Published online last month in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), the study on the new technique, which for the first time successfully employed a biomaterial to deliver oxygen locally to islet cells, represents a major step toward the goal of developing an alternative site for housing transplanted islets.
Led by Cherie Stabler, Ph.D., assistant professor of biomedical engineering and surgery, and director of the DRI’s Tissue Engineering Program, the DRI team designed and developed a novel material, PDMS-CaO2, which has the capacity to spontaneously generate oxygen when exposed to water. Adequate oxygenation is critical for the development of an alternative site for islet cell – or any cell-based – transplants because in the days following initial implantation, cells do not yet have a functioning vascular network feeding them oxygen, and they become oxygen-starved and die in large numbers.
“We have been working to create an optimal environment, akin to a ‘mini organ,’ for housing transplanted islets that mimics the native pancreas, and this study represents a significant step toward that goal,” Stabler said. “This oxygen-generating biomaterial provides the supplemental oxygen needed by the islets and serves as a bridge until the vascular bed is formed, providing natural oxygen delivery to the islet’s insulin-producing beta cells. This is critical because islets are like super athletes of the cell world – they require large amounts of oxygen to survive and function. For example, in the native pancreas, islets make up only 1 percent of the pancreas, but they receive 10 percent of the blood flow.”
Pioneered by Camillo Ricordi, M.D., professor of medicine and surgery and the director of the DRI, successful islet cell transplants give patients with type 1 diabetes the ability to produce their own insulin and achieve insulin independence – but only for a time. Although donor islet cells are usually transplanted in the blood vessels of the liver, where their direct access to blood keeps them oxygenated and they begin producing insulin quickly, their presence triggers a strong inflammatory response. As a result, more than half of the islets die in the first week, limiting their longer-term function.
Searching for ways to improve islet survival, scientists have tried for years to bioengineer an alternative site for islet transplantation, but could not overcome the challenge of inadequate oxygen.
In their study, “Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials,” Stabler, Ricordi and their team showed that PDMS-CaO2 creates a nutrient-rich environment with sustained oxygen supplementation for more than six weeks.
They also showed that the unique biomaterial system, for which they have a pending patent, allows the duration and amount of oxygen generated to be elegantly controlled and monitored, providing an ideal environment for the cells – and one superior to the liver, where they are widely distributed and cannot be retrieved or monitored.
Using a 3D model, similar to a bioengineered scaffold, the researchers also demonstrated that the oxygen-generating material was able to prevent cell death due to inadequate oxygen levels.
“We are very encouraged by the outcome of this study and its implications toward our goal of translating these findings to the millions of people living with diabetes,” Stabler said.
“This novel method for sustained oxygen delivery within the microenvironment of tissue-engineered sites could be critically important to improve the survival of transplanted cellular products,” Ricordi said. “The new platform technology could be particularly useful during the delicate post-implantation phase, in which new blood vessels are growing to provide full nutritional and oxygen support to the transplanted tissue.”
Stabler and her co-authors also note that PDMS-CaO2 could have application well beyond islet cell transplantation. “Ensuring adequate oxygenation is a universal challenge for all cell-based transplants, so this could work for skin grafts, for example, where assuring viability is critical until they become vascularized,’’ she said.
In addition to Stabler and Ricordi, other DRI co-authors on the study, which was partially funded by the Diabetes Research Institute Foundation, are lead author Eileen Pedraza, and Maria M. Coronel, both biomedical engineering graduate students, and Christopher A. Fraker, Ph.D., research assistant professor of surgery. Pedraza’s work on the study is the cornerstone project for her Ph.D. thesis in biomedical engineering.