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Tethered spheroids as an in vitro hepatocyte model for drug safety screening |
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| Authors: | Xia Lei Sakban Rashidah Binte Qu Yinghua Hong Xin Zhang Wenxia Nugraha Bramasta Tong Wen Hao Ananthanarayanan Abhishek Zheng Baixue Chau Ian Yin-Yan Jia Ruirui McMillian Michael Silva Jose Dallas Shannon Yu Hanry |
| Institution: | a Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Clinical Research Center, #04-25, Singapore 117597, Singapore b Institute of Bioengineering and Nanotechnology, A∗STAR, The Nanos, #04-01, 31 Biopolis Way, Singapore 138669, Singapore c NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), #05-01, 28 Medical Drive, Singapore 117576, Singapore d Mechanobiology Institute of Singapore, Temasek Laboratories, National University of Singapore, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore e Singapore-MIT Alliance, Computational and System Biology Program, E4-04-10, 4 Engineering Drive 3, Singapore 117576, Singapore f Medical Engineering Program, Faculty of Engineering, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region, China g Drug Safety Sciences, Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA h NUS Tissue Engineering Program, DSO Labs, National University of Singapore, Singapore 117597, Singapore i Singapore-MIT Alliance for Research and Technology, 3 Science Drive 2, S16-05-08, Singapore 117543, Singapore j Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA |
| Abstract: | Hepatocyte spheroids mimic many in vivo liver-tissue phenotypes but increase in size during extended culture which limits their application in drug testing applications. We have developed an improved hepatocyte 3D spheroid model, namely tethered spheroids, on RGD and galactose-conjugated membranes using an optimized hybrid ratio of the two bioactive ligands. Cells in the spheroid configuration maintained 3D morphology and uncompromised differentiated hepatocyte functions (urea and albumin production), while the spheroid bottom was firmly tethered to the substratum maintaining the spheroid size in multi-well plates. The oblate shape of the tethered spheroids, with an average height of 32 μm, ensured efficient nutrient, oxygen and drug access to all the cells within the spheroid structure. Cytochrome P450 induction by prototypical inducers was demonstrated in the tethered spheroids and was comparable or better than that observed with hepatocyte sandwich cultures. These data suggested that tethered 3D hepatocyte spheroids may be an excellent alternative to 2D hepatocyte culture models for drug safety applications. |
| Keywords: | 3D hepatocyte model Xenobiotics RGD Galactose CYP450 enzymes Drug safety testing |
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