Compact yet powerful – soft tissue and tumour visualisation

In October 1895, German physicist Wilhelm Conrad Röntgen was in his laboratory experimenting with cathode rays. He set up a Crookes tube - an electrical discharge tube with a partial vacuum - and fitted it with an anode and cathode; he then covered the tube with lightproof cardboard and passed an electric current through it.

Similar experiments had been performed before, but the circumstances of this one were different. The room was dark, and on a table lay a sheet of fluorescent material. When discharging the current, Röntgen noticed that despite the lightproof jacket, the fluorescent material was glowing. This meant there must be another hitherto unknown type of ray emanating from the tube. Given the mysterious nature of the finding, he named the phenomenon an 'X'-ray.

Subsequent experiments demonstrated that the X-ray could pass through human flesh but not hard substances like bone, enabling the human skeleton to be scanned and photographed. The first X-ray image was of the hand of Röntgen's wife's; on seeing its ghostly glow, she reportedly remarked, "I have seen my own death".

Today, 120 years since the discovery, the X-ray is still unimpeachable as a tool for examining hard internal matter such as bones and teeth. Image contrast is dependent on X-ray absorption, and these body parts, thanks to high calcium content, absorb large amounts of X-rays - but a major goal of researchers has been to improve X-ray imaging of fleshy parts of the body too, which are very difficult to accurately picture using current methods. Organs and tissue are full of air, which gives them similar X-ray absorption coefficients to foreign bodies like tumours. This makes it difficult to tell what should or shouldn't be present in the body.

Some research being carried out in Munich - the same city in which Röntgen made his discovery - has broken significant ground in this area. In April 2015, Franz Pfeiffer, professor of biomedical physics at Technische Universität München (TU München), and his team used a relatively new X-ray source known as a compact laser-driven synchrotron to clearly pick out these areas of soft tissue. But to understand the significance of this, it's important to first look at the development of the synchrotron.

The search for the right wave

Being able to tell what's what on an X-ray scan is dependent on differences in brightness and contrast. Instead of focusing purely on the absorption of X-rays - the basis for existing CT scans - scientists are increasingly looking at phase-contrast and dark-field CT to help illuminate soft tissue. The former creates contrast according to how bodily tissue refracts and scatters incoming X-rays, while the latter excludes scattered X-ray beams from an image, making the field around the tissue dark. To carry out these functions, you need to produce X-rays that are coherent - monochromatic, with the same frequency and amplitude: something which is beyond the scope of conventional X-ray tubes. For that, you have to gain access to a synchrotron.

A synchrotron is a kind of particle accelerator. It is circular, can be several kilometres in length, and uses radio frequency waves and electromagnets to accelerate electrons to extremely high energy levels, and periodically make them change direction. When this happens, the electrons omit a brilliant, highly focused spectrum of X-rays, which can be split into individual beams and harnessed by researchers.

Synchrotron-produced X-rays are 108 times more powerful than conventional X-rays and are spatially coherent as required, meaning they can help produce accurate phase-contrast and dark-field images. But they are huge and incredibly expensive to build, so researchers have been working for years to compress their force into a much smaller package.

The development of the compact light source (CLS) by Lycean Technologies, a spin-off of the California-based SLAC National Accelerator Laboratory, is a major step forward. The CLS uses a laser to accelerate electrons to almost the speed of light in a miniature version of a synchrotron's storage ring. When the electrons change direction, a beam with many of the favourable qualities of synchrotron light is created - but through apparatus a fraction of the size and for a fraction of the cost than previous models.

"The compact synchrotron is beneficial over standard X-ray tubes as it provides a quasimonochromatic X-ray beam," says Elena Eggl, doctoral candidate at the chair of biomedical physics at TU München, who worked on the experiment. "It is possible to install a compact synchrotron on any research campus due to its size, unlike large-scale synchrotron sources, where one has to apply for beam times.

"Monochromatic radiation is much better suited for measuring other parameters, in addition to absorption. This is because it does not lead to artefacts that deteriorate the image quality."

