肝脏药物代谢研究中的微流控模型

doi:10.5246/jcps.2019.07.044

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (7): 449-467.DOI: 10.5246/jcps.2019.07.044

• 【综述】 • 下一篇

肝脏药物代谢研究中的微流控模型

赵琳, 姜勇, 屠鹏飞, 艾晓妮^*, 郭晓宇^*

北京大学药学院天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2019-04-12 修回日期:2019-05-18 出版日期:2019-07-31 发布日期:2019-06-04
通讯作者: Tel.: +86-010-82805641; +86-010-82802750; E-mail: guoxiaoyu@bjmu.edu.cn; aixn@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81573684 and 81530097), Beijing Municipal Science and Technology Project (Grant No. Z181100002218028) and National Key Technology R & D Program “New Drug Innovation” of China (Grant No. 2018ZX09711001-008-003).

Microfluidic models in liver drug metabolism research

Lin Zhao, Yong Jiang, Pengfei Tu, Xiaoni Ai^*, Xiaoyu Guo^*

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Received:2019-04-12 Revised:2019-05-18 Online:2019-07-31 Published:2019-06-04
Contact: Tel.: +86-010-82805641; +86-010-82802750; E-mail: guoxiaoyu@bjmu.edu.cn; aixn@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81573684 and 81530097), Beijing Municipal Science and Technology Project (Grant No. Z181100002218028) and National Key Technology R & D Program “New Drug Innovation” of China (Grant No. 2018ZX09711001-008-003).

摘要/Abstract

摘要：

在新药研发临床前研究阶段,建立更接近人体内代谢情况的体外模型尤为重要,旨在减少实验动物的数量,并对药物在人体内的代谢情况进行更为准确的预测。利用微流控技术,通过结合亚细胞组分、肝细胞以及肝脏组织,可以建立更加完善的体外肝脏代谢模型,从而开展药物代谢的相关研究。微流控平台通过对流体的精确控制可建立动态培养环境,通过设计3D结构可模拟人体内的肝组织结构。此外,在芯片上进行不同细胞的共培养还可模拟人体器官的互作,提升体外模型的仿生性。本综述更新了自2011年以来基于微流控技术构建的肝脏药物代谢模型,并分别对不同的芯片载体(亚细胞组分、原代肝细胞及组织切片)进行了综述。

关键词: 微流控芯片, 肝脏模型, 药物代谢

Abstract:

In pre-clinical phase of new drug development, it is particularly important to establish an in vitro model to mimic the metabolism situation of human body. The aim of the in vitro model is to reduce the usage of experimental animals and to make a more accurate prediction of the drug metabolism in vivo. Microfluidic chip is an emerging technology to establish predictive models. By integrating subcellular fractions, hepatocytes or liver tissue in the microfluidic chips, more predictive in vitro metabolismmodels can be established for drug development. The microfluidic platform offers dynamic and controlled fluids, as well as sophisticated liver tissue assembly to remodel the physiological and pathological microenvironment of liver in the human body. This review updates the microfluidic-based liver drug metabolism models since 2011, and summarizes the development of different models based on different chip vectors (subcellular components, primary hepatocytes, and tissue sections). It serves as a guide for newcomers to this dynamic field.

Key words: Microfluidic chip, Liver models, Drug metabolism

中图分类号:

R284

Supporting:

赵琳, 姜勇, 屠鹏飞, 艾晓妮, 郭晓宇. 肝脏药物代谢研究中的微流控模型[J]. 中国药学(英文版), 2019, 28(7): 449-467.

Lin Zhao, Yong Jiang, Pengfei Tu, Xiaoni Ai, Xiaoyu Guo. Microfluidic models in liver drug metabolism research[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(7): 449-467.

参考文献

[1] Kirchmair, J.; Göller, A.H.; Lang, D.; Kunze, J.; Testa, B.; Wilson, I.D.; Glen, R.C.; Schneider, G. Predicting drug metabolism: experiment and/or computation? Nat. Rev. Drug Discov. 2015, 14, 387-404.

