Epub 2010 Jan 5.
Drug discovery is often impeded by the poor predictability of in vitro assays for drug toxicity. One primary reason for this observation is the inability to reproduce the pharmacokinetics (PK) of drugs in vitro. Mathematical models to predict the pharmacokinetics-pharmacodynamics (PK-PD) of drugs are available, but have several limitations, preventing broader application. A microscale cell culture analog (microCCA) is a microfluidic device based on a PK-PD model, where multiple cell culture chambers are connected with fluidic channels to mimic multi-organ interactions and test drug toxicity in a pharmacokinetic-based manner. One critical issue with microfluidics, including the microCCA, is that specialized techniques are required for assembly and operation, limiting its usability to non-experts. Here, we describe a novel design, with enhanced usability while allowing hydrogel-cell cultures of multiple types. Gravity-induced flow enables pumpless operation and prevents bubble formation. Three cell lines representing the liver, tumor and marrow were cultured in the three-chamber microCCA to test the toxicity of an anticancer drug, 5-fluorouracil. The result was analyzed with a PK-PD model of the device, and compared with the result in static conditions. Each cell type exhibited differential responses to 5-FU, and the responses in the microfluidic environment were different from those in static environment. Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.
药物发现常常受到体外药物毒性检测预测性差的阻碍。造成这种现象的一个主要原因是无法在体外重现药物的药代动力学（PK）。目前已有用于预测药物药代动力学-药效学（PK-PD）的数学模型，但这些模型存在一些局限性，限制了其更广泛的应用。微尺度细胞培养模拟物（microCCA）是一种基于 PK-PD 模型的微流控装置，其中多个细胞培养室通过流体通道连接，以模拟多器官相互作用，并以基于药代动力学的方式测试药物毒性。微流控技术（包括 microCCA）的一个关键问题是，组装和操作需要专门的技术，这限制了非专家对其的使用。在这里，我们描述了一种新的设计，在提高可用性的同时允许进行多种类型的水凝胶细胞培养。重力诱导的流动实现了无泵操作，并防止气泡形成。三种细胞系（代表肝脏、肿瘤和骨髓）在三腔 microCCA 中培养，以测试抗癌药物 5-氟尿嘧啶的毒性。使用该设备的 PK-PD 模型对结果进行分析，并与静态条件下的结果进行比较。每种细胞类型对 5-FU 的反应都不同，并且在微流控环境中的反应与静态环境中的反应不同。数学建模方法（PK-PD 建模）和体外实验方法（microCCA）的结合提供了一个具有改进预测性的新型平台，用于测试药物毒性，并帮助研究人员更好地了解药物的作用机制。
