Northwestern University researchers have developed a thermoresponsive antioxidant biomaterial that they suggest may in the future be used to help improve the survival and function of islet cells in patients with chronic pancreatitis (CP) who undergo a procedure in which the pancreas is removed, and some of its islet cells are transplanted elsewhere in the body.

Reporting in Science Advances on their preclinical studies, the researchers describe transplanting islets from the pancreas to the omentum—the large, flat, fatty tissue that covers the intestines—rather than into the liver, which is the current procedure. To create a healthier microenvironment for the islets the researchers adhered the islets to the omentum using an inherently antioxidant and anti-inflammatory citrate-containing biomaterial—Poly(polyethylene) glycol citrate-co-N-isopropylacrylamide (PPCN)—that rapidly transforms from a liquid to a gel when exposed to body temperature.

In tests in mouse and in non-human primates (NHPs) the gel successfully prevented oxidative stress and inflammatory reactions, significantly improving survival and preserving function of transplanted islets. The study marks the first time a synthetic antioxidant gel has been used to preserve function of transplanted islets.

This images shows transplanted islets (darker purple) and the blood vessels (the red/dark pink areas are blood cells trapped within the blood vessels).
This images shows transplanted islets (darker purple) and the blood vessels (the red/dark pink areas are blood cells trapped within the blood vessels). [Northwestern University]

“Although islet transplantation has improved over the years, long-term outcomes remain poor,” said Northwestern’s Guillermo A. Ameer, PhD, who led the study. “There is clearly a need for alternative solutions. We have engineered a cutting-edge synthetic material that provides a supportive microenvironment for islet function. When tested in animals, we were successful. It kept islet function maximized and restored normal blood sugar levels. We also report a reduction in units of insulin that animals required.”

The researchers suggest the new hydrogel also could be used for various cell replacement therapies, including stem cell-derived beta cells for treating diabetes.

Ameer and colleagues describe their work in a paper titled “Phase- changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum.”

Chronic pancreatitis is a disease characterized by the progressive inflammation of pancreatic tissue, the authors explained. Patients with CP suffer from chronic abdominal pain, which commonly leads to hospitalization. As the disease progresses pancreatic tissue is destroyed and insulin-producing beta cell mass is significantly reduced. “There is no all-encompassing treatment for this disease,” the authors wrote. “Management includes lifestyle modifications, optimization of pain medications, and nutrition. Surgical intervention is the last resort for relieving pain when pharmacological options no longer work.”

When symptoms of CP become too severe and less invasive measures are not sufficient, patients commonly have their pancreas removed, a process known as total pancreatectomy (TP), and also undergo intrahepatic islet autologous transplantation (IAT). In IAT some of insulin-producing pancreatic islet tissue is harvested from the pancreas and transplanted back into the liver vasculature. The goal of TP-IAT is to preserve the patient’s ability to control their blood glucose levels without the need for insulin injections.

The current standard of care for preserving islets often leads to poor outcomes. After the surgery to remove the pancreas, The isolated islets are transplanted to the liver through portal vein infusion. This intraportal perfusion procedure has several common complications. Islets in direct contact with blood flow undergo an inflammatory response, more than half of the islets die, and transplanted islets can cause dangerous clots in the liver. “Deleterious conditions such as liver thrombosis, the instant blood-mediated inflammatory reaction (IBMIR), and oxidative stress are reported to contribute to substantial damage to the transplanted islets.”

Overall, the process can also inadvertently destroy 50–80% of islets, and one-third of patients become diabetic after surgery, the team noted. Three years post-surgery, 70% of patients require insulin injections, which are accompanied by a list of side effects, including weight gain, hypoglycemia and fatigue.

For those reasons, physicians and researchers have been searching for an alternate transplantation site. “There is a need for an alternative, extrahepatic islet transplant site and new islet delivery methods that provide a supportive microenvironment for islet function to improve the outcome of TP-IAT for patients with CP,” the authors stated.

From the clinical perspective, the great omentum is an ideal location for islet transplantation due to its large, well-vascularized area and accessibility via minimally invasive procedures, the scientists explained. However, there are challenges. “… since its physiological role involves protecting the peritoneal cavity from invading infectious diseases, the proinflammatory environment at the omentum site may result in unexpected severe inflammatory responses toward the transplanted islets and the biomaterial used to deliver them.”

In previous clinical studies, researchers transplanted islets to the omentum instead of the liver in order to bypass issues with clotting. To secure the islets on the omentum, physicians used plasma from the patients’ own blood to form a biologic gel. While the omentum appeared to work better than the liver as a transplantation site, several issues, including clots and inflammation, remained.

