Inspired by the way squid use jets to propel themselves through the ocean and shoot clouds of ink, researchers at MIT and Novo Nordisk have developed an ingestible capsule that releases a blast of drugs directly into the lining of the stomach or other organs of the digestive tract. .
This capsule could offer an alternative way to administer drugs that 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, either as a vaccine or as a therapeutic molecule to treat diabetes, obesity and other metabolic disorders.
One of the long-standing challenges we are exploring is the development of systems that enable oral delivery of macromolecules that typically require an injection to deliver. This work represents one of the next major advances in this progression. »
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 in collaboration with researchers from Brigham and Women's Hospital and Novo Nordisk. Graham Arrick SM '20 and Novo Nordisk scientists Drago Sticker and Aghiad Ghazal are lead authors of the paper, which appears today in Nature.
Inspired by cephalopods
Medications made from large proteins or RNA generally cannot be taken orally because they break down easily in the digestive tract. For several years, Traverso's lab has been working on ways to administer these drugs orally by encapsulating them in small devices that protect them from degradation, then injecting them directly into the lining of the digestive tract.
Most of these capsules use a small needle or set of microneedles to deliver medications once the device enters the digestive tract. In the new study, Traverso and colleagues wanted to explore ways to administer these molecules without any sort of needle, which could reduce the risk of tissue damage.
To achieve this, they took inspiration from cephalopods. Squid and octopuses can propel themselves by filling their mantle cavity with water, then quickly expelling it through their siphon. By changing the force of water expulsion and pointing the siphon in different directions, animals can control their speed and direction of movement. The siphon organ also allows cephalopods to shoot jets of ink, forming decoy clouds to distract predators.
The researchers found two ways to mimic this throwing action, using compressed carbon dioxide or tightly wound springs to generate the force needed to propel the liquid medications out of the capsule. The gas or spring is held in a compressed state by a carbohydrate trigger, 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, propelling a stream of medication out of the capsule.
In a series of experiments using tissue from the digestive tract, researchers calculated the pressures needed to expel drugs with enough force for them to penetrate the submucosal tissue and accumulate there, creating a deposit that would then release the drugs into the tissues.
» Besides eliminating sharps, another potential advantage of high-velocity column jets is their robustness to localization issues. Unlike a small needle, which must have intimate contact with the tissue, our experiments indicated that a jet might be capable of delivering most of the dose from a distance or at a slight angle,” says Arrick.
The researchers also designed the capsules so that they could target different parts of the digestive tract. A version of the capsule, with a flat bottom and a tall dome, can sit on a surface, such as the stomach lining, and eject the medication downward into the tissues. This capsule, inspired by previous research from Traverso's lab on self-directing capsules, is about the size of a blueberry and can hold 80 microliters of medication.
The second version has a tubular shape that allows it to align within a long tubular organ such as the esophagus or small intestine. In this case, the medicine is ejected towards the side wall rather than down. This version can deliver 200 microliters of medication.
Made of metal and plastic, the capsules can pass through the digestive tract and are excreted after releasing their drug load.
Needle-free medication administration
In animal tests, researchers showed that they could use these capsules to deliver insulin, a GLP-1 receptor agonist similar to the diabetes 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 treating many genetic disorders.
They also showed that the concentration of the drugs in the animals' blood reached levels of the same order of magnitude as those observed when the drugs were injected with a syringe.
Researchers envision that the ingestible capsule could be used at home by patients who need to take frequent insulin or other injected medications. In addition to making medication administration easier, especially for patients who don't like needles, this approach also eliminates the need to dispose of sharp needles. The researchers also created and tested a version of the device that could be attached to an endoscope, allowing doctors to use it in an endoscopy suite or operating room to administer medication to a patient.
The researchers did not detect any tissue damage caused by the release of the drug. They now plan to develop the capsules further, hoping to test 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 Advanced Research Projects Agency for Health.
