When swallowed, the capsule releases a dose of medication directly into the walls of the digestive tract, inspired by The Jets…

Inspired by the way squids navigate the ocean using jets and shoot clouds of ink, scientists at MIT and Novo Nordisk have developed an ingestible capsule that releases a dose of drugs directly into the stomach wall or other organs of the digestive tract.

This capsule could provide an alternative way to deliver drugs that would normally need to be injected, such as insulin and other large proteins, including antibodies. This needle-free strategy could also be used to deliver RNA as a vaccine or therapeutic molecule for the treatment of diabetes, obesity and other metabolic disorders.

One of the long-standing challenges we are investigating is the development of systems that enable oral delivery of macromolecules that typically require injection. This work represents one of the next significant advances in this process.”

Giovanni Traverso, director of the Translational Engineering Laboratory and associate professor of mechanical engineering at MIT, gastroenterologist at Brigham and Women’s Hospital, associate member of the Broad Institute and senior author of the study

Traverso and his MIT students developed the new capsule along with researchers from Brigham and Women’s Hospital and Novo Nordisk. The main authors of the article that appears today in .

Inspired by cephalopods

Medicines composed of large proteins or RNA usually cannot be taken orally because they are easily broken down in the gastrointestinal tract. For several years, the Traverso laboratory has been working on methods of oral administration of such drugs by encapsulating them in small devices that protect the drugs against degradation and then injecting them directly into the gastrointestinal mucosa.

Most of these capsules use a small needle or set of microneedles to deliver medications once the device reaches the digestive tract. In the new study, Traverso and his colleagues wanted to explore ways to deliver these molecules without using any needle, which could reduce the risk of tissue damage.

To achieve this, they took inspiration from cephalopods. Squid and octopuses can move on their own by filling their mantle cavity with water and then quickly releasing it through a siphon. By changing the force of the water push and directing the siphon in different directions, animals can control the speed and direction of movement. The siphon organ also allows the cephalopods to shoot jets of ink, creating clouds of decoys that distract predators.

Scientists have come up with two ways to mimic this ejection action, using compressed carbon dioxide or tightly wound springs to create the force needed to push liquid drugs out of the capsule. The gas or spring is held in a compressed state by a carbohydrate trigger, which is designed to dissolve when exposed to moisture or an acidic environment such as the stomach. When the trigger dissolves, the gas or spring can expand, ejecting a stream of medication from the capsule.

In a series of experiments using gastrointestinal tissue, researchers calculated the pressure needed to expel drugs so forcefully that they penetrated the submucosal tissue and accumulated there, creating a depot that then released the drugs into the tissue.

“In addition to eliminating sharp objects, another potential advantage of high-velocity columnar jets is their immunity to localization issues. Unlike a small needle that must be in close contact with the tissue, our experiments have shown that the jet may be able to deliver most of the dose from a long distance or at a shallow angle,” Arrick says.

Scientists also designed the capsules so that they could act on different parts of the digestive tract. One version of the capsule, which has a flat bottom and a tall dome, can be placed on a surface such as the stomach lining and eject the drug down into the tissue. Inspired by previous research in the Traverso lab on self-orienting capsules, this capsule is about the size of a blueberry and can hold 80 microliters of drug.

The second version is tube-shaped, so it can fit into a long tubular organ such as the esophagus or small intestine. In this case, the drug is thrown towards the side wall rather than down. This version can deliver 200 microliters of medicine.

Made of metal and plastic, the capsules can pass through the digestive tract and be expelled after releasing the medicine they contain.

Needle-free drug delivery

In animal tests, scientists showed that the capsules could deliver insulin, a GLP-1 receptor agonist similar to the antidiabetic drug Ozempic, and a type of RNA called short interfering RNA (siRNA). This type of RNA can be used to silence genes, making it potentially useful in the treatment of many genetic diseases.

They also showed that drug concentrations in the animals’ bloodstreams reached levels of the same order of magnitude as those observed after injecting drugs with a syringe.

The researchers anticipate that the swallowable capsule could be used at home by patients who need to frequently take insulin or other injectable medications. In addition to making medication administration easier, especially for patients who don’t like needles, this approach also eliminates the need to throw away sharp needles. The researchers also created and tested a version of the device that can be attached to an endoscope, allowing doctors to use it in an endoscopy suite or operating room to administer medications to a patient.

Scientists did not detect any tissue damage caused by the release of the drug. Now they plan to continue developing the capsules in hopes of testing them on humans.

The research was funded by Novo Nordisk, the Natural Sciences and Engineering Research Council of Canada, the MIT Department of Mechanical Engineering, Brigham and Women’s Hospital and the Health Advanced Research Projects Agency.