“There’s been significant interest in the research and medical communities to find an alternate islet transplantation site,” Ameer said. “The results from the omentum study were encouraging, but outcomes were varied. We believe that’s because the use of the patients’ blood and the added components required to create the biologic gel can affect reproducibility among patients.”

An expert in regenerative engineering, Ameer is the Daniel Hale Williams Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering, a Professor of Surgery at Northwestern University Feinberg School of Medicine and founding director of the Center for Advanced Regenerative Engineering.

To protect the islets and improve outcomes, Ameer turned to a citrate-based biomaterials platform with inherent antioxidant properties, which was developed in his laboratory. Used in products approved by FDA for musculoskeletal surgeries, citrate-based biomaterials have demonstrated the ability to control the body’s inflammatory responses. “Our laboratory pioneered the development of citrate- based biomaterials (CBBs) for regenerative engineering and regenerative medicine applications,” the team stated. “CBBs have reached a major translational milestone as they are used in bioresorbable implantable medical devices recently cleared by the U.S. Food and Drug Administration (FDA) for use in musculoskeletal surgeries with commercial applications in ankle, knee, and shoulder reconstruction.”

For their newly reported work Ameer and colleagues set out to investigate whether a version of these biomaterials with biodegradable and temperature-responsive phase-changing properties would provide a superior alternative to a biologic gel obtained from blood. “… we set out to investigate whether the omentum could potentially be a viable transplantation site for patients with CP if a scaffold can provide the proper microenvironment to protect and support the islets.” The authors stated. “We hypothesized that PPCN protects islets isolated from patients with CP against oxidative stress and prolongs their function in vitro and during extrahepatic islet transplantation.”

Their tests showed that in cell cultures, both mouse and human islets stored within the citrate-based gel maintained viability much longer than islets in other solutions. When exposed to glucose, the islets secreted insulin, demonstrating normal functionality. “… culturing islets in PPCN preserve sensitivity to glucose and associated insulin secretion function, likely by minimizing oxidation,” the investigators wrote.

Moving beyond cell cultures, Ameer’s team then tested the gel in small and large animal models. Liquid at room temperature, the material turns into a gel at body temperature, so it’s simple to apply and easily stays in place.

In the reported in vivo studies the gel effectively secured the islets onto the omentum of the animals. The results showed that when compared with the current methods, more islets survived, and, over time, the animals restored normal blood glucose levels. “… we demonstrate that PPCN can support IAT in an NHP model for over 100 days, resulting in vascularized islets and minimal exogenous insulin requirements,” the team stated.

This histological image shows the presence of insulin within the islets (brown stain).
This histological image shows the presence of insulin within the islets (brown stain). [Northwestern University]

.According to Ameer, the success is partially due to the new material’s biocompatibility and antioxidant nature. “Islets are very sensitive to oxygen,” Ameer said. “They are affected by both too little oxygen and too much oxygen. The material’s innate antioxidant properties protect the cells. Plasma from your own blood doesn’t offer the same level of protection.” After about three months, the body resorbed 80-90% of the biocompatible gel. But, at that point, it was no longer needed.


“What was fascinating is that the islets regenerated blood vessels,” Ameer said. “The body generated a network of new blood vessels to reconnect the islets with the body. That is a major breakthrough because the blood vessels keep the islets alive and healthy. Meanwhile, our gel is simply resorbed into the surrounding tissue, leaving little evidence behind.”

“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 first author Jacqueline Burke, a research assistant professor of biomedical engineering at Northwestern.

Noting limitations of their study, the authros concluded, “Given our results in mice and NHPs that demonstrate improved islet transplantation outcomes using PPCN and the practical and biological challenges with intraportal islet delivery such as liver thrombosis and IBMIRs, phase- changing antioxidant biomaterials such as PPCN can play an important role in islet function preservation, extrahepatic engrafment, and improving the quality of life of patients with CP.”

For patients living without a pancreas, side effects such as managing blood-sugar levels can be a lifelong struggle. By secreting insulin in response to glucose, islets help the body maintain glycemic control. Without functioning islets, people must closely monitor their blood-sugar levels and frequently inject insulin.

“Living without functional islets places a great burden on patients,” Burke said. “They must learn to count carbs, dose insulin at the appropriate time and continuously monitor blood glucose. This consumes much of their time and mental energy. Even with great care, exogeneous insulin therapy is not as effective as islets for maintaining glucose control. Patients with out-of-range blood glucose will develop complications, such as blindness and amputation. Our goal is for this biomaterial to preserve the islets, so patients can live a normal life—a life without diabetes.”

Ameer added “It’s a compromised quality of life. Instead of multiple insulin injections, we would love to collect and preserve as many islets as possible.” Next, Ameer aims to test his hydrogel in animal models over a longer period of time. He said the new hydrogel also could be used for various cell replacement therapies, including stem cell-derived beta cells for treating diabetes.

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