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Liver tissue engineering
- 1. LIVER TISSUE ENGINEERING Kolla Srivalli 201709010 MScSystems Biology Manipal School of Lifesciences
- 2. Liver • Liver islarge meaty organ which sits on right side of belly. • Contain gall bladder which is used for the synthesis of bile juice. • Functions - Biochemical defense - Synthesis of bile - Regulator of plasma glucose and ammonia levels - Optimal function of brain • Loss of liver function leads to “hepatic encephalopathy” and sometimes leads to coma.
- 3. Liver cells CELL TYPESFUNCTIONS Parenchymal cells - hepatocytes Metabolism of proteins , steroids, fats ,bile secretion xenobiotic metabolism Non parenchymal cells –sinusoidal cells(LSECS) Filtration & transport of nutrients , adhesion for leukocytes ,Ag presentation , secretion of cytokines ,ECM components Kupffer cells (macrophages) Phagocytosis, inflammatory response and iron metabolism Hepatic stellate cells (HSC) (Fibroblast) Fat storing cells, vit-A storage , control and turnover of ECM components, secretion of growth factors
- 4. Complications of liver •Hepatitis – liver inflammation • Cirrhosis – long term damage to liver which lead to permanent scarring • Liver failure – may be due to infection, genetic diseases and excessive alcohol • Ascites – liver leaks fluids into belly • Gall stones – gall stone stuck can result in hepatitis and bile duct infection • Hemochromatosis – iron deposition in liver
- 5. History Extracorporeal bioartificial liver devices 3Dscaffolds ECM engineered scaffold Implantable liver constructs, whole organ engineering
- 6. Implantable technologies forliver therapies • It overcomes the limitations of current cell-therapy strategies, including lack of engraftment and inherent lag phase. • These are typically developed by immobilizing or encapsulating hepatic cells in scaffolds made of different biomaterials in conjugation with strategies to optimize hepatocyte survival and function. • For therapeutic liver development , functional hepatocytes with efficient transport of nutrients and which secretes hepatic factors must be present . • Long term implantation in host is necessary . • Similar cell-cell interactions ,cell-matrix interactions must be maintained. • Methods – Cell encapsulation , 3D printing , scaffolds ,decellularization- recellularization technologies.
- 7. 1. Cell encapsulation •Human hepatocytes are cultured on alginate micro beads invitro for 3 days produced albumin and urea. • Intraperitoneal transplantation of hepatocyte micro beads improved liver function in acute liver failure. • Hepatocytes derived from inducible pluripotent stem cells(iPSCs) are encapsulated in alginate beads together with human hepatic stellate cells. • Aimed in exploring specific diseased models where additional parallel strategies are involved for reducing foreign body fibrotic reactions.
- 8. 2. 3D- Printing •Uses ink which support cell differentiation and function. • Techniques to 3D print hepatic-like structures are biomimicry and mini tissue building blocks. • Cells of hepatic cell line Hepg2 were printed with alginate as the crosslinking agent. • Gelatin is used to ensure the control of ink thickness and higher printability. • 3D-printed tissues were fabricated using iPSC-derived hepatocytes mixed with alginate hydrogels. It increased level of metabolic function during in vitro development. • Ideal bio ink – analyze the composition and distribution of ECM proteins in decellularized tissue scaffold.
- 9. 3. Artificial andnatural scaffolds • Synthetic – easily manufactured but lack physiological bioactivity and the biomechanics of natural ECM. • Synthetic polymers – polylactide co-glycoslide , PEG , polycaprolactone. • Natural polymers – alginates , celluloses, polyethylene. • ECM is made of collagen type 1. • ECM hydrogels have been proposed which can be used for increasing viability and improved hepatic functions.
- 10. 4.Decellularization and whole organ engineering •Used for development of perfusable ECM derived scaffolds with preserved vascular integrity. • Liver bioengineering can be used for transplantation and drug toxicity testing in 3D in invitro cultures. • Decellularization–recellularization technologies provide a valuable platform for liver bioengineering through the repopulation of liver ECM scaffolds with parenchymal and nonparenchymal liver cells. • Tissues from other organisms may lead to incompatibility and hence human organisms’ tissues must be collected and engineered.
- 11. Decellularization • First decellularizationwas done to develop acellular heart from mice by using retrograde coronary perfusion at constant pressure. • Decellularization – removal of cellular material while preserving vascular network , ECM composition, and 3D architecture of native tissue. • Liver decellularization used antegrade perfusion through portal vein at constant flow rate which obtained the translucent acellular tissue. • The first successful decellularization of a human liver was done by using a novel retrograde, two-step, perfusion flow-rate methodology able to preserve the fine 3D hepatic architecture and the liver ECM biochemical composition is same. •Repopulation of rat acellular liver scaffold 2010 •Repopulation of pig liver scaffold with human fetal hepatocytes and stem cells 2012 •First successful decellularization of liver 2015
- 12. Whole liver engineering •Whole liver engineering was based on Perfusion decellularization and recellularization strategies. • Decellularized organs act as a platform for whole liver tissue engineering as it provides 3D- vascularized scaffold for nutrient delivery and provides Environment which is necessary for progenitor hepatic cells to grow and differentiate to maintain functionality.
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