Synchronized Swimming under the Microscope

Scientists steer swimming microrobots and genetically modified bacteria with optical signals—edging closer to a prototype that could navigate the human bloodstream to deliver precision medicine.
01 October 2019
By Sophia Chen
Artist rendering of microswimmers in a blood vessel.
Artist rendering of microswimmers in a blood vessel. Credit: Jinyao Tang

Jinyao Tang builds tiny swimming robots the size of dust specks. Magnified, they resemble miniature mascara applicators: each robot consists of a stem made of silicon and a brush tip made of titanium oxide bristles. He and his team engineered these machines to swim toward light. Under the microscope, they chase a blinking LED spot like a cat after a laser pointer.

Tang, a chemist at the University of Hong Kong, envisions a future in which doctors dispatch these robots into a patient's bloodstream, where the machines could deliver drugs directly to a tumor or perform intricate incisions in a small surgery. This science fiction isn't so far-fetched, he says. In 2015, for example, researchers at the University of British Columbia showed they could use self-propelling microscopic particles, attached to coagulants, to stop bleeding in live mice and pigs. When applied as a powder to the animals' wounds, the particles pushed against the flow to the source of the bleeding by fizzing like crushed seltzer tablets, boosted by their own bubbles.

Now, researchers like Tang are further developing such micron-scale motors to make them steerable. These machines, broadly known as microswimmers, range in size from a few hundred nanometers to a few microns, and their materials, geometries, and propulsion mechanisms vary. One potential steering control: light.

Light makes for a versatile control signal because it has a lot of properties, says Tang. An engineer can exploit different wavelengths and polarizations for multi-channel control, for example. "We can fit a lot of information in light to do very complicated maneuvers," he says.

Tang's team engineered their robots to respond to different colors of light by soaking them in three different dyes. Depending on its dye, the robot swims toward either red, blue, or green light, while mostly ignoring the other two colors of light. In other words, they can mix three colors of robots together and steer each type independently. Tang's team also recently completed a study in which they use light's polarization angle to orient the microswimmer.

But Tang doesn't use light just to steer. The light also activates the fuel that powers the robots. His team tested the robots in a toxic hydrogen peroxide solution, as well as a more biologically friendly solution of water mixed with hydroquinone, an organic compound. In both solutions, when the light hits a microswimmer, it triggers a chemical reaction in the liquid. The silicon stem absorbs light to produce negative hydroxide ions, while the titanium oxide bristles generate positive hydrogen ions. Because opposite charges attract, the ions move toward each other, pulling the liquid with them, which causes the robot to move toward the light. The robots can move at tens or hundreds of microns per second, depending on the intensity of the light source.

It's still unclear what material and shape make for the best microswimmers for any particular application, and effective designs must contend with the alien effects of microscopic fluid dynamics. "Swimming at the microscale doesn't work as it does at the macroscale," says chemist Juliane Simmchen of TU Dresden in Germany.

When tadpoles, fish, or humans swim, they create turbulent flow in the water that continues to carry them forward even if they stop moving. In other words, macroscopic objects can coast, even if just for a moment. But microscopic objects can't coast at all. They have to constantly propel themselves to move forward because water is an incredibly thick medium relative to their size. For them, it's like swimming through pudding. "If you want to move something continuously on the microscale, you have to put in energy continuously," says Simmchen.

To overcome these challenges, some researchers have opted to borrow chassis from nature, rather than making robots from scratch, like Tang. They outfit biological cells, such as E. coli, sperm, and varieties of algae, into microscopic cyborgs they can control.

These organisms have evolved efficient and intricate machinery over billions of years to navigate their environments. "I don't think, in our lifetime, that we can make something as complex as a bacterium artificially," says Simmchen. Some algae, for example, can move more than ten times their body length per second, which is more than a speeding car can do on the highway. Researchers can leapfrog technical challenges by hijacking these natural structures.

Researchers play with organisms that naturally respond to light, an ability known as phototaxis. So-called phototactic organisms include a variety of algae, which include the prokaryotic blue-green cyanobacteria, which produced much of Earth's oxygen during our planet's early years, along with other types of eukaryotic algae. You might find these microbes in a drop of your local pondwater.

Generally, phototactic organisms live and grow by undergoing photosynthesis: they make their own food via a set of chemical reactions that convert light, carbon dioxide, and water into usable energy. Thus, their sensitivity to light has allowed them to thrive over billions of years. "They're really ancient species, and they exist because they've been highly successful," says mathematical biologist Kirsty Wan of the University of Exeter (UK).

For example, the single-celled alga Chlamydomonas, about ten microns in diameter, has a primitive light-sensitive structure known as its eyespot. "This is a localized region of the cell, which acts essentially as a single-pixel camera," says biophysicist Marco Polin of the University of Warwick in the UK. When photons hit the cell's eyespot, they cause ions in the cell to flow and generate an electrical current. In a cascade of chemical reactions, this current ultimately triggers the organism to alter the motion of its two whiplike flagella to steer the cell toward or away from light.

Chlamydomonas.

Chlamydomonas. Credit: Louisa Howard, Dartmouth College

The mechanisms that govern such light-triggered motion vary among different species of organisms. The cyanobacterium Synechocystis, just two microns in diameter, does not have an eyespot. Instead, the microbe senses the direction of incoming light because its body acts as a tiny spherical lens, Annegret Wilde of the University of Freiburg and colleagues reported in 2016. This lensing focuses the incoming light at the opposite edge of the cell, indicating the direction of the light source.

