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Improving Liver Pharmacokinetic Model

Improving Liver Pharmacokinetic Model. Olga Filippova, Munir Nahri, Akash Patel Group 1. Liver Introduction. Lobules = Functional Unit Vascular Triads Hepatocyte Plate Sinusoids Endothelial, Pit, Kupffer, Fat-Storing ECM Collagen, glycoproteins Drug Metabolism Urea Production.

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Improving Liver Pharmacokinetic Model

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  1. Improving Liver Pharmacokinetic Model Olga Filippova, Munir Nahri, Akash Patel Group 1

  2. Liver Introduction • Lobules = Functional Unit • Vascular Triads • Hepatocyte Plate Sinusoids • Endothelial, Pit, Kupffer, Fat-Storing • ECM • Collagen, glycoproteins • Drug Metabolism • Urea Production www.ece.ncsu.edu/imaging/MedImg/SIMS/GE1_3.html

  3. Solid Freeform Fabrication • Computer Aided Design • Sinusoid Shape • Reproducibility • 3D Structures • Cell Addition Chang et al

  4. Article Overview • Chang R, Nam J, and Sun W. Direct cell writing of 3D microorgan for in vitro pharmacokinetic model. Tissue Engineering 14, 157, 2008. • In vitro pharmacokinetic model • 2D vs 3D solid freeform fabrication • Layer-by-layer addition • Hepatocyte-encapsulated alginate • Structural feasibility and reproducibility • Cell viability and function Hepatocytes Alginate

  5. Formability of 3D Construct • Reproducibility at micro-order dimensional specifications • 3 sinusoidal layers • Consistent strut diameter • 250 µm Chang et al Chang et al Chang et al

  6. Characterization of 3D Construct • Viability • Proliferation • Hepatocyte-Specific Function VS Standard 2D Monolayer Computer-Aided 3D Construct

  7. Effect of Direct Cell Writing on cell viability • DECREASED Cell Viability Hepatocyte Cell Viability as a Function of DCW Process and Crosslinking Static 2D monolayer control Dynamic 3D bioprinted experimental group

  8. Effect of Direct Cell Writing on cell proliferation • SIMILAR Cell Proliferation Media w/o cells Std Method cell suspension using conventional pipet

  9. Effect of Direct Cell Writing on cell-specific function • IMPROVED Hepatocyte Specific Function

  10. Analysis of Results Cell Viability Cell Cell Function Proliferation Resemble In Vivo Tissue: Importance: DCW 3D Constructs Offer: • Function/behavior • Differentiation • Proliferation • Cell-cell communication • Direct contact • Paracrine • ECM production from neighboring cell • Tight control of spatial dist. • High cell density • Co-culture multiple cell types

  11. Matrigel • Natural hydrogel • Basement membrane from EHS mouse sarcoma • Advantages • Laminin, Collagen IV • Thermal Crosslinking – 37oC • Outstanding biocompatibility • Promotes differentiation • Disadvantages • Uncontrolled composition • Poor gelation kinetics • Lower mechanical integrity • Little cell proliferation Gelain et al

  12. Proposal • Computer Aided 3D Solid Freeform Fabrication of Co-cultured Cell-Laiden Matrigel Constructs for an Improved In Vitro Pharmacokinetic Model • Aims • Improve current model • Increase hepatocyte viability and function • Set-up • Control – Alginate w/Hepatocytes, Alginate w/Hepatocytes and Endothelial • Experimental – Matrigel w/Hepatocytes, Matrigel w/Hepatocytes and Endothelial

  13. Applications of Model • Drug screening and development • Relatively inexpensile test • Replicable • Parallel tests • Interconnected organ networks • Simulate effects on major organ systems

  14. References • Bedossa P, and Paradis V. Liver extracellular matrix in health and disease. Journal of Pathology 200, 504, 2003. • Chang R, Nam J, and Sun W. Computer-aided design, modeling, and freeform fabrication of 3D tissue constructs for drug metabolism studies. Computer-Aided Design and Applications 5, 363, 2008. • Chang R, Nam J, and Sun W. Direct cell writing of 3D microorgan for in vitro pharmacokinetic model. Tissue Engineering 14, 157, 2008. • Lee, J., Cuddihy, M.J., and Kotov, N.A. Three-Dimensional Cell Culture Matrices: State of the Art. Tissue Engineering 14, 2008, 61. •  Kleinman, H.K., and Matrin, G.R. Matrigel: Basement membrane matrix with biological activity. Seminars in Cancer Biology 15, 2005, 378. • Gelain F, Bottai D, Cescovi A, and Zhang S. Designer self-assembling peptide nanofiber scaffolds for adult mouse stem cell 3-dimensional cultures. PLoS ONE 1, 119, 2006. • Chang R, Nam J, and Sun W. Effects of dispensing pressure and nozzle diameter on cell survival from solid freeform fabrication-based direct cell writing. Tissue Engineering 14, 41, 2008.

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