|It has taken a very long time from the conception of a bio-artificial pancreas to the creation of the first really practical device, the Islet Sheet. The reason is, this is a very difficult thing to do.
This page is devoted to explaining our view of how to go about developing such a device. To read about the experiments we have done along the way and the results of those experiments, click here. Readers with an interest in theory may wish to read this page before going on to the experiments.
Theory and Background
In this section we describe the background of our approach to developing a thin sheet bio-artificial pancreas. In an industry with a history of failure, our unique view lead us to identify the right polymer and develop methods of microencapsulation that led to prototyping of the sheet. Animal studies are underway that should lead to clinical trials.
A High-Performance Bio-Artificial Organ
Our bio-artificial endocrine pancreas replaces nonfunctioning islets of Langerhans. It responds to changing blood composition with release of hormones including insulin. Several sheets are implanted into the peritoneal cavity of the diabetic. Each sheet is several centimeters in diameter, 0.3 millimeter thick, and contains two to three million cells. Four to six sheets contain enough islet tissue to cure diabetes in an adult.
Islets are kept alive by diffusion of oxygen, glucose and other nutrients into the sheet; insulin, hormones and waste products diffuse out of the sheet. The sheet is so thin that diffusion alone allows sufficient nutrients to reach the center of the sheet. A coat on the exterior of the sheet prevents contact between the cells inside and immune effector cells of the host as well as inhibiting diffusion of antibody and complement. No immune suppression drugs are needed. The sheet may be removed or replaced at any time.
An Industry with a History of Failure
Many ventures have been founded in the past 20 years to try to profit from the opportunity for the bio-artificial pancreas. More than $200 million has been invested. No product is on the market.
Our Unique View
In contrast to prior approaches, our bio-artificial pancreas is designed from the "islet's point of view" for maximum islet viability. Our approach is unique in that it has at least a theoretical chance of success it could work. For a variety of reasons, this is not true of other approaches.
Biocompatible Alginate and Microencapsulation
The first problem to be solved was a suitable polymer for the "artificial" part of the device. In the end several researchers (including Randy Dorian, a founder of ISM) concluded that the best polymer is hyper-purified alginate. This polymer is made from kelp, and has the very useful property of quickly gelling when mixed with calcium salts. Only with great effort are all impurities removed so that alginate is biocompatible.
We then set out to develop methods to make small microcapsules, that is, islets with a very thin, conforming coating. Success came with a combination of electrostatic micro-drop formation, overcoating with a spinning disc device, and crosslinking with fancy ion chemistry. In 1993 we implanted canine islets so coated into a diabetic dog at the University of California - Davis (click here to read more about research at the University of California). This dog remains off insulin, nearly six years later. Recently this approach was confirmed in the canine allograft model by workers at the University of California - Los Angeles supported by the current licensee of this UC microencapsulation technology, Islet Technology, Inc. This product is promising and may reach the market at about the same time as the Islet Sheet.
Microencapsulated (or "coated") islets are the first generation bio-artificial pancreas. Having worked for years to make microencapsulation work, we appreciated that the ideal bio-artificial pancreas would be retrievable. We thought that a retrievable sheet would be the second-generation device. We manufactured prototype sheets and studied their properties, including strength, thickness and diffusion characteristics (click here for more.). The methods were successful, so we filed our first patent application on October 13, 1995.
Work on the Islet Sheet was suspended while we were engaged in setting up our new research enterprise, Hanuman Medical, and working to find a corporate partner for our hemostatic technology, PlasmaSeal. At the end of 1997 we completed negotiations on a partnership for PlasmaSeal allowing us to devote more resources to the Islet Sheet project. In June 1998 we raised $300,000 in "angel" money (including $80,000 from the founders) to do experiments designed to show that we could make sheets that fit the criteria for the perfect passive diffusion bio-artificial pancreas.
Studies in Large Animals
In June, 1998 we began investigations in vivo to develop and prove methods to make "perfect" bio-artificial sheets. Sheets made by many methods were implanted in rodents and dogs. At our laboratory in San Francisco we refined sheet fabrication methods. At the University of Chicago Prof. Rilo isolated islets and implanted test sheets into dogs, both diabetic and nondiabetic. Evaluation of biocompatibility took place at commercial laboratories. Several significant problems came to light and were overcome. Islet Sheets implanted into a dog in May 1999 were shown to fulfill the design criteria. In particular, sheets retrieved after 12 days in the diabetic dog were shown to produce insulin in response to stimulation, proof that live islets were in the retrieved sheets. Further research showed improved methods for making the sheet biocompatible. By the end of 1999 we were ready to resume large animal studies.
Click here to read more about our sheet research.
Our best sheet entered preclinical studies (canine) in February, 2000. The results so far are very encouraging: Islet Sheets maintain euglycemia in pancreatectomized dogs. Through 2000 we intend to expand these canine studies in multiple research centers and in addition do limited monkey studies. We hope that the results will justify clinical studies in 2001.
Click here to read more about our preclinical research.
Clinical studies will take place when the device is proven in diabetic animals. The FDA has already approved clinical investigation of first-generation encapsulated islets. Initial studies will be with sheets protecting allografts, that is, human islets.
Human islets in the Islet Sheet will be a profitable product but one with a market limited by the availability of human pancreases. Therefore, while human allografts are in clinical studies, research on xenografts (e.g., pig islets) and cells grown in culture will be pursued, using advanced cell culture of genetically engineered cells. These methods have the potential to produce fully functional, immunologically human islets and a lower cost than primary human islets. We are already in collaborative studies with some organizations producing such islets and cells.