Status and Future of 3D Cell Culture in Toxicity Testing

Abstract

Drug-induced liver injury is a major reason for safety-related attrition in the pharmaceutical industry. There is continued search for in vitro models that can be used to consistently and reliably select compounds with reduced liability for liver injury. 2D in vitro models, such as liver cell lines and primary hepatocytes have been used for many decades prior to advancement to micropatterned 2D liver models; the latter have improved metabolic activity and can be cultured for long periods without loss of function/viability. The emergence of 3D liver models, including spheroids, 3D bioprinted livers, and liver-on-chip have the potential to revolutionize in vitro liver toxicity testing. These models have been collectively coined as microphysiological systems (MPS). The MPS models can be maintained in culture for at least 1-month during which they retain significant drug metabolism capability. Some MPS models can also be cocultured with other nonparenchymal supporting cells, such as endothelial, Kupffer, and stellate cells, which increases the versatility of the models for toxicity assessment. An added benefit of some MPS models is the ability to sample supernatant for biomarker measurements. There are several contexts of use for which MPS models can be applied, and the most likely use will be for candidate drug screening and mechanistic studies.