Martin, F. L. | Search bioRxiv

bioRxiv2024

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

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.

cell biology↗

bioRxiv2022

Introducing CELLBLOKS: a novel organ-on-a-chip platform allowing a plug-and-play approach towards building organotypic models

Human organs are structurally and functionally complex systems. Their function is driven by interactions between many specialised cell types, which is difficult to unravel on a standard petri-dish format. Conventional "petri-dish" approaches to culturing cells are static and self-limiting. However, current organ-on-a-chip technologies are difficult to use, have a limited throughput and lack compatibility with standard workflow conditions. We developed CELLBLOKS(R) as a novel "plug & play" organ-on-a-chip platform that enables straightforward creation of multiple-cell type organ specific microenvironments and demonstrate its advantages by building a liver model representative of live tissue function. CELLBLOKS(R) allows one to systematically test and identify various cell combinations that replicate optimal hepatic relevance. The combined interactions of fibroblasts, endothelial cells and hepatocytes were analysed using hepatic biochemistry (CYP3A4 and urea), cellular proliferation and transporter activities (albumin). The results demonstrate that optimal liver functional can be achieved in cross talk co-culture combinations compared to conventional mono-culture. The optimised CELLBLOKS(R) liver model was tested to analyse drug-induced liver toxicity using tamoxifen. The data suggests that our CELLBLOKS(R) liver model is highly sensitive to toxic insult compared to mono-culture liver model. In summary, CELLBLOKS(R) provides a novel cell culture technology for creating human relevant organotypic models that are easy and straightforward to establish in laboratory settings.

cell biology↗