New antioxidant biomaterial may help patients with chronic pancreatitis

Northwestern University researchers have developed a new antioxidant biomaterial that may one day provide much-needed relief to people suffering from chronic pancreatitis.

The study is scheduled to be published in the journal Neurology on June 7th. Scientific progress.

Before removing the pancreas from patients with severe and painful chronic pancreatitis, surgeons first harvest chunks of insulin-producing tissue called islets and transplant them into the liver's vasculature, with the goal of helping the patient maintain the ability to control their own blood sugar levels without insulin injections.

Unfortunately, this procedure unintentionally destroys 50-80% of the islets, and one-third of patients develop diabetes after the procedure. Three years after the procedure, 70% of patients require insulin injections, which come with a series of side effects, including weight gain, hypoglycemia, and fatigue.

In the new study, the researchers transplanted islets from the pancreas into the omentum (a large, flat, fatty tissue that covers the intestine) rather than into the liver, and to create a healthier microenvironment for the islets, they attached them to the omentum using a biomaterial that rapidly transforms from a liquid to a gel when exposed to body heat, essentially providing antioxidant and anti-inflammatory properties.

In studies using mice and non-human primates, the gel effectively prevented oxidative stress and inflammatory responses, significantly improving the survival and maintaining the function of transplanted islets. This is the first time a synthetic antioxidant gel has been used to maintain the function of transplanted islets.

“Although islet transplantation has improved over the years, long-term outcomes remain poor,” said Guillermo A. Amer of Northwestern University, who led the study. “It is clear that alternative solutions are needed. We have developed a cutting-edge synthetic material that provides a microenvironment that supports islet function. We tested it in animals and it was successful, preserving maximal islet function and returning blood glucose levels to normal. We also report that the animals required fewer units of insulin.”

“With this new approach, we hope patients will no longer have to choose between living with the physical pain of chronic pancreatitis or living with the complications of diabetes.”

Jacqueline Burke, a research assistant professor of biomedical engineering at Northwestern University and lead author of the paper.

Amir, an expert in regenerative engineering, is the Daniel Hale Williams Professor of Biomedical Engineering at Northwestern University's McCormick School of Engineering, a professor of surgery at Northwestern University's Feinberg School of Medicine, and founding director of the Center for Advanced Regenerative Engineering.

“Decreased quality of life”

For patients without a pancreas, side effects such as managing blood sugar levels can be a lifelong struggle. Pancreatic islets help the body control blood sugar levels by secreting insulin in response to glucose. Without functioning islets, patients must closely monitor their blood sugar levels and receive frequent insulin injections.

“Living without functioning islets is a huge burden for patients,” says Burke. “Patients must learn to count carbohydrates, take insulin at the right time, and continually monitor their blood glucose levels, which takes up a lot of time and mental energy. Even with the utmost care, exogenous insulin therapy is not as effective at managing blood glucose levels as islets. Patients whose blood glucose levels exceed thresholds suffer complications such as blindness and amputation. Our goal is to preserve the islets with this biomaterial and enable patients to live normal, diabetes-free lives.”

“This compromises quality of life,” Amir says. “Instead of giving them multiple insulin injections, we want to harvest and preserve as many islets as possible.”

Unfortunately, the current standard of care to preserve islets often produces poor outcomes. After surgery to remove the pancreas, surgeons separate the islets from the pancreas and transplant them into the liver via portal vein infusion. This intraportal perfusion procedure has several common complications: islets in direct contact with the bloodstream can develop an inflammatory response, causing more than half of the islets to die, and transplanted islets can cause dangerous blood clots in the liver. For these reasons, doctors and researchers have been searching for alternative transplant sites.

In previous clinical studies, researchers transplanted islets into the omentum rather than the liver to avoid clotting problems. To anchor the islets to the omentum, doctors used plasma from the patient's own blood to form a biological gel. Although the omentum seemed a better transplant site than the liver, some problems remained, such as blood clots and inflammation.

“There is great interest among researchers and the medical community in finding alternative sites for islet transplantation,” Amir says. “Results from the omental studies have been promising, but results have been mixed. We believe this is because the use of patient blood and the additional components required to make the biological gel may affect reproducibility between patients.”

Citric Acid Solution

To protect the islets and improve treatment outcomes, Amir turned to a citrate-based biomaterial platform developed in his lab that has inherent antioxidant properties. Used in U.S. Food and Drug Administration-approved products for musculoskeletal surgery, citrate-based biomaterials have demonstrated the ability to control the body's inflammatory response. Amir set out to investigate whether versions of these biomaterials, which are biodegradable and have temperature-responsive phase-change properties, could be a better alternative to blood-derived biological gels.

In cell culture, mouse and human islets preserved in the citrate-based gel maintained viability much longer than islets in other solutions. When exposed to glucose, the islets secreted insulin, demonstrating normal function. Beyond cell culture, Amir's team tested the gel in small and large animal models. The material, which is liquid at room temperature, transforms into a gel at body temperature, making it easy to apply and stay in place easily.

In animal studies, the gel effectively anchored pancreatic islets to the animals' omentum. Compared to current methods, more islets survived and over time the animals' blood sugar levels returned to normal. Amir attributes this success in part to the new material's biocompatibility and antioxidant properties.

“Pancreatic islets are very sensitive to oxygen,” Amir says, “They are affected by either too little or too much oxygen. The natural antioxidant properties of this substance protect the cells. Plasma taken from your own blood doesn't offer the same level of protection.”

Integration into the organization

After about three months, 80-90% of the biocompatible gel had been absorbed by the body, but at that point, the gel was no longer needed.

“What's interesting is that the islets revascularized,” Amir says. “The body generated a network of new blood vessels to reconnect the islets to the body. This is a major advance, because blood vessels keep the islets alive and healthy. Meanwhile, our gel was absorbed by the surrounding tissue, leaving almost no trace behind.”

Amir next aims to test the hydrogel over time in animal models, and he said the new hydrogel could also be used in a variety of cell replacement therapies, such as stem cell-derived beta cells for treating diabetes.

The research, “Phase-changing citrate polymer combats oxidative damage to pancreatic islets, enabling them to transplant and function in the omentum,” was supported by the Department of Defense and the National Science Foundation.