Changing the size of cell-carrying spheres may surmount the difficulties that have bedeviled diabetes researchers trying to ferry insulin-producing islet cells into hosts as a way to treat type 1 diabetes.
New findings published in the journal Nature Materials suggest that for the spherical capsules, bigger may be better. Tiny gel capsules carrying islet cells allow insulin to seep out, and nutrients to get in, through microscopic holes. The holes are small enough, however, to isolate and protect the encapsulated cells from the cells of host's immune system, which would otherwise recognize them as foreign and destroy them. Encapsulating islet cells in a semi-permeable, biocompatible material has held promise for type 1 diabetes because it would eliminate the need to take lifelong immunosuppressive drugs. But the approach has been stymied in early clinical trials because scar tissue has formed on the surface of the capsules, choking off the flow of nutrients and oxygen to the islet cells inside.
The problem may be circumvented simply by increasing the size of the capsules, say the researchers. "This changes everything - this finding completely overturns what we thought about the biocompatibility of implantable spheres," said Dr. Jose Oberholzer, chief of transplantation surgery and director of cell and pancreas transplantation at the University of Illinois Hospital & Health Sciences System and an author on the paper.
"We always thought very small spheres were necessary for encapsulating cells, in order to minimize the diffusion distance for insulin to reach the bloodstream," Oberholzer said. Smaller spheres were also thought to minimize the formation of scar tissue. "But we now know that these small spheres are actually not nearly as biocompatible as larger spheres."
People with type 1 diabetes have an overactive immune system that destroys cells in islets of the pancreas that produce insulin, a hormone needed to convert sugars into usable energy. Patients must receive daily injections of insulin to compensate. Islet cells have been successfully transplanted to treat type 1 diabetes, but patients then must take immunosuppressive drugs to prevent destruction of the foreign cells.
The new research, a collaboration led by scientists at the Massachusetts Institute of Technology, shows that spheres made of different biocompatible materials, 1.5 millimeters in diameter or larger - significantly bigger than the spheres used in previous clinical trials, which ranged from 0.1 to 1 millimeter in diameter - triggered lower levels of immune response in the host and developed less scar tissue on their surface.
In a series of experiments in which spheres of different sizes and materials were implanted into mice, and later into non-human primates, the immune system's scout cells, called macrophages, seemed almost to ignore spheres at least 1.5 millimeters in diameter, while smaller spheres were recognized and attacked.
In a mouse model of diabetes, animals treated with islet cells encased in 1.5 millimeter capsules maintained normalized blood glucose levels for up to 180 days -- five times longer than mice treated with 0.5 millimeter spheres.
Using a specialized microfluidics device developed at the University of Illinois at Chicago under a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, Oberholzer and his UIC colleagues delivered minute amounts of glucose into a tiny well containing encapsulated islet cells and measured the amount and movement of insulin excreted by the cells in real time. The UIC team showed that rat islet cells in 1.5 millimeter hydrogel spheres were able to sense glucose and respond by producing insulin with no significant delay in diffusion compared to cells in 0.5 millimeter spheres. The device was developed to evaluate the function of human islet cells by measuring the movement of not only insulin, but also calcium, which must first enter the cells in order for them to release their insulin. The device can measure extremely small amounts of insulin produced by just a handful of cells.
"The larger spheres don't pose a problem by slowing the speed of diffusion of glucose or insulin," Oberholzer said. "Just by increasing the size of the capsules used to carry insulin-producing cells, we show that the cells can be kept alive, perform their function, avoid destruction by the immune system, and seem to resist scar tissue buildup."
Oberholzer says the next step is to test the safety and efficacy of the larger spheres for islet-cell transplantation in clinical trials.
"We have pegged encapsulated islet cells as a cure for type 1 diabetes for so long - but trials always end with the capsules engulfed in scar tissue and the cells dying," he said. "If we can get around this simply by increasing the size of the capsules, then we may have a viable cure for type 1 diabetes within reach."
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Co-authors on the Nature Materials paper are Matthew Bochenek, Joshua Mendoza-Elias, Yong Wang and Merigeng Qi of UIC; Omid Veiseh, Joshua Doloff, Minglin Ma, Arturo Vegas, Hok Hei Tam, Andrew Bader, Jie Li, Erin Langan, Jeffrey Wyckoff, Whitney Loo, Siddharth Jhunjhunwala, Alan Chiu, Sean Siebert, Katherine Tang Stephanie Aresta-Dasilva, Danya Lavin, Michael Chen, Nimit Dholakia, Raj Thakrar, Robert Langer and Daniel Anderson of the Massachusetts Institute of Technology; Igor Lacik of the Polymer Institute of the Slovak Academy of Sciences; Gordon Weir of the Joslin Diabetes Center; and Dale Greiner of the University of Massachusetts Medical School in Worcester.
The work was supported by the Juvenile Diabetes Research Foundation grant 17-2007-1063, Leona M. and Harry B. Helmsley Charitable Trust Foundation grant 09PG-T1D027, National Institutes of Health grants EB000244, EB000351, DE013023 and CA151884, R01DK091526, Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, and a gift from the Tayebati Family Foundation.