Ruoß Marc, Rebholz Silas, Weimer Marina, Grom-Baumgarten Carl, Athanasopulu Kiriaki, Kemkemer Ralf, Käß Hanno, Ehnert Sabrina, Nussler Andreas K
Department of Traumatology, Siegfried Weller Institute, Eberhard Karls University, 72076 Tübingen, Germany.
Faculty of Applied Chemistry, Reutlingen University, 72762 Reutlingen, Germany.
J Funct Biomater. 2020 Mar 14;11(1):17. doi: 10.3390/jfb11010017.
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.
药物性肝毒性是药物在临床试验中失败以及频繁退出市场的最常见原因之一。此类失败的原因包括体内研究预测能力低，这主要是由人和动物之间的代谢差异以及种内差异引起的。除了年龄和遗传背景等因素外，肝脏疾病相关的变化也会导致药物代谢的改变。在临床环境中也观察到了这种代谢变化，例如，与肝纤维化改变的一个主要特征——肝脏硬度变化有关。为了在体外模型中模拟这些变化，本研究旨在开发代表健康和纤维化肝组织硬度的支架。我们观察到，与接种在较硬支架上的细胞相比，接种在代表健康肝脏硬度的支架上的肝细胞表现出更高的代谢活性。此外，我们检测到预先用含胎牛血清（FCS）的培养基包被的支架具有积极作用。这种预孵育导致在将细胞接种到支架上的过程中细胞黏附增加。总之，我们开发了一种基于支架的三维模型，该模型模拟了药物代谢中依赖肝脏硬度的变化，可能更容易预测患病肝脏中的药物相互作用。
