The Liver is Super Super Awesome Olga Filippova, Munir Nahri, Akash Patel BMES 471

Anatomy of the Liver1 Most metabolically complex organ 2 main, 2 smaller lobe Eight segments Lobules Dual blood supply Portal vein (75%) Hepatic artery (25%) Sinusoidal hepatocyte plates Endothelial, Kupffer’s, Fat-storing, Pit http://education.vetmed.vt.edu/curriculum/vm8054/labs/Lab20/LAB20.HTM The liver is the most metabolically complex organ. It is made up of two main lobes, the right and the left, and two smaller lobes, the posterior and inferior. The lobes are divided into eight segments by the distribution of the circulatory system. The smallest functional unit of the liver is the lobule, which is bound by four to five portal triads, and contains a central hepatic venule. The liver is serviced by a dual blood supply, with 75% of the blood coming from the portal vein and 25% from the hepatic artery. The lobules are made up of hepatocyte plates arranged into a sinusoid. The lining of the sinusoids is made up of 4 types of cells – endothelial cells, which help in endocytosis, Kupffer’s cells, which are involved in the removal of noxious substances, fat-storing cells, which store vitamin A, and pit cells, which act as natural killer cells. http://www.chinaphar.com/1671-4083/24/figs/4747f2.jpg http://www.cpmc.org/images/liver/topics/liver_segments.jpg

Functions of the Liver1 Metabolism Bile synthesis Glucose regulation Amino acid catabolism Drug neutralization Bile synthesis Digestion of fat Cholesterol catabolism Stored in gallbladder Released by CCK from SI The main function of the liver is metabolism of carbohydrates, proteins and fats. It also functions in glucose level stabilization. When the blood concentration of glucose is too high, the liver uptakes and stores glucose as glycogen, through the process of glycogenesis. When the blood concentration of glucose is too low, the liver breaks down the stored glycogen back into glucose via glycogenolysis. Other metabolic functions of the liver include animo acid catabolism and drug detoxification. Bile synthesis is another main function of the liver. Bile is needed by the body for the digestion and absorption of fats. Bile is made in the liver by cholesterol catabolism, and stored in the gallbladder for future use. Bile release is signaled by the secretion of cholecystokinin by the small intestine. http://www.genesishealth.com/services/bariatric_surgery/digestive_diagram.aspx

Current State of Liver TE2 Regeneration - One of few organs able to regenerate - Full functional recovery after 80% hepatectomy In Situ Regeneration -Vascularization for increasing hepatocyte trasplants in vivo -Ohashi et al. have developed a method to form stable transplants of liver cells under the kidney capsule in the mice Yokoyama, T., Ohashi, K., Kuge, H., Kanehiro, H., Iwata, H., Yamato, M. and Nakajima, Y. (2006) In vivo engineering of metabolically active hepatic tissues in a neovascularized subcutaneous cavity. American Journal of Transplantation, 6, 50± 59.

Current State of Liver TE2 Multicellular Aggregates Improvements to the homotypic aggregation Co-cultures replacing current generic lines with non-parenchymal cells Sinusoidal endothelial, stellate, etc. Abu-Absi et al.3 Scaffolds Provide improved architectural template Alginate scaffolds Including fully encapsulated hepatocyte cell lines Du et al.4

Current State of Liver TE2 -Bioreactors -zonation of hepatocyte functioning. -improved delivery of oxygen and nutrients -enhanced viability and functionality if transportation is required -miniaturisation of engineered tissue for higher throughput assay http://www.oulu.fi/spareparts/ebook_topics_in_t_e_vol3/abstracts/catapano_01.pdf Microtechnology and Cell Patterning -Building microscale architecture of liver lobule models -Combined microfabrication and microcontact printing -Microfluidic structures mimicking sinusoids of the liver Chang et al.5

Room for Improvement Simple functions of the liver may be maintained in current tissue-engineered liver systems, more complex functions are always lost Display zonal liver functions that mimic anatomical structure of liver Recreating complex spatial and flow relationships Development of predictive animal models to evaluate live therapies Limited supply of primary human cells Primary human cells are preferred source of cellular therapies Worldwide Prevalence of Liver Disease Annually

Room for Improvement Pgusighisghsdg

Future of Liver TE6 Development of complex 3D Liver models Artificial or Bioartificial Liver (BAL) Vascular network capable of providing oxygen and nutrients to tissue [3] Ability to restore liver natural function and able to maintain hemostasis Capable of bidirectional mass transport Optimal results Mimic natural liver Size of BAL Spatial arrangement Viable cell source Progenitor stem cells  Promote phenotypic stability and tissue morphogenesis [4] Key success: Ability to control differentiation and proliferation of stem cells Proper signaling to introduce other key cells in liver regeneration Ultimate goal fully functional tissue engineered implantable liver

Future of Liver TE6 Extracorporeal bioartificial liver Devices Bidirectional mass transport Stable microenviornment Hepatocytes require specific environment to maintain function8 Scale Up Examples: Hollow fiber devices, Flat plate systems, perfusion bed/ scaffolds, suspension and encapsulation8

References Hilsden, R.J., Shaffer, E.A. Chapter 14: The Liver, 1. Liver Structure and Function. First Principles of Gastroenterology: the basis of Disease and an Approach to Management. Canadian Association Pf Gastroenterology. 1994. Shakesheff, K. Chapter 19: Liver Tissue Engineering. Tissue Engineering Using Ceramics and Polymers. London: Woodhead Publishing limited, 2007. Abu-Absi, S.F., Friend, J. R., Hansen L. K., Hu W.S. Structural Polarity and Functional Bile Canaliculi in Rat Hepatocyte Spheroids. Experimental Cell Research. 274, 56, 2002. Du, Y., Han, R. Wen, F., San, S.N.S., Xia, L., Wohland, T., Leo, H.L., Yu, H. Synthetic Sandwich culture of 3D Hepatocyte Monolayer. Biomaterials. 29, 290, 2008. Chang, R. Nam, J., 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. Gerlach, J.C., Zeilinger, K., Patzer, J.F. II. Bioartificial Liver Systems: Why, What, Whither? Regenerative Medicine. 3, 575, 2008. Behnia, K., Bhatia, S., Jastromb, N., Balis, U., Sullivan, S., Yarmush, M., Toner, M. Xenobiotic Metabolism by Cultured Primary Porcine Hepatocytes. Tissue Engineering. 6, 467, 2000. Allen, J.W., Bhatia S. N. Engineering Liver Therapies for the Future. Tissue Engineering. 8, 725, 2002.

Hilsden, R. J. , Shaffer, E. A. Chapter 14: The Liver, 1 Hilsden, R.J., Shaffer, E.A. Chapter 14: The Liver, 1. Liver Structure and Function. First Principles of Gastroenterology: the basis of Disease and an Approach to Management. Canadian Association Pf Gastroenterology. 1994. Gerlach, J.C., Zeilinger, K., Patzer, J.F. II. Bioartificial Liver Systems: Why, What, Whither? Regenerative Medicine. 3, 575, 2008. Cortesini, R. Stem cells, tissue engineering and organogenesis in transplantation. Transplant Immunology, 15, 81, 2005. Allen, J.W., Bhatia S. N. Engineering Liver Therapies for the Future. Tissue Engineering. 8, 725, 2002.

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