If transplanting an organ or a cell into a person came without the risk of rejection, patients would be able to receive donated organs and cells with more ease.
The fact of the matter, however, is that when a foreign organ or cell is transplanted into the human body, it will recognize that this is not its own “self” and will take measures to reject it. The same holds true when donor islets are transplanted into a person with type 1 diabetes. Not only will the patient’s immune system reject the foreign cells, but the islets will be destroyed by the same autoimmune attack that caused the onset of diabetes.
Scientists at the Diabetes Research Institute (DRI) are at the forefront of developing technologies to protect transplanted islets from being attacked and keeping them stable, efficient and long lasting.
No Two Islets are Alike
The DRI is developing ways to protect the integrity of transplanted islets by encapsulating or “hiding” them from the host’s immune system.
Over the years, however, the DRI has learned that there is more to protecting transplanted islets than just sticking them in a capsule and throwing them in a site where they can fit in patients.
Like snowflakes, no two islets are alike. They are actually cell clusters, with each islet cell containing 2,000-4,000 cells inside, depending on the size of the islet itself. Each of those cells within the islet requires oxygen to survive – and lots of it.
In the past, traditional capsules were designed to accommodate the largest-sized islets. Oftentimes, this resulted in capsules that were too large for the smaller islets, leaving extra space inside the capsule, which delayed access to oxygen and nutrients, and caused the islet to die.
All that extra room inside the capsule delayed the islet’s main function, which is sensing blood glucose and releasing the right amount of insulin to maintain normal blood sugar levels (Normal is 70-110). Large capsules also limited where they could be placed in the body because they needed too much space.
A Solution: Conformal Coating
In collaboration with Ècole Polytechnique Fèdèrale de Lausanne (EPFL) in Switzerland, the DRI has ushered out the “one-size-fits-all” capsule of yesterday. In its place, its researchers have developed a new process of “conformal coating” islets that, in essence, creates a tight-fitting, “shrink-wrapped” shield around each cell.
Alice Tomei, Ph.D., (left) director of the DRI’s Islet Immunoengineering Laboratory , has invented and continues to optimize new technologies to individually coat the islets. To make the coatings even better, Dr. Tomei in 2015 brought in Diana Velluto Ph.D., (right) an assistant scientist and polymer chemist whose expertise is working with biomaterials – synthetic materials that mimic natural materials.
Dr. Velluto was thrilled to be joining the DRI team. Ever since her grandmother passed away from diabetes complications, she has wanted to put her skills to work in a way that could help other people with diabetes. Prior to being on staff at the DRI, both Drs. Velluto and Tomei were colleagues, working together with Jeffrey Hubbell, Ph.D., who was professor of biomedical engineering at the EPFL during that time and is currently Barry L. MacLean Professor of Molecular Engineering Innovation and Enterprise at the University of Chicago.
“Dr. Tomei works on making biocompatible capsules to protect pancreatic islets during transplantation,” says Dr. Velluto. “My research area of expertise is preparing biomaterials of different compositions to make those capsules and also improve the environment inside the capsules…I am able to improve their stability over time in vivo, modify the materials in order to incorporate any kind of products [such as drugs, nutrients etc.], and to control the release of their content.”
A Very Fine Net…but Not Too Fine
Encapsulating islets with a conformal coating takes the concept of putting a protective barrier around the islet to the next level. Dr. Tomei says you need to put something around the islet that allows oxygen to be transported through this barrier so that the islet is allowed to breathe.
“You need something so that food can get in and waste can get out, so that the islet can actually live in this new home that you are creating for it,” says Dr. Tomei, who likens the conformal coating process to using a very fine net that is not too fine.
By designing a thin, complete and uniform coating of similar thickness on different-sized islets, the incorporation of oxygen and other products improve the transport of food and waste, reducing the time necessary for oxygen to go from the blood vessels that will be surrounding the capsules to the islet’s surface. Delivering oxygen and anti-inflammatory agents to the deepest cells within the islets will help them survive and thrive.
“The size of the islet does not really matter,” says Dr. Velluto. “What matters is the thickness of the coating around the islet. The uniformity makes the flow of the products constant.”
An Upgrade Over Previous Encapsulation Techniques
The conformal coated capsules are made of biomaterials, and offer DRI investigators opportunities to further improve the technology. Because the material used for conformal coating is designed to be passive, it does not react with proteins or other molecules at the transplant site.
According to Dr. Velluto, the biomaterials that she develops will serve to enhance the shape, size and thickness of the capsules. They also enable the team to incorporate anti-inflammatory agents, oxygen promoters and other factors key to the health of islets.
“So far I have been able to design and develop different types of biocompatible nanocarriers. They are different in shape, size and stability,” she explained. “Those nanocarriers are all able to load products, such as drugs or oxygen, in an efficient manner, and they are not toxic in vitro or in vivo.”
Normal Blood Sugars Achieved for 100 Days
According to a recent study published in the Proceedings of the National Academy of Sciences, DRI researchers found that conformal coating allows for complete encapsulation of islets with a thin continuous layer of hydrogel.
In diabetic mice transplanted with conformal coated islets, the function of the islets protected by encapsulation were comparable to that of un-encapsulated islets. These models also maintained normal blood glucose for 100 days with no foreign-body reaction and normal revascularization.
In experiments comparing conformal coated islets with un-encapsulated islets, both demonstrated the same ability to sense glucose and release insulin efficiently. This showed that the capsule did not delay the diffusion rate.
Through the conformal-coating process combined with her new nanotechnology strategies and her biomaterials, Dr. Velluto expects to further promote the survival of the transplanted islets.
“I am really confident that the biomaterials are stable and biocompatible, but also very versatile so that I can modify them based on the results we get in the experimental models,” she says.
Dr. Velluto concludes that the critical point is the composition of the material to make the capsules.
“Despite the fact that, in the last decade, many new biomaterials have been developed, they still need to be optimized for their stability, biocompatibility and versatility in order to make them ideal for cell encapsulation, and mostly for the conformal coating technique. I am strongly dedicated to reaching this goal.”