Clear contrast

Pfeiffer's team at TU München were the first to buy a CLS, in December 2012, and began using it for biomedical and material science imaging experiments. In April 2015, they published a paper called 'X-ray phase-contrast tomography with a compact laser-driven synchrotron source' in the Proceedings of the National Academy of Sciences of the United States of America journal. The paper, in Pfeiffer's view, outlines the "first phase-contrast tomography acquired at a compact light source", demonstrating for the first time that the mini synchrotron can be as effective as its older brother.

The scientists took the CLS and inserted into the X-ray beam an optical grating - grating-based imaging being one of the common X-ray phase-contrast imaging techniques, along with analyser and proportion-based imaging. The grating is a device with thousands of slits etched into it, and it allows you to ascertain the different wavelengths and colours in a beam of light. This means that in addition to measuring the absorption of X-rays, it can detect even the smallest phase shifts and radiation scattering.

The team took 361 attenuation (conventional hospital standard), phase-contrast and dark-field scans of an infant mouse from all angles, creating a kind of cross-section of the animal. As expected, the phase-contrast and dark-field scans produced clearer images of soft tissue than the attenuation scans, but the detail of these images surprised the team. Not only could they identify internal organs of the mouse, but also different colours of fat tissue.

"Several internal organs, such as the heart and liver, and structures within the organs, can be recognised in the phase-contrast images, but not in the attenuation image; in the sagittal as well as in the axial images," Eggl writes. "The dark-field image displays strong scattering at the bones and at air-filled organs... With phase contrast and dark-field contrast, brown adipose tissue and white adipose tissue are visible and can be discriminated."

She concludes, "The results show that a compact synchrotron source is a very promising X-ray source that could close the gap between conventional X-ray tubes and large-scale synchrotron facilities. With a footprint suitable for normal laboratory sizes, it provides a level of coherence and monochromaticity otherwise only available at synchrotrons."

Taking wing

In July 2015, another team, led by Pfeiffer and Stefan Kirsch, a researcher at the Max Planck Institute for Quantum Optics and professor at Ludwig-Maximilians-Universität München, produced a paper in Nature that took this idea further: 'Quantitative X-ray phase-contrast microtomography from a compact laser-driven betatron source'.

The team built a miniature laser-driven X-ray betatron source - a betatron being a type of particle accelerator similar to a synchrotron but less powerful. Betatron X-rays are produced when a laser is directed at plasma of positively charged electrons, causing them to oscillate and accelerate. These X-rays have a wavelength of around 0.1nm, and a single pulse lasts about five femtoseconds. The X-rays produced are spatially coherent, making them suitable for the creation of high-quality phase-contrast scans.

The team combined this laser-driven X-ray source with phase-contrast X-ray tomography, as used in the earlier experiment, taking 1,500 scans of a small fly from all angles to build up a detailed 3D image. They were able to capture images in which you could see the individual hairs on the fly's wings, representing the first time, according to Johannes Wenz, a researcher at the Max Planck Institute of Quantum Optics who worked on the experiment, that "[we] were able to record and quantitatively reconstruct a phase tomogram of a complex object".

"A laser-driven plasma wave accelerates and wiggles electrons, giving rise to a brilliant keV X-ray emission," Wenz writes. "This so-called betatron radiation is emitted in a collimated beam with excellent spatial coherence and remarkable spectral stability."

From the lab to the hospital

The work in Munich could be a huge breakthrough for medical imaging. Lasers have harnessed the power of the synchrotron and compressed it into a box no bigger than a car. Combined with improving phase-contrast and dark-field scans, focusing on the refraction rather than absorption of X-rays, it is a formidable tool for detecting the smallest of tumours.

Eggl, who was part of the team that conducted the CLS experiment, says that, for the time being, the Munich CLS is scheduled only for preclinical research, and no thought has yet been given to potential commercialisation.

Wenz optimistically concludes, "This result demonstrates that laser-driven X-ray sources have reached the verge of practical usefulness for application-driven research. If further progress regarding mean photon flux can be made, laser-driven sources, due to their compactness, relatively low cost and high peak brilliance, might become valuable tools for university-scale research and medical application, particularly in early detection of tumours with low-dose diagnostics."

Given the relatively early stage of investigation, and the expense of CLS and miniature laser-driven betatrons, it will be a while until hospitals are taking advantage of laser-powered ways of creating X-rays. But given the speed with which this technology has advanced in the space of one year, in one country, it may not be as far away as you think.