On a bright autumn evening in 2006, Dr. Sylvain Martel held his breath as a technician loaded an anesthetic pig into a rotating fMRI machine. His eyes gazed at a computer screen that showed a magnetic bead hanging in a thin pig blood vessel. The tension in the room could be felt physically. Suddenly the balloon came to life and slid over the vessel like a microscopic submarine heading for its destination. The team burst into applause.
Martel and his team were testing a new way to remotely control tiny objects inside a living animal by manipulating the machine's magnetic forces. And for the first time it worked.
Scientists and writers have long dreamed of tiny robots that move through the body's vast circulatory system like space explorers studying galaxies and their inhabitants. The potential is huge: tiny medical robots could, for example, transfer radioactive drugs to cancer clusters, perform surgery inside the body, or cleanse blood clots deep inside the heart or brain.
A dream, a dream, but with the help of robots, says Dr. Bradley Nelson of the Polytechnic University of Zurich, people could plunge directly into the bloodstream to perform brain surgery.
At the moment, medical micro-robots are mostly fictional, but this may change in the next decade. This week, Dr Mariana Medina-Sánchez and Oliver Schmidt of the Leibniz Institute for Solids and Materials Research in Dresden, Germany, published a paper in Nature that turned from big screens to nanoengineering labs, outlining priorities and realistic tests to revive these tiny surgeons.
Creation of movers
Medical micro-robots are part of medicine's journey into miniaturization. In 2001, the Israeli company introduced the PillCam, a candy-sized plastic capsule equipped with a camera, battery and wireless module. While traveling through the alimentary canal, the PillCam periodically sent back images wirelessly, offering a more sensitive and less toxic diagnostic method than traditional endoscopy or radiography.
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The PillCam is gigantic for a perfect microrobot, making it only fit for the relatively wide tube of our digestive system. This pill was also passive and could not linger in interesting places for a more detailed examination.
“A real medical robot has to move and progress through a complex network of fluid-filled tubules in tissues deep in the body,” explains Martel.
The body, unfortunately, is not very welcoming to outside guests. Micro-robots must withstand corrosive gastric juices and float upstream in the bloodstream without a motor.
Laboratories around the world are trying to come up with sensible alternatives to solve the nutritional problem. One idea is to create chemical rockets: cylindrical microrobots with "fuel" - a metal or other catalyst - that reacts with stomach juices or other fluids, emitting bubbles from the back of the cylinder.
"These motors are difficult to control," say Medina-Sanchez and Schmidt. We can roughly control their direction using chemical gradients, but they are not robust or effective enough. Designing non-toxic fuels based on sugar, urea, or other bodily fluids also faces challenges.
A better alternative would be metallic physical motors that could be activated by changes in the magnetic field. Martel, as shown in his bead-in-pig demonstration, was one of the first to investigate such engines.
The MRI machine is ideal for controlling and imaging metal prototype microrobots, Martel explains. The machine has several sets of magnetic coils: the main set magnetizes the microrobot after it is introduced into the bloodstream through a catheter. Then, by manipulating the MRI gradient coils, we can generate weak magnetic fields to push the microrobot through blood vessels or other biological tubes.
In subsequent experiments, Martel made iron and cobalt nanoparticles coated with an anticancer drug and injected these tiny soldiers into rabbits. Using a computer program to automatically change the magnetic field, his team aimed the bots right on target. While there were no actual tumors in this particular study, Martel says projects like these could be useful in fighting liver cancer and other tumors with relatively large vessels.
Why not small vessels? The problem is again energy. Martel was able to shrink the robot to a few hundred micrometers - anything less requires magnetic gradients so large that they disrupt neurons in the brain.
Microcyborgs
A more elegant solution is to use biological motors that already exist in nature. Bacteria and sperm are armed with whiplash tails that naturally propel them through winding tunnels and body cavities to carry out biological reactions.
By combining mechanical parts with biological parts, one could make these two components complement each other when one fails.
An example is a sperm bot. Schmidt designed tiny metal coils that wrap around the lazy sperm, giving it the mobility to reach the egg. The sperm can also be loaded with drugs associated with the magnetic microstructure to treat cancers in the reproductive tract.
There are also specialized groups of MC-1 bacteria that align with the earth's magnetic field. By generating a relatively weak field - enough to overcome Earth's - scientists can orient the bacteria's internal compass towards a new target like cancer.
Unfortunately, MC-1 bacteria can only survive in warm blood for 40 minutes, and most are not strong enough to swim against the bloodstream. Martel wants to create a hybrid system of bacteria and fat bladders. Bubbles loaded with magnetic particles and bacteria will be directed into larger vessels using strong magnetic fields until they enter the narrower ones. Then they burst and release a swarm of bacteria, which in the same way, using weak magnetic fields, will complete their journey.
Moving forward
While scientists have sketched a bunch of ideas about propulsion, tracking the microrobots once they've been implanted into the body remains a huge challenge.
Combinations of different imaging techniques can help. Ultrasound, MRI and infrared imaging are too slow to observe the operations of microrobots deep in the body. But by combining light, sound and electromagnetic waves, we could increase resolution and sensitivity.
Ideally, an imaging technique should be able to track micromotors at a depth of 10 centimeters under the skin, in 3D and in real time, moving at a minimum speed of tens of micrometers per second, Medina-Sanchez and Schmidt say.
At the moment, this is difficult to achieve, but scientists hope that state-of-the-art optoacoustic techniques, combining infrared and ultrasound imaging, may become good enough to track microrobots in a few years.
And then the question remains, what to do with the robots at the end of their mission. Leaving them to drift inside the body is a sign of clotting or other catastrophic side effects such as metal poisoning. Getting robots back to their starting point (mouth, eyes, and other natural openings) can be overwhelming. Therefore, scientists are considering better options: removing robots naturally or creating them from biodegradable materials.
The latter has a separate plus: if the materials are sensitive to heat, acidity or other bodily factors, they could be used to create autonomous biorobots that work without batteries. For example, scientists have already made small star-shaped "graspers" that close around tissue when exposed to heat. When placed around diseased organs or tissues, the grapple could biopsy in situ, offering a less invasive method for screening for colon cancer or tracking chronic inflammatory bowel disease.
“The goal is to create microrobots that can sense, diagnose, and act autonomously while humans are watching and staying under control in the event of a malfunction,” said Medina-Sanchez and Schmidt.
The fantastic journey of medical micro-robots is just beginning.
All combinations of materials, microorganisms and microstructures will have to be tested indefinitely to make sure they are safe, first on animals and then on humans. Scientists are also awaiting assistance from regulators.
But the optimism of scientists does not dry out.
“Through coordinated initiatives, the microrobots can lead us into the era of non-invasive therapies for ten years,” the researchers say.
ILYA KHEL