Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals

Author(s): Tomoaki Inoue, Norihiko Iwazaki*, Tetsuro Araki, Hiroko Hitotsumachi

Journal Name: Current Pharmaceutical Biotechnology

Volume 21 , Issue 9 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Human hepatocytes are essential cell types for pharmacokinetics and the safety evaluation of pharmaceuticals. However, widely used primary hepatocytes with individual variations in liver function lose those functions rapidly in culture. Hepatic cell lines are convenient to use but have low liver functions. Human-Induced Pluripotent Stem (hiPS) cells can be expanded and potentially differentiated into any cell or tissue, including the liver. HiPS cell-derived Hepatocyte-Like Cells (hiPSHeps) are expected to be extensively used as consistent functional human hepatocytes. Many laboratories are investigating methods of using hiPS cells to differentiate hepatocytes, but the derived cells still have immature liver functions. In this paper, we describe the current uses and limitations of conventional hepatic cells, evaluating the suitability of hiPS-Heps to pharmacokinetics and the safety evaluation of pharmaceuticals, and discuss the potential future use of non-conventional non-monolayer culture methods to derive fully functional hiPS-Heps.

Keywords: hiPS-Heps, primary human hepatocytes (PHHs), drug-induced liver injury (DILI), cytochrome P450, HepG2, microphysiological systems.

Shi, J.; Wang, X.; Lyu, L.; Jiang, H.; Zhu, H.J. Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes. Drug Metab. Pharmacokinet., 2018, 33(2), 133-140.
[] [PMID: 29610054]
Yokoyama, Y.; Sasaki, Y.; Terasaki, N.; Kawataki, T.; Takekawa, K.; Iwase, Y.; Shimizu, T.; Sanoh, S.; Ohta, S. Comparison of drug metabolism and its related hepatotoxic effects in HepaRG, cryopreserved human hepatocytes, and HepG2 cell lines. Biol. Pharm. Bull., 2018, 41(5), 722-732.
[] [PMID: 29445054]
Takayama, K.; Hagihara, Y.; Toba, Y.; Sekiguchi, K.; Sakurai, F.; Mizuguchi, H. Enrichment of high-functioning human iPS cell derived hepatocyte-like cells for pharmaceutical research. Biomaterials, 2018, 161, 24-32.
[] [PMID: 29421559]
Yamazoe, T.; Shiraki, N.; Kume, S. Hepatic differentiation from murine and human iPS cells using nanofiber scaffolds. Methods Mol. Biol., 2016, 1357, 475-483.
[] [PMID: 25410288]
Sgodda, M.; Dai, Z.; Zweigerdt, R.; Sharma, A.D.; Ott, M.; Cantz, T. A scalable approach for the generation of human pluripotent stem cell-derived hepatic organoids with sensitive hepatotoxicity features. Stem Cells Dev., 2017, 26(20), 1490-1504.
[] [PMID: 28699415]
Tomizawa, M.; Shinozaki, F.; Motoyoshi, Y.; Sugiyama, T.; Yamamoto, S.; Ishige, N. 2-Deoxy-D-glucose initiates hepatocyte differentiation in human induced pluripotent stem cells. Mol. Med. Rep., 2017, 15(5), 3083-3087.
[] [PMID: 28358426]
Hirata, M.; Yamaoka, T. Hepatocytic differentiation of iPS cells on decellularized liver tissue. J. Artif. Organs, 2017, 20(4), 318-325.
[] [PMID: 28776092]
Heslop, J.A.; Kia, R.; Pridgeon, C.S.; Sison-Young, R.L.; Liloglou, T.; Elmasry, M.; Fenwick, S.W.; Mills, J.S.; Kitteringham, N.R.; Goldring, C.E.; Park, B.K. Donor-dependent and other nondefined factors have greater influence on the hepatic phenotype than the starting cell type in induced pluripotent stem cell derived hepatocyte-like cells. Stem Cells Transl. Med., 2017, 6(5), 1321-1331.
