Project team documents strong vascular response to implanted Islet Sheets
Working with mice and a new imaging technique, researchers from the Islet Sheet project team at UC Irvine were able to monitor in real time a “brisk vascular response” to implanted Islet Sheets containing islets from different sources, including porcine islets. Within 7 days of implantation, images obtained through windows in the backs of mice showed significant neovascularization; arteriolar, venular and venous dilatation; and the formation of nascent arteriovenous connections in tissues around the implant site, resulting in increased blood flow and hemoglobin oxygen saturation in those tissues. This experiment addresses one of the main problems with encapsulated islets: making enough oxygen available for the islets to thrive and deliver insulin as needed to the body of a person with diabetes.
Rahul Krishnan led development of the vascular response monitoring for the UCI team, which is headed by Dr. Jonathan Lakey. The data were presented at the 24th International Congress of the Transplantation Society in Berlin, in July 2012. View the data; read a news story.
Large-animal trials begin
In early 2012, the Islet Sheet Project embarked on the long-awaited and critical phase of metabolic studies in large animals. The definitive experimental model for implantation with the Islet Sheet is mammals such as dogs, pigs, or monkeys made diabetic by total removal of the pancreas. In contrast to rats and mice, such animals can easily accommodate the 5-centimeter-square Islet Sheet designed for humans. See Large-Animal Studies for more detail on this key phase.
Hanuman Medical Foundation continues its robust support of this research, with donor commitments to fund the collaboration through definitive large mammal studies. Presuming the results are as expected, clinical studies will follow very quickly. See Current & Planned Research.
Islet Sheet Project expands to Europe
In 2011, new collaborators affiliated with Oxford University and the University Medical Center in Groningen, Netherlands, joined the Islet Sheet Project. Professor Paul Johnson’s laboratory at Oxford is collaborating with Jon Lakey at UC Irvine in histological and functional analysis of Islet Sheets following implantation in animals. We anticipate that large-animal studies will be performed at Oxford to support the rational for human clinical studies, and that this may be the first site for European clinical trials of the Islet Sheet. Professor Paul de Vos’s group at Groningen has access to many state-of-the-art imaging modalities. Currently they are studying tissue samples from the rodent Islet Sheet studies at UC Irvine, with the goal of identifying the nature of cellular reaction to Islet Sheet Medical’s alginate and Islet Sheets.
New Zealand company in clinical studies with microencapsulated islets
2010 saw a milestone in the long-developing field of islet encapsulation: Living Cell Technologies of New Zealand was granted a license to sell its Diabecell® product— microencapsulated porcine islets—in Russia, the first commercial license for such a therapy anywhere. Clinical trials of the therapy continue in Auckland. The achievement is especially impressive given the extreme regulatory scrutiny that xenografts attract. Hanuman Medical Foundation and the Islet Sheet Project maintain cordial relations with LCT; we hope to have the opportunity to encapsulate the company’s pig islets in the Islet Sheet.
Small-animal studies in retrospect
The Islet Sheet’s ability to normalize blood sugar in diabetic rats is robust. The model used was the streptozotocin rat; this drug kills the insulin-making beta cells in the islets. In summer 2010 the team began to remove Islet Sheets from the rats to study engraftment and determine the reaction of the tissue surrounding the sheet. We expected the rats to return to the diabetic state they presented after streptozotocin treatment, but they did not. Their islets had regenerated—a well-known limitation to all chemical models of autoimmune diabetes.
Based on findings published by Dr. Lakey’s group, it is clear that the measures required to make streptozotocin rats truly diabetic are formidable. And curing these truly diabetic rats requires a vastly larger dose of islets than previously reported—preliminary data suggest more than ten times the human dose! As a practical matter, these new facts have eliminated the streptozotocin rat as a useful model for Islet Sheet research. Nonetheless, at relatively minor cost the team learned much about islet dosing, potential implantation sites, and stability of various Islet Sheet fabrication methods in several rat sites. This knowledge will contribute to the large-animal studies.