[2] Cook, N.; Jodrell, D.I.; Tuveson, D.A. Predictive in vivo animal models and translation to clinical trials. Drug Discov. Today. 2012, 17, 253-260.

[3] DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ. 2016, 47, 20-33.

[4] Neuži, P.; Giselbrecht, S.; Länge, K.; Huang, T.J.; Manz, A. Revisiting lab-on-a-chip technology for drug discovery. Nat. Rev. Drug Discov. 2012, 11, 620-632.

[5] Whitesides, G.M. The origins and the future of microfluidics. Nature. 2006, 442, 368-373.

[6] Feng, B.; Varma, M.V.; Costales, C.; Zhang, H.; Tremaine, L. In vitro and in vivo approaches to characterize transporter-mediated disposition in drug discovery. Expert Opin. Drug Discov. 2014, 9, 873-890.

[7] Ugolini, G.S.; Cruz-Moreira, D.; Visone, R.; Redaelli, A.; Rasponi, M. Microfabricated physiological models for in vitro drug screening applications. Micromachines (Basel). 2016, 7, E233.

[8] van Midwoud, P.M.; Verpoorte, E.; Groothuis, G.M. Microfluidic devices for in vitro studies on liver drug metabolism and toxicity. Integr. Biol (Camb). 2011, 3, 509-521.

[9] Costa, A.; Sarmento, B.; Seabra, V. An evaluation of the latest in vitro tools for drug metabolism studies. Expert Opin. Drug Metab. Toxicol. 2014, 10, 103-119.

[10] Asha, S.; Vidyavathi, M. Role of human liver microsomes in in vitro metabolism of drugs-a review. Appl. Biochem. Biotechnol. 2010, 160, 1699-1722.

[11] Benetton, S.; Kameoka, J.; Tan, A.; Wachs, T.; Craighead, H.; Henion, J.D. Chip-Based P450 Drug Metabolism Coupled to Electrospray Ionization-Mass Spectrometry Detection. Anal. Chem, 2003, 75, 6430-6436.

[12] Ma, B.; Zhang, G.; Qin, J.; Lin, B. Characterization of drug metabolites and cytotoxicity assay simultaneously using an integrated microfluidic device. Lab. Chip. 2009, 9, 232-238.

[13] Lee, J.; Kim, S.H.; Kim, Y.C.; Choi, I.; Sung, J.H. Fabrication and characterization of microfluidic liver-on-a-chip using microsomal enzymes. Enzyme Microb. Technol. 2013, 53, 159-164.

[14] Yang, H.Y.; Zheng, Y.T.; Zhao, B.; Shao, T.F.; Shi, Q.L.; Zhou, N.; Cai, W.M. Encapsulation of liver microsomes into a thermosensitive hydrogel for characterization of drug metabolism and toxicity. Biomaterials. 2013, 34, 9770-9778.

[15] Wu, Q.; Gao, D.; Wei, J.T.; Jin, F.; Xie, W.Y.; Jiang, Y.Y.; Liu, H.X. Development of a novel multi-layer microfluidic device towards characterization of drug metabolism and cytotoxicity for drug screening. Chem. Commun. (Camb.). 2014, 50, 2762-2764.

[16] Yang, H.Y.; Li, J.F.; Zheng, Y.T.; Zhou, L.; Tong, S.S.; Zhao, B.; Cai, W.M. Drug activity screening based on microsomes-hydrogel system in predicting metabolism induced antitumor effect of oroxylin A. Sci. Rep. 2016, 6, 21604.

[17] Wasalathanthri, D.P.; Faria, R.C.; Malla, S.; Joshi, A.A.; Schenkman, J.B.; Rusling, J.F. Screening reactive metabolites bioactivated by multiple enzyme pathways using a multiplexed microfluidic system. Analyst. 2013, 138, 171-178.

