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The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors

机译：具有集成溶解氧传感器的三室微型细胞培养模拟设备的设计和制造

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Whole animal testing is an essential part in evaluating the toxicological and pharmacological profiles of chemicals and pharmaceuticals, but these experiments are expensive and cumbersome. A cell culture analog (CCA) system, when used in conjunction with a physiologically based pharmacokinetic (PBPK) model, provides an in vitro supplement to animal studies and the possibility of a human surrogate for predicting human response in clinical trials. A PBPK model mathematically simulates animal metabolism by modeling the absorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. A CCA uses mammalian cells cultured in interconnected chambers to physically represent the corresponding PBPK. These compartments are connected by recirculating tissue culture medium that acts as a blood surrogate. The purpose of this article is to describe the design and basic operation of the microscale manifestation of such a system. Microscale CCAs offer the potential for inexpensive, relatively high throughput evaluation of chemicals while minimizing demand for reagents and cells. Using microfabrication technology, a three-chamber ("lung"-"liver"-"other") microscale cell culture analog (muCCA) device was fabricated on a 1 in. (2.54 cm) square silicon chip. With a design flow rate of 1.76 muL/min, this muCCA device achieves approximate physiological liquid-to-cell ratio and hydrodynamic shear stress while replicating the liquid residence time parameters in the PBPK model. A dissolved oxygen sensor based on collision quenching of a fluorescent ruthenium complex by oxygen molecules was integrated into the system, demonstrating the potential to integrate real-time sensors into such devices.
机译：整个动物测试是评估化学药品和药物的毒理学和药理学特性的重要组成部分，但是这些实验既昂贵又麻烦。细胞培养类似物（CCA）系统与基于生理学的药代动力学（PBPK）模型结合使用时，可为动物研究提供体外补充，并为临床试验中人替代物预测人的反应提供了可能性。 PBPK模型通过对相互连接的组织隔室内化学物质的吸收，分布，代谢和消除动力学进行建模，从而在数学上模拟动物的代谢。 CCA使用在相互连通的小室中培养的哺乳动物细胞来物理代表相应的PBPK。这些隔室通过再循环用作血液替代物的组织培养基连接起来。本文的目的是描述这种系统的微观表现形式的设计和基本操作。微型CCA提供了对化学品进行廉价，较高通量评估的潜力，同时最大程度地减少了对试剂和细胞的需求。使用微制造技术，在1英寸（2.54厘米）见方的硅芯片上制造了三腔（“肺”-“肝”-“其他”）微型细胞培养类似物（muCCA）器件。这种muCCA装置的设计流速为1.76μL/ min，在复制PBPK模型中的液体停留时间参数的同时，可达到近似的生理液-细胞比和流体动力剪切应力。基于氧分子对荧光钌络合物进行碰撞猝灭的溶解氧传感器已集成到系统中，证明了将实时传感器集成到此类设备中的潜力。

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