Little wonders

26 October 2018

A recent breakthrough in nanophotonics that is a potential game-changer for medical device development is nanotweezers. They allow particle manipulation at the nanoscale, which could lead to better diagnosis, monitoring and treatment. Yuebing Zheng, the assistant professor of mechanical engineering at the University of Texas, speaks to Medical Device Developments about how these nanotweezers work and the ways in which they could be used by the industry.

In October of this year, Arthur Ashkin received a Nobel Prize in Physics for the invention of optical tweezers and their application in biology. Known as the ‘father of optical tweezers’, at the age of 96, Ashkin is the oldest person to have received the award. The Royal Swedish Academy of Sciences, who administered the prize, honoured his research, saying it was, “an old dream of science fiction”. Ashkin started his work on manipulation of microparticles with laser light in the late 1960s, resulting in the invention of optical tweezers in 1986.

Since their invention, optical tweezers have provided deeper insights into many different areas of science. Also known as ‘laser tweezers’, these devices use a laser to capture, trap and manipulate small particles that range in size from tens of micrometres down to a fraction of a nanometre. The tweezers are based on the force of radiation pressure, which arises from the momentum of light. They are able to capture single particles, collections of dielectric, metal or liquid particles, as well as single atoms or molecules in vacuum, air or liquid environments. Optical tweezers are used in many fields within the physical, chemical and biological sciences, but although these devices have helped to significantly advance scientific study, they have a number of limitations, which restrict their applicability.

High power

One of the main limitations of conventional optical tweezers is their need for high laser power (tens to hundreds of milliwatts) in order to manipulate nanoparticles.

“They need high power because the nature of the manipulation is optical gradient of force,” explains Yuebing Zheng, the assistant professor of mechanical engineering at the University of Texas. The high power becomes particularly problematic when working with smaller particles, such as those at the nanoscale. “The force will be reduced as function of the size goes down, so in order to trap in smaller particles, a significantly higher power is needed,” he states. This restricts the size of particles that can be studied because the high power can damage smaller particles.

The other limitation of conventional optical tweezers is the high degree of control required for the technology to work effectively. “Usually, they need a really high-quality laser beam and it has to be well controlled and extremely focused,” Zheng explains. Achieving this high-quality laser beam is a challenging task, which requires specialisation. “It is usually a complex system; it needs a highly trained professional,” he states.

The heat is on

Zheng and his team have developed optothermoelectric nanotweezers (OTENT), which use an alternative low-power technique to address the restrictions of conventional optical tweezers. These tweezers use a different type of gradient that eliminates the need for high power.

“Instead of using gradient of force, we use a temperature gradient. So we are not limited by using high power,” Zheng explains. This technique causes a particular response in the nanoparticles. “The particles of biological cells will move under the temperature gradient. So they will move from a high-temperature location to a low-temperature location, or from a low-temperature location to a hightemperature location,” he states. This movement of particles in response to a temperature gradient is a phenomenon called thermophoresis.

This research is a particularly exciting development for nanophotonics, the study of light-matter interaction on the nanometre scale. ‘‘Until now, we simply did not know how to manipulate nanoparticles using optical heating,” Zheng explains. “With our nanotweezers, we can not only control particles at the nanoscale, we can also analyse the particles and control the coupling in situ.”

What is useful about this technique is the way in which different nanoparticles respond to the temperature gradient. Small ions in solutions that are subject to a temperature gradient tend to diffuse, at different rates, from relatively hot to relatively cold regions in the mixture.

“On the temperature gradient, these different types of particles will move away from the laser spots, because laser spots are the hotter region, but they move at a different speed: the micelle moves faster and the ion moves slowest,” Zheng explains. Due to the different electrical charge between the micelle and the ion, an electrical field is created. “This electrical field basically acts on the particle we’re interested in to confine the particle at the lever spots through an electrical field. So that’s why we call them opto-thermoelectric tweezers,” he says.

The key advantage of the nanotweezers developed by Zheng and his colleagues is the low power required compared with conventional optical tweezers. The lack of reliance on a highquality laser beam also makes for a simple set-up. “We are just using the light and heating the substrate. So this makes the device really simple, and it can be portable,” Zheng explains.

Developing these OTENT tweezers was not without challenges. “We started by thinking about using a temperature gradient; but a lot of the time, the particle will move from a hotter to a colder region. Basically, instead of a move towards the laser beam, the laser beam pushes away the particle. That’s one challenge we’ve overcome through development of a different type of particle separation that introduces a charge,” Zheng explains.

He and his team are also facing existing challenges. “The limitation we are currently facing is how we can ensure the particle we add doesn’t affect any biological processes,” he states. This is particularly important for the manipulation of living cells and biomolecules required for biomedical applications. “Biocompatibility is one of the important issues we should solve if we want to use nanotweezers in more general biomedical applications,” he says.

Caught in a trap

So far, researchers have successfully trapped silicon nanospheres, silica beads, polystyrene beads, silicon nanowires, germanium nanowires and metal nanostructures using OTENT nanotweezers. These also have a number of important applications for the medical device industry.

“The ability to manipulate and to separate the biological particles, cells and even cellular materials is important for early disease diagnosis,” Zheng explains. He and his team are particularly focused on the application of nanotweezers for cancer diagnostics. “We are pushing towards using them for cancer cell diagnosis. By using this type of device, hopefully we can capture those low-concentrated, circulated tumour cells for early cancer diagnosis,” he says. This opens the door to early diagnosis and the discovery of nanomedicine.

Zheng is also working on developing cancer therapies using this technology. “We are using these tweezers to hold the biological cells, and to study them at the single cell level,” he explains.

Zheng and his team are especially interested in immunotherapy, through targeting immune cells. “We are using the tweezers to pick out the best immune cells for specific cancer therapies,” Zheng says. In light of the recent Nobel Prize awarded to James Allison and Tasuku Honjo for their work on immunotherapy for cancer, this work is likely to be a particularly fruitful endeavour.

Thinking big

Zheng also has big plans for future research with his team at the University of Texas. ‘‘We hope that we can integrate these nanotweezers into lab-on-a-chip devices,” Zheng explains. These devices, which integrate optical components into micro or nanofluidic systems, enable an unprecedented level of interrogation and control of colloidal particles, biological cells and molecules.

The simplicity of the system and the lower power requirements also make the nanotweezers well suited to point-of-care devices. “We are able to have a compatible system so people can use it for point-ofcare devices, for personal use at home, for therapy situations, or even for disease prevention by monitoring your blood cell quality or other types of body signals,” Zheng explains.

Zheng is confident the technology will be commercialised; this includes the adaption of nanotweezers for use in a smartphone app, similar to a modern-day Swiss army knife. They have the potential to be an important mobile diagnostic tool, giving individuals more autonomy over their healthcare. The nanotweezers could also act as a valuable educational tool for students. “We also see great opportunities in outreach education, perhaps for students who want to see what a cell really looks like,” Zheng explains.

These future applications have exciting implications, inside and outside the medical industry. “The whole community are going to benefit a lot. With the tweezers, we handle a lot of cells, a lot of particles. With the emergence of machine learning, artificial intelligence and a lot of advanced microscopy, I think that by integrating with these things, we can make future medical devices more powerful, more personalised and more accurate,” Zheng states.

Nanotweezers have been used to manipulate yeast cells into formations – the word “NANO” (a), from a Y to a T shape (b) and a 4×4 optical lattice (c).
Reversible distance control between a pair of yeast cells and the arrangement of yeast cells into a ring shape.

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