[18] Shay, J.W.; Wright, W.E. Hayflick, his limit, and cellular ageing. Nat. Rev. Mol. Cell Biol. 2000, 1, 72-76.

[19] Castell, J.V.; Jover, R.; Martínez-Jiménez, C.P.; Gómez-Lechón, M.J. Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin. Drug Metab. Toxicol. 2006, 2, 183-212.

[20] Kimura, H.; Ikeda, T.; Nakayama, H.; Sakai, Y.; Fujii, T. An on-chip small intestine-liver model for pharmacokinetic studies. J. Lab. Autom. 2015, 20, 265-273.

[21] Bavli, D.; Prill, S.; Ezra, E.; Levy, G.; Cohen, M.; Vinken, M.; Vanfleteren, J.; Jaeger, M.; Nahmias, Y. Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA. 2016, 113, E2231-E2240.

[22] Yu, K.N.; Nadanaciva, S.; Rana, P.; Lee, D.W.; Ku, B.; Roth, A.D.; Dordick, J.S.; Will, Y.; Lee, M.Y. Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays. Arch. Toxicol. 2018, 92, 1295-1310.

[23] Kwon, S.J.; Lee, D.W.; Shah, D.A.; Ku, B.; Jeon, S.Y.; Solanki, K.; Ryan, J.D.; Clark, D.S.; Dordick, J.S.; Lee, M.Y. High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening. Nat. Commun. 2014, 5, 3739.

[24] Rennert, K.; Steinborn, S.; Gröger, M.; Ungerböck, B.; Jank, A.M.; Ehgartner, J.; Nietzsche, S.; Dinger, J.L.; Kiehntopf, M.; Funke, H.; Peters, F.T.; Lupp, A.; Gärtner, C.; Mayr, T.; Bauer, M.; Huber, O.; Mosig, A.S. A microfluidically perfused three dimensional human liver model. Biomaterials. 2015, 71, 119-131.

[25] Ma, L.D.; Wang, Y.T.; Wang, J.R.; Wu, J.L.; Meng, X.S.; Hu, P.; Mu, X.; Liang, Q.L.; Luo, G.A. Design and fabrication of a liver-on-a-chip platform for convenient, highly efficient, and safe in situ perfusion culture of 3D hepatic spheroids. Lab. Chip. 2018, 18, 2547-2562.

[26] Leclerc, E.; Sakai, Y.; Fujii, T. Microfluidic PDMS (polydimethylsiloxane) bioreactor for large-scale culture of hepatocytes. Biotechnol. Prog. 2004, 20, 750-755.

[27] Ju, S.M.; Jang, H.J.; Kim, K.B.; Kim, J. High-throughput cytotoxicity testing system of acetaminophen using a microfluidic device (MFD) in HepG2 cells. J. Toxicol. Environ. Health Part A. 2015, 78, 1063-1072.

[28] Neal, A.; Rountree, A.M.; Philips, C.W.; Kavanagh, T.J.; Williams, D.P.; Newham, P.; Khalil, G.; Cook, D.L.; Sweet, I.R. Quantification of low-level drug effects using real-time, in vitro measurement of oxygen consumption rate. Toxicol. Sci. 2015, 148, 594-602.

[29] Ronaldson-Bouchard, K.; Vunjak-Novakovic, G. Organs-on-a-chip: A fast track for engineered human tissues in drug development. Cell Stem. Cell. 2018, 22, 310-324.

[30] Donato, M.T.; Jover, R.; Gómez-Lechón, M.J. Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering. Curr. Drug Metab. 2013, 14, 946-968.

[31] Ramaiahgari, S.C.; den Braver, M.W.; Herpers, B.; Terpstra, V.; Commandeur, J.N.; van de Water, B.; Price, L.S. A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies. Arch. Toxicol. 2014, 88, 1083-1095.

