human Whole pancreas: Weighs 70 g
Diabetes: Current Treatment
http://www.sciencemuseum.org http://www.diabetes-and-diabetics.com http://www.diabetes-and-diabetics.com
The Pancreas
Insulin, a hormone secreted by the pancreas, is responsible for monitoring blood sugar levels
Without insulin, patients have chronic high blood glucose levels, which can lead to further complications, such as retinopathy (damage of the eye), neuropathy (damage of the brain), and nephropathy (damage of the kidney). 2
The Pancreas (cont.)
-cells, cells that produce insulin, are located in cell cluster called islets of Langerhans
Surprisingly, these make up of only 1%-2% of the total mass of the pancreas.
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Diabetes
Type 1 diabetes, also known as insulindependent diabetes mellitus, occurs when pancreatic islet cells are unable to produce insulin
The patients own immune system launches an immunological attack on the islet cells.
Why do we need an artificial pancreas?
Present methods of diabetes treatment improve, but dont normalize, blood glucose levels Burden of care extremely high
Reversal Of Insulin Dependency
Closed-loop artificial pancreas (engineered sensing and insulin delivery) Transplantation of insulin-producing cells (natural sensing and insulin secretion) Cell Source
Engineered BG Sensing And Insulin Delivery
Design elements for artificial -cell
1.
Insulin pump to accurately and precisely deliver variable amounts of insulin Continuous glucose sensor to accurately determine ambient glucose levels Effective algorithms to vary insulin delivery rates based on real-time glucose sensor outputs
2.
3.
Components of an Algorithm for Insulin Delivery
(the Non-Engineers Approach)
When glucose is high, give more insulin When glucose is low, give less insulin When glucose is rising, increase insulin delivery When glucose is falling, reduce insulin delivery
In Vivo Physiological Insulin Secretion
Blood Glucose
Insulin
Algorithm Components
Blood Glucose
Insulin Derivative Integrative Proportional
External Closed-loop Development Step 2: Algorithm for Insulin Delivery
Proportional to the glucose level Derivative rate-of-change of the glucose Integrative slowly adaptive basal rate
Prototypic closed-loop system
Sensor signals transmitted to a laptop computer that displays the sensor glucose and calculates rate of insulin delivery Rate of insulin delivery is transmitted to the insulin pump
Reversal Of Insulin Dependency
Closed-loop artificial pancreas (engineered sensing and insulin delivery) Transplantation of insulin-producing cells (natural sensing and insulin secretion) Cell Source
Bioartificial Pancreas
Sourcing of functional cells
Products Out (Insulin, other metabolites) Semi-Permeable Membrane (poly -L-lysine) Insulin-Secreting Cells Big Molecules (e.g. Antibodies), CytotoxicCells Alginate Layer Nutrients In (for Improved (glucose, oxygen, Biocompatibility ) etc.)
Cell technology
Materials Architecture for construct function and preservation
Construct technology
Immune acceptance Monitoring for in vivo function
Technologies for integration into living systems
Bioartificial Pancreas Structure
Synthetic materials and functional islets
cells are very sensitive to hypoxia (low oxygen), infectious agents, oxidants, chemical toxins. Encapsulation can allow these cells to be protected from immune system without immune suppressants. It also makes it possible to use islet cells from non-human donors, reducing the problem of donor scarcity. However, the membrane must be semipermeable since to allow oxygen nutrients and to diffuse in and wastes and insulin to diffuse out while blocking antibody entrance. It provides tighter blood glucose control without the need for immunosuppressive drugs, which can lead sometimes lead to further health problems.
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
Structure (cont.)
Semipermeable membrane
Protects the islet cells from the host immune response Permits exchange of nutrients, glucose, insulin, oxygen, waste products Many different types of materials have been used for encapsulation, including alginate, agarose, engineered tissues, and poly ethylene glycol (PEG) 3
Alginate
commonly used natural polymer for cell immunoisolation
Non-toxic Non immunogenic
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
Bio-artificial pancreas
research targets
Cell engineering Matrix Selection Islets oxygenation
Impediments to Progress
http://www.medgadget.com
The major obstacle to progress in cell encapsulation is fibrotic overgrowth
Materials used for encapsulation can introduce foreign body and inflammatory reactions
This leads to chronic inflammation and causes fibrous tissue overgrowth. The presence of this fibrotic tissue prevents nutrient and oxygen diffusion, leading to loss of islet functionality. Earlier problems of immune rejection caused by exposure of foreign cells to the immune system have been overcome by controlling the pore size of the membrane used. 3
Immunoisolation Barriers
Lack of oxygen Fibrosis
Hypoxia-induced Central Islet Necrosis
Devices Designed To Improve O2 Supply To Transplanted Islets
Addition of 02carriers
(c Ricordi)
H20 electrolysis
(C Colton)
Reversal Of Insulin Dependency
Closed-loop artificial pancreas (engineered sensing and insulin delivery) Transplantation of insulin-producing cells (natural sensi...