Implantable devices that release insulin into the body show promise as an alternative way to treat diabetes without insulin injections or cannula insertions. However, one obstacle that has prevented their use so far is that the immune system attacks them after implantation, forming a thick layer of scar tissue that blocks the release of insulin.
This phenomenon, known as the foreign body reaction, can also interfere with many other types of implantable medical devices. However, a team of MIT engineers and collaborators has now found a way to overcome this response. In a mouse study, they showed that when they incorporated mechanical actuation into a soft robotic device, the device remained functional much longer than a typical drug delivery implant.
The device is repeatedly inflated and deflated for five minutes every 12 hours, and this mechanical deviation prevents immune cells from accumulating around the device, the researchers found.
“We’re using this kind of motion to extend the life and effectiveness of these implanted reservoirs that can deliver drugs like insulin, and we think this platform can be extended beyond this application,” says Ellen Roche, career development associate for the Latham family. Professor of Mechanical Engineering and Fellow of the Institute for Medical Engineering and Science at MIT.
Among other possible applications, the researchers now plan to see if they can use the device to deliver pancreatic islet cells that could act as a “bioartificial pancreas” to help treat diabetes.
Roche is co-lead author of the study, along with Eimear Dolan, a former postdoc in his lab who is now a faculty member at the National University of Ireland in Galway. Garry Duffy, also a professor at NUI Galway, is a key contributor on the job, which appears in Nature Communication. MIT postdocs William Whyte and Debkalpa Goswami, along with visiting scholar Sophie Wang, are the lead authors of the paper.
Modulation of immune cells
Most patients with type 1 diabetes, and some with type 2 diabetes, need to inject insulin daily. Some patients use portable insulin pumps attached to the skin that deliver insulin through a tube inserted under the skin, or patches that can deliver insulin without a tube.
For many years, scientists have been working on insulin delivery devices that could be implanted under the skin. However, the fibrous capsules that form around these devices can lead to device failure within weeks or months.
Researchers have tried many approaches to prevent the formation of this type of scar tissue, including local administration of immunosuppressants. The MIT team took a different approach that doesn’t require any medication — instead, their implant includes a soft, mechanically-actuated robotic device that can be inflated and deflated. In a 2019 study, Roche and colleagues (with Dolan as first author) showed that this type of oscillation can modulate how nearby immune cells respond to an implanted device.
In the new study, the researchers wanted to see if this immunomodulatory effect could help improve drug delivery. They constructed a two-chambered device out of polyurethane, a plastic that has similar elasticity to the extracellular matrix that surrounds tissue. One of the chambers acts as a drug reservoir and the other acts as a flexible, inflatable actuator. Using an external controller, researchers can stimulate the actuator to inflate and deflate on a specific schedule. For this study, they performed the actuation every 12 hours, for five minutes at a time.
This mechanical activation wards off immune cells called neutrophils, the cells that initiate the process that leads to the formation of scar tissue. When the researchers implanted these devices in mice, they found that it took much longer for scar tissue to grow around the devices. The scar tissue eventually formed, but its structure was unusual: instead of the tangled collagen fibers that accumulated around the static devices, the collagen fibers surrounding the actuated devices were more tightly aligned, which the researchers say , could help drug molecules pass through tissues.
“In the short term, we see that there are fewer neutrophils surrounding the device in the tissues, then in the long term, we see that there are differences in the architecture of the collagen, which may be related to the reason why we have better drug delivery throughout the eight-week period,” says Wang.
Sustained drug delivery
To demonstrate the potential usefulness of this device, the researchers showed that it could be used to deliver insulin to mice. The device is designed so that insulin can slowly seep through the pores of the drug reservoir or be released in a large burst controlled by the actuator.
The researchers assessed the efficiency of insulin release by measuring subsequent changes in the mice’s blood sugar levels. They found that in mice with the device powered on, effective insulin delivery was maintained throughout the eight weeks of the study. However, in mice that did not receive actuation, delivery efficiency began to decline after only two weeks, and after eight weeks, almost no insulin was able to pass through the fibrous capsule.
The authors also created a human-sized version of the device, 120 millimeters by 80 millimeters, and showed that it could be successfully implanted in the abdomen of a human corpse.
“This was a proof-of-concept to show that there is a minimally invasive surgical technique that could potentially be used for a larger, human-scale device,” Goswami said.
Working with Jeffrey Millman of Washington University School of Medicine in St. Louis, the researchers now plan to adapt the device so that it can be used to deliver stem cell-derived pancreatic cells that would sense glucose levels and secrete insulin when glucose is too high. Such an implant could eliminate the need for patients to constantly measure their blood sugar and inject insulin.
“The idea would be that the cells reside in the reservoir and act like an insulin factory,” Roche explains. “They would sense blood glucose levels and then release insulin based on what was needed.”
Other possible applications researchers have explored for this type of device include delivering immunotherapy to treat ovarian cancer and delivering drugs to the heart to prevent heart failure in patients who have had heart attacks.
“You can imagine that we can apply this technology to anything that’s bothered by a foreign body response or a fibrous capsule, and have a long-lasting effect,” says Roche. “I think any type of implantable drug delivery device could benefit from this.”
The research was funded, in part, by the Science Foundation Ireland, the Juvenile Diabetes Research Foundation and the National Institutes of Health.