Purpose

The Solving Diabetes Project’s quest is to develop an improved diabetes therapy using thin sheet encapsulation technology that normalizes blood sugar without the use of immunosuppressant drugs or insulin. Islet transplantation by the Edmonton Protocol is the best therapy developed to date, but requires chronic immune suppression drugs with serious side effects and therefore falls short of our goal. The Islet Sheet technology is a barrier designed to protect islets so they can release insulin and normalize blood sugar without the need for drugs. In addition, the thin sheet will make possible the use of a greater range of islets including animal islets and islets from stem cells.

The Solving diabetes project is a collaboration between Prof. Jonathan Lakey of the University of California Irvine, Medical School Department of Surgery and Cerco Medical of San Francisco.

Prof. Jonathan Lakey, who made the islets used to developed the Edmonton Protocol, and the Cerco Medical team believe that the Islet Sheet has the promise to deliver the metabolic benefits of islet transplantation without the drugs. The Hanuman Medical Foundation is excited about supporting the Solving Diabetes Project and the research at the University of California Irvine and Cerco Medical to develop this therapy. To learn more about diabetes and the scope of this project you can continue reading below or click on one of the links that interests you.

• Research Plan
• Progress
• Straight Talk
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Diabetes

Diabetes is a major health problem (0.7% incidence). The existing therapy (insulin injections) is unsatisfactory. The metabolic pathology of type 1 diabetes is very well understood: a total failure of insulin secretion. On average diabetics on insulin injection therapy cost the health care system three times average. High blood sugar defines diabetes that over time causes vascular failure throughout the body leading to blindness, kidney failure, amputations and other vascular diseases. Nature has found a good balance between fuel needs and vascular decay by keeping blood sugar at a constant 80 milligrams per deciliter.

In a healthy person the blood sugar will stray only slightly during conditions of feast or famine. All body tissues participate because they all metabolize (and several synthesize) sugar. The islets of Langerhans cells within the pancreas coordinate this metabolic activity. And the key hormone islets make is insulin, named after the islets. The main effects of insulin are to reduce the rate the liver makes new sugar and increase the rates the liver and muscles take up sugar from the blood.

Existing therapies are variations of exogenous insulin delivery, by injections or insulin-releasing implants (pumps, polymers or cells). On-demand blood sugar measurements, coupled with insulin pumps and new and useful insulin formulations, have greatly expanded therapeutic options. A dedicated diabetic can achieve blood sugar stability that can largely protect him or her from vascular decay. But the inconvenience is great and few are able to maintain the needed diligence for long. The cost in supplies is high, as well as risk of low blood sugar. In the end, although the usual therapy of injected insulin and diet has been improving in recent years, it remains a poor substitute for fully functional islets.

Many new therapies are under development. Such therapies are compared using an agreed standard: reestablishment of euglycemia (normal blood sugar). In fact, continuous euglycemia is a perfect surrogate end point for curing diabetes. (The vascular disease that ultimately kills diabetics is the result of blood sugar abnormalities.) “Normal” insulin injection therapy usually results in average blood sugar around 200% of normal, and even “tight” control methods (diligent monitoring of blood sugar, exercise and eating) results in average blood sugar around 150% of normal.

Islets: the Cells in Charge of Insulin

The islets are clusters of cells that make up one fiftieth of the pancreas, a small amount of tissue. Like all cells, they are fed by nutrients brought by blood flowing through blood vessels. Nutrients diffuse from blood to the cells, where they are metabolized. The limiting nutrient in the short term is oxygen, transported by red cells in the blood.

The islets are conscious of the body’s metabolic state because they respond to changes almost as quickly as the brain. Changes in insulin secretion can be measured within a minute of changes in blood sugar. Sometimes islets even secrete insulin before you eat in anticipation!

Islet Transplantation

Transplantation of islets of Langerhans using an immune suppression protocol developed at the University of Alberta (the Edmonton Protocol, first reported in 2000) is an attractive therapy for diabetes. Primary human islets are isolated from cadaver pancreases and implanted into the liver via the portal vein where they lodge in the liver and secrete insulin as needed. Most islet transplant recipients have normal blood sugars for years. Following implantation, blood vessels from the liver grow into the islets. The implanted islets respond to changes in blood sugar with the release of insulin. The insulin moves through the body and is taken up by tissues just like insulin from a pancreatic islet, until the fuel level returns to normal.

This procedure falls well short of a cure for three reasons. First, the side effects of the immune suppression drugs are severe (sometimes leading to discontinuance then graft failure). Second, pharmaceutical immune suppression sufficient to prevent allograft rejection is insufficient to prevent autoimmune islet death so the graft fails in a few years. (T cells auto-reactive to islet cells remain for years following the original autoimmune disease.) Third, the supply of islets from cadavers is small so only a few thousand patients could be treated annually. At this time islet transplantation is limited to patients with complicated forms of diabetes where the additional risk is clinically justified. In the absence of drugs, the host immune system will kill the implant within days. Immune system cells normally kill the implanted tissue through direct cell contact. Immune suppression drugs work by partly suppressing the response of these cells, inhibiting the immune system’s capacity to reject the islets.

