More than 300 years ago, British architect and scientist Sir Christopher Wren became interested in drug delivery, hoping to find a way to directly inject drugs or liquids into the human body. He made a simple syringe using tools such as goose feathers and metal tubes, and for the first time attempted to inject drug solution into a dog's veins through injection. Since then, "injection" has gradually become a widely used method of drug delivery. Today, many large molecule biologics, such as recombinant insulin, monoclonal antibodies, and vaccines, are mainly injected into the human body to exert their therapeutic effects.

However, the pain and trouble caused by injection are self-evident, especially when treating chronic diseases such as diabetes or cancer that require frequent medication, injection has brought considerable burden to patients' daily life. So, in recent years, many scientists have been actively seeking innovative methods for drug delivery systems: without the need for injections, they can allow large molecule drugs such as insulin and antibodies to enter the bloodstream through a simpler oral route.

But to take these drugs orally, a series of problems need to be solved. Firstly, the stability of the drug. Insulin or monoclonal antibodies are easily degraded by digestive juices in the gastrointestinal tract, making it difficult to maintain their biological activity. Secondly, the larger size of macromolecular drugs makes it difficult for them to be efficiently absorbed by the gastrointestinal tract.

To overcome these challenges, Professor Giovanni Traverso from MIT has collaborated with scientists from pharmaceutical company Novo Nordisk for many years. Recently, inspired by cephalopods such as squid and octopus, they have developed a high-tech capsule. This capsule can automatically "spray" the drugs contained in it directly into the inner wall of the human gastrointestinal tract like squid inkjet, without the need for any needles throughout the process.
In the latest issue of Nature, the research team presented their new achievement: the "Octopus Capsule" achieved drug absorption rate technology that is no less than traditional injection, which is expected to bring solutions for the delivery of insulin, antibodies, RNA or other macromolecules.

Squids are often threatened by predators, so they have developed many ways to protect themselves, and inkjet printing is one of the most well-known techniques. They rely on the strong muscle contraction of their mantle to quickly eject ink from their ink sacs through funnel holes, forming a dense and rapidly spreading black cloud that blocks the enemy's line of sight. In addition to inkjet printing, this flexible spraying system can also spray water by changing the thrust of the water and the direction of the funnel water pipe to control its own movement speed and direction.

Researchers drew inspiration from this and designed two simulated squid jet microjet delivery (MiDe) systems that can be applied to different parts of the gastrointestinal tract. A medication about the size of a blueberry, capable of carrying 80 microliters, suitable for axial spraying in spherical areas such as the stomach and colon; Another type is in the form of a thin tube, which can provide 200 microliters of medication at a time and is suitable for radial spraying in narrow and elongated areas such as the esophagus and small intestine.

The thrust of the jet comes from the spring or compressed carbon dioxide gas inside the capsule. Before the capsule is swallowed, the spring or gas remains compressed under the action of the trigger; After the capsule is swallowed into the stomach, the moist and acidic environment unique to the stomach will dissolve the trigger, causing the spring to pop out or the gas to expand, thereby ejecting the medication.

In order to ensure that the capsule is sprayed at the appropriate position, researchers calculated the required thrust, matching nozzle size, and spray angle for spraying at different positions through a series of experiments. The experimental results show that the capsule can produce the desired effect without direct contact with the surface of gastrointestinal tissue. As for the capsule itself, it can be excreted through the digestive tract after completing the spraying task.

The prototype of this capsule was published in Science in 2019, and subsequent expanded versions have also appeared in the Nature journal, demonstrating the potential for delivering insulin and monoclonal antibody drugs. But previous versions all designed biodegradable microneedles inside the capsule, which requires the capsule to "stick" itself into the digestive tract wall to release the drug. This new version does not require needles at all, greatly reducing the possibility of tissue damage.

In the latest study, researchers used animals such as pigs and dogs as test subjects to test the effectiveness of two needle free capsules in delivering biomacromolecule drugs in vivo. They successfully delivered different types of macromolecular drugs such as insulin, GLP-1 analogs, siRNA (short interfering RNA, which can be used to treat genetic diseases) into the animals, and the drug concentration in the blood reached the same order of magnitude as that seen when injecting drugs with a syringe.

In addition to allowing patients to self administer, researchers have also designed capsule versions suitable for endoscopes, so that doctors can replace endoscopic injection needles during endoscopic examinations or surgeries in the future.

These devices not only achieve drug absorption rates comparable to or higher than traditional injections, but also have the potential to change the management and treatment experience of chronic diseases, "concluded the journal Nature.

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