Three-dimensional liver models: state of the art and their application for hepatotoxicity evaluation

Abstract

While alternative methods for toxicity testing using re-constructed human skin and cornea have been written into guidelines and adopted by regulatory authorities, three-dimensional (3D) liver models are currently applied in the industrial settings for hepatotoxicity screening and prediction. These 3D liver models can recapitulate the architecture, functionality and toxicity response of the native liver, demonstrated by a set of related hallmarks. In this comprehensive review, non-scaffold and scaffold-based methods available for 3D liver model formation are introduced, with an emphasis on their advantages and drawbacks. We then focus on the characteristics of primary human hepatocytes, stem cell derived hepatocyte like cells, and immortalized hepatic cell lines as cell resources for model reconstruction. Primary hepatocytes are generally regarded to be superior to other cell types due to their comparable metabolic profiles to the native liver. Additionally, the application of 3D liver models (mostly liver spheroids) on the evaluation of drug induced liver injury and chronic liver diseases (steatosis, cirrhosis, cholestasis), as well as the potential of nanomaterials to introduce hepatotoxicity are summarized. Finally, the global 3D cell market from 3D liver model manufacturing to the contract service of in vitro hepatotoxicity testing using the models is extensively explored. However, 3D liver models face cultural and regulatory barriers in different countries, and therefore the business development of 3D liver models is not easy. Toxicologists, material scientists, engineers should work together to develop, validate and apply 3D liver models for hepatotoxicity testing under the support from industrial organizations and governmental agencies.

Keywords:

• 3D liver model
• hepatotoxicity
• spheroid
• liver injury
• hepatocytes
• cell market

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

The authors sincerely thank Dr. Jing Fan from Hopstem Biotechnology Co., Ltd who provided scientific information for hiPSC and ESC derived hepatocyte-like cells. We also had a lively discussion with Dr. Zhou Zhou from Terns Pharmaceuticals China and thank for her big-picture perspective on the potential of 3D liver model in the development of anti-NASH disease drugs. Finally, we thank Mr. Linfeng Zhao, the Chairman of Suzhou Jestar Mold Technology Co., Ltd for manufacturing a prototype of a miniature mold for our research.

Declaration of interest

This work was supported by the Key Project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province [grant number 17KJA310003]; National Natural Science Foundation of China [grant number 31771104], [grant number 31971319]; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection for financial support. The affiliations of all authors are as shown on the cover page. The authors are fully responsible for the writing and content of this review. No author has appeared in any regulatory or legal proceedings related to the content of this article.