For people with type 1 diabetes, the onset of hypoglycemia or hypoglycemia is an ever-present threat. When glucose levels are very low, standard care treatments create life-threatening situations in which the hormone glucagon is injected.
As an emergency backup, if patients may not notice that their blood glucose levels have fallen to dangerous levels, MIT engineers have designed an implantable reservoir that remains under the skin and causes glucagon to be released if blood glucose levels are too low.
This approach is also useful if hypoglycemia occurs during sleep or if you have diabetic children who are unable to give the injections themselves.
“This is a small emergency device that can be placed under the skin that is ready to act if a patient's blood glucose level is too low,” says Daniel Anderson, a professor at MIT's Department of Chemical Engineering, a member of MIT's Institute of Integrated Cancer Research and Medical Engineering Sciences (IMES) and senior author of the study. “Our goal was to build a device that was always ready to protect patients from hypoglycemia. I think this will also help alleviate the fear of hypoglycemia that many patients and their parents suffer.”
The researchers have shown that the device can be used to provide emergency doses of epinephrine, a drug used to treat heart attacks and that can prevent severe allergic reactions, including anaphylactic shock.
Siddharth Krishnan, a former MIT research scientist and currently an assistant professor of electrical engineering at Stanford University, is the lead author of the work that appears today in essential biomedical engineering.
Emergency response
Most patients with type 1 diabetes use daily insulin injections to ensure that their bodies absorb sugar and don't get too high in blood sugar. However, if your blood sugar levels get too low, hypoglycemia can lead to confusion and seizures, which can be fatal without treatment.
To combat hypoglycemia, some patients carry preloaded syringes of glucagon, a hormone that stimulates the liver and releases glucose into the bloodstream. However, it is not always easy for people, especially children, to know that it will become a hypoglycemic drug.
“Some patients can feel when their blood sugar levels are low, and they can eat something or give them glucagon,” says Anderson. “But some people don't realize they have hypoglycemia, while others don't realize that they can lead to confusion or coma. This is also a problem when patients sleep. Because when sugar is dangerously low, they rely on glucose sensor alarms to wake them up.”
To help combat hypoglycemia, the MIT team has begun designing emergency devices that users can trigger, or emergency devices that can be triggered automatically by sensors.
The quarterly sized device includes a small drug reservoir made of 3D printed polymers. The reservoir is sealed with a special material known as shape memory alloys and can be programmed to change shape upon heating. In this case, the researchers used nickel titanium alloy and were programmed to curl from flat slabs into a U-shaped shape when heated to 40 degrees Celsius.
Like many other proteins and peptide drugs, glucagon tends to break quickly, so liquids cannot be stored in the body for long periods of time. Instead, the MIT team created a powdered version of the drug. The drug remains stable forever and remains in the reservoir until it is released.
Each device can carry one or four doses of glucagon. It also includes antennas that are tuned to respond to specific frequencies in the radio frequency range. This will be triggered remotely to turn on a small current. This is used to heat shape memory alloys. When the temperature reaches a 40°C threshold, the slab bends into a U-shaped shape, releasing the contents of the reservoir.
Because the device can receive wireless signals, it can also be designed so that a glucose monitor will trigger drug release when the wearer's blood glucose level falls below a certain level.
“One of the key features of this type of digital drug delivery system is that it can talk to sensors,” says Krishnan. “In this case, the ongoing glucose monitoring techniques used by many patients are easy for these types of devices to interface.”
Reversal of hypoglycemia
After implanting the device in diabetic mice, researchers used it to induce the release of glucagon while the blood glucose level in the animal was falling. Less than 10 minutes after activating drug release, my glucose levels began to flatten, staying within normal ranges, and avoiding hypoglycemia.
The researchers also tested the device with a powdered version of epinephrine. They found that within 10 minutes of drug release, epinephrine levels in the bloodstream increased and heart rate increased.
In the study, researchers implanted the device for up to four weeks, but are currently planning to see if the time can be extended to at least one year.
“The idea is that we have enough doses to provide this therapeutic rescue event for quite some time. We don't know exactly what it is. We're working on establishing what the optimal lifespan is, perhaps a year, several years, and now.
Usually, when medical devices are implanted inside the body, scar tissue can develop around the device, which can interfere with its function. However, in this study, the researchers showed that drug release can be successfully triggered even after fibrous tissue has been formed around the implant.
Researchers are currently planning additional animal studies and hope to begin testing the device in clinical trials within the next three years.
“It's really exciting to see our team achieve this and hope that one day we can provide a new paradigm to help diabetics and provide emergency care more broadly,” says Robert Langer, professor of David H. Koch Institute at MIT and author of the paper.
Other authors of this paper include Laura O'Keefe, Alnab Rudra, Delin Gumstop, Nima Katib, Claudia Liu, Jawai Yang, Athena Wang, Matthew Bochenek, Yen Chun Lu, Suman Bose and Kaern Reed.
This study was funded by Leona M. and Harry B. Helmsley Charible Trust, National Institutes of Health, JDRF Postdoc Fellowship, and National Institutes of Biomedical Imaging and Bioengineering.