[] [PMID: 28456008]
Benesic, A.; Leitl, A.; Gerbes, A.L. Monocyte-derived hepatocyte like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut, 2016, 65(9), 1555-1563.
[] [PMID: 26045135]
Utkarsh, D.; Loretz, C.; Li, A.P. In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries. Chem. Biol. Interact., 2016, 255, 12-22.
[] [PMID: 26718876]
Kratochwil, N.A.; Meille, C.; Fowler, S.; Klammers, F.; Ekiciler, A.; Molitor, B.; Simon, S.; Walter, I.; McGinnis, C.; Walther, J.; Leonard, B.; Triyatni, M.; Javanbakht, H.; Funk, C.; Schuler, F.; Lavé, T.; Parrott, N.J. Metabolic profiling of human long-term liver models and hepatic clearance predictions from in vitro data using nonlinear mixed-effects modeling. AAPS J., 2017, 19(2), 534-550.
[] [PMID: 28050713]
Takayama, K.; Morisaki, Y.; Kuno, S.; Nagamoto, Y.; Harada, K.; Furukawa, N.; Ohtaka, M.; Nishimura, K.; Imagawa, K.; Sakurai, F.; Tachibana, M.; Sumazaki, R.; Noguchi, E.; Nakanishi, M.; Hirata, K.; Kawabata, K.; Mizuguchi, H. Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes. Proc. Natl. Acad. Sci. USA, 2014, 111(47), 16772-16777.
[] [PMID: 25385620]
Roy-Chowdhury, N.; Wang, X.; Guha, C.; Roy-Chowdhury, J. Hepatocyte-like cells derived from induced pluripotent stem cells. Hepatol. Int., 2017, 11(1), 54-69.
[] [PMID: 27530815]
Araki, T.; Iwazaki, N.; Ishiguro, N.; Sakamoto, A.; Nagata, K.; Ohbuchi, M.; Moriguchi, H.; Motoi, M.; Shinkyo, R.; Homma, T.; Sakamoto, S.; Iwase, Y.; Ise, R.; Nakanishi, Y.; Uto, M.; Inoue, T. Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals. Fund. Toxicol. Sci., 2016, 3(3), 89-99.
Murayama, N.; Yamazaki, H. Cytochrome P450-dependent drug oxidation activities in commercially available hepatocytes derived from human induced pluripotent stem cells cultured for 3 weeks. J. Toxicol. Sci., 2018, 43(4), 241-245.
[] [PMID: 29618712]
Nakai, S.; Shibata, I.; Shitamichi, T.; Yamaguchi, H.; Takagi, N.; Inoue, T.; Nakagawa, T.; Kiyokawa, J.; Wakabayashi, S.; Miyoshi, T.; Higashi, E.; Ishida, S.; Shiraki, N.; Kume, S. Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells. Biol. Open, 2019, 8(7) bio042192
[] [PMID: 31182631]
Oizumi, K.; Sekine, S.; Fukagai, M.; Susukida, T.; Ito, K. Identification of bile acids responsible for inhibiting the bile salt export pump, leading to bile acid accumulation and cell toxicity in rat hepatocytes. J. Pharm. Sci., 2017, 106(9), 2412-2419.
[] [PMID: 28552691]
Garzel, B.; Yang, H.; Zhang, L.; Huang, S-M.; Polli, J.E.; Wang, H. The role of bile salt export pump gene repression in drug induced cholestatic liver toxicity. Drug Metab. Dispos., 2014, 42(3), 318-322.
[] [PMID: 24335466]
Jackson, J.P.; Freemen, K.M.; St. Claire, R.L.; Black, C.B.; Brouwer, K.R. Choleststic drug induced liver injury: A function of bile salt export pump inhibition and farnesoid X receptor antagonism. Appl. In Vitro Toxicol., 2018, 4(3), 265-279.
Ni, X.; Gao, Y.; Wu, Z.; Ma, L.; Chen, C.; Wang, L.; Lin, Y.; Hui, L.; Pan, G. Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model. Sci. Rep., 2016, 6, 38694.
