Competition for the Company’s first product, the Islet Sheet, is of two forms:
existing treatment methods
new treatment devices in development
Existing Treatment Methods
The current medical protocol of frequent blood glucose monitoring, insulin injections and exercise (called “intensive therapy”) is proven to help minimize (but not eliminate) vascular disease. To be truly successful intensive therapy requires a constant effort which is very burdensome to the individual diabetic. New formulations of insulin such as Lantus® from Novartis are being developed which make available a sustained, steady insulin release over nearly 24 hours. Glucose monitoring products that require smaller amounts of blood are being developed, as are alternative delivery sites for insulin such as inhaled insulin. None of these products will radically alter intensive therapy, but will merely decrease the inconvenience of standard therapy using insulin and frequent blood glucose monitoring.
New Treatment Devices in Development
Several technologies in various stages of research and development aim at achieving sustained good blood sugar. Such technologies are potentially competitive with the Islet Sheet. Islet transplantation under the Edmonton Protocol comes close to achieving this aim, but is fettered by the side effects of immune suppression. The technology most likely to safely achieve sustained good blood sugar without immune suppression is the artificial pancreas.
MECHANICAL ARTIFICIAL PANCREAS
MiniMed long term sensor
The mechanical artificial pancreas is comprised of three components: a glucose sensor, an insulin pump and a computer which determines the rate of insulin delivery. The implanted sensor may reside in the vena cava, the large vein leading to the heart, and may require periodic replacement. The leader in this approach is Medtronic MiniMed.
Although a mechanical artificial pancreas could theoretically regulate glucose well, glucose sensor development has been challenged by the difficulty of creating a sensitive, stable and accurate sensor. Moreover, an error in sensing, computation or delivery could result in insulin overdosing which is potentially life-threatening. Therefore, low blood sugar remains an unacceptable potential side effect. It is also very difficult to produce a mechanical artificial pancreas that responds quickly enough to changes in blood sugar (islets respond in less than ten minutes.) A further problem identified in animal studies has been weight gain apparently caused by physiologically inappropriate insulin dosing.
BIO-ARTIFICIAL PANCREAS
A less mechanical (more biological) approach is termed the bio-artificial pancreas. Devices in this category are implants that protect viable islets with membrane barriers instead of immune suppression drugs. As with the Edmonton Protocol, the “decision” to secrete insulin is made by the cells that naturally make and secrete insulin in people without diabetes. Studies have shown that beyond a threshold number of islets the islets will secrete exactly the amount on insulin needed, and even with an islet dose of five times the threshold the insulin secreted is not excessive. Islets are completely self-regulating and therefore pose no risk of insulin overdose and low blood sugar.
Three classes of bio-artificial pancreas differ in how nutrients and cell products are transferred between the islets and the host’s circulation. The three configurations are:
Vascular shunt devices in which the islets are contained in a chamber surrounding an arteriovenous shunt (similar to a dialysis graft)
eovascularized devices in which the islets are in a compartment into which blood vessels are encouraged to grow
Passive diffusion devices (usually implanted into the peritoneal cavity) that derive nutrients passively from adjacent vascularized tissue. There are three configurations:
hollow fibers filled with islets
microcapsules each with a single islet
thin sheets filled with islets (the Islet Sheet).
VASCULAR SHUNT
The vascular shunt approach, which was the first to receive FDA clearance for a clinical study, has been abandoned for safety reasons by its sponsor, Circe Biomedical. In the final preclinical canine study the vascular shunt to the artificial pancreas broke and the dog bled to death. The probability of bleeding death has prevented clinical studies from going forward. At present there are no commercial ventures in the vascular shunt niche.
NEOVASCULARIZED DEVICES
The most studied neovascularizing device is sold as a research product by TheraCyte, Inc. The outer surface is a proprietary material that promotes development of new blood vessels to help feed the cells inside.
Unfortunately the largest device holds only 10,000 islets. About 80 such devices would be needed to treat an 80-kilogram human, making implantation and retrieval inconvenient. The difficulty of retrieval is further complicated by growth of surrounding tissue into the device.
PASSIVE DIFFUSION DEVICES (INCLUDING THE ISLET SHEET)
The best long-term data have come from devices with an outer surface designed to produce no reaction. Rather than promote vascular development, passive diffusion devices are designed to be “bio-invisible” and cause minimal or no host reaction. Insulin-producing cells within the devices maintain good blood sugar by passive diffusion of oxygen, glucose and other nutrients in, and insulin and other hormones out to adjacent tissue. All such devices include a membrane barrier to protect islets from host immune system rejection thereby obviating the need for pharmaceutical immune suppression. They differ in the physical configuration (tube, microcapsule and sheet) and in the materials and methods used in fabrication.
Many early passive diffusion devices were made from hollow fibers of the sort used in kidney dialysis machines. Unfortunately the number of islets that can be implanted in hollow fibers is insufficient to achieve good blood sugar, so this configuration has been abandoned.
All present-day passive diffusion device research is on either microcapsules (each islet in its own capsule) or the Islet Sheet thin sheet. Companies doing research on microcapsules include Novocell, Inc.Living CellTechnology and MicroIslet Inc.,.