Researchers have begun to adapt these organisms into controllable microswimmers. For example, Takayuki Shibata of Toyohashi University of Technology in Japan and colleagues used light to direct colonies of the multicellular algae Volvox to push a range of millimeter and submillimeter-scale blocks on a platform. They controlled the algae's motion by switching LEDs on and off around the platform, which exploited Volvox's natural phototaxis.

Researchers have also built biohybrids out of Chlamydomonas cells. Metin Sitti of the Max Planck Institute for Intelligent Systems and colleagues reported attaching drug-mimicking molecules to the cells and studying their swimming in various fluids such as human cell culture medium, bovine plasma, and mouse blood. However, they didn't take advantage of the algae's phototaxis to control the motion; instead, they stuck tiny magnetic spheres onto the algae and steered them with an externally applied magnetic field.

Researchers are also engineering light sensitivity in naturally light-insensitive bacteria. E. coli, for instance, doesn't exhibit much phototaxis. But some researchers have genetically modified the bacteria to produce proteorhodopsin, a light-responsive protein naturally found on the membranes of some marine organisms. This protein acts like a microscopic solar panel for the bacterium by helping it convert light into motion. In 2018, Roberto Di Leonardo of Sapienza University of Rome and colleagues showed that they could shepherd swarms of this modified bacteria using a light projector beamed into a microscope objective. By changing the projected light patterns, they directed millions of bacteria to arrange themselves into microscopic portraits of Mona Lisa, Albert Einstein, and Charles Darwin.

Einstein and Darwin

Genetically engineered E. coli respond to light, forming images of Albert Einstein and Charles Darwin in response to a projected image. Credit: eLife 2018; 7:e36608

Still, basic design questions remain. Researchers don't understand which conditions make certain materials stick to bacteria, says Simmchen. For example, she and her colleagues have attached small spheres made of silicon dioxide, metal-capped on one side, onto E. coli. The bacteria like to stick to the metal side rather than the silicon dioxide, and they're not sure why. So she is conducting experiments to better understand the surface properties of these organisms, to optimize cargo design. "We want to tune materials to attach to the bacteria," she says.

In addition, researchers don't fully understand the organisms' biology. Sometimes they move toward light, and other times they move away from light. This makes sense from an evolutionary perspective: "Too much light becomes damaging," says Wan. Algae move toward or away from light given their needs, but scientists don't understand the response process in detail, she says.

This response is so complicated because light plays two roles that feed off each other: it orients the direction of the cell, and it's also a source of energy. The orientation of the cell depends on whether the organism needs energy, and vice versa. Polin is currently studying the relationship between an organism's metabolism and its motion. "We want to understand this crosstalk," he says.

Tang prefers to work with fully synthetic robots, so that he can avoid these unknowns. "We understand the details of which part is which and what function does what," he says.

The simplicity of synthetic microswimmers also allows researchers to isolate and study the basic physics of fluid, robot, and light interactions. Celia Lozano of the University of Konstanz in Germany has taken this minimalist approach—her robots are simple microscopic spheres made of transparent silica that are half-coated in carbon.

Placing the spheres in a mixture of water and lutidine, an organic compound, she and her colleagues found that the spheres could propel themselves when illuminated uniformly with a green laser. The laser heats the particle's carbon-coated hemisphere more, which causes the lutidine and water to separate. This creates a concentration gradient. To balance out the gradient, liquid moves along the sphere from its transparent face toward its carbon-coated face. This flow propels the sphere transparent-face first, like a rocket jettisoning fuel. "The particles were able to feel this gradient of light to move in a preferred direction, something that was unexpected," says Lozano. With these same spheres, Lozano has shown that she can use light pulses to make the particles gather like the cells that make up an amoeba.

The simplicity of Lozano's particles illustrates a fundamental aspect about phototactic organisms. To make a microscopic particle respond to light, it just needs to be asymmetrical in some way. For example, her spheres have two different faces. The asymmetry gives her particles a sense of direction: light interacts with one side of the particle differently than the other.

Biomedical applications will take some time, says Simmchen. Researchers haven't studied these microswimmers enough in conditions close enough to the interior of the human body. The bloodstream teems with salts, proteins, and other particles that would interact with the robots—a far more dynamic environment than researchers' idealized lab conditions, she says.

The microswimmers may prove useful in nonmedical applications, first. Simmchen's team has made small spherical particles that like to stick to tiny microplastic fragments. They can steer these particles through water using UV light, and they show that the particles accumulate microplastics as they move. They then deploy the particles on samples of cosmetic products and real seawater that contain microplastics. "I don't want to say we can clean the ocean, but at least we can clean the microscope slide," says Simmchen.

Researchers also need to study the human immune response to these objects, says Simmchen. To this end, over the next few years, Tang wants to improve the biocompatibility of his robots so that he can begin to test them in live animals. He anticipates being ready for these tests in five to ten years.

But the future of these robots doesn't just depend on technical success. "It's one thing for the technology to be ready," says Tang. "It's another thing for society to be ready." The question remains whether people will allow these tiny swimmers into their bodies.

-Sophia Chen contributes to WIRED, Science, and Physics Girl. She is a freelance writer based in Tucson, Arizona.

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