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RESEARCH ARTICLE

Bioprinting of a Hepatic Tissue Model Using Human-

Induced Pluripotent Stem Cell-derived Hepatocytes for

Drug-Induced Hepatotoxicity Evaluation

Jianyu He 1,2,3,† , Jinglin Wang 4,5,† , Yuan Pang 1,2,3 , Hang Yu , Xueqian Qin , Ke Su , Tao Xu 1,2,3, *,
4
4,5
4,5
Haozhen Ren *
4,5,
1 Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Beijing, 100084, China
2 Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Beijing, 100084, China
3 Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, 100084, China
4 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School,
Hepatobiliary Institute of Nanjing University, Nanjing, 210008, China
5 Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of
Chinese Medicine, Nanjing, China
†These authors have contributed equally to this work.

Abstract: Three-dimensional (3D) bioprinting technology is an effective method for exploring the biological functions of
hepatocytes by building biomimetic 3D microenvironments. Various hepatic tissue models have been developed for disease
modeling, drug screening, and tissue regeneration using 3D bioprinting technology. Human-induced pluripotent stem cells
(hiPSCs) are a promising cell source for the generation of functional hepatocytes for bioprinting. In this study, we introduced
hiPSC-derived hepatocytes (hiPSC-Heps) as mature hepatocytes for the bioprinting of a 3D hepatic tissue model. The
3D-printed (3DP) model facilitated the formation of hiPSC-Hep spheroids with higher viability and proliferation than the
commonly used non-printed sandwich-cultured model. hiPSC-Heps in the 3DP model exhibited higher mRNA expression of
liver-specific functions than those in the two-dimensional-cultured model. Moreover, enhanced secretion of liver function-
related proteins, including α-1-antitrypsin, albumin, and blood urea nitrogen, was observed in the 3DP model. For the
evaluation of acetaminophen-induced hepatotoxicity, the 3DP model exhibited a favorable drug response with upregulation
of the drug metabolism-related gene cytochrome P450-1A2 (CYP1A2). Overall, the bioprinted hepatic tissue model showed
great biofunctional and drug-responsive performance, which could be potentially applied in in vitro toxicological studies.
Keywords: 3D bioprinting; Human-induced pluripotent stem cell; Hepatocytes; Sandwich culture; Hepatic model;
Acetaminophen; Drug-induced hepatotoxicity

*Correspondence to: Haozhen Ren, Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical
School, Hepatobiliary Institute of Nanjing University, Nanjing, 210008, China; renhaozhen1984@163.com; Tao Xu, Department of Mechanical
Engineering, Tsinghua University, Beijing, 100084, China; taoxu@mail.tsinghua.edu.cn

Received: February 18, 2022; Accepted: April 26, 2022; Published Online: June 14, 2022
(This article belongs to the Special Issue: 3D Printing in tissue engineering)
Citation: He J, Wang J, Pang Y, et al., 2022, Bioprinting of a Hepatic Tissue Model Using Human-Induced Pluripotent Stem Cell-derived
Hepatocytes for Drug-Induced Hepatotoxicity Evaluation. Int J Bioprint, 8(3): 581. http://doi.org/10.18063/ijb.v8i3.581

1. Introduction biomaterials provides an effective method for
Three-dimensional (3D) bioprinting is an emerging and reconstruction of the native cellular microenvironment
[1]
promising technology for the construction of in vitro for cell growth and biofunction maintenance . Cells,
tissue and organ models. Incorporation of biocompatible biomaterials, and growth factors can be spatially arranged
© 2022 Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution and
reproduction in any medium, provided the original work is cited.
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