[] [PMID: 27934920]
Luckert, C.; Braeuning, A.; de Sousa, G.; Durinck, S.; Katsanou, E.S.; Konstantinidou, P.; Machera, K.; Milani, E.S.; Peijnenburg, A.A.C.M.; Rahmani, R.; Rajkovic, A.; Rijkers, D.; Spyropoulou, A.; Stamou, M.; Stoopen, G.; Sturla, S.; Wollscheid, B.; Zucchini-Pascal, N.; Lampen, A. Adverse outcome pathway-driven analysis of liver steatosis in vitro: A case study with cyproconazole. Chem. Res. Toxicol., 2018, 31(8), 784-798.
[] [PMID: 29995386]
Mellor, C.L.; Steinmetz, F.P.; Cronin, M.T. The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways. Crit. Rev. Toxicol., 2016, 46(2), 138-152.
[] [PMID: 26451809]
Angrish, M.M.; McQueen, C.A.; Cohen-Hubal, E.; Bruno, M.; Ge, Y.; Chorley, B.N. Mechanistic toxicity tests based on an adverse outcome pathway network for hepatic steatosis. Toxicol. Sci., 2017, 159(1), 159-169.
[] [PMID: 28903485]
Paech, F.; Mingard, C.; Grünig, D.; Abegg, V.F.; Bouitbir, J.; Krähenbühl, S. Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells. Toxicology, 2018, 395, 34-44.
[] [PMID: 29341879]
Hassan, H. M.; Yousef, B. A.; Guo, H.; Liu, X.; Zhang, L; Jiang, Z. Investigating the CYP2E1 potential role in the mechanisms behind INH/LPS-induced hepatotoxicity. Frontiers Pharmacol., 2018, 9, 198/1-198/14.
Deffa, O.; Aissaoui, H.; Mekkiou, R.; Menad, A.; Benayache, F.; Benayache, S.; Ameddah, S. Heliotropium undulatum attenuates hydrazine induced hepatotoxicity: involvement of cytochrome P450 CYP2E1 and oxidative stress. World J. Pharm. Res., 2018, 7(5), 1-15.
Godoy, P.; Hewitt, N.J.; Albrecht, U.; Andersen, M.E.; Ansari, N.; Bhattacharya, S.; Bode, J.G.; Bolleyn, J.; Borner, C.; Böttger, J.; Braeuning, A.; Budinsky, R.A.; Burkhardt, B.; Cameron, N.R.; Camussi, G.; Cho, C.S.; Choi, Y.J.; Craig Rowlands, J.; Dahmen, U.; Damm, G.; Dirsch, O.; Donato, M.T.; Dong, J.; Dooley, S.; Drasdo, D.; Eakins, R.; Ferreira, K.S.; Fonsato, V.; Fraczek, J.; Gebhardt, R.; Gibson, A.; Glanemann, M.; Goldring, C.E.; Gómez-Lechón, M.J.; Groothuis, G.M.; Gustavsson, L.; Guyot, C.; Hallifax, D.; Hammad, S.; Hayward, A.; Häussinger, D.; Hellerbrand, C.; Hewitt, P.; Hoehme, S.; Holzhütter, H.G.; Houston, J.B.; Hrach, J.; Ito, K.; Jaeschke, H.; Keitel, V.; Kelm, J.M.; Kevin Park, B.; Kordes, C.; Kullak-Ublick, G.A.; LeCluyse, E.L.; Lu, P.; Luebke-Wheeler, J.; Lutz, A.; Maltman, D.J.; Matz-Soja, M.; McMullen, P.; Merfort, I.; Messner, S.; Meyer, C.; Mwinyi, J.; Naisbitt, D.J.; Nussler, A.K.; Olinga, P.; Pampaloni, F.; Pi, J.; Pluta, L.; Przyborski, S.A.; Ramachandran, A.; Rogiers, V. Rowe, C.; Schelcher, C.; Schmich, K.; Schwarz, M.; Singh, B.; Stelzer, E.H.; Stieger, B.; Stöber, R.; Sugiyama, Y.; Tetta, C.; Thasler, W.E.; Vanhaecke, T.; Vinken, M.; Weiss, T.S.; Widera, A.; Woods, C.G.; Xu, J.J.; Yarborough, K.M.; Hengstler, J.G. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch. Toxicol., 2013, 87(8), 1315-1530.
