RESEARCH AT THE UNIVERSITY OF CALIFORNIA

The soil from which ISM sprouted can be traced back to work that began in 1979 at UCSF and later UCD, in Dr. Kent Cochrum's laboratory using a method relying on salt bonds between cell surface proteins and acidic and basic polymers (click here). This method reportedly worked well with clean, hand-picked islets. Several pilot pre clinical animal experiments in the 1980's demonstrated that islets coated by this method can function for years in a diabetic dog with no degradation of function. Limitation of this coating technology included its inability to adhere to dead tissue, permitting immune destruction by host cell invasion through membrane imperfections.

Subsequent research focused on developing methods for coating islets that have dead tissue attached to them. This required the development of new polymers and new techniques. Randy Dorian was added to the team at Davis in 1991 for these purposes. Taking the work in a new direction, Randy developed methods to purify alginate sufficiently to prevent a foreign body reaction (click here to read about these methods). He then worked at UCD and at the Metabolex corporate laboratory on improved methods for fabrication of coatings using the new polymers. Several methods for fabricating coatings were invented and tested in diabetic mice.

In 1993 a greatly improved method (coating & overcoating) was developed by Randy Dorian and Kent Cochrum. It was found by microscopic examination to produce better than 99%+ coating efficiency, and islets protected by this method function in diabetic mice. A dog made diabetic by total surgical removal of the pancreas (pancreatectomy) was implanted using dog islets coated by this method in March 1993; no drugs were used. The figure to the left illustrates the results. (Cochrum, K., Jemtrud, S., and Dorian, R., Successful Xenografts in Mice with Microencapsulated Rat and Dog Islets. Transplant Proc, (1995) 27, 3297-3301) Coated islets were introduced on three separate days over a two-week period into the peritoneal cavity. After allowing the coated islets to acclimatize, insulin injections were slowly reduced to zero. The dog has maintained a euglycemic state to the present, more than six years later.

Several patents have been obtained by the University of California on these technologies. One covers alginate purified to make it "bioinvisible." Others are focused on methods of making thin coatings, including electrostatic droplet formation ("coating") and overcoating with a spinning disk ("overcoating") The van de Graaf generator used to make the small capsules is shown to the right.

A major deficiency of this experiment is that it cannot be proven that the implanted coated islets were the cause of the diabetes cure because they cannot be completely removed. However, this work has been reproduced at an independent laboratory at UCLA (Maniyama, M., S. Arita, et al. (1999). ?Biocompatibility Assessment of Alginates for Islet Microencpasulation.? Cell Transplantation 8(2): 176).

Summary of research accomplishments at UC Davis

  • Methods for purification of alginate
  • Purified alginate shown to be nonfibrogenic in mice and dogs
  • Methods for thin coating with purified alginate developed
  • Methods for thin overcoating with purified alginate developed
  • Overcoating method shown to cover 99% of islets
  • Coated + overcoated islets function over four years in a nonimmunosuppressed dog with little decay in function