[32] Bachmann, A.; Moll, M.; Gottwald, E.; Nies, C.; Zantl, R.; Wagner, H.; Burkhardt, B.; Sánchez, J.; Ladurner, R.; Thasler, W.; Damm, G.; Nussler, A. 3D cultivation techniques for primary human hepatocytes. Microarrays. 2015, 4, 64-83.

[33] Alexander, F. Jr, Eggert, S.; Wiest, J. A novel lab-on-a-chip platform for spheroid metabolism monitoring. Cytotechnology. 2018, 70, 375-386.

[34] Eggert, S.; Alexander, F.A.; Wiest, J. Enabling 3D hepatocyte spheroids for microphysiometry. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2017, 2017, 1617-1620.

[35] Gerets, H.H.; Tilmant, K.; Gerin, B.; Chanteux, H.; Depelchin, B.O.; Dhalluin, S.; Atienzar, F.A. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol. Toxicol. 2012, 28, 69-87.

[36] Gómez-Lechón, M.J.; Tolosa, L.; Conde, I.; Donato, M.T. Competency of different cell models to predict human hepatotoxic drugs. Expert Opin Drug Metab. Toxicol. 2014, 10, 1553-1568.

[37] Aninat, C.; Piton, A.; Glaise, D.; Le Charpentier, T.; Langouët, S.; Morel, F.; Guguen-Guillouzo, C.; Guillouzo, A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab. Dispos. 2006, 34, 75-83.

[38] Andersson, T.B.; Kanebratt, K.P.; Kenna, J.G. The HepaRG cell line: a unique in vitro tool for understanding drug metabolism and toxicology in human. Expert Opin. Drug Metab. Toxicol. 2012, 8, 909-920.

[39] Rodrigues, R.M.; Bouhifd, M.; Bories, G.; Sacco, M.G.; Gribaldo, L.; Fabbri, M.; Coecke, S.; Whelan, M.P. Assessment of an automated in vitro basal cytotoxicity test system based on metabolically-competent cells. Toxicol. In Vitro. 2013, 27, 760-767.

[40] Klein, S.; Mueller, D.; Schevchenko, V.; Noor, F. Long-term maintenance of HepaRG cells in serum-free conditions and application in a repeated dose study. J. Appl. Toxicol. 2014, 34, 1078-1086.

[41] Landesmann, B.; Mennecozzi, M.; Berggren, E.; Whelan, M. Adverse outcome pathway-based screening strategies for an animal-free safety assessment of chemicals. Altern Lab. Anim. 2013, 41, 461-471.

[42] Materne, E.M.; Maschmeyer, I.; Lorenz, A.K.; Horland, R.; Schimek, K.M.S.; Busek, M.; Sonntag, F.; Lauster, R.; Marx, U. The multi-organ chip - A microfluidic platform for long-term multi-tissue coculture. J. Vis. Exp. 2015, 28, e52526.

[43] Samatov, T.R.; Shkurnikov, M.U.; Tonevitskaya, S.A.; Tonevitsky, A.G. Modelling the metastatic cascade by in vitro microfluidic platforms. Prog. Histochem. Cytochem. 2015, 49, 21-29.

[44] Ong, L.J.Y.; Chong, L.H.; Jin, L.; Singh, P.K.; Lee, P.S.; Yu, H.; Ananthanarayanan, A.; Leo, H.L.; Toh, Y.C. A pump-free microfluidic 3D perfusion platform for the efficient differentiation of human hepatocyte-like cells. Biotechnol. Bioeng. 2017, 114, 2360-2370.

[45] Jang, M.; Kleber, A.; Ruckelshausen, T.; Betzholz, R.; Manz, A. Differentiation of the human liver progenitor cell line (HepaRG) on a microfluidic-based biochip. J. Tissue Eng. Regen. Med. 2019, 13, 482-494.

[46] Andersson, T.B. Evolution of novel 3D culture systems for studies of human liver function and assessments of the hepatotoxicity of drugs and drug candidates. Basic Clin. Pharmacol. Toxicol. 2017, 121, 234-238.

