Joining the dots

The ultimate icon of high technology, lasers, are now a part of everyday life as essential components in audio-visual systems. But despite their ubiquity, lasers still occupy a cutting edge position in every sense. And in the medical field, a flurry of recent developments is set to give rise to a new generation of powerful, versatile and, above all, affordable devices.

The EU is pumping €10m (almost £8m) into these products, via a project called FAST-DOT. Based at Dundee University, and involving 18 collaborators in academia and industry, the project aims to develop laser systems about the size of a matchbox, capable of performing the same functions as a fixed, heavy, shoebox-sized laser - and more - for a tenth of the cost and consuming an even smaller fraction of the energy. Potential applications range from precise and bleeding-free surgery to analysis of biological samples.

‘This project will revolutionise the use of lasers in the biomedical field,’ claimed research director Edik Rafailov of Dundee’s photonics and nanoscience group.

At the centre of these developments is a relatively new type of laser based on semiconductor trickery. Whereas most lasers up to now have used a solid chunk of material, a bulk liquid or gas as the medium which produces laser energy, these new devices are based around a structure called a quantum dot - a custom-built crystal, pieced together atom by atom, to form what is in effect a cage to hold electrons.

When semiconductors conduct electricity, the electrons that can move around in the structure have a series of energies known as an energy band. Change the semiconductor’s structure to confine the movement of the electrons -for example, by forcing atoms of different sizes into the semiconductor crystal -and those bands get narrower. Confine their movement enough, and the electrons can only absorb specific amounts of energy.

This is what happens inside a quantum dot. Based on semiconducting compounds such as indium arsenide and gallium indium arsenide, their structures confine electrons in all three dimensions. This creates a system where designers can define the energy the electrons can absorb, which also means they can define the energy they emit.

Effectively, this means when you shine light (or any other form of electromagnetic energy) on to a quantum dot, it will emit light back. But the wavelength of light doesn’t depend on the type of material. Because it’s the way electrons are constrained that produces the effect, the characteristic that defines the light emission is the space the electrons have to move; in other words, the size of the quantum dot. The bigger the dot, the longer the wavelength -the more towards the blue end of the spectrum -is the emitted light.

This emission is very efficient, virtually all the energy put into the quantum dot is emitted. Because of this property, it’s possible to make a material where the emission of energy from one quantum dot is absorbed by another, which emits the energy into another, and so on. This energy cascade is the essential mechanism to form laser light.

Quantum dot lasers were first made in the early 1990s and their variety of properties made them interesting subjects for studies. They have a very low threshold; that is, the amount of input energy needed to produce a laser effect. They are relatively insensitive to temperature; and have a very stable power output.

But, Rafailov explained, they weren’t suitable for most medical applications. They were developed for continuous wave devices, a mode of operation useful for telecommunications, for example, but not medicine. Using lasers for surgery requires a very fast pulsed delivery of the energy, so the laser can cut through tissues too fast for the heat they generate to flow into and damage surrounding areas.

‘We’ve now demonstrated that we can use these devices for this sort of ultra-fast physics,’ said Rafailov.

The only company in the world making quantum dot lasers commercially is Innolume, based in Dortmund, Germany. Guido Vogel, its business development director, said one major advantage of quantum dot lasers is that their output wavelength is extremely tuneable. Existing types of semiconductor laser, which work on a different principle, are made from two different materials, gallium arsenide or indium phosphide.

‘Conventional gallium arsenide lasers operate between 1,064 and 1,080nm, and for indium phosphide lasers, the wavelength range starts about 1,300nm. So there’s a big gap. What quantum dot lasers do, potentially, is fill that gap,’ said Vogel.

And it’s an important gap, because within that range is a variety of applications that are extremely promising in medicine. For example, in 2006, a team led by Rox Anderson of the Harvard Medical School discovered that a laser wavelength of 1,210nm will liquefy fat cells without damaging the skin above them. Anderson chose two interesting possible applications for this.

The first, and most likely to be exploited, is destroying the overactive sebaceous glands that cause the most severe and disfiguring forms of acne, currently treated using a drug implicated in causing birth defects. Further ahead, Anderson proposes a system to destroy or stabilise fatty deposits inside arteries, which restrict bloodflow, increase blood pressure and can flake and rupture, causing heart attacks and strokes. ‘We can envision a fat-seeking laser, and we’re heading down that path now,’ he said.

Also within the quantum dot range is an application discovered in 2005 by Axel Rolle of Coswig Specialised Hospital in Dresden. Working with a then-new type of solid state ruby laser, Rolle discovered that a wavelength of 1,318nm had the capacity to cut through lung tissue and simultaneously cauterise the wound. ‘Lung tissue is very soft and contains a lot of blood; it’s very difficult to cut without causing a large amount of bleeding,’ Vogel explained. ‘This technique would get around that problem.’
Innolume is part of the FAST-DOT consortium, and Vogel agrees that the fast-pulsed lasers are likely to be the most useful for surgical applications.

