Nov. 6, 1998 DURHAM, N.C. -- Duke University chemists led by assistant professor Mark Grinstaff are developing novel liquid polymers that can be solidified by a quick flash of laser light to seal transplanted insulin-producing cells inside a selectively permeable capsule, thus preventing rejection by diabetics' immune systems.
An interdisciplinary collaboration, involving Duke's department of chemistry as well as its medical center and School of Engineering, has already reduced the excessive blood sugar levels of experimental diabetic rats for as long as eight days after transplanting such insulin-secreting microcapsules into those animals' bodies.
Grinstaff's group prepared their report for presentation Thursday during the American Chemical Society's 50th southeastern regional meeting. The research is funded by Research To Prevent Blindness, Inc., The North Carolina Biotechnology Center, the Whitaker Foundation and the National Institutes of Health.
Each microcapsule encloses an individually-transplanted cell tissue cluster called an islet of Langerhans. Normally residing in the pancreas, these islets are "little endocrine organs" that "make insulin and multiple hormones in addition to insulin," said Diane Hatchell, a Duke professor of ophthalmology and cell biology who adds her medical expertise to the collaboration.
"The trick is to see if we can design a system in which we can transplant the islets from one species into another species by using our microcapsule," Grinstaff said.
Diabetes, the third leading cause of death in the United States, involves disruptions to normal pancreatic production of insulin, which serves to regulate glucose levels in the bloodstream.
Medical researchers have explored the transplantation into diabetics of healthy Islets of Langerhans, perhaps from the pancreases of pigs, as one possible diabetes therapy. But the immune system would normally identify such transplanted islets as "foreign," and thus target them for destruction.
The microcapsules being developed in Grinstaff's lab would avoid this dilemma by not allowing large molecules such as immunoglobin G (IgG) antibodies, a key part of the immune system's defenses against foreign invaders, to enter the microcapsule. The microcapsules wrap each islet in a semipermeable mesh.
"IgG has a molecular weight of about 150,000, and insulin's is about 6,000," Grinstaff said. "That's a very big difference. So the idea is that we build a filter that can keep antibodies from entering but which is permeable to small molecular weight materials like insulin or glucose or oxygen or other nutrients."
The islet-enclosing microcapsules are made of hyrogels, a class of long-chain polymer molecules that possesses a high water content. In this case, the polymer chains are links of simple sugars and are thus known as polysaccharides.
The polysaccharide used in the experiments, hyaluronic acid, is a natural component of the lubricating fluid in human joints as well as the vitreous gel that fills the eye. It is therefore "well-known by the body's immune system," Grinstaff noted.
During the last 1? years, Grinstaff, postdoctoral researcher Anne Pfister-Serres and graduate student Kim Smeds have developed techniques using laser light to "photo cross-link" viscous liquid hyaluronic acid so that its molecular chains mesh together into solid gels.
Meanwhile, Hatchell faces her own set of medical challenges in extracting the islet cells for transplantation. "We have to use a very harsh enzyme called collagenase to dissolve the connective tissue of the pancreas and get out these little clusters that contain 1,000 or so cells, without damaging them," she said.
One problem is that removing islets separates them from the blood supply that normally keeps them healthy, Hatchell added. "We don't understand how much injury we do to the islets during this isolation procedure. It's been difficult to even show that the free islets are functional immediately after isolation."
Despite those obstacles, Duke researchers have already done their first preliminary trials in animals, harvesting islets from dogs, surrounding them with polymer, and transplanting the encapsulated islets into the inter-peritoneal cavity of diabetic rats. In their best results so far, high blood sugar levels were reduced for eight days in one rat, but have not dropped to normal.
"We have been able to do a transplant and see a reduction in blood glucose, and that was very encouraging," Grinstaff said. "It leaves a lot more questions for us to go after, and a lot more work for us to do."
If islet transplantation ever becomes a reality, Hatchell said pigs would likely be the "donors of choice." That's because "porcine insulin is what diabetics took for years until there was recombinant human insulin," she added. "We know the human body can tolerate it."
Grinstaff's chemistry team also has been studying how well different sized meshes of crosslinked polymer block entry of IgG antibodies while allowing insulin and other nutrients to successfully diffuse. For some of these evaluations, the researchers have worked with David Katz, a professor of biomedical engineering whose laboratory has extensive experience in measuring diffusion properties of hydrogel materials.
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