[] [PMID: 23974980]
Kim, D.E.; Jang, M-J.; Kim, Y.R.; Lee, J-Y.; Cho, E.B.; Kim, E.; Kim, Y.; Kim, M.Y.; Jeong, W.I.; Kim, S.; Han, Y.M.; Lee, S.H. Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells. Toxicology, 2017, 387, 1-9.
[] [PMID: 28645575]
Koyama, Y.; Brenner, D.A. Liver inflammation and fibrosis. J. Clin. Invest., 2017, 127(1), 55-64.
[] [PMID: 28045404]
Norona, L.M.; Nguyen, D.G.; Gerber, D.A.; Presnell, S.C.; Le- Cluyse, E.L. Editor’s Highlight: Modeling compound-induced fibrogenesis in vitro using three-dimensional bioprinted human liver tissues. Toxicol. Sci., 2016, 154(2), 354-367.
[] [PMID: 27605418]
Kim, S-H.; Naisbitt, D.J. Update on advances in research on idiosyncratic drug-induced liver injury. Allergy Asthma Immunol. Res., 2016, 8(1), 3-11.
[] [PMID: 26540496]
Iorga, A.; Dara, L.; Kaplowitz, N. Drug-induced liver injury: Cascade of events leading to cell death, apoptosis or necrosis. Int. J. Mol. Sci., 2017, 18(5), 1018.
[] [PMID: 28486401]
Kullak-Ublick, G.A.; Andrade, R.J.; Merz, M.; End, P.; Benesic, A.; Gerbes, A.L.; Aithal, G.P. Drug-induced liver injury: Recent advances in diagnosis and risk assessment. Gut, 2017, 66(6), 1154-1164.
[] [PMID: 28341748]
Kaneko, S. In vitro generation of antigen-specific T cells from induced pluripotent stem cells of antigen-specific T cell origin. Methods Mol. Biol., 2016, 1393, 67-73.
[] [PMID: 27033216]
Miyoshi, M.; Kakinuma, S.; Kamiya, A.; Tsunoda, T.; Tsuchiya, J.; Sato, A.; Kaneko, S.; Nitta, S.; Kawai-Kitahata, F.; Murakawa, M.; Itsui, Y.; Nakagawa, M.; Azuma, S.; Nakauchi, H.; Asahina, Y.; Watanabe, M. LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. Sci. Rep., 2019, 9(1), 2072.
[] [PMID: 30765795]
Senju, S.; Haruta, M.; Matsunaga, Y.; Fukushima, S.; Ikeda, T.; Takahashi, K.; Okita, K.; Yamanaka, S.; Nishimura, Y. Characterization of dendritic cells and macrophages generated by directed differentiation from mouse induced pluripotent stem cells. Stem Cells, 2009, 27(5), 1021-1031.
[] [PMID: 19415766]
Yamamoto, N.; Wu, J.; Zhang, Y.; Catana, A.M.; Cai, H.; Strom, S.; Novikoff, P.M.; Zern, M.A. An optimal culture condition maintains human hepatocyte phenotype after long-term culture. Hepatol. Res., 2006, 35(3), 169-177.
[PMID: 16807086]
Schyschka, L.; Sánchez, J.J.M.; Wang, Z.; Burkhardt, B.; Müller-Vieira, U.; Zeilinger, K.; Bachmann, A.; Nadalin, S.; Damm, G.; Nussler, A.K. Hepatic 3D cultures but not 2D cultures preserve specific transporter activity for acetaminophen-induced hepatotoxicity. Arch. Toxicol., 2013, 87(8), 1581-1593.
[] [PMID: 23728527]
Hamilton, G.A.; Jolley, S.L.; Gilbert, D.; Coon, D.J.; Barros, S.; LeCluyse, E.L. Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactions. Cell Tissue Res., 2001, 306(1), 85-99.
