Most people prefer to take medicine as pills rather than injections, but absorbing the contents requires overcoming the harsh environment of the gut. Despite decades of development, nearly all pills still have the same overall surface and structure. Researchers are now challenging the 3D structure of pills by using a custom-built microscale 3D printer. They print the pills with pillars or arrows to improve gut retention before the contents are transferred across the intestinal barrier into the bloodstream.
Pills were described for the first time on ancient Egyptian papyrus rolls, where bread dough, honey or fat were mixed into small balls to make beneficial plant powders or spices glide down more easily. Since then, science has come a long way – so far that medicine in the future can be administered in small biologically powered and degradable microcontainers. When they reach their final destination, they drop an anchor, and only then does the tiny lid open to release the medicine to work exactly where it should.
“We can already fabricate radiopaque microcontainers with medicine the size of a sugar crystal and equip them with a lid that opens in the gut. But medicine released in the middle of the gut is destroyed, so we developed a tiny 3D printer to create structures on the surface that make the pill adhere to the intestinal wall, which substantially increases the chances of the medicine getting through. In addition, we can now monitor the microcontainers as they travel through the gut, so we can determine whether they are slowed down along the way and how long they are retained in the intestine. This can be decisive for delivering new types of medicine in pill form,” explains Anja Boisen, Professor, Department of Health Technology, Technical University of Denmark, Kongens Lyngby.
Hacking a Blu-ray player
There are plenty of obstacles when medicine must go through the dangerous journey from the mouth to the gut, where the medicine is ultimately absorbed into the blood and transported around the body. Bile salts, enzymes, pancreatic secretions as well as strong acid and alkaline fluctuations can destroy even the most stubborn chemical compounds. In addition, the surface of the gut is covered with a mucus layer of varying thickness: a last line of defence for the body to avoid absorbing unwanted substances.
“If the drugs just travel through your gut and are then expelled, then they were never really inside your body, completely wasting a drug dose. We therefore need to create tiny structures on the surface of the pills, such as pillars, arrows or anchors, that help to adhere to the mucus that covers the surface of the intestine so that the pills stay there long enough for the substances to cross the gut barrier. We have therefore worked intensively on fabricating and testing these microdevices,” says Anja Boisen.
This gave the researchers the idea to 3D print the structures on the pill surfaces. The problem, however, was that they were smaller than what you would normally be able to print within a manageable time frame: less than 1 µm. No printer existed to fit this purpose until Anja Boisen’s colleague, Edwin En-Te Hwu, hacked a Blu-ray player and reused the readout head to make a 3D printer for relatively rapid microscale printing.
“This is unique because this tiny printer can print with really high microscale resolution and is more rapid than other similar 3D printers on the market. Further, it is not that expensive to build. We can use the 3D printer to easily add various structures to the surface of our microdevices. For example, we tested an arrow shape – a kind of anchor – so that when the pill moves through your intestines, the arrow will sporadically adhere to the surface of the intestine and then penetrate slightly into the mucosal tissue, which can increase the time the pill is retained through the entire gut,” explains a lead author, Rolf Bech Kjeldsen, Postdoctoral Fellow, Department of Health Technology, Technical University of Denmark, Kongens Lyngby.
Optimising retention time
While Rolf Bech Kjeldsen’s postdoctoral colleague Tien-Jen Chang 3D-printed the pill surfaces with various structures, he investigated whether these structures actually increased the retention time in the gut and thus the time the pill container had to dispense the medicine.
“We needed imaging to determine whether we actually increased the retention time. We did this by using X-ray contrast agent, so that we could see the small microcontainers with CT scanning. That way we could get a qualitative sense of where the microcontainers were,” says Rolf Bech Kjeldsen.
The initial experiments took place in rats, and the researchers had to dissect the rats to determine whether these microcontainers were actually located in the places they could see with CT scanning. The researchers now hope to be able to completely avoid dissecting animals in studying how the pills move in the future.
“In addition to sparing the lives of laboratory animals, dissection is also extremely time-consuming. Most importantly, dissecting an animal only provides a snapshot, and this is not the same as being able to determine what is happening live. How are these specific microdevices distributed and how do they move through the gut? We can now monitor this directly through CT scanning,” explains Rolf Bech Kjeldsen.
Equipped with a 3D printer and a CT scanner, the researchers were now ready to assess how the micron-sized surface structures of various kinds such as arrows or pillars interacted with the mucus layer of the intestines. The researchers experimented with previously tested structures such as micropillars to test the method but then opted for the slightly more radical arrow structures.
“An anchor inspired the arrow structure. Imagine that when the microdevice moves through your intestines, the anchor-shaped arrow interacts with the intestine at some point and penetrates the mucus layer to thereby increase retention time. We actually did find slightly increased gastrointestinal retention for this type of device,” says Anja Boisen.
Converting the body’s energy
The search for more and even better microstructures continues, and whether these anchors will find their way to the pills available at pharmacies is still too early to say. In any case, the search for increasingly advanced and targeted pills will certainly continue in the coming years.
“We have now found that we can blend contrast agents such as barium sulfate into the microdevices without problems. Now we are experimenting with also mixing in magnetic materials, so that we can actually control externally where the pills go, how long they are retained and when they unfold,” explains Anja Boisen.
According to the researchers, even more specific targeting of the pills will not only increase their effectiveness and prolong the release of the medicine but will also enable completely new functions. In fact, the research group is also working on equipping the pills with a micromotor that converts the body’s own energy into the fuel that drives the pills forward.
“This will enable them to carry out complex tasks, including targeted drug delivery, but also microsurgery, measurements and perhaps even separating different types of molecules in the body. Combining all of this is going to be complicated, but we have knowledge from the individual fields now. And then we just have to solve the puzzle and try to put everything together,” concludes Rolf Bech Kjeldsen.
