Defeating Diabetes

Advances in Cell Encapsulation Technology

A young boy is rushed into the Emergency Department after being discovered unconscious. He’s with his mother, who reports that earlier that evening, her son had been thirsty, nauseous, and urinating frequently. He’s now gasping for air, and his breath smells fruity and sweet, like a sugary pear candy. It’s the smell of ketone bodies, molecules produced by the liver that cells use as fuel, and their presence is indicative of ketoacidosis—a dangerous complication of diabetes. Ketone bodies are acidic, so as they accumulate, the blood’s pH drops, leading to hyperventilation, nausea, and, in extreme cases, severe neurological and cardiac complications.

Given his symptoms, the boy likely suffers from type 1 diabetes, an autoimmune disease in which the patient’s immune system destroys islet cells in his pancreas. These cells are responsible for producing insulin, a hormone that helps your body absorb glucose from the bloodstream. Without sufficient insulin, blood sugar levels increase and contribute to disease. Diabetic ketoacidosis is a rapid-onset complication of type 1 diabetes that occurs because glucose is trapped in the bloodstream, so cells need an alternative source of energy—the ketone bodies—to keep functioning.

Diabetes treatments focus on maintaining normal insulin levels with daily injections, which sound easier than they are. These insulin injections can be uncomfortable, and remembering to keep to a schedule can be stressful and tiring. Furthermore, figuring out correct doses can be challenging, as these injections serve multiple purposes: patients must inject to maintain background levels of insulin, prepare for meals, and correct high blood sugar. Complicating the issue, different insulin products act on different time scales, and each person’s insulin sensitivity is unique. There is always the risk of overdose, especially after a missed meal, which could lower blood sugar beyond safe levels. For these reasons, researchers at Cornell University are improving designs on an alternative treatment for type 1 diabetes: cell transplantation. “Instead of delivering insulin through injection, we are trying to develop a technology to deliver cells, which can sense the glucose concentration and secrete insulin autonomously,” said Duo An, the PhD candidate at Cornell who led the research.

As with any transplant procedure, islet cell transplantation has risks. Since the cells are foreign to the host, the body recognizes them as invaders and launches an immune response. To prevent transplant rejection, patients must take immunosuppressive medications for the remainder of their lives, decreasing their ability to fight infectious diseases. Despite its dangers, immunosuppression is often a necessity unless the transplanted cells can be protected against the host’s immune system, as Cornell’s team is trying to do with cell encapsulation, a technique where they deliver cells within special membranes.

Cell encapsulation is not a new procedure. Attempts to coat transplanted materials with protective membranes occurred in as early as the 1960s; however, the technology is far from perfect. Even a current and promising cell encapsulation system, called hydrogel microcapsules, has a critical flaw: the microcapsules are difficult to retrieve completely after implantation. “To cure type 1 diabetes patients, we estimate that 500,000 pancreatic cell aggregates are required, which means you need to put tens of thousands of these microcapsules into the patients,” said An. “Because they are individual microcapsules, it’s almost impossible to retrieve all of the materials.” Without a better way to remove the microcapsules from a patient, clinical application of these devices has been restricted. If the membrane failed or the cells died and the microcapsules could not be safely removed, the situation could be dangerous to the recipient. Recognizing this obstacle to cell encapsulation technology, the Cornell research team sought to design an encapsulation device that was therapeutically successful, scalable, and retrievable.

Their original concept was simple. “At the beginning, we were thinking, ‘What if we used a thread to connect all of these microcapsules, like a necklace. Then they can be easily implanted and retrieved through a simple procedure,’” An said. Interestingly, this preliminary design was inspired by a spider’s web—the necklace-like structure would look like a strand of spider silk collecting droplets of dew, and the thread itself would mimic the properties of adhesive spider silk. In the final design, however, the hydrogel was layered uniformly around the string and islet cells more closely resembling a tube than a strand with beads.

While the concept was simple, the design proved to be more difficult. The hydrogel, the islet cells, and the modified sutures used to make the underlying thread all had to be compatible. Coordinating these components required a diverse array of knowledge, which challenged the researchers. “I needed to learn from basic chemistry, materials science, cellular biology, and biomedical engineering. I even needed to have some medical knowledge for the surgical procedure,” An said. In the end, the team’s efforts paid off, and they built a successful device.

The base layer for the device is a nylon suture, a biocompatible, medical-grade material that is often used for stiches. The suture was a good starting point, since it is commercially available and has been proven safe, yet it lacked certain properties that the researchers desired. They modified the sutures with a chemical solution to contain small pores and to release calcium chloride. Both of these modifications improved the thread’s ability to bind uniformly to the hydrogel: the porous surface allowed the hydrogel to penetrate the thread and strengthen the adhesion, and calcium promoted chemical bonds between the materials.

Once the modified thread had been made, the researchers cross-linked it with a hydrogel made from alginate, a biomaterial obtained from brown seaweed. The uniform layer of alginate hydrogel made the device biocompatible and prevented fibrosis, the thickening and scarring of tissue that sometimes occurs when foreign materials are implanted into animals. Blocking fibrosis around the device was critically important, since fibrosis would have blocked substances from diffusing to and from the device. While the cell encapsulation system is designed to protect transplanted cells from the immune system, it must still be semi-permeable so oxygen and nutrients can reach the cells.

After fabricating the device, the researchers tested the system’s biocompatibility and its ability to correct diabetes in mice. They also performed experiments in dogs to test whether they could increase the scale of transplantation in a larger mammal. The thread-reinforced hydrogel microcapsule system was successful in each trial, causing little to no fibrosis around sites of implantation, demonstrating therapeutic potential in diabetic mice, and remaining intact for complete retrieval from dogs. These results are a major step forward for cell encapsulation technology, as the new device will likely minimize the risks associated with this type of transplantation, making it a more viable option for treating type 1 diabetes.

At the moment, the Cornell team hopes to improve their cell encapsulation system, modifying it to become even more biocompatible and mechanically stable. They also want to scale up further, so they can deliver enough cells to cure a human patient. Research is ongoing in all of these areas, and eventually the team hopes to get the device into clinical trials.

Type 1 diabetes currently affects over one million Americans and is most often diagnosed in children and young adults. For these children, the leading cause of diabetes-related death is diabetic ketoacidosis, and it occurs most frequently when someone fails to administer a proper dose of insulin. “The final goal of this research is to find a cure to type 1 diabetes, so that patients no longer need to get painful and tedious insulin injections every day,” An said. While we are still far from curing type 1 diabetes, a cell encapsulation device could simplify management of this disease, reducing its burden on millions of lives.