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Hydrogel utilized to safely transplant insulin-producing islet cells for diabetes treatment

By Joseph Bennington-Castro July 12, 2017
Two vascularized islets side-by-side in a mouse’s epididymal fat pad, which were transplanted using a new hydrogel. One islet is green and the other is not visible because it is not labeled with fluorescent proteins; the vascular architecture is magenta. Credit: Jessica Weaver.

For many years, a promising treatment for type 1 diabetes has been the transplantation of insulin-producing islet cells. But the effectiveness and widespread use of this technique is hindered by the low survival rate of donor pancreatic islet cells that are transplanted into a patient’s liver. Researchers with the Georgia Institute of Technology (Georgie Tech) have now introduced a hydrogel platform to safely deliver islet cells to non-liver bodily sites that are potentially more hospitable to the cells and aid in their vascularization, engraftment, and function. Reported recently in Science Advances, the hydrogel, when combined with a growth factor to promote blood vessel growth, reversed type 1 diabetes in 75% of mice within 2 weeks when transplanted into an area called the epididymal fat pad, located near the epididymis.

“Using a synthetic hydrogel vehicle to promote vascularization of the islets resulted in an improvement in the survival and engraftment of the cells transplanted,” says study first author Jessica Weaver, a postdoctoral fellow in Prof. Andrés García’s laboratory. “If translated to the clinic, I think [the vehicle] would greatly reduce the burden on organ donors and the shortage of organ donations.”

Type 1 diabetes is a type of autoimmune disease wherein the body’s immune system attacks islet cells, which are produced in the pancreas and secrete glucose-regulating insulin. To treat this devastating disease, experts sometimes isolate islet cells—which are actually packages of 1000 to 2000 cells with their own vasculature—from cadaveric donor pancreas and inject them into the portal vein of the liver, where they become trapped in the liver tissue vasculature. In this easily accessible location, Weaver says, the islet cells are in close proximity to the blood stream, allowing them to respond to blood sugar levels by secreting insulin when needed.

The problem, however, is that islet cells are sensitive and their survival rate when transplanted into the liver is very low due to inflammatory responses. “When you try to transplant into the liver, you lose approximately 60% of the cells immediately,” Weaver says. In the following weeks, another 10–30% of cells die in the waste- and toxin-heavy environment of the liver. Because of this low cell survival rate, many patients need two to three islet transplantations—a non-ideal situation given the dearth of donor organs.

In recent years, researchers have sought to find alternative transportation sites in the body; the two most promising sites are under the skin (subcutaneous) and in the omentum, a highly vascularized vestigial structure in the abdominal cavity. Scientists have yet to come to a consensus about where to transplant the cells, in part because the material or device to transplant the cells is typically site-specific, making it difficult to adequately compare sites, Weaver says.

To resolve this issue, Weaver and her colleagues created a type of “plug-and-play” hydrogel vehicle. The hydrogel has several important components: a four-arm poly(ethylene glycol)

(PEG)-maleimide monomer; protease-degradable peptides that crosslink the monomers into a network; an adhesive RGD [tripeptide Arg-Gly-Asp] peptide to promote cell adhesion and ingrowth; and vascular endothelial growth factor (VEGF) to promote vascularization. The gel results in an onsite crosslinking solution that adheres to tissue. “One of the issues with islets is that they’re metabolically active cells, so if you deliver them in a big clump they will succumb to necrosis and die as they compete with each other for nutrients,” Weaver says. “So we’ve developed a matrix to deliver them so that they are spread out, yet [remain] localized to the site.” To deliver the islet cells, the researchers mix the monomers, peptides, and VEGF with the islet cells and add it to the tissue; they mix all components at the site of implantation where they rapidly gel.

The researchers investigated three different extrahepatic (outside of the liver) transplant sites in mice: subcutaneous, epididymal fat pad (analogous to the human omentum), and small bowel mesentery (a vascularized connective tissue in the abdominal cavity), and compared these sites to intrahepatic delivery using standard protocols (that is, without the new hydrogel). They found that compared with the other two extrahepatic sites, the subcutaneous site had a low level of vasculature and a heightened immune response. For islet cells to survive, however, a strong blood vessel network to integrate into and low levels of immune responses are both required. The epididymal fat pad appeared to have ideal conditions, with the highest degree of vascularization and lowest immune system response.

Weaver and her colleagues tested the long-term viability of the cells in the three different locations, as well as islets delivered to the liver vasculature, in diabetic mice. They used islet cells from transgenic mice whose cells express the light-generating enzyme luciferase and green fluorescent protein, allowing them to track the cells over time using in vivo bioluminescent imaging. As anticipated from the initial experiments, the fat pad location proved to be the best: 60% of the mice reverted to normal blood sugar levels within four weeks when VEGF was not incorporated into the PEG hydrogel, and 75% reverted to normal levels within just two weeks with the PEG-VEGF hydrogel. In comparison, no mice returned to normal blood glucose levels within 30 days with standard intrahepatic islet delivery.

“I am impressed with the authors’ detailed and innovative research and look forward to clinical application as much as they do,” says David Sutherland, an emeritus professor of surgery at the University of Minnesota, who helped perform the world’s first clinical islet transplant in 1974. But Sutherland, who was not involved in the study, notes that the researchers did not test the intrahepatic site itself with their hydrogel. In his experience with cases of autotransplantation—wherein patients are treated with islet cells from their own diseased pancreas instead of donor cells, which are more likely to be rejected—70% achieve insulin independence and it lasts for up to 10 years in 50% of patients, he says. “This is not to say that extra-hepatic sites could not be superior but I don’t think the authors should be as negative as they are [about the intrahepatic site].”

However, García notes that there is an inherent difficulty and danger in trying to inject the hydrogel into the intrahepatic vasculature, as it would clog it or create blood clots. But if successful in further experiments, the new material could be useful not only for patients with type 1 diabetes, but also those who become diabetic after having their pancreas removed due to severe pancreatitis. “If the results are as promising as they look, I think we could see a lot fewer patients getting on insulin after a pancreatectomy,” Weaver says.

Read the article in Science Advances