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For individuals with Type 1 diabetes, experiencing hypoglycemia, or diminished blood sugar, is a constant risk. When glucose levels plummet to extreme lows, it can lead to a perilous situation, necessitating the administration of a hormone known as glucagon as the conventional treatment.
As a precautionary measure, in situations where patients might not be aware that their blood sugar is dropping to critical levels, engineers from MIT have developed an implantable reservoir that can sit just beneath the skin and be activated to dispense glucagon when blood sugar levels fall too low.
This method might also be beneficial in scenarios where hypoglycemia arises during sleep or for young diabetics who cannot self-administer injections.
“This is a compact, emergency-response device that can be implanted under the skin, ready to take action if the patient’s blood sugar dips too low,” states Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the Institute for Medical Engineering and Science (IMES), who is the principal author of the study. “Our aim was to create a device that is constantly prepared to safeguard patients from low blood sugar. We believe this can also mitigate the anxiety of hypoglycemia that numerous patients, along with their parents, experience.”
The researchers demonstrated that this gadget could also be utilized to deliver emergency doses of epinephrine, a medication employed to manage heart attacks and to avert severe allergic reactions, including anaphylactic shock.
Siddharth Krishnan, a former research scientist at MIT who currently serves as an assistant professor of electrical engineering at Stanford University, is the primary author of the study, published today in Nature Biomedical Engineering.
Emergency intervention
The majority of individuals with type 1 diabetes rely on daily insulin injections to assist their body in absorbing sugar and to keep their blood sugar levels from rising too high. However, if their blood sugar levels decline too much, they may develop hypoglycemia, which can result in confusion and seizures, and may even prove fatal if not addressed.
In order to counter low blood sugar, some patients carry pre-filled syringes of glucagon, a hormone that prompts the liver to release glucose into the bloodstream. Nevertheless, it is not always straightforward for individuals, particularly children, to recognize when they are becoming hypoglycemic.
“Some patients are able to sense when their blood sugar is low and then eat something or administer glucagon,” Anderson explains. “But others may be oblivious to their hypoglycemia and can swiftly descend into confusion and unconsciousness. This is also an issue when patients are asleep, as they depend on glucose sensor alarms to awaken them if their sugar levels drop dangerously low.”
To simplify the response to hypoglycemia, the MIT team aimed to develop an emergency device that could be activated by the user or automatically through a sensor.
The device, which is roughly the diameter of a quarter, consists of a small drug reservoir constructed from a 3D-printed polymer. The reservoir is sealed with a unique material known as a shape-memory alloy, capable of being programmed to alter its shape when heated. In this instance, the researchers utilized a nickel-titanium alloy designed to contour from a flat slab to a U-shape when heated to 40 degrees Celsius.
Like many other peptide-based medications, glucagon tends to degrade rapidly, meaning the liquid form cannot be stored long-term in the body. Therefore, the MIT team developed a powdered formulation of the drug, which remains stable for a more extended period and stays in the reservoir until it is dispensed.
Each device can hold either one or four doses of glucagon and features an antenna optimized to respond to a specific frequency in the radiofrequency spectrum. This capability allows it to be remotely activated to initiate a small electrical current, which heats the shape-memory alloy. As the temperature reaches the 40-degree threshold, the slab bends into a U-shape, thereby releasing the contents of the reservoir.
Since the device can receive wireless signals, it could also be designed to trigger drug release via a glucose monitor when the wearer’s blood sugar drops below a specified level.
“A key characteristic of this type of digital drug delivery system is that it can communicate with sensors,” Krishnan remarks. “In this case, the continuous glucose-monitoring technology utilized by many patients is something with which these devices can easily interface.”
Counteracting hypoglycemia
After implanting the device in diabetic mice, the researchers utilized it to initiate glucagon release as the animals’ blood sugar levels fell. Within under 10 minutes of activating the drug release, blood sugar levels began to stabilize, allowing them to remain within the normal range and prevent hypoglycemia.
The researchers also evaluated the device with a powdered formulation of epinephrine and discovered that within 10 minutes of drug release, epinephrine concentrations in the bloodstream rose and heart rates increased.
In this investigation, the researchers left the devices implanted for a duration of up to four weeks but now plan to determine if they can prolong that period to at least a year.
“The concept is to provide sufficient doses for this therapeutic rescue event to extend over a significant timeframe. We are still uncertain what that is—perhaps a year, possibly several years—and we are actively working on identifying the optimal lifespan. After that, it would need to be replaced,” Krishnan adds.
Typically, following the implantation of a medical device within the body, scar tissue forms around it, which could disrupt its functionality. However, in this study, the researchers demonstrated that even after fibrotic tissue developed around the implant, they could successfully initiate drug release.
The researchers are now strategizing for further animal studies and hope to commence clinical trials within the next three years.
“It’s genuinely thrilling to witness our team’s achievement, which I hope will someday benefit diabetic patients and could more broadly revolutionize the delivery of any emergency medication,” states Robert Langer, the David H. Koch Institute Professor at MIT and a co-author of the paper.
Other contributors to the paper include Laura O’Keeffe, Arnab Rudra, Derin Gumustop, Nima Khatib, Claudia Liu, Jiawei Yang, Athena Wang, Matthew Bochenek, Yen-Chun Lu, Suman Bose, and Kaelan Reed.
This research was supported by the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, a JDRF postdoctoral fellowship, and the National Institute of Biomedical Imaging and Bioengineering.
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