However, there are many spectroscopic applications, such as flow cytometry, which uses laser-induced fluorescence to count and analyse cells in biological samples, and optical coherence tomography, a powerful form of microscopy, which use continuous wave devices. Because of this, the company is proceeding with launching a range of quantum dot laser components.

‘There are several institutes and universities in the world that can grow quantum dot material on a small scale and with fairly bad quality, but we have the expertise to grow them in commercial volumes and high quality,’ he claimed.

Innolume’s technical team has devised a way to control the output wavelength of the quantum dot by varying the amount of indium in a semiconductor material based on gallium arsenide.

‘The quantum dot is a three-dimensional structure, as opposed to quantum wells, the other type of semiconductor laser, which are essentially two-dimensional,’ explained Vogel. ‘And because it’s three-dimensional, we can implant more indium into the structure without causing stress to the crystal lattice.

‘The more indium we add, the longer the wavelength gets. Because of this, we can make a quantum dot material to produce any wavelength that’s specified. It’s not a one-to-one relationship, though; it’s very tricky, there’s some magic to it. But, we have the best quantum dot growers in the world here,’ he said.

Innolume’s team came from the Ioffe Physico-Technical Institute in St Petersburg, where the semiconductor laser was invented.

Back in Dundee, the FAST-DOT team is looking forward to some of that magic. Rafailov’s team’s big advance is to demonstrate how the quantum dot lasers can be made to pulse: in simple terms, this involves building a semiconductor chip with two sections.

‘One we will apply in forward bias, like a conventional laser,’ he said. ‘The other we apply in reverse bias, so it acts as an energy absorber. And in that way, it develops pulses.’ The team has already demonstrated a material which will pulse at 400 femtoseconds (a femtosecond is 10 to the -15 seconds).

Neil Stewart, FAST-DOT project manager, said the four-year project will open up applications currently only possible with the larger, heavier solid-state lasers. ‘With these lasers we should be able to take [the focus of the beam] down to about a very few microns. And because of the differences in the way the energy is controlled, it enables us to deliver very controlled amounts of energy, so we are going to be investigating things like tissue welding.’

Another possible application of quantum dot lasers is likely to be optical tweezers. These use a strange property of a highly-focused laser beam to attract and move charged particles around the micrometre-to-nanometre scale: at the point where the beam is focused, there is a very strong electric field that pulls the charged particle in towards the beam. Using a nanometre-scale charged bead, chemically bound on to a molecule of interest, as a ‘handle’, they can also be used to stretch, move and manipulate single molecules, such as proteins and DNA.

Optical tweezers can be used for research applications. Researchers at the Massachusetts Institute of Technology (MIT) recently used them to explore how the proteins which make up the skeleton of biological cells are held together. Such experiments depend on solid-state lasers, but FAST-DOT’s Stewart believes smaller, cheaper and more efficient quantum dot versions could also be used for highly-precise microsurgery.

The quantum dot world faces a difficult task, and it’s one that is often faced by companies operating in new technological areas.

Vogel of Innolume explains: ‘We don’t make laser systems: we supply the essential equipment for the laser, the quantum dot chip. So what we are trying to do now is to identify the applications requiring these new laser wavelengths. The customers need to understand that there are new wavelengths available, they need to understand what they can do with them, and they need to design entirely new systems to take advantage of these wavelengths.’
SIDEBAR: Exciting Quantum Dots

While most of the interest in quantum dots springs from their use as lasers, they are also being studied for use in cancer treatment. Researchers from the University of Virginia, working on a treatment called photodynamic therapy, are using quantum dots to destroy cancer cells.

In photodynamic therapy, a drug known as a photosensitiser is injected into the body where tumour cells absorb a higher concentration than healthy cells. When this photosensitiser absorbs visible light, it splits oxygen atoms away from surrounding molecules to form free radical singlet oxygen, which is highly toxic and destroys the structure of cancer cells.

‘The problem with photosensitisers is that they are only excited by visible light, which has very limited penetration through the skin, so they can only be used on superficial cancers,’ explained research director Ke Sheng. ‘So initially, we were looking at using quantum dots as an internal light source to excite the photosensitisers.’

The idea is that the quantum dot is coated with a non-toxic polymer which, in turn, is chemically bound to the photosensitiser molecule, and this complex is injected into the tumour. ‘We can then excite the quantum dot using X-ray radiation, which is much more penetrating than visible light,’ said Sheng. ‘The quantum dot converts the X-ray to visible light and transfers this energy to the photosensitiser, which subsequently generates singlet oxygen and kills the cancer cells.’

Although the quantum dots are not being used as lasers, they are structurally identical to those being researched by the FAST-DOT consortium. Sheng’s team is investigating the toxicity of the semiconductor particles.

The research is still at an early stage, with studies on cancer cells only carried out in vitro; they are currently performing animal studies to find the best way to administer the quantum dot-photsensitiser complex. ‘For prostate cancer, for example, it would be fairly easy to inject the drug directly into the tumour; for others, such as lung cancer, it would be more difficult, and we’re looking at transfusion,’ said Sheng.