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Bio artificial pancreas BAP: cells, matrix and in between

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Title: Bio artificial pancreas BAP: cells, matrix and in between


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
cells1 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
300
Blood glucose (mg/dl)
200
100
0
2
4
6
8
10
12
2
4
6
8
10
12
a.m.
p.m.
Time of day
11
Edmonton protocol (2003)Complications related
to therapy
  • Portal vein thrombosis (n2/54)
  • Expanding hematoma requiring surgery (1/2)
  • Bleeding (n4), requiring transfusion (3/4).
  • Transient disturbed liver function (46).
  • Development of hypercholesterolemia (65)
  • Development of hypertension (53).

12
Immunoisolation suboptimal 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
RINmHP
RINm
19
Bio-artificial pancreas research 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
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24
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

25
Bio-artificial pancreas research targets
  • Cell engineering
  • Matrix Selection
  • Islets oxygenation

26
Immunoisolation Barriers
Lack of oxygen
Fibrosis
27
Hypoxia-induced Central Islet Necrosis
28
Devices Designed To Improve O2 Supply To
Transplanted Islets
  • Addition of 02carriers
  • (c Ricordi)
  • H20 electrolysis
  • (C Colton)

29
How to overcome the obstacle of insufficient O2
diffusion Is it possible to develop a
miniature oxygen generator
30
Photosynthesis
light
6H2O 6CO2 ------gt C6H12O6 6O2
Carbon dioxide is converted to sugars
31
Earth atmosphere
Atmospheric oxygen built up in the early history
of the Earth as the waste product of
photosynthetic organisms (micro-algae)
32
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33
Algae
Unicelullar algae
Multicellular algae
34
Alga Requirements
  • Thermophylic
  • Non toxic
  • Photosynthesizing

35
Microalga Adaptation To Extreme Environment
36
Microalga Symbiosis
The green color of sea anemone, hydra and coral
is due to symbiotic algae living within their
tissues.
37
Pancreatic islets/microalge co-culture
encapsulated islets
encapsulated algae islets
38
Chlorella Diameter 1 um Temperature
37C Non-toxic, edible
10 algal cells compensate the respiration of 1
islet cell
39
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40
  • System optimization
  • Light intensity
  • Algal cell density
  • Algae Islets ratio
  • Medium for both

41
Effects of irradiance and algae density on
photosynthetic 02 production
irradiance
cell density
42
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
43
Alga/islets co-culture Perifusion test under
anoxia

44
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45
Micro-alga as Photosynthetic Oxygen Generator
for Bio-Artificial Pancreas
46
Light Emitting Diodes ( LEDs )
47
In a celebrated experiment in 1772, Joseph
Priestley kept a mouse in a jar of air until it
collapsed. He found that a mouse kept with a
plant would survive.
48
The Team
K Yavriyanz
P Vardi
K Bloch
M Vorobeychik
Collaborators
Lozinsky V Moscow State University, Russia
Beer S Tel Aviv University Israel
Galaev I Lund University Sweden
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