Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
ACS Biomater Sci Eng. 2021 Aug 9;7(8):3648-3657. doi: 10.1021/acsbiomaterials.1c00642. Epub 2021 Jul 20.
A liver-on-a-chip (liver-chip) is a microfluidic device carrying liver cells such as human hepatocytes. It is used to reproduce a part of liver function. Many microfluidic devices are composed of polydimethylsiloxane (PDMS), which is a type of silicone elastomer. PDMS is easy to process and suitable for cell observation, but its high hydrophobicity carries the risk of drug absorption. In this study, we evaluated drug absorption to the PDMS device and investigated the drug responsiveness of human hepatocytes cultured in the PDMS device (hepatocyte-chips). First, the absorption rates of 12 compounds to the PDMS device were measured. The absorption rates of midazolam, bufuralol, cyclosporine A, and verapamil were 92.9, 71.7, 71.4, and 99.6%, respectively, but the other compounds were poorly absorbed. Importantly, the absorption rate of the compounds was correlated with their octanol/water distribution coefficient (log ) values ( = 0.76). Next, hepatocyte-chips were used to examine the response to drugs, which are typically used to evaluate hepatic functions. Using the hepatocyte-chips, we could confirm the responsiveness of drugs including cytochrome P450 (CYP) inducers and farnesoid X receptor (FXR) ligands. We believe that our findings will contribute to drug discovery research using PDMS-based liver-chips.
肝芯片（liver-chip）是一种携带肝细胞（如人肝细胞）的微流控装置。它用于复制部分肝功能。许多微流控装置由聚二甲基硅氧烷（PDMS）组成，PDMS 是一种硅酮弹性体。PDMS 易于加工，适合细胞观察，但它的高疏水性存在药物吸收的风险。在这项研究中，我们评估了 PDMS 装置对药物的吸收，并研究了在 PDMS 装置中培养的人肝细胞（肝细胞芯片）对药物的反应性。首先，测量了 12 种化合物对 PDMS 装置的吸收速率。咪达唑仑、布他洛尔、环孢素 A 和维拉帕米的吸收速率分别为 92.9%、71.7%、71.4%和 99.6%，但其他化合物吸收较差。重要的是，化合物的吸收速率与其辛醇/水分配系数（log P）值呈正相关（r = 0.76）。接下来，使用肝细胞芯片来检测对药物的反应，这些药物通常用于评估肝功能。使用肝细胞芯片，我们可以确认包括细胞色素 P450（CYP）诱导剂和法尼醇 X 受体（FXR）配体在内的药物的反应性。我们相信，我们的研究结果将有助于使用基于 PDMS 的肝芯片进行药物发现研究。
