University of Twente Student Theses


Modeling zonal and progressive liver fibrosis : 3D in vitro model of a fibrotic liver lobule using anisotropic nanocomposite hydrogel

Heide, D. van der (2020) Modeling zonal and progressive liver fibrosis : 3D in vitro model of a fibrotic liver lobule using anisotropic nanocomposite hydrogel.

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Abstract:Sustained liver injury leads to the accumulation of extracellular matrix (ECM) proteins in the liver, which can result in liver fibrosis and ultimately, cirrhosis, liver failure and hepatocellular carcinoma (or liver cancer). Currently, organ transplantation is the only option available for advanced stages for this disease. However, more than 40% of patients listed on organ waiting lists do not receive a donor match, and eventually die from liver failure. Hence, there is an unmet need for therapeutics for the treatment of liver diseases. The development of therapeutics is hindered due to the lack of human disease resembling models. Currently used preclinical in vivo animal models don’t represent human disease completely and several drugs that were proven efficacious in animal models failed in the clinical trials due to lack of efficacy and/or toxic effects. The available 2D and 3D in vitro models not fully recapitulate the complex pathology of liver disease and importantly zonal fibrosis of the liver lobule, which is slowing down the development of novel therapies. Therefore, there is a significant need to develop new 3D liver disease models that replicate the healthy and diseased in vivo liver tissue properties in order to advance our understanding in the mechanisms and progression of liver fibrosis, while also serving as an in vitro platform for the testing and screening of novel therapies. The overall aim of this work was to develop a 3D in vitro model of a fibrotic liver lobule using an anisotropic nanocomposite hydrogel and to study the influence of fibrosis induced stiffness on liver macrophages. Macrophages, the major immune cells in our body, are key players in the development of liver fibrosis. Hepatic macrophages are a heterogeneous population of immune cells that carry out diverse functions in liver homeostasis, disease progression and regression after injury. A low-intensity magnetic field was used to align mosaic iron oxide nanoparticles (IOPs) within gelatin methacryloyl (GelMA) hydrogel. The created matrices were characterized, assessed for biocompatibility, and finally the effect of the matrices on macrophage (THP-1 cell-line) polarization was evaluated. In conclusion, in this project, the synthesis and fabrication of anisotropic nanocomposite hydrogels with macrophages for the development of 3D matrices is shown. This is a first step for the generation of a 3D in vitro model of a fibrotic liver lobule, which will enable high-throughput drug screening, fasten drug discovery, and advance our understanding of the mechanisms involved in the progression of liver fibrosis.
Item Type:Essay (Master)
Faculty:TNW: Science and Technology
Subject:02 science and culture in general, 33 physics, 42 biology
Programme:Biomedical Engineering MSc (66226)
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