$4.9 Million NIH Grant Funds “Organ on a Chip” for Diabetes Research
A trio of Miller School of Medicine investigators has received a $4.9 million grant from the National Institutes of Health for a collaborative effort to move the search for novel treatments for diabetes to a new level. The grant, one of only four awarded, is a part of the Consortium on Human Islet Biomimetics, a group under the newly formed Human Islet Research Network.
The development of the cross-disciplinary project was assisted by the Diabetes Research Institute (DRI) and the Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute at the University of Miami (BioNIUM), which was founded in 2012 to encourage research collaborations throughout UM.
Over the next five years, the three scientists will engineer a human physiomimetic islet microsystem — colloquially called an “organ on a chip” — that they believe will help them learn more about many of the still-unexplained workings of pancreatic islets and the insulin-producing beta cells they contain. The team hopes to use the microchips to increase the current amount of islets available to transplant into patients with diabetes, screen pharmaceuticals for patients with diabetes and/or create beta cells from stem cells.
“The idea is to fabricate a microchip capable of mimicking the native islet,” said Cherie Stabler, Ph.D., associate professor of biomedical engineering and surgery, and Director of the Tissue Engineering Program at the DRI, who is one of the researchers who received the grant. “These platforms can then serve as a screening tool to understand drugs that may impair or enhance islet function, as well as to identify conditions that can help islets survive better.”
In a healthy person, beta cells sense rising levels of glucose in the blood — such as after a meal — and produce insulin to bring the glucose back down to normal levels. In people with type 1 diabetes, however, the beta cells are treated like an invading virus and destroyed by the body’s immune system. In type 2 diabetes, people slowly acquire insulin dysfunction, which prevents appropriate blood sugar control.
Beta cells are clustered — 3,000 to 4,000 strong — in pancreatic structures known as islets; it is estimated that a healthy, adult pancreas contains approximately one million islets. DRI researchers have already demonstrated that islets transplanted into diabetic patients can function for more than 12 years. The challenges are that the only source of islets for transplantation is human cadavers, making supply very limited; scientists are still searching for the optimal site in the body in which to transplant islets; and transplant patients must take anti-rejection drugs for the rest of their lives.
“The goal of my research laboratory is to duplicate the organ level functionality and complexity outside the human body and within fluidic microsystems,” said another of the researchers, Ashutosh Agarwal, Ph.D., assistant professor of biomedical engineering and pathology. “These organs on chips can serve as powerful tools in the hands of clinicians and bioengineers.”
The platform itself, he explained, is a structure about the size of a cell phone and is made of specialty glass, polymers and plastics. Its features — channels, valves, pumps and multiple wells — are in the size of microns, hence the microchip analogy. Each well, which will house islet cells embedded within coatings being tested, can be connected to its own plumbing line to receive nutrients and can have its own oxygen supply.
“A muffin pan on a micro scale is a good analogy, but think of each cup as having its own automated supply of ingredients instead of having to be filled manually,” said Agarwal. “This approach also will give us the opportunity to conduct experiments without using animal models. If we have a platform that successfully mimics human physiology and fools the cells into thinking they are still inside the body, then we can replace animal models and make our preclinical trials cheaper, better and more predictive of human outcomes.”
“If we take islets out of the pancreas, we can only culture them for a few days; they have to be put into a patient,” said Stabler. “We still don’t know how to culture islets properly. In fact, it’s one of the few primary cells we cannot effectively culture. Once we identify the parameters that will support islet culture, we will have an efficient, high-content approach to maintaining islets or even generating new ones from stem cells.”
The key is to create and support an environment that keeps the islets healthy, said DRI Director Camillo Ricordi, M.D., Stacy Joy Goodman Professor of Surgery, Distinguished Professor of Medicine, professor of biomedical engineering, microbiology and immunology, and Director of the Cell Transplant Program. He is the physician-scientist of the trio, and he will head up the project’s screening efforts with human insulin-producing cells.
“The proposed technologies will help us develop novel strategies to optimize survival, function and regeneration of insulin-producing cells, and will also help us define improved methods of producing islets from stem cells,” he said. “That capability would enable us to overcome the supply problem and help millions of people we cannot help now. This effort exemplifies the benefits of team science, and the collaborative interdisciplinary strategy that has always been central to DRI’s cure-focused research mission.”
“This project represents exactly the kind of work BioNIUM was intended to foster — cutting-edge science that addresses important problems in human health, crossing multiple disciplines and bringing together the brightest minds from across the University of Miami,” said Richard J. Cote, M.D., professor and Chair of the Department of Pathology, professor of biochemistry and molecular biology, and Director of BioNIUM. “One way we are fostering interdisciplinary research is by providing resources to recruit brilliant scientists who are not classical medical researchers. This is proof of principle that BioNIUM is bringing people together to promote research in a measurable way.”