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Development of Scaffolds with Adjusted Stiffness for Mimicking Disease-Related Alterations of Liver Rigidity
Marc Ruoß1, Silas Rebholz1, Marina Weimer1,2
1Department of Traumatology, Siegfried Weller Institute, Eberhard Karls University, 72076 Tübingen, Germany.
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.
Insights
Developing novel scaffolds to mimic liver stiffness improves drug metabolism prediction. This 3D model enhances understanding of drug-induced liver toxicity in diseased livers, addressing limitations of current in vivo studies.
Area of Science:
- Hepatology
- Biomaterials Engineering
- Drug Development
Background:
- Drug-induced liver toxicity is a major cause of clinical trial failure and market withdrawal.
- Existing in vivo models have low predictive power due to metabolic differences between species and individuals.
- Liver disease, such as fibrosis, alters liver stiffness and impacts drug metabolism.
Purpose of the Study:
- To develop scaffold-based 3D models that mimic the mechanical properties (stiffness) of healthy and fibrotic liver tissue.
- To investigate the effect of liver stiffness on cellular metabolic activity and drug metabolism in vitro.
- To create a more predictive model for drug-induced liver toxicity in diseased livers.
Main Methods:
- Fabrication of scaffolds with varying rigidity to represent healthy and fibrotic liver tissue.
- Culturing liver cells on these scaffolds to assess metabolic activity and cell adherence.
- Evaluating the impact of scaffold pre-coating with fetal calf serum (FCS)-containing media.
Main Results:
- Liver cells cultured on scaffolds mimicking healthy liver stiffness exhibited higher metabolic activity compared to those on stiffer scaffolds.
- Pre-coating scaffolds with FCS-containing media enhanced cell adherence during seeding.
- The developed scaffold model demonstrated liver stiffness-dependent changes in drug metabolism.
Conclusions:
- Scaffold-based 3D models can effectively mimic liver stiffness and its impact on drug metabolism.
- This approach offers a promising in vitro tool for predicting drug-induced liver toxicity in diseased livers.
- The model addresses limitations of current in vivo studies by incorporating disease-specific mechanical cues.
