Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, Gyungbuk 790-784, Republic of Korea.
Biofabrication. 2019 Jan 16;11(2):025001. doi: 10.1088/1758-5090/aaf9fa.
To overcome the drawbacks of in vitro liver testing during drug development, numerous liver-on-a-chip models have been developed. However, current liver-on-a-chip technologies are labor-intensive, lack extracellular matrix (ECM) essential for liver cells, and lack a biliary system essential for excreting bile acids, which contribute to intestinal digestion but are known to be toxic to hepatocytes. Therefore, fabrication methods for development of liver-on-a-chip models that overcome the above limitations are required. Cell-printing technology enables construction of complex 3D structures with multiple cell types and biomaterials. We used cell-printing to develop a 3D liver-on-a-chip with multiple cell types for co-culture of liver cells, liver decellularized ECM bioink for a 3D microenvironment, and vascular/biliary fluidic channels for creating vascular and biliary systems. A chip with a biliary fluidic channel induced better biliary system creation and liver-specific gene expression and functions compared to a chip without a biliary system. Further, the 3D liver-on-a-chip showed better functionalities than 2D or 3D cultures. The chip was evaluated using acetaminophen and it showed an effective drug response. In summary, our results demonstrate that the 3D liver-on-a-chip we developed is promising in vitro liver test platform for drug discovery.
为了克服药物开发过程中体外肝脏测试的缺陷，已经开发了许多类器官芯片模型。然而，目前的类器官芯片技术劳动强度大，缺乏肝脏细胞所必需的细胞外基质（ECM），也缺乏胆汁系统，而后者对于排泄胆汁酸至关重要，胆汁酸有助于肠道消化，但已知对肝细胞有毒性。因此，需要开发能够克服上述限制的类器官芯片模型的制造方法。细胞打印技术能够构建具有多种细胞类型和生物材料的复杂 3D 结构。我们使用细胞打印技术开发了一种具有多种细胞类型的 3D 类器官芯片，用于肝细胞共培养，肝脏脱细胞 ECM 生物墨水用于 3D 微环境，以及用于创建血管和胆管系统的血管/胆管流体通道。与没有胆管系统的芯片相比，具有胆管流体通道的芯片可更好地诱导胆管系统的形成以及肝脏特异性基因的表达和功能。此外，3D 类器官芯片表现出比 2D 或 3D 培养更好的功能。该芯片使用对乙酰氨基酚进行了评估，结果表明其具有有效的药物反应。总之，我们的研究结果表明，我们开发的 3D 类器官芯片是一种有前途的用于药物发现的体外肝脏测试平台。
