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Review ListTheoretical and Experimental Simulation of Hepatic Cells and their Functionalities On-a-chip
Sharifi, Fatemeh | 2020
657
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- Type of Document: Ph.D. Dissertation
- Language: Farsi
- Document No: 53548 (08)
- University: Sharif University of Technology
- Department: Mechanical Engineering
- Advisor(s): Firoozabadi, Bahar; Firoozbakhsh, Keikhosrow
- Abstract:
- Liver is the largest internal organ of the human body which serves many vital functionalities. Recently, liver-on-a-chip systems have been used to model some of the vital liver specific-functions and to investigate its related diseases. The purpose of the present study was simulation of some of these liver specific functionalities on-a-chip and using the obtained results in predicting hepatocellular functionalities i.e. production of some metabolites and modeling some of the liver-related diseases which have been done numerically and experimentally. Numerical simulations have been developed in two-dimensional and three-dimensional forms. In the 2D simulation, the governing equations i.e. fluid dynamics, as well as mass transfer equations across the channel were solved and the distribution of velocity, shear, ammonia, and urea concentrations was obtained. Ammonia to urea conversion was modeled using the urea four-enzymatic cycle. Then the presented model was used in modeling and predicting urea cycle-related diseases.In the 3D simulation, hepatocytes were considered as spheroids, encapsulated in the hydrogel inside the bioreactor. Oxygen consumption of the hepatocytes is high due to their high metabolic activities. The flow rate was considered to be 0.004 m/s based on the two criteria namely sufficient oxygenation delivery to the hepatocytes and shear stress threshold applied to them (shear stress should be less than 0.03 Pa). Then some of the main liver-specific activities like albumin production, glutamine consumption, glucose intake, ammonia consumption, and urea production were modeled. Finally, parametric studies were conducted to investigate the effect of the change in parameters affecting oxygen delivery to hepatocytes. The obtained results have been shown that hepatic albumin production was equal to 40 ng/hr/106 cells over a period of seven days. Also, oxygen deficiency might occur in spheroids with a diameter greater than 200 μm in diameter, especially in the hepatocytes located near the center of the spheroids.In the experimental section of the presented study, a hepatocellular carcinoma cell migration-on-a-chip platform was developed to model and track hepatocellular carcinoma (HCC)-bone metastasis. The bioreactor consisted of two chambers, one accommodating encapsulated HepG2 cells and one bone-mimetic niche containing hydroxyapatite (HAp). The number of migrated HepG2 cells to the bone compartment was about 2.5 times higher in the presence of HAp in the hydrogel. In the next step, the inhibitory effect of an anti-cancer compound in hindering the proliferation and migration of liver cancer cells into the bone compartment, thymoquinone (TQ), was investigated. Different concentration of TQ was tested and a concentration of 50 µg mL−1 at the vicinity of IC50 was chosen for analyzing the inhibitory effect of TQ on HCC migration. HCC migration towards the bone-like chamber under the effect of free TQ, chitosan nanoparticles, and TQ-encapsulated chitosan nanoparticles were investigated dynamically for up to 21 days. Results demonstrated that the growth and viability of hepatic cancerous cells were considerably decreased to about 10 and 20 times, respectively, showing the great inhibitory effects of TQ on suppressing hepatocarcinogenesis
- Keywords:
- Numerical Simulation ; Hepatocyte ; Chitosan Nanoparticles ; Thymoquinon ; Liver-on-a-Chip ; Liver Tissue
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