Abstract

Drug induced liver injury (DILI) continues to be the leading cause of attrition during drug development in all phases of clinical trials as well as number one cause of post-market drug withdrawal, accounting for 20-40 % of all cases.
Current preclinical in-vivo animal models often fail to predict drug adverse reactions in humans (hepatotoxicity by 50--60% ) due to substantial differences of drug metabolising enzymes between animals and humans, and existing in-vitro cell culture models do not represent complex organotypic conditions.

Typically cells are grown in 2-D surfaces and in isolation containing only one cell type. In these environments cells become flattered, lack cell-cell communication vital for replicating biological relevance and behave in aberrant fashion.

In this study we build a liver model by using our novel cell culture platform, CELLBLOKS®.  The multiple cell type nature of liver was modelled by using a combination of three different cell types which included HepG2 hepatocytes, NIH/3T3 fibroblasts and HUVEC endothelial cells. Hepatic function of co-cultures was determined by measuring Albumin, Urea and CYP3A4 production. In CELLBLOKS® cells were grown in non-contact cell-cell communication set-up where different combinations of mono-cultures (cells in isolation), co-cultures and tri-cultures  were tested to determine optimal conditions that enabled hepatic relevance. This model was then compared to a standard well-plate format set-up where cells were grown in contact co-culture combinations.

Albumin, Urea and CYP3A4 production measured in HepG2 cells was significantly higher in non-contact CELLBLOKS® platform compared to contact cell cultures in standard 12 well-plate leading to up to three times increase in production. The data from this study shows that hepatic function is significantly improved in non-contact co-cultures compared to mono-cultures indicating the need incorporation of co-cultures in DILI drug screening.

CELLBLOKS® is easy to use novel and first of its kind modular "plug and play" co-culture platform enabling researcher to more closely replicate complex cell-cell interaction studies. CELLBLOKS® aims to increase the success rate of drug screening by prioritising candidates that are likely to succeed and eliminates those likely to fail in human clinical trials, particularly in Phase 1 and at the same time reducing the reliance on animal testing.