Researchers at Northwestern University have developed a new antioxidant biomaterial that could one day provide much-needed relief to people living with chronic pancreatitis.
The study will be published on June 7 in the journal. Scientific advances.
Before surgeons remove the pancreas from patients with severe, painful chronic pancreatitis, they first collect clumps of insulin-producing tissue, called islets, and transplant them into the liver vasculature. The goal of transplant is to preserve the patient’s ability to control their own blood glucose levels without insulin injections.
Unfortunately, the process inadvertently destroys 50% to 80% of islets and one-third of patients become diabetic after surgery. Three years after surgery, 70% of patients require insulin injections, which are accompanied by a list of side effects, including weight gain, hypoglycemia and fatigue.
In the new study, researchers transplanted islets from the pancreas to the omentum (the large, flat fatty tissue that covers the intestines) instead of the liver. And, to create a healthier microenvironment for the islets, the researchers attached the islets to the omentum with an inherently antioxidant and anti-inflammatory biomaterial, which rapidly transforms from liquid to gel when exposed to body temperature.
In studies with mice and non-human primates, the gel successfully prevented oxidative stress and inflammatory reactions, significantly improving survival and preserving function of transplanted islets. This is the first time that a synthetic antioxidant gel has been used to preserve the function of transplanted islets.
“Although islet transplantation has improved over the years, long-term outcomes remain poor,” said Guillermo A. Ameer of Northwestern, who led the study. “There is clearly a need for alternative solutions. We have designed a cutting-edge synthetic material that provides a supportive microenvironment for islet function. When we tested it in animals, we were successful. It kept islet function maximized and restored normal levels of blood sugar. They also report a reduction in the units of insulin that the animals required.
“With this new approach, we hope that patients will no longer have to choose between living with the physical pain of chronic pancreatitis or the complications of diabetes,” added Jacqueline Burke, research assistant professor of biomedical engineering at Northwestern and first author of the article. .
An expert in regenerative engineering, Ameer is the Daniel Hale Williams Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering, Professor of Surgery at Northwestern University’s Feinberg School of Medicine, and founding director of the Center for Advanced Regenerative Engineering.
‘Committed quality of life’
For patients living without a pancreas, side effects, such as controlling blood sugar levels, can be a lifelong struggle. By secreting insulin in response to glucose, islets help the body maintain glycemic control. Without functional islets, people must closely monitor their blood sugar levels and inject insulin frequently.
“Living without functional islets puts a huge burden on patients,” Burke said. “They must learn to count carbohydrates, dose insulin at the right time, and continually monitor blood glucose. This consumes much of their time and mental energy. Even with great care, exogenous insulin therapy is not as effective as islets to maintain glucose control. Patients with blood glucose levels out of range will develop complications, such as blindness and amputation. Our goal is for this biomaterial to preserve the islets, so that patients can live a normal life, a life. without diabetes.”
“It’s a compromised quality of life,” Ameer said. “Instead of multiple insulin injections, we would love to collect and preserve as many islets as possible.”
But unfortunately, the current standard of care for islet preservation often leads to poor outcomes. After surgery to remove the pancreas, surgeons isolate islets from the pancreas and transplant them to the liver through an infusion into the portal vein. This intraportal perfusion procedure has several common complications. Islets in direct contact with blood flow suffer an inflammatory response, more than half of islets die, and transplanted islets can cause dangerous clots in the liver. For those reasons, doctors and researchers have been searching for an alternative transplant site.
In previous clinical studies, researchers transplanted islets to the omentum instead of the liver to avoid clotting problems. To secure the islets in the omentum, doctors used plasma from the patients’ own blood to form a biological gel. Although the omentum seemed to perform better than the liver as a transplant site, several problems remained, including clots and inflammation.
“There has been significant interest in the medical and research communities in finding an alternative site for islet transplantation,” Ameer said. “The results of the omentum study were encouraging but varied. We believe this is because the use of patients’ blood and the added components needed to create the biologic gel may affect reproducibility between patients.”
a citrate solution
To protect islets and improve outcomes, Ameer turned to the citrate-based biomaterials platform with inherent antioxidant properties developed in his lab. Used in products approved by the US Food and Drug Administration for musculoskeletal surgeries, citrate-based biomaterials have demonstrated the ability to control the body’s inflammatory responses. Ameer set out to investigate whether a version of these biomaterials with biodegradable and temperature-sensitive phase change properties would provide a superior alternative to a biological gel obtained from blood.
In cell cultures, both mouse and human islets stored within the citrate-based gel maintained their viability much longer than islets in other solutions. When exposed to glucose, islets secrete insulin, demonstrating normal functionality. Beyond cell cultures, Ameer’s team tested the gel in small and large animal models. Liquid at room temperature, the material turns to gel at body temperature, making it easy to apply and stays in place with ease.
In animal studies, the gel effectively fixed islets in the animals’ omentum. Compared to current methods, more islets survived and, over time, the animals restored normal blood glucose levels. According to Ameer, the success is due in part to the biocompatibility and antioxidant nature of the new material.
“Islets are very sensitive to oxygen,” Ameer said. “They are affected by both lack of oxygen and excess oxygen. The innate antioxidant properties of the material protect the cells. The plasma of the blood itself does not offer the same level of protection.”
Integrate into tissues
After about three months, 80 to 90% of the biocompatible gel was reabsorbed by the body. But at that point it was no longer necessary.
“What’s fascinating is that the islets regenerated blood vessels,” Ameer said. “The body generated a network of new blood vessels to reconnect the islets to the body. This is a breakthrough because the blood vessels keep the islets alive and healthy. Meanwhile, our gel simply reabsorbs into the surrounding tissue, leaving little evidence behind. “.
Ameer intends to test its hydrogel in animal models over a longer period of time. He said the new hydrogel could also be used for various cell replacement therapies, including stem cell-derived beta cells for the treatment of diabetes.
The study, “Phase change citrate macromolecule combats oxidative damage to pancreatic islets, enables islet engraftment and function in the omentum,” was supported by the U.S. Department of Defense and the National Science Foundation.