[47] Gunness, P.; Mueller, D.; Shevchenko, V.; Heinzle, E.; Ingelman-Sundberg, M.; Noor, F. 3D organotypic cultures of human HepaRG cells: a tool for in vitro toxicity studies. Toxicol. Sci. 2013, 133, 67-78.

[48] Li, A.P. Human hepatocytes: isolation, cryopreservation and applications in drug development. Chem. Biol. Interact. 2007, 168, 16-29.

[49] Han, W.J.; Wu, Q.; Zhang, X.H.; Duan, Z.P. Innovation for hepatotoxicity in vitro research models: A review. J. Appl. Toxicol. 2019, 39, 146-162.

[50] Sherratt, A.J.; Damani, L.A. Activities of cytosolic and microsomal drug oxidases of rat hepatocytes in primary culture. Drug Metab. Dispos. 1989, 17, 20-25.

[51] Gómez-Lechón, M.J.; Donato, M.T.; Castell, J.V.; Jover, R. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr. Drug Metab. 2004, 5, 443-462.

[52] Rodríguez-Antona, C.; Donato, M.T.; Boobis, A.; Edwards, R.J.; Watts, P.S.; Castell, J.V.; Gómez-Lechón, M.J. Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells. Xenobiotica. 2002, 32, 505-520.

[53] Chao, P.; Maguire, T.; Novik, E.; Cheng, K.C.; Yarmush, M.L. Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem. Pharmacol. 2009, 78, 625-632.

[54] Lee, P.J.; Hung, P.J.; Lee, L.P. An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol. Bioeng. 2007, 97, 1340-1346.

[55] Du, Y.; Li, N.; Yang, H.; Luo, C.H.; Gong, Y.X.; Tong, C.F.; Gao, Y.X.; Lü, S.Q.; Long, M. Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip. Lab. Chip. 2017, 17, 782-794.

[56] Meissner, R.; Eker, B.; Kasi, H.; Bertsch, A.; Renaud, P. Distinguishing drug-induced minor morphological changes from major cellular damage via label-free impedimetric toxicity screening. Lab. Chip. 2011, 11, 2352-2361.

[57] Anene-Nzelu, C.G.; Peh, K.Y.; Fraiszudeen, A.; Kuan, Y.H.; Ng, S.H.; Toh, Y.C.; Leo, H.L.; Yu, H. Scalable alignment of three-dimensional cellular constructs in a microfluidic chip. Lab. Chip. 2013, 13, 4124-4133.

[58] Gori, M.; Simonelli, M.C.; Giannitelli, S.M.; Businaro, L.; Trombetta, M.; Rainer, A. Investigating nonalcoholic fatty liver disease in a liver-on-a-chip microfluidic device. PLoS One. 2016, 11, e0159729.

[59] Vernetti, L.; Gough, A.; Baetz, N.; Blutt, S.; Broughman, J.R.; Brown, J.A.; Foulke-Abel, J.; Hasan, N.; In, J.; Kelly, E.; Kovbasnjuk, O.; Repper, J.; Senutovitch, N.; Stabb, J.; Yeung, C.; Zachos, N.C.; Donowitz, M.; Estes, M.; Himmelfarb, J.; Truskey, G.; Wikswo, J.P.; Taylor, D.L. Corrigendum: functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci. Rep. 2017, 7, 44517.

[60] Toh, Y.C.; Raja, A.; Yu, H.; van Noort, D. A 3D microfluidic model to recapitulate cancer cell migration and invasion. Bioengineering (Basel). 2018, 5, E29.

[61] Legendre, A.; Baudoin, R.; Alberto, G.; Paullier, P.; Naudot, M.; Bricks, T.; Brocheton, J.; Jacques, S.; Cotton, J.; Leclerc, E. Metabolic characterization of primary rat hepatocytes cultivated in parallel microfluidic biochips. J. Pharm. Sci. 2013, 102, 3264-3276.

