Presentation on theme: "The Liver is Super Super Awesome"— Presentation transcript:
1The Liver is Super Super Awesome Olga Filippova, Munir Nahri, Akash PatelBMES 471
2Anatomy of the Liver1 Most metabolically complex organ 2 main, 2 smaller lobeEight segmentsLobulesDual blood supplyPortal vein (75%)Hepatic artery (25%)Sinusoidal hepatocyte platesEndothelial, Kupffer’s, Fat-storing, PitThe 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.
3Functions of the Liver1 Metabolism Bile synthesis Glucose regulation Amino acid catabolismDrug neutralizationBile synthesisDigestion of fatCholesterol catabolismStored in gallbladderReleased by CCK from SIThe 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.
4Current State of Liver TE2 Regeneration- One of few organs able to regenerate- Full functional recovery after 80% hepatectomyIn Situ Regeneration-Vascularization for increasing hepatocyte trasplants in vivo-Ohashi et al. have developed a method to form stabletransplants of liver cells under the kidney capsule in the miceYokoyama, T., Ohashi, K., Kuge, H., Kanehiro, H., Iwata, H., Yamato, M. and Nakajima,Y. (2006) In vivo engineering of metabolically active hepatic tissues in aneovascularized subcutaneous cavity. American Journal of Transplantation, 6, 50±59.
5Current State of Liver TE2 Multicellular AggregatesImprovements to the homotypic aggregationCo-cultures replacing current generic lines with non-parenchymal cellsSinusoidal endothelial, stellate, etc.Abu-Absi et al.3ScaffoldsProvide improved architectural templateAlginate scaffoldsIncluding fully encapsulated hepatocyte cell linesDu et al.4
6Current 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 assayMicrotechnology and Cell Patterning-Building microscale architecture of liver lobule models-Combined microfabrication and microcontact printing-Microfluidic structures mimicking sinusoids of the liverChang et al.5
7Room for ImprovementSimple functions of the liver may be maintained in current tissue-engineered liver systems, more complex functions are always lostDisplay zonal liver functions that mimic anatomical structure of liverRecreating complex spatial and flow relationshipsDevelopment of predictive animal models to evaluate live therapiesLimited supply of primary human cellsPrimary human cells are preferred source of cellular therapiesWorldwide Prevalence of Liver DiseaseAnnually
9Future of Liver TE6 Development of complex 3D Liver models Artificial or Bioartificial Liver (BAL)Vascular network capable of providing oxygen and nutrients to tissue Ability to restore liver natural function and able to maintain hemostasisCapable of bidirectional mass transportOptimal resultsMimic natural liverSize of BALSpatial arrangementViable cell sourceProgenitor stem cells Promote phenotypic stability and tissue morphogenesis Key success:Ability to control differentiation and proliferation of stem cellsProper signaling to introduce other key cells in liver regenerationUltimate goal fully functional tissue engineered implantable liver
10Future of Liver TE6 Extracorporeal bioartificial liver Devices Bidirectional mass transportStable microenviornmentHepatocytes require specific environment to maintain function8Scale UpExamples:Hollow fiber devices, Flat plate systems, perfusion bed/ scaffolds, suspension and encapsulation8
11ReferencesHilsden, 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 GastroenterologyShakesheff, 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.
12Hilsden, 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 GastroenterologyGerlach, 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.