Sustain Islet Function
The key requirements to keeping transplanted islets alive and functioning are:
Material in contact with islets must be biocompatible
Here we specifically define “biocompatible” as both materials and methods nondeleterious to the cells contained in the device.
The material used to make the immuno-isolation barrier must be compatible with the cells inside as well as the host outside. The material comprising the device and all solvents and reagents used to make it must be nontoxic. For example, organic solvents can desiccate living tissue.
The Islet Sheet uses a highly purified alginate to completely encapsulate the other components. A central core region contains islets suspended in alginate; this and a reinforcing mesh are surrounded by and bonded to acellular immuno-protective alginate layers Alginate, derived from sea kelp, is readily available commercially from numerous sources. Islet Sheet Medical has developed proprietary methods to purify and process this substance, resulting in alginate gels with the specific properties required for the Islet Sheet, including purity and molecular permselectivy and biostability.
Fabrication process must not damage islets
In addition to the material, the fabrication method must not damage the islets. For example, some methods of forming droplets around islets produce high shear forces that damage islet cells. Free-radical polymerization can damage the cell membrane.
The method used to make the sheet produces minimal shear forces, and the biochemical environment is isotonic and free of reactive chemical species. The reaction that forms the bonds holding the sheet together is effected by calcium, an ion naturally present in the body. Studies at the University of California, Irvine, demonstrate that the viability of islets following sheet encapsulation is undiminished, and the functionality of the islets (capacity to secrete insulin) actually increases over time in comparison with unencapsulated control islets.
Dimensions must permit rapid diffusion of nutrients and insulin
The nutritional requirements of islets are not fully understood. It is certain that many small molecules are consumed fairly rapidly and must be freely available. It is also known that some larger molecules are necessary, but these larger molecules are not consumed at the same high rate. Thus it is sufficient if the larger molecules diffuse slowly through the device.
It is clear from a variety of studies that, under most conditions and at least in the short term, the limiting nutrient is oxygen. Islet Sheet Medical has developed computer models to evaluate various parameters affecting oxygen diffusion to islets from the tissue surrounding the Islet Sheet device.
Islet Sheet Medical has addressed this design issue empirically as well as with modeling by simple, straightforward experiments. Using well-understood chemistry, they have demonstrated tight regulation of the molecular permeability of the alginate matrix surrounding and protecting the islets in Islet Sheets. In fact, it is possible to fabricate an Islet Sheet that is freely permeable to even the largest nutrients thought to be required for long-term islet function.
Insulin diffusion is likewise critical: the Islet Sheets must respond quickly to changes in glucose. A device or coating that will not allow islets to respond rapidly to changes in blood sugar will not cure diabetes. If the islets are far from the surface of the immunoisolation membrane—as for instance in a hollow fiber—many minutes may pass from normalization of blood glucose to normalization in the fluid immediately surrounding the islets. This can result in overshooting, leading to potentially dangerous hypoglycemia.
Figure xx shows the appearance of insulin following a glucose challenge. First, an islet releases a burst of insulin (first phase response) followed by steady secretion (second phase). When the glucose disappears, insulin secretion declines to baseline in a few minutes. Second, an islet in a small capsule produces a similar but somewhat blunted curve. Insulin must diffuse through the small capsules, but not far. In contrast the hollow fiber is so big that insulin diffusion takes many minutes, and the insulin curve takes over 30 minutes to return to baseline. Hollow fibers have been reported to cause hypoglycemia in animals.
The Islet Sheet responds quickly because of the small dimensions needed to allow oxygen diffusion. The thin sheet curve is similar to the small capsules curve.