[62] Jellali, R.; Bricks, T.; Jacques, S.; Fleury, M.J.; Paullier, P.; Merlier, F.; Leclerc, E. Long-term human primary hepatocyte cultures in a microfluidic liver biochip show maintenance of mRNA levels and higher drug metabolism compared with Petri cultures. Biopharm. Drug Dispos. 2016, 37, 264-275.

[63] Liu, Y.W.; Hu, K.; Wang, Y.H. Primary hepatocytes cultured on a fiber-embedded PDMS chip to study drug metabolism. Polymers (Basel). 2017, 9, E215.

[64] Tan, K.; Keegan, P.; Rogers, M.; Lu, M.J.; Gosset, J.R.; Charest, J.; Bale, S.S. A high-throughput microfluidic microphysiological system (PREDICT-96) to recapitulate hepatocyte function in dynamic, re-circulating flow conditions. Lab. Chip. 2019, 19, 1556-1566.

[65] Khetani, S.R.; Berger, D.R.; Ballinger, K.R.; Davidson, M.D.; Lin, C.; Ware, B.R. Microengineered liver tissues for drug testing. J. Lab. Autom. 2015, 20, 216-250.

[66] Imura, Y.; Sato, K.; Yoshimura, E. Micro total bioassay system for ingested substances: assessment of intestinal absorption, hepatic metabolism, and bioactivity. Anal. Chem. 2010, 82, 9983-9988.

[67] Maschmeyer, I.; Hasenberg, T.; Jaenicke, A.; Lindner, M.; Lorenz, A.K.; Zech, J.; Garbe, L.A.; Sonntag, F.; Hayden, P.; Ayehunie, S.; Lauster, R.; Marx, U.; Materne, E.M. Chip-based human liver-intestine and liver-skin co-cultures: A first step toward systemic repeated dose substance testing in vitro. Eur. J. Pharm. Biopharm. 2015, 95, 77-87.

[68] Choe, A.; Ha, S.K.; Choi, I.; Choi, N.; Sung, J.H. Microfluidic Gut-liver chip for reproducing the first pass metabolism. Biomed. Microdevices. 2017, 19, 4.

[69] Lee, D.W.; Ha, S.K.; Choi, I.; Sung, J.H. 3D gut-liver chip with a PK model for prediction of first-pass metabolism. Biomed. Microdevices. 2017, 19, 100.

[70] Viravaidya, K.; Shuler, M.L. Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies. Biotechnol. Prog. 2004, 20, 590-597.

[71] Sin, A.; Chin, K.C.; Jamil, M.F.; Kostov, Y.; Rao, G.; Shuler, M.L. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol. Prog. 2004, 20, 338-345.

[72] Xu, H.; Wu, J.; Chu, C.C.; Shuler, M.L. Development of disposable PDMS micro cell culture analog devices with photopolymerizable hydrogel encapsulating living cells. Biomed. Microdevices. 2012, 14, 409-418.

[73] Sung, J.H.; Wang, Y.I.; Narasimhan Sriram, N.; Jackson, M.; Long, C.; Hickman, J.J.; Shuler, M.L. Recent advances in body-on-a-chip systems. Anal. Chem. 2019, 91, 330-351.

[74] Oleaga, C.; Bernabini, C.; Smith, A.S.; Srinivasan, B.; Jackson, M.; McLamb, W.; Platt, V.; Bridges, R.; Cai, Y.Q.; Santhanam, N.; Berry, B.; Najjar, S.; Akanda, N.; Guo, X.F.; Martin, C.; Ekman, G.; Esch, M.B.; Langer, J.; Ouedraogo, G.; Cotovio, J.; Breton, L.; Shuler, M.L.; Hickman, J.J. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci. Rep. 2016, 6, 20030.

[75] Chen, H.J.; Miller, P.; Shuler, M.L. A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells. Lab. Chip. 2018, 18, 2036-2046.

