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Development of Bio-Artificial Pancreas

Development of Bio-Artificial Pancreas. Laboratory of Diabetes Research, Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University. TYPE I DIABETES Challenges. Prevention of diabetes Improve life of diabetic patients Reverse insulin dependent state.

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Development of Bio-Artificial Pancreas

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  1. Development of Bio-Artificial Pancreas Laboratory of Diabetes Research, Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University

  2. TYPE I DIABETESChallenges • Prevention of diabetes • Improve life of diabetic patients • Reverse insulin dependent state

  3. Endogenous Insulin Secretion Insulin response Daily insulin secretion profile

  4. Reversal Of Insulin Dependency • Closed-loop artificial pancreas (engineered sensing and insulin delivery) • Transplantation of insulin-producing cells (natural sensing and insulin secretion) • Induction of insulin production in non beta-cells

  5. Engineered BG Sensing And Insulin Delivery A suboptimal solution

  6. Whole human pancreas: Weighs 70 g Contains 1 000 000 islets =1-2% 500-1500 cells=1 islet 80% - beta cells

  7. The Islet Transplant

  8. Islets Transplantation Obstacles Cells Source human, animals, stem cells Protection from autoimmunity and rejection general, local

  9. Protection Approaches • General • Immunosupression drugs • Local • Immunoisolation, using matrix • with controlled trans-membranal • passage of compounds

  10. 600 Pre-transplant 500 400 Blood glucose (mg/dl) 300 200 100 0 600 500 Post-transplant 400 Blood glucose (mg/dl) 300 200 100 0 2 4 6 12 2 4 8 10 12 6 8 10 a.m. p.m. Time of day

  11. Edmonton protocol (2003)Complications related to therapy • Portal vein thrombosis(n=2/54) • Expanding hematoma requiring surgery (1/2) • Bleeding(n=4), requiring transfusion (3/4). • Transient disturbed liver function(46%). • Development of hypercholesterolemia (65%) • Development of hypertension(53%).

  12. Immunoisolationsuboptimal solution • Free trans membranal penetration of small injurious molecules (cytokines, free radicals) • Islet central Hypoxia

  13. Bio-artificial Pancreasresearch targets • Cell engineering • Matrix Selection • Islets oxygenation

  14. Cell Engineering Beta-cell low defense system is reflected by Beta-cell high fragility to • Autoimmunity • Infectious agents • Chemical toxins

  15. H202-Dependent -cell Injury • H202 produces highly toxic hydrogen radicals, causing lipid peroxidation and cell death. • The -cell is extremely sensitive to oxidative stress induced by H202 due to very low level of catalase(enzyme accountable for H202 inactivation) in -cell

  16. Improvement Of Beta Cell Defense Capacity(literature reports) Gene transfection and overexpression of • Anti-oxidants (catalase, glutathione peroxidase) • Anti-apoptotis (Bcl-2)

  17. Cell selection technology Exposure to H2O2, STZ, Alloxan, cytokines Resistant cells Mass production Immunoisolation in BAP Transplantation Bloch & Vardi,, Diabetologia, 1998

  18. H202 selection ProcedureResults CAT RINm RINmHP

  19. Bio-artificial pancreasresearch targets • Cell engineering • Matrix Selection • Islets oxygenation

  20. Polymeric Matrix Requisites • Semipermeable, cell supporting, and cell protective system • Biocompatible • Highly porous (oxygen diffusion, prevents islets clumping) • Induce blood vessels formation • Mechanically stable • Easy insertion and removal

  21. Alginate commonly used natural polymer for cell immunoisolation Non-toxic Non immunogenic

  22. Islets Morphology In Cryogel Sponge Culture

  23. Reaction Of Islets Transplanted In Macroporous Cryogels • Higher basal insulin secretion after short and long culture in cryogel • Fail to respond to high glucose stimulation after 14 days • 2-fold lower insulin content

  24. Bio-artificial pancreasresearch targets • Cell engineering • Matrix Selection • Islets oxygenation

  25. Immunoisolation Barriers Fibrosis Lack of oxygen

  26. Hypoxia-induced Central Islet Necrosis

  27. Devices Designed To Improve O2 Supply To Transplanted Islets • Addition of 02carriers • (c Ricordi) • H20 electrolysis • (C Colton)

  28. How to overcome the obstacle of insufficient O2 diffusion Is it possible to develop a miniature oxygen generator

  29. . Photosynthesis light 6H2O + 6CO2 ------> C6H12O6+ 6O2 Carbon dioxide is converted to sugars

  30. . Earth atmosphere Atmospheric oxygenbuilt up in the early history of theEarthas the waste product of photosynthetic organisms (micro-algae)

  31. Algae Unicelullar algae Multicellular algae

  32. Alga Requirements Thermophylic Non toxic Photosynthesizing

  33. Microalga Adaptation To Extreme Environment

  34. Microalga Symbiosis The green color of sea anemone, hydra and coral is due to symbiotic algae living within their tissues.

  35. Pancreatic islets/microalge co-culture encapsulated islets encapsulated algae & islets

  36. Chlorella Diameter : 1 um Temperature : 37C Non-toxic, edible 10 algal cells compensate the respiration of 1 islet cell

  37. System optimization: • Light intensity • Algal cell density • Algae Islets ratio • Medium for both

  38. Effects of irradiance and algae density on photosynthetic 02 production irradiance cell density

  39. Determination of algal cells number able to compensate pancreatic cells oxygen consumption at 2 different irradiances. 10 alga cells are sufficient to compensate the respiration of 1 islet cell

  40. Alga/islets co-culture Perifusion test under anoxia

  41. Micro-alga as Photosynthetic Oxygen Generator for Bio-Artificial Pancreas

  42. Light Emitting Diodes ( LEDs )

  43. In a celebrated experiment in 1772, Joseph Priestleykept a mouse in a jar of air until it collapsed. He found that a mouse kept with a plant would survive.

  44. The Team P Vardi K Yavriyanz M Vorobeychik K Bloch Collaborators Lozinsky V Moscow State University, Russia Beer S Tel Aviv University Israel Galaev I Lund University Sweden

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