Abstract
Drug-induced liver toxicity is one of the most common reasons for the failure of drugs in clinical trials and frequent withdrawal from the market. Reasons for such failures include the low predictive power of in vivo studies, that is mainly caused by metabolic differences between humans and animals, and intraspecific variances. In addition to factors such as age and genetic background, changes in drug metabolism can also be caused by disease-related changes in the liver. Such metabolic changes have also been observed in clinical settings, for example, in association with a change in liver stiffness, a major characteristic of an altered fibrotic liver. For mimicking these changes in an in vitro model, this study aimed to develop scaffolds that represent the rigidity of healthy and fibrotic liver tissue. We observed that liver cells plated on scaffolds representing the stiffness of healthy livers showed a higher metabolic activity compared to cells plated on stiffer scaffolds. Additionally, we detected a positive effect of a scaffold pre-coated with fetal calf serum (FCS)-containing media. This pre-incubation resulted in increased cell adherence during cell seeding onto the scaffolds. In summary, we developed a scaffold-based 3D model that mimics liver stiffness-dependent changes in drug metabolism that may more easily predict drug interaction in diseased livers.
Highlights
Today the testing of new drugs is mainly performed in animals due to a lack of predictive in vitro models [1]
The use of human liver cells for the testing of new substances is limited since human hepatocytes are scarcely available and suffer frequently from the loss of metabolic function during long-term cultivation [5,6]
The results indicate that due to preincubation with fetal calf serum (FCS)-containing medium, the cell adherence to both scaffold types could be increased, which is why this type of pre-incubation was used for both scaffolds later in the study
Summary
Today the testing of new drugs is mainly performed in animals due to a lack of predictive in vitro models [1]. Animal experiments have several limitations in predicting liver toxicity of new substances, due to differences between the drug-metabolizing enzymes in humans and animals [2]. New models that are able to foresee the in vivo situation more accurately are needed. The use of human liver cells for the testing of new substances is limited since human hepatocytes are scarcely available and suffer frequently from the loss of metabolic function during long-term cultivation [5,6]. In recent years continuously available liver cell lines were established as an alternative to human hepatocytes to overcome these limitations [7]
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