[76] Zhang, C.; Zhao, Z.Q.; Abdul Rahim, N.A.; van Noort, D.; Yu, H. Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenviron-ments. Lab. Chip. 2009, 9, 3185-3192.

[77] Lauschke, V.M.; Shafagh, R.Z.; Hendriks, D.F.G.; Ingelman-Sundberg, M. 3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: emerging culture paradigms and applications. Biotechnol. J. 2019, 14, e1800347.

[78] Morin, O.; Normand, C. Long-term maintenance of hepatocyte functional activity in co-culture: requirements for sinusoidal endothelial cells and dexamethasone. J. Cell. Physiol. 1986, 129, 103-110.

[79] Shimaoka, S.; Nakamura, T.; Ichihara, A. Stimulation of growth of primary cultured adult rat hepatocytes without growth factors by coculture with nonparenchymal liver cells. Exp. Cell Res. 1987, 172, 228-242.

[80] Khetani, S.R.; Bhatia, S.N. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 2008, 26, 120-126.

[81] Kidambi, S.; Sheng, L.F.; Yarmush, M.L.; Toner, M.; Lee, I.; Chan, C. Patterned co-culture of primary hepatocytes and fibroblasts using polyelectrolyte multilayer templates. Macromol. Biosci. 2007, 7, 344-353.

[82] Cho, C.H.; Park, J.; Tilles, A.W.; Berthiaume, F.; Toner, M.; Yarmush, M.L. Layered patterning of hepatocytes in co-culture systems using microfabricated stencils. Biotechniques. 2010, 48, 47-52.

[83] Otsuka, H.; Sasaki, K.; Okimura, S.; Nagamura, M.; Nakasone, Y. Micropatterned co-culture of hepatocyte spheroids layered on non-parenchymal cells to understand heterotypic cellular interactions. Sci. Technol. Adv. Mater. 2013, 14, 065003.

[84] Bale, S.S.; Sridharan, G.V.; Golberg, I.; Prodanov, L.; McCarty, W.J.; Usta, O.B.; Jindal, R.; Yarmush, M.L. A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity. Technology. 2015, 3, 155-162.

[85] An, F.; Qu, Y.Y.; Luo, Y.; Fang, N.; Liu, Y.; Gao, Z.G.; Zhao, W.J.; Lin, B.C. A laminated microfluidic device for comprehensive preclinical testing in the drug ADME process. Sci. Rep. 2016, 6, 25022.

[86] Esch, M.B.; Prot, J.M.; Wang, Y.I.; Miller, P.; Llamas-Vidales, J.R.; Naughton, B.A.; Applegate, D.R.; Shuler, M.L. Multi-cellular 3D human primary liver cell culture elevates metabolic activity under fluidic flow. Lab. Chip. 2015, 15, 2269-2277.

[87] Kang, Y.B.; Sodunke, T.R.; Lamontagne, J.; Cirillo, J.; Rajiv, C.; Bouchard, M.J.; Noh, M. Liver sinusoid on a chip: Long-term layered co-culture of primary rat hepatocytes and endothelial cells in microfluidic platforms. Biotechnol. Bioeng. 2015, 112, 2571-2582.

[88] Chen, W.L.K.; Edington, C.; Suter, E.; Yu, J.J.; Velazquez, J.J.; Velazquez, J.G.; Shockley, M.; Large, E.M.; Venkataramanan, R.; Hughes, D.J.; Stokes, C.L.; Trumper, D.L.; Carrier, R.L.; Cirit, M.; Griffith, L.G.; Lauffenburger, D.A. Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk. Biotechnol. Bioeng. 2017, 114, 2648-2659.

[89] Yoon No, D.; Lee, K.H.; Lee, J.; Lee, S.H. 3D liver models on a microplatform: well-defined culture, engineering of liver tissue and liver-on-a-chip. Lab. Chip. 2015, 15, 3822-3837.