[] [PMID: 11683185]
Mazza, G.; Al-Akkad, W.; Telese, A.; Longato, L.; Urbani, L.; Robinson, B.; Hall, A.; Kong, K.; Frenguelli, L.; Marrone, G.; Willacy, O.; Shaeri, M.; Burns, A.; Malago, M.; Gilbertson, J.; Rendell, N.; Moore, K.; Hughes, D.; Notingher, I.; Jell, G.; Del Rio Hernandez, A.; De Coppi, P.; Rombouts, K.; Pinzani, M. Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization. Sci. Rep., 2017, 7(1), 5534.
[] [PMID: 28717194]
Wencel, A.; Zakrzewska, K.E.; Samluk, A.; Noszczyk, B.H.; Pijanowska, D.G.; Pluta, K.D. Dried human skin fibroblasts as a new substratum for functional culture of hepatic cells. Acta Biochim. Pol., 2017, 64(2), 357-363.
[] [PMID: 28600910]
Kizawa, H.; Nagao, E.; Shimamura, M.; Zhang, G.; Torii, H. Scaffold-free 3D bio-printed human liver tissue stably maintain useful for drug discovery. Biochem. Biophys. Rep., 2017, 10, 186-191.
[] [PMID: 28955746]
Nguyen, D.G.; Funk, J.; Robbins, J.B.; Crogan-Grundy, C.; Presnell, S.C.; Singer, T.; Roth, A.B. Bioprinted 3D primary liver tissues allow assessment of organ-level response to clinical drug induced toxicity in vitro. PLoS One, 2016, 11(7) e0158674
[] [PMID: 27387377]
Khetani, S.R.; Bhatia, S.N. Microscale culture of human liver cells for drug development. Nat. Biotechnol., 2008, 26(1), 120-126.
[] [PMID: 18026090]
Mosedale, M.; Eaddy, J.S.; Trask, O.J., Jr; Holman, N.S.; Wolf, K.K.; LeCluyse, E.; Ware, B.R.; Khetani, S.R.; Lu, J.; Brock, W.J.; Roth, S.E.; Watkins, P.B. miR-122 Release in exosomes precedes overt tolvaptan-induced necrosis in a primary human hepatocyte micropatterned coculture model. Toxicol. Sci., 2018, 161(1), 149-158.
[] [PMID: 29029277]
Trask, O.J., Jr; Moore, A.; LeCluyse, E.L. A micropatterned hepatocyte coculture model for assessment of liver toxicity using high-content imaging analysis. Assay Drug Dev. Technol., 2014, 12(1), 16-27.
[] [PMID: 24444127]
Khetani, S.R.; Kanchagar, C.; Ukairo, O.; Krzyzewski, S.; Moore, A.; Shi, J.; Aoyama, S.; Aleo, M.; Will, Y. Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. Toxicol. Sci., 2013, 132(1), 107-117.
[] [PMID: 23152190]
Berger, D.R.; Ware, B.R.; Davidson, M.D.; Allsup, S.R.; Khetani, S.R. Enhancing the functional maturity of induced pluripotent stem cell-derived human hepatocytes by controlled presentation of cell-cell interactions in vitro. Hepatology, 2015, 61(4), 1370-1381.
[] [PMID: 25421237]
Ware, B.R.; Berger, D.R.; Khetani, S.R. Prediction of drug-induced liver injury in micropatterned co-cultures containing iPSC-derived human hepatocytes. Toxicol. Sci., 2015, 145(2), 252-262.
[] [PMID: 25716675]
Baze, A.; Parmentier, C.; Hendriks, D.F.G.; Hurrell, T.; Heyd, B.; Bachellier, P.; Schuster, C.; Ingelman-Sundberg, M.; Richert, L. Three-dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Eng. Part C Methods, 2018, 24(9), 534-545.
[] [PMID: 30101670]
Wang, B.; Jakus, A.E.; Baptista, P.M.; Soker, S.; Soto-Gutierrez, A.; Abecassis, M.M.; Shah, R.N.; Wertheim, J.A. Functional maturation of induced pluripotent stem cell hepatocytes in extracellular matrix - A comparative analysis of bioartificial liver microenvironments. Stem Cells Transl. Med., 2016, 5(9), 1257-1267.