In 1999 Dr. James Shapiro of the University of Alberta (in Edmonton, Canada) developed a new drug cocktail that permits continuing islet function while preventing rejection of islets. His colleague at Edmonton Prof. Jonathan Lakey developed improved methods for extracting human islets from donor pancreases. Together these breakthrough technologies are known as the Edmonton Protocol for islet transplantation.

More than 500 people with type 1 diabetes have been given islet transplants by the Edmonton Protocol at scores of institutions worldwide. Most of these people have reduced insulin needs, and in many cases no longer require insulin injections. Because of continuing autoimmune disease and immune suppressive drug toxicity, islet function declines over the years as the transplanted cells die and at five years most patients require insulin injections. The Edmonton Protocol drugs, like all immune suppression drugs, are expensive and have serious side effects.

A Living Cell Graft Device

Cerco Medical’s solution to diabetes is to transplant islet cells encapsulated in a living cell graft device, the Islet Sheet. An islet in a capsule relies on nutrients from surrounding tissue which must diffuse through the capsule to feed the islets. As the sugar level increases, encapsulated islets respond just like normal islets, releasing insulin as needed. The capsule membrane prevents contact with host immune cells and thus immune destruction.

An encapsulated islet is not vascularized, so the flux of nutrients from surrounding tissue is limited by diffusion distance. The oxygen consumed by the islet must diffuse from the surrounding living tissue to the islet. Many capsules developed in the past were too thick to provide sufficient oxygen. As a result, the core of the islets died of oxygen starvation and the remaining cells functioned poorly. The Islet Sheet is only 0.3 millimeters thick; both theoretical modeling and experimental data prove the islets will thrive.

Another problem has been technologies that produce flawed capsules. The immune cells can squeeze through even a small hole and destroy the entire islet. This sensitization of the immune system can lead to subsequent destruction of islets that are completely covered. Cerco Medical’s encapsulation technologies completely cover 100% of the islets.

In addition to preventing direct cell contact the capsule must control which substances are permitted to diffuse in and out. Cerco Medical’s polymer barrier is as permeable as water for small molecules, so nutrients and insulin diffuse at peak rates. Larger molecules such as antibodies are greatly inhibited. Prevention of inflammation, also called the foreign body or fibrotic response, is an especially difficult technical challenge. The material used for encapsulation must be benign, and the surface must be extremely smooth, at least from the point of view of the fibroblast cells that build the fibrotic capsule. The encapsulation methods developed at Cerco Medical produce a surface that is very smooth, and does not induce any significant fibrosis.

The Islet Sheet

Islet transplantation would become a major therapy for type 1 diabetes if encapsulation could prevent rejection without drugs and a source of islets were established.

The Islet Sheets, each the size and appearance of a transparent business card, would permit removal and replacement of the insulin delivery device, making the device the safest of its class. Experiments have shown the Islet Sheet to be the first macro capsule that does not cause a significant fibrotic response. The sheet is designed to prevent allograft rejection and autoimmune cell death, as well as permit nutrients to rapidly diffuse to the islet cells and insulin to diffuse out.

Encapsulation within a membrane barrier (as an alternative to systemic immune suppression) promises to address all three major drawbacks of islet transplantation. First, encapsulation should prevent direct T cell contact with islets and thus reduce or eliminate both allorejection and recapitulation of autoimmune islet destruction. Second, chronic drugs will not be needed. Third, encapsulation should permit transplantation of islets from new sources (cell culture, stem cells, xenografts), that otherwise would be vulnerable to allorejection and/or autoimmune destruction.

Each sheet the size of a business card can sustain approximately 100,000 islets so six such sheets should be sufficient to achieve euglycemia, and these sheets can be easily retrieved and replaced as necessary. Key features of the Islet Sheet include completeness of islet encapsulation, thinness and uniformity of the coating, mechanical durability, in vivo stability, bioneutrality (lack of fibrosis) and retrievability.

Cerco Medical uses a polymer derived from sea kelp harvested off the California coast. Following fabrication, the surface of the sheet is extremely smooth and 100% of the islets are completely covered. The thin sheet is uniformly 0.3mm thick, and can be made in whatever size and shape is best for the implant site. Each standard sheet contains 100,000 islets of Langerhans; sutured in place during simple, laparascopic surgery, the thin sheet can be retrieved and replaced as needed. Cerco Medical’s thin sheet design has all the advantages of other encapsulation technologies with the additional advantages that the device is both retrievable and replaceable.