HepaPredict uses the 3D spheroid system developed in an academic frame at Karolinska Institutet (Stockholm, Sweden), which has been published in peer-reviewed scientific publications (Bell et al., SciRep, 2016, Hendriks et al., SciRep, 2016, Vorrink et al., FASEB J, 2017 and Bell et al., Drug Met Disp, 2017). The system is based on 3D cultures of primary human hepatocytes, which have been extensively characterized on transcriptomic, proteomic, and metabolomic levels as shown in these papers.
Importantly, the platform offers multiple advantages over alternative in vitro systems and animal models:
1) Hepatocytes in the HepaPredict platform closely resemble liver cells in vivo on transcriptomic, proteomic and metabolomic level, thus providing a physiologically replicative in vitro system that facilitates translation of results to patients.
2) The HepaPredict spheroid system is functionally stable and suitable for chronic applications, thus allowing to assess long-term toxicity, pharmacokinetics and induction not supported by conventional in vitro systems due to the rapid loss of hepatic phenotypes and functions.
3) The HepaPredict system is optimized to support co-cultures with non-parenchymal cells, such as Kupffer, biliary and Stellate cells, to more closely resemble the cellular repertoire of the liver, which allows studies of inflammatory processes reliant on hepatocyte-immune cell interactions and permits to capture complex DILI events. Furthermore, this feature enables the emulation of hepatic diseases that require an interplay of multiple cell types, such as non-alcoholic steatohepatitis (NASH) and fibrosis.
4) The use of human cells instead of animal models allows direct translation of findings to patients.
5) The HepaPredict system captures the phenotypic inter-individual variability observed in vivo in an in vitro setting and thus allows to simulate small “clinical trials” by employing cells from multiple donors, which considerably reduces costs and time of pharmacological or toxicological assessments. Alternatively pooled hepatocytes can be used to assess intrinsic DILI risk.
6) Scalability and high-throughput compatibility of the system in 96-well format allows screening of dozens of conditions and/or drug candidates with multiple replicates in a single experiment.
7) Controlled experimental conditions, such as precisely defined spheroid sizes and chemically-defined, serum-free culture conditions ensure maximal reproducibility and facilitate mechanistic insights, which can aid in targeted compound optimizations to circumvent toxicity.