[90] Wu, X.; Roberto, J.B.; Knupp, A.; Kenerson, H.L.; Truong, C.D.; Yuen, S.Y.; Brempelis, K.J.; Tuefferd, M.; Chen, A.; Horton, H.; Yeung, R.S.; Crispe, I.N. Precision-cut human liver slice cultures as an immunological platform. J. Immunol. Methods 2018, 455, 71-79.

[91] Heinonen, J.T.; Sidhu, J.S.; Reilly, M.T.; Farin, F.M.; Omiecinski, C.J.; Eaton, D.L.; Kavanagh, T.J. Assessment of regional cytochrome P450 activities in rat liver slices using resorufin substrates and fluorescence confocal laser cytometry. Environ. Health Perspect. 1996, 104, 536-543.

[92] van Midwoud, P.M.; Merema, M.T.; Verweij, N.; Groothuis, G.M.; Verpoorte, E. Hydrogel embedding of precision-cut liver slices in a microfluidic device improves drug metabolic activity. Biotechnol. Bioeng. 2011, 108, 1404-1412.

[93] Sivashankar, S.; Puttaswamy, S.V.; Lin, L.H.; Dai, T.S.; Yeh, C.T.; Liu, C.H. Culturing of transgenic mice liver tissue slices in three-dimensional microfluidic structures of PEG-DA (poly(ethylene glycol) diacrylate). Sens. Actuators B Chem. 2013, 176, 1081-1089.

[94] Catterton, M.A.; Dunn, A.F.; Pompano, R.R. User-defined local stimulation of live tissue through a movable microfluidic port. Lab. Chip. 2018, 18, 2003-2012.

[95] Fisher, R.L.; Vickers, A.E. Preparation and culture of precision-cut organ slices from human and animal. Xenobiotica. 2013, 43, 8-14.

肝脏药物代谢研究中的微流控模型

Microfluidic models in liver drug metabolism research

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 8

编辑推荐

Metrics

本文评价

[1]	逯颖媛, 张梅, 尹胜菊, 董晓娜, 张志远, 程海旭, 屠鹏飞, 窦桂芳, 车永胜, 徐争辉, 徐枫, 王宪, 吕闯, 楼雅卿, 章国良. 异源物代谢的表观遗传学变异影响抗癫痫药3,4-DCPB药物代谢动力学表型个体差异[J]. 中国药学(英文版), 2023, 32(1): 1-16.
[2]	李静云, 李健, 王思媛, 袁茵, 苏青虹, 卢炜, 周田彦. 液相质谱串联法同时测定舒尼替尼及其活性代谢产物SU12662在BABL/c裸鼠血浆中的浓度及其药物动力学研究[J]. 中国药学(英文版), 2015, 24(4): 217-224.
[3]	彭锐, 张洪, 张英. SNP新颖方法和个体化用药方案的研究进展[J]. 中国药学(英文版), 2014, 23(10): 731-738.
[4]	洪燕君, 高凌波, 曾苏^*. 手性药物代谢研究中的对映体分析方法[J]. , 2008, 17(3): 177-182.
[5]	艾国, 陈知航, 单成启, 车津晶, 侯禹男, 程远国^*. 醋酸艾塞那肽在Wistar大鼠体内的药物代谢动力学研究[J]. , 2008, 17(1): 6-10.
[6]	刘薏, 杨振军^*, BOUDINOTF.Douglas, CHU Chung Kuang, 张礼和. 2',3'-二脱氢-2',3'-二脱氧-2-氨基-6-环丙胺基嘌呤核糖核苷在大鼠体内的药物代谢动力学和生物利用度[J]. , 2004, 13(1): 37-41.
[7]	徐宏祥, 刘志强. 双波长差示一阶导数分光光度法用于体外外源性化学物质的微粒体代谢中生成一氧化碳的定性和定量测定[J]. , 1997, 6(2): 105-110.
[8]	弋苹, 全钰珠. 西米替丁降低吡喹酮在大鼠体内的消除[J]. , 1993, 2(2): 127-132.