Multicellular, fluid flow-inclusive hepatic in vitro models using NANOSTACKS™: a human-relevant model for drug response prediction

Abstract

Drug-induced liver injury (DILI) continues to be the leading cause of drug attrition during clinical trials as well as the number one cause of post-market drug withdrawal due to the limited predictive accuracy of preclinical animal and conventional in vitro models. In this study, the NANOSTACKSTM platform was introduced as a novel in vitro tool to build in vivo-relevant organ models for predicting drug responses. In particular, hepatic models including monocultures of primary human hepatocytes (PHH), tricultures of PHH, human stellate cells (HSC) and human liver endothelial cells (LECs), and tetracultures of PHH, HSC, LECs and human Kupffer cells (KC) were developed under static and fluid flow-inclusive conditions. All hepatic models were characterised by assessing albumin, urea, CYP3A4 and ATP production. In addition, the preclinical DILI screening potential of the fluid flow-inclusive monoculture and triculture models were assessed by testing the hepatotoxicity of Zileuton, Buspirone and Cyclophosphamide. NANOSTACKS represents a promising tool for the development of complex in vitro models.