In an effort to create needle-less administration of drugs, researchers at MIT and Novo Nordisk have taken inspiration from the jet propulsion mechanisms of cephalopods to develop an innovative ingestible capsule. This capsule delivers a drug payload directly into the digestive tract lining without needles.
“One of the longstanding challenges that we’ve been exploring is the development of systems that enable the oral delivery of macromolecules that usually require an injection to be administered,” said Giovanni Traverso, PhD, MIT and Brigham Women’s Hospital. “This work represents one of the next major advances in that progression.”
The Traverso team’s research paper titled, “Cephalopod-inspired jetting devices for gastrointestinal drug delivery,” was published in Nature.
Oral drug administration is not a possibility for many drugs, including large proteins or RNAs, as those materials are easily digested. Traverso’s team addresses this issue with their small capsule designs. Previous designs were small and utilized microneedles to deliver the drug payload to digestive tract tissues.
The current capsules were designed to deliver the contents without needles, instead using jet propulsion. The team drew inspiration from nature, specifically cephalopods like squids, which are known for their ink ejection abilities. To mimic this natural mechanism, the researchers created capsules containing compressed carbon dioxide or tightly coiled springs to create the necessary propulsion force.
“Adapting the jet mechanism for drug delivery required addressing several key challenges: precision, safety, and miniaturization,” Traverso told GEN. “Generating enough pressure to deliver drugs effectively without causing tissue damage was a critical hurdle. Fine-tuning the pressure, velocity, and incident wobble angle of the jets was essential to ensure consistent penetration and minimize trauma.”
He continued, “Translating the jet mechanism into a compact, ingestible format posed significant engineering challenges. This included integrating fluid reservoirs, jet actuation systems, and power sources while ensuring biocompatibility.”
Triggering the propulsion mechanism at the right time was another challenge. The capsule contains a carbohydrate cover that dissolves when exposed to moisture or acids. Once the trigger dissolves, the drugs are propelled out of the capsule. The researchers calculated controlled parameters for the ejection pressure, which Traverso said, “can be tailored to accommodate drugs with different viscosities and molecular sizes.”
Lead author Graham Arrick, MIT, added, “Aside from the elimination of sharps, another potential advantage of high-velocity columnated jets is their robustness to localization issues. In contrast to a small needle, which needs to have intimate contact with the tissue, our experiments indicated that a jet may be able to deliver most of the dose from a distance or at a slight angle.”
To this point, different capsules were designed to deliver materials to different regions of the digestive system. One capsule is dome-shaped and designed for downward ejection of the 80 µl volume, while an alternate design is a larger, tube-shaped capsule with a volume of 200 µl, which propels the drug payload to the sides.
Traverso told GEN, “The capsule design is highly adaptable and was intentionally developed to handle a wide range of drug types.” Further, their newly designed capsules “include interchangeable drug reservoirs, allowing for delivery of solutions, suspensions, and particulate formulations like nanoparticles.”
This delivery system is nearing clinical readiness, having been tested in vivo in pigs and dogs for efficacy and safety. They found the concentration of drugs in the animals’ bloodstream reached the same levels in capsule trials as with injections using GLP-1 receptor agonists and siRNAs. The team is continuing studies for targets including oncology, rare disease treatments, and vaccinations.
As the research progresses to clinical applications, Traverso stressed that safety is a primary concern: “Preclinical studies include histological analysis to ensure that jet delivery does not cause lasting tissue damage or inflammation. For chronic conditions requiring repeated use, the system will undergo rigorous testing to evaluate potential cumulative effects, such as altered tissue response or mechanical wear.”
Traverso shared with GEN that the team is “finalizing design iterations to ensure scalability and manufacturability.” With consideration of the endpoint of all materials traveling through a digestive tract, he explained that “the capsule is designed to disassemble or be excreted naturally through the gastrointestinal tract without residue. Animal studies have confirmed this pathway.” He also pointed out that “all capsule components are made from FDA-approved, biocompatible materials to minimize the risk of adverse reactions.”
Looking ahead, Traverso expressed excitement at “the opportunity to address unmet clinical needs and provide needle-free solutions for conditions that currently rely on invasive or less efficient delivery methods.” He concluded: “We’re particularly excited about the broad applicability of this technology and the potential for global impact.”