[] [PMID: 27421950]
Luo, Y.; Lou, C.; Zhang, S.; Zhu, Z.; Xing, Q.; Wang, P.; Liu, T.; Liu, H.; Li, C.; Shi, W.; Du, Z.; Gao, Y. Three-dimensional hydrogel culture conditions promote the differentiation of human induced pluripotent stem cells into hepatocytes. Cytotherapy, 2018, 20(1), 95-107.
[] [PMID: 28969895]
Freyer, N.; Knöspel, F.; Strahl, N.; Amini, L.; Schrade, P.; Bachmann, S.; Damm, G.; Seehofer, D.; Jacobs, F.; Monshouwer, M.; Zeilinger, K. Schrade, Bachmann, S.; Damm, G.; Seehofer, D.; Jacobs, F.; Monshouwer, M.; Zeilinger, K. Hepatic differentiation of human induced pluripotent stem cells in a perfused three-dimensional multicompartment bioreactor. Biores. Open Access, 2016, 5(1), 235-248.
[] [PMID: 27610270]
Koui, Y.; Kido, T.; Ito, T.; Oyama, H.; Chen, S-W.; Katou, Y.; Shirahige, K.; Miyajima, A. An in vitro human liver model by iPSC-derived parenchymal and non-parenchymal cells. Stem Cell Reports, 2017, 9(2), 490-498.
[] [PMID: 28757162]
Kamei, K.; Yoshioka, M.; Terada, S.; Tokunaga, Y.; Chen, Y. Robust direct differentiation and maturation of human pluripotent stem cells to hepatocyte-like cells. bioRxiv. Bioengineering (Basel), 2017, 1-30.
McAleer, C.W.; Long, C.J.; Elbrecht, D.; Sasserath, T.; Bridges, L.R.; Rumsey, J.W.; Martin, C.; Schnepper, M.; Wang, Y.; Schuler, F.; Roth, A.B.; Funk, C.; Shuler, M.L.; Hickman, J.J. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. Sci. Transl. Med., 2019, 11(497), 11.
[] [PMID: 31217335]
Rowe, C.; Shaeri, M.; Large, E.; Cornforth, T.; Robinson, A.; Kostrzewski, T.; Sison-Young, R.; Goldring, C.; Park, K.; Hughes, D. Perfused human hepatocyte microtissues identify reactive metabolite-forming and mitochondria-perturbing hepatotoxins. Toxicol. In Vitro, 2018, 46, 29-38.
[] [PMID: 28919358]
Foster, A.J.; Chouhan, B.; Regan, S.L.; Rollison, H.; Amberntsson, S.; Andersson, L.C.; Srivastava, A.; Darnell, M.; Cairns, J.; Lazic, S.E.; Jang, K.J.; Petropolis, D.B.; Kodella, K.; Rubins, J.E.; Williams, D.; Hamilton, G.A.; Ewart, L.; Morgan, P. Integrated in vitro models for hepatic safety and metabolism: Evaluation of a human liver-chip and liver spheroid. Arch. Toxicol., 2019, 93(4), 1021-1037.
[] [PMID: 30915487]
Satoh, T.; Sugiura, S.; Shin, K.; Onuki-Nagasaki, R.; Ishida, S.; Kikuchi, K.; Kakiki, M.; Kanamori, T. A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure driven medium circulation platform. Lab Chip, 2017, 18(1), 115-125.
[] [PMID: 29184959]
Tetsuka, K.; Ohbuchi, M.; Tabata, K. Recent progress in hepatocyte culture models and their application to the assessment of drug metabolism, transport, and toxicity in drug discovery: The value of tissue engineering for the successful development of a microphysiological system. J. Pharm. Sci., 2017, 106(9), 2302-2311.
[] [PMID: 28533121]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [773 - 779]
Pages: 7
DOI: 10.2174/1389201021666200131123524
Price: $65

Article Metrics

PDF: 38