Drug development is often hindered by the failure of preclinical models to accurately assess and predict the efficacy and safety of drug candidates. Body‐on‐a‐chip (BOC) microfluidic devices, a subset of microphysiological systems (MPS), are being created to better predict human responses to drugs. Each BOC is designed with separate organ chambers interconnected with microfluidic channels mimicking blood recirculation. Here, we describe the design of the first pumpless, unidirectional, multiorgan system and apply this design concept for testing anticancer drug treatments. HCT‐116 colon cancer spheroids, HepG2/C3A hepatocytes, and HL‐60 promyeloblasts were embedded in collagen hydrogels and cultured within compartments representing “colon tumor”, “liver,” and “bone marrow” tissue, respectively. Operating on a pumpless platform, the microfluidic channel design provides unidirectional perfusion at physiologically realistic ratios to multiple channels simultaneously. The metabolism‐dependent toxic effect of Tegafur, an oral prodrug of 5‐fluorouracil, combined with uracil was examined in each cell type. Tegafur‐uracil treatment induced substantial cell death in HCT‐116 cells and this cytotoxic response was reduced for multicellular spheroids compared to single cells, likely due to diffusion‐limited drug penetration. Additionally, off‐target toxicity was detected by HL‐60 cells, which demonstrate that such systems can provide useful information on dose‐limiting side effects. Collectively, this microscale cell culture analog is a valuable physiologically‐based pharmacokinetic drug screening platform that may be used to support cancer drug development.

中文翻译：

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用于测试代谢依赖性化疗毒性的无泵单向微生理系统

由于临床前模型未能准确评估和预测候选药物的功效和安全性，药物开发常常受到阻碍。片上身体 (BOC) 微流体设备是微生理系统 (MPS) 的一个子集，旨在更好地预测人类对药物的反应。每个 BOC 都设计有独立的器官室，这些器官室与模拟血液再循环的微流体通道互连。在这里，我们描述了第一个无泵、单向、多器官系统的设计，并将这种设计理念应用于测试抗癌药物治疗。HCT-116 结肠癌球体、HepG2/C3A 肝细胞和 HL-60 早幼粒细胞嵌入胶原水凝胶中，并分别在代表“结肠肿瘤”、“肝脏”和“骨髓”组织的隔室中培养。在无泵平台上运行，微流体通道设计以生理上真实的比例同时向多个通道提供单向灌注。在每种细胞类型中检查了替加氟​​（一种 5-氟尿嘧啶的口服前药）与尿嘧啶联合的代谢依赖性毒性作用。替加氟尿嘧啶治疗在 HCT-116 细胞中诱导大量细胞死亡，与单细胞相比，多细胞球体的这种细胞毒性反应降低，可能是由于扩散限制的药物渗透。此外，HL-60 细胞检测到脱靶毒性，这表明此类系统可以提供有关剂量限制副作用的有用信息。总的来说，这种微型细胞培养类似物是一个有价值的基于生理学的药代动力学药物筛选平台，可用于支持癌症药物的开发。