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2022, Vol. 26 ›› Issue (19): 3100-3107

Assessment of in vitro 3D large-scale hepatocyte proliferation culture system and automated and intelligent bioreactor systems

Li Ke1, 2, Zhang Guanghao1, 2, Zhang Cheng1, 2, Yang Jiayi1, 2, Wu Changzhe1, 2, 3, Huo Xiaolin1, 2   

  1. 1Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; 2University of Chinese Academy of Sciences, Beijing 100049, China; 3ZhuJiang Hospital of Southern Medical University, Guangzhou 510280, Guangdong Province, China

  • Received:2021-04-23 Revised:2021-05-26 Accepted:2021-06-25 Online:2022-07-08 Published:2021-12-29

  • Contact: Huo Xiaolin, MD, Researcher, Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China Wu Changzhe, Master, Senior engineer, Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China; ZhuJiang Hospital of Southern Medical University, Guangzhou 510280, Guangdong Province, China

  • About author:Li Ke, Doctoral candidate, Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China

  • Supported by:

    the National Key Research & Development Program of China, No. 2018YFC1106400, 2018YFA0108200 (both to WCZ [project participant]); the National Natural Science Foundation of China, No. 61671428 (to WCZ)



Abstract: BACKGROUND: How to obtain sufficient quantity and quality of hepatocytes in vitro is the core problem to be solved urgently in the clinical application of bioartificial liver.
OBJECTIVE: To summarize the main research contents of the in vitro 3D large-scale expansion culture system of hepatocytes, summarize the current main sources of seed cells, 3D culture methods, bioreactor system, and the progress and limitations of real-time online monitoring of key indicators of the culture process, and prospects for the further development of automated and intelligent bioreactor systems.
METHODS: The first author searched the Web of Science core database, ScienceDirect, EI, PubMed, and CNKI databases. The English and Chinese search terms were “hepatocyte, 3D culture, proliferate, bioreactor system, monitor and control”. The literature search time range was from January 2005 to March 2021. The types of articles included original research works, reviews and meta-analysis. Totally, 93 papers were selected for analysis.

RESULTS AND CONCLUSION: (1) Researches on liver seed cell sources, 3D culture methods, bioreactor system construction, and real-time online monitoring methods for key biochemical indicators have all made progress, laying a solid foundation for the further construction of a large-scale in vitro 3D hepatocyte culture system. (2) Human hepatocarcinoma cell lines, immortalized hepatocytes, stem cell differentiation and other hepatocytes can be cultured and proliferated in vitro and express liver function. Among them, hepatocyte-like cells obtained from stem cell differentiation and direct reprogramming have cells similar to mature liver cells morphology, function, and gene expression profile will have greater application prospects in the future. (3) 3D suspension culture has excellent performance in terms of culture density and mass transfer efficiency, and has the advantages of easy amplification, convenient inoculation, and convenient access. It is the main development direction of in vitro 3D culture of hepatocytes. (4) Although the existing bioreactor system can realize in vitro culture and expansion of hepatocytes, it has a low degree of automation and lacks a real-time online detection method for key biochemical indicators. In addition, the current degree of mutual integration of these several aspects of research also restricts the progress of the in vitro 3D large-scale culture system of hepatocytes. (5) The future research is to combine the growth characteristics of liver seed cells from different sources, select suitable culture methods, and establish a real-time online monitoring method for key parameters during the culture process, so as to construct a highly automated and intelligent bioreactor system to achieve in vitro scale of liver cells large-scale preparation.

Key words:bioartificial liver, hepatocytes, 3D culture, proliferation, large-scale, bioreactor system, real-time online


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