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SIEMENS

Research & Development
Technology Press and Innovation Communications

Dr. Ulrich Eberl
Herr Dr. Ulrich Eberl
  • Wittelsbacherplatz 2
  • 80333 Munich
  • Germany
Dr. Ulrich Eberl
Herr Florian Martini
  • Wittelsbacherplatz 2
  • 80333 Munich
  • Germany
pictures

Some illnesses produce a unique molecular signature in a patient’s breath. Researchers are confident that quadrupole mass spectroscopy will make rapid diagnoses possible.

Sensors react to a range of molecules, including those of acetone.

Siemens researchers are developing a range of sensitive breath analysis tests.

A light sensor directs near-infrared rays onto the spot under examination.

Sniffing out Diseases

Very soon, revolutionary analysis technology from Siemens could be improving the lives of asthma patients, enabling the early diagnosis of life-threatening illnesses, and making surgical procedures safer. The goal is to create a universal device that can diagnose cancer, allergies, and infections.

Image Sensors react to a range of molecules, including those of acetone
Image Prof. Maximilian Fleischer is researching new materials applicable to breath diagnostics
Image Test tubes with breath samples are providing the basis for further examinations
Image A light sensor directs near-infrared rays onto the spot under examination
Image Siemens researchers are developing a range of sensitive breath analysis tests.

Professor Maximilian Fleischer has a special reason for visiting lots of doctors these days. A top researcher at Siemens Corporate Technology in Munich, Fleischer observes their work and asks them about their methods for diagnosing and treating diseases — specifically the kind of analysis equipment that might support them. “For example,” says Fleischer, “there is still no reliable way to make an early diagnosis of lung cancer. By the time the first symptoms appear it’s usually too late. On average, patients live for only about two years after their condition has been diagnosed.” Yet lung cancer would be largely curable if it could be recognized early.

The case is similar for tuberculosis, a dangerous lung disease, where late diagnosis can spell fatal consequences. “The patient is contagious for a long time without knowing it, exposing other people to this highly infectious disease,” Fleischer explains. In a recent report, the World Health Organization (WHO) estimates that 3,800 people die every day from tuberculosis — mostly in developing nations. Even though the number of new infections is declining, the explosive nature of new outbreaks is on the rise as more and more of the bacterial strains that cause the disease are demonstrating increased resistance to common antibiotics. An easy and reliable method for the early diagnosis of this life-threatening disease — such as a breath test, for example — is at the top of many doctors’ wish lists. That’s why Fleischer’s team is working on equipment that analyses people’s breath.

“Chinese doctors have known for two thousand years that specific illnesses can be identified by changes in the smell of a person’s breath,” explains Fleischer. Western medicine has been slower to catch on to the significance of this phenomenon. However, ever since the medical journal Lancet featured a report about a dog that was able to detect it’s owner’s skin cancer, things have changed. In fact, the worldwide search for gaseous bodily emissions that could betray the presence of disease has been in high gear. In most cases, detection is a matter of analyzing “cocktails” made up of a number of highly complex molecules, which are also to be found in the breath or bodily emissions of healthy people, just in different proportions.

Today, most research groups are looking for these suspicious mixtures of substances with detection arrays made up of eight to ten different sensors. “But that hasn’t really worked well yet,” reports Fleischer. With this in mind, Siemens researchers are employing a classic analytical method from the chemical laboratory — quadrupole mass spectroscopy. When a breath sample enters this device the first thing that happens is that it is bombarded with ionized mercury particles. This procedure gives an electric charge to the substances in the sample.

The charged particles are then passed through an electric field and are finally slammed into a detector. Because they don’t weigh the same, the degree to which the particles are deflected in the electric field varies. The result is that they land in different places on the detector, producing a characteristic impact pattern — a sort of fingerprint that exposes diseases.

The first breath tests from cancer and tuberculosis patients were very promising. “But to be sure that this method really works, we have to do additional testing on samples from several hundred patients,” reports Fleischer. It could be that the concentrations in a characteristic gas “cocktail” are also influenced by a patient’s sex, age, ethnicity, or eating habits, for example.

The researchers also want to know if this kind of diagnosis would work with smokers. But if the first results with the new method are confirmed, things could progress very quickly. That’s because shrinking the spectrometer equipment down to about the size of a suitcase and perfecting the software for use in a doctor’s office or clinic is a matter of pretty routine engineering according to Fleischer. Meanwhile, the scientists want to go ahead and see if the new method can be applied to the diagnoses of other illnesses as well. Their goal is to create a universal device that offers a wide spectrum of diagnostic possibilities. It should not only be able to recognize different forms of cancer, but also detect allergies and infections.

A Test that Predicts Asthma Attacks. A forerunner of Fleischer’s breath analyzer is a device designed for asthma patients that should soon be available on the market. The device detects the imminent onset of an asthma attack. What’s more, because it is about the same size as a CD box, asthma sufferers can easily carry it around. “Basically, in order to know the status of a patient’s asthma, all that’s necessary is to establish the proportion of a single, easily detectable type of molecule in the patient’s breath,” explains Fleischer. That substance is nitric oxide (NO) and it can rise to five times its normal levels several hours before an asthma attack. The gas is therefore a clear indicator of inflammation processes in the respiratory tract.

Fleischer’s new detection device is equipped with a roughly dime-sized sensor that contains the colorant phthalocyanine. This blue dye, which is also used for coloring eggs, binds very selectively with NO molecules thus changing their electrical properties. “And that’s something that we can measure very easily,” says Fleischer. That’s because the dye comes into contact with a microchip equipped with a field-effect transistor (FET). When NO molecules accumulate on the chip, the FET measures high voltages and sends a signal to the electronic evaluation system.
The system is extremely sensitive. Normally, human breath contains, at most, 30 NO molecules per billion other molecules (30 ppb). But if this concentration rises to 100 ppb the sensor can detect the change. For comparison, that’s the equivalent of finding the molecules of a sugar cube dissolved in a large swimming pool. The sensing system, which is now at the prototype stage, doesn’t react to other things, such as alcohol, acetone or bad breath. With this device, people afflicted with asthma will be better equipped to prevent asthma attacks, against which they can then proactively inhale a large dose of bronchodilators and anti-inflammatory medication.
Most people probably know acetone as a solvent, but it is also a by-product of our metabolism. “Achieving a concentration of about one ppm — meaning one molecule of acetone per million other molecules — in a breath sample, is the ideal way to actually lose weight when exercising,” says Fleischer. Building such a sensor won’t be a problem, either. In fact, the researchers are already on the lookout for a partner company that will mass produce the small devices.

Tissue Analysis with Light. Another point of focus for Fleischer’s team is measurement technology that would literally shed light on things during difficