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Powering the Future of Science

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From witnessing the first catalytic nanomotors to advancing the way we think about modern medical treatment and more, Ayusman Sen and Thomas Mallouk are making big discoveries on the nanoscale.

02 June 2014

Although more than ten years have passed since Ayusman Sen and Thomas Mallouk first Ayusman Senstarted collaborating on nanomotor research, you would think it happened just yesterday when you hear them talk. Their curiosity about the natural world and infectious enthusiasm for discovery has aided them on their long collaborative journey into the world of nanomotors.

In 2003, Sen and Mallouk were both on Walter Paxton’s doctoral thesis committee. Before Paxton’s first-year meeting with his thesis committee, he went to Sen with a few ideas, and Sen encouraged him to think big: “He really left the field wide open. He told me, ‘You can do whatever you want as long as it’s good science,’” said Paxton.Tom Mallouk

Sen’s enthusiasm and encouragement helped Paxton decide that he wanted study the feasibility of a catalytic nanomotor. He thought he had some great ideas to make it work, and Sen and Mallouk were intrigued. “We told him, let’s try it right now, today,” said Mallouk.

A catalytic nanomotor is a tiny particle that is powered into motion by a chemical reaction. Previous research done at Harvard University by Rustem Ismagilov and George Whitesides had found that a macroscopic motor equipped with a platinum strip would move on the surface of a tank of hydrogen peroxide and water like a miniature boat. Paxton’s nanorod motor idea took this to another level: much smaller motors, going from centimeter-sized to two microns by 350 nanometers; and a much more challenging environment, as the tiny rods were immersed in the solution instead of on top of it.

Using gold-platinum rods Mallouk had from an unrelated metal project, Sen and Mallouk helped Paxton test his idea. The nanorods moved, autonomously, in a solution of hydrogen peroxide, and to the team’s delight, bore “an eerie resemblance under the microscope to live swimming bacteria,” Sen and Mallouk wrote in a 2009 article in Scientific American.

But why did they move? Sen and Mallouk were curious, and it was then that their mutual interest and subsequent research collaboration on nanomotors was born.

Small Particles, Big Challenge

Nanomachines have a bright future. Their implementation could spark innovations in a variety of fields, including modern medicine, technology, energy, and even environmental conservation.

The fact that Paxton’s idea for a nanomotor had worked was significant because for years, scientists had been hitting a scientific wall when it came making nanomachines move. While scientists could envision many ways to build tiny nanomachines and improve upon earlier designs, many sophisticated nanomachine designs were literally sitting idle.

Because of the miniature scale of nanoparticles, there are many challenges in making them move. One cannot  just shrink down a ship to nanoproportions and expect it to work the same as it does in the normal large size. Not only is water thick and hard to propel through at that level, but researchers also have to consider Brownian motion.

Mallouk explained Brownian motion as motion that we see caused by random collisions of molecules with solid particles. The effect of Brownian motion is more dramatic as an object is smaller, because a single molecular collision has a greater impact. “For objects the size of human cells (roughly a 15-micron diameter), Brownian motion is hardly perceptible in water. For objects ten times that small (bacteria or nanorod motors), it is strong enough to reorient the particle every second or so,” he said.

Nanomotors groupThe catalytic nanomotors research group from 2004. 
Back (left to right): Paul Lammert, Jeffrey Catchmark, Vincent Crespi, and Ayusman Sen. 
Front (left to right): Yanyan Cao, Timothy Kline, Shyamala Subramanian, Walter Paxton, and Tom Mallouk. 
Credit: Sen and Mallouk labs

Not only was the environment they were working in challenging, so were their early findings. In 2004, a team including Paxton, Sen, Mallouk, and Department of Physics colleague Vincent Crespi published a paper on the nanorods, explaining their hypothesis that the rods moved as a result of being pushed through the solution by a catalytically generated surface tension gradient. But that’s not exactly how it worked, they would discover.

“There was so much we didn’t understand. This was an entirely new area, not just for me as a graduate student, but also for Ayusman and Tom,” says Paxton. “They were both undaunted. With Ayusman’s encouragement and excitement about the research, and Tom’s contagious optimism, we pressed forward and learned many things about the chemistry and physics of small catalytic objects.”

The nanomotors were powered in a more fascinating way, as the team discovered and explained a year after the first paper was published. At the nanoscale level, the law of inertia is outweighed by drag, so that remaining in motion as a “jet propulsion” reaction is nearly impossible for a nanomotor. A nanomotor can only glide for about a microsecond, which amounts to about one hundredth of a nanometer.

Instead, the nanorods were applying a continuous force to get through the drag. And because the rods had two different metals on the ends, two interesting reactions were taking place to power the nanorod. At the gold end, protons and electrons were combining with the hydrogen peroxide to create two water molecules. At the platinum end, protons were being formed by the oxidation of hydrogen peroxide to molecular oxygen.  The two reactions created an imbalance in proton concentration. The resulting electric field exerted a force on the negatively charged nanorods, propelling the nanorod in the direction of the platinum end.

Learn more about Nanomotors Collaboration

Soon after this discovery, the team learned to steer the nanomotors with magnetic fields, and even have the motors pull plastic sphere “cargo” containers through fluids. But the motors, being fueled by reactions between metals in hydrogen peroxide, were not safe for their ultimate research fantasy: a “Fantastic Voyage”-style trip among living cells.

The Journey to the Human Body

Many of the practical applications of nanomotor technology exist in healthcare fields. Possibilities abound in that realm, including nanomachines acting as tiny surgeons and more targeted approaches to curing disease on the molecular scale. But in order for Sen and Mallouk’s nanomotors to be viable for healthcare innovations, they needed to fuel the motors with something other than concentrated hydrogen peroxide, which can be toxic inside a human body.

Where did they look for inspiration? Nature is full of nanotechnology—small particles exist everywhere, moving on their own without external power to complete biological processes. Cell division, intracellular transport, and muscular movement are all examples of autonomous nanoparticles at work. Sen and Mallouk wanted to find out how these processes worked so that their nanomotors could mimic biological processes and move without toxic fuel for propulsion. Though their project involved synthetic creations, they hoped to understand the natural world better with their experiments.

Ultrasound Power

HeLa cell microscope image

Optical microscope image of a HeLa cell containing several gold-ruthenium nanomotors. Arrows indicate the trajectories of the nanomotors, and the solid white line shows propulsion. Near the center of the image, a spindle of several nanomotors is spinning. Inset: Electron micrograph of a gold-ruthenium nanomotor. The scattering of sound waves from the two ends results in propulsion.  Credit: Mallouk lab

A breakthrough on this front came while Mallouk was on sabbatical at Ecole Normale Supérieure in France in 2010. He was presenting a physics seminar at neighboring school ESPCI (Paris Tech). After the presentation, several ESPCI researchers interested in the physics of colloidal particles (like live bacteria, which Sen and Mallouk were trying to imitate with their nanomotors), approached Mallouk.

One of those researchers was French physicist Mauricio Hoyos, an expert in acoustics. Hoyos had been studying the differences between chemically powered nanomotors and bacteria when it came to their interactions with cell surfaces, using an ultrasonic transducer to create a standing wave to lift the particles off the cell floor. But the ultrasound did more to the metal nanorods—they started “shooting around like bullets and spinning,” according to Mallouk.

The movement was due to the high acoustic contrast that the metals had with the surrounding fluid. But the idea had taken root with Mallouk—nanomotors could be powered by something used safely in medical procedures already: ultrasound.

Mallouk returned home to Penn State and together with a team that included his graduate student Wei Wang and Assistant Professor of Engineering Science and Mechanics Tony Huang, decided to incubate the nanorods with HeLa cells, an immortal line of human cervical cancer cells, to test the abilities of ultrasound to power the rods. After twenty-four hours, the HeLa cells had eaten the nanorods, which meant that the rods were physically inside of the living cells. The team still does not understand this phenomenon entirely, but believes it to be similar to phagocytosis, a process where a cell engulfs and digests bacteria before the bacteria can cause an infection.

Inside the HeLa cells, the motor rods were still responding to attempts to power them with ultrasound. When the ultrasonic power was increased, Mallouk’s team did something no other research team had done—moved a nanomotor from inside a live cell. “And it lived,” Mallouk joked about the cell remaining alive during the process.

So far Mallouk’s team has learned that the motors can scramble a cell’s inner contents, similar to an eggbeater, or act as a battering ram to puncture the cell’s membrane. A potential application of this idea is that a nanomotor could effectively destroy a cell that ingests it, which could be used in medical treatment. Better yet is that the nanomotors inside the cells can move autonomously rather than in a group, so the nanomotors could be used in diagnostic or even surgical applications that require them to act independently.

Fixing Bone Cracks

While Mallouk was working on moving nanomotors with ultrasound, Sen had been pursuing another way to safely power nanoparticles in a human body with a graduate student in his lab, Vinita Yadav. Together with Yadav and a Boston University biomedical engineering laboratory led by Mark Grinstaff, he was exploring a novel way to use nanoparticles to heal microcracks in bones, a common occurrence for those with osteoporosis or other bone conditions. Patients with those types of conditions benefit greatly from healing the microcracks before they turn into actual breaks of the bone.

Nanomotors bone crackThis graphic shows how nanomotors are electrically charged to fill a bone crack. In the dark image, the fluorescent cells shown are nanomotors carrying an osteoporosis drug to a bone crack. Credit: Sen lab

Current methods to treat microcracks in bones rely on a medicine passively traveling through a patient’s bloodstream, eventually arriving at the microcrack. The problem with this method is that by the time the medicine gets to the crack, the dosage might not be high enough to treat the crack. Sen and his team hoped a nanoparticle approach would prove to be a more targeted way to treat this condition.

When a bone cracks, the bone’s minerals are disrupted, causing charged ions to leach out of the bone and create an electric field. This meant that charged nanoparticles could be attracted to the crack, either to fill in the crack or to treat it with medicine. The pull of the electric field would serve as both the trigger and the energy source for the nanomotor, eliminating the need for any sort of fuel to power it.

“Working on bone crack repair was like venturing into uncharted waters,” said Yadav. “Although we were novice in the biomedical field, we succeeded because we played on our strength: nanomaterials chemistry.”

The teams at both Penn State and Boston University performed series of tests using bone from a human tibia and femur, starting with synthetic nanoparticles tagged with fluorescence for better visibility. After successful separate test runs with first synthetic nanomotors and then organic material, the team pushed the idea further to include a combination of the synthetic and biological materials. The idea was that a synthetic material could attach to a biological material and carry it to the bone crack. In this case, the biological material would be a drug used to treat the crack or the condition causing it (an osteoporosis drug, for example), and the synthetic material an FDA-approved substance already widely used in medical devices, polyactic-co-glycolic acid.

Yadav said, “We had expertise in propelling our nanomotors, and we applied the same to a biological environment instead of an inorganic one. This was particularly exciting since nanomotors have for long been touted for their possible impact in medical research.”

To test this idea, the team watched the fluorescent motor’s progress through the microscope. The test was successful. “Our experiments show that this bio-safe nanomotor can, in fact, successfully carry the osteoporosis drug to a fresh crack in a human bone,” Sen said.  

In the team’s final set of experiments, done in Grinstaff’s lab at Boston University, the test was performed on live human bone cells, which proved that the method for repairing human bones was viable in the live cells also.

“We can now actively target the damaged sites,” said Yadav. “Our technique also uses the damaged substrate itself as both the trigger and fuel, obliterating the need for an external power supply.”

The research will need many more tests before it can be considered safe and ready for use, but the implications for future healthcare innovations are exciting. “What makes our nanomotors different is that they can actively and naturally deliver medications to a targeted area, such as a bone crack,” Sen said.

And for Yadav, the discovery was only part of the positive experience she had working with Sen, who is her adviser: “It’s an absolute joy to work with him. He gives you the freedom to drive your own research, intervening only when required.” Even when she gets stressed, Sen is able to help her refocus: “Talking to him is a great stress-buster. Not only does he provide the right direction, but also the enthusiasm to push your project to completion.”


Nanomotors as Microscopic Pumps

The applications of Sen and Mallouk’s nanomotor research reach beyond healthcare to other fields and industries. The team has been working with a variety of researchers from all over the country and world on possible other applications.

When a nanomotor is immobilized, its mechanical force is transferred to the surrounding fluid, turning it into a self-powered pump. The nanomotor can pump any kind of fluid past itself and can even deliver drugs in response. An implanted pump could deliver insulin automatically in response to high glucose level in the blood, for example. But the pump also opens up other doors outside of healthcare.

Enzyme micropump

This illustration shows the process of an enzyme acting as a micropump.  The rate that the enzyme pumps out fluid is dependent on the level of glucose in the surrounding solution. This enzyme micropump could be a model for insulin regulation in the body. Credit: Sen lab

The pumping action of the nanomotor could be used to remove valuable substances from hard-to-access places, like the traces of crude oil left in tiny pores in oil wells. Nanomotors can also be used to purify fluids, an example being making fresh water out of brackish or saltwater.  

And then there’s the capability for improving public safety: nanomotors could help protect against agents of chemical warfare. Using the example of nerve gas, a nanomotor could use the nerve agent as fuel and could be programmed to pump an antidote out. Sen and Department of Chemistry colleague Scott Phillips just received a grant from the U.S. Defense Threat Reduction Agency to pursue the foundational research for this idea.

While possibilities proliferate for nanomotors to contribute to society in a variety of life-changing ways, Sen and Mallouk are happy to pursue just one simple goal for their research in the future: to understand biology better.

“We are trying to mimic the living systems as closely as possible,” said Sen.

As they continue to explore the nanolevel of cell biology and better understand motion as it occurs on that level, the possibilities of making the motors act like real cells is a goal they will continue to aim for. Sen would be happy if the nanomotors could be very much like living cells, except in one way: “I want them to do everything that living cells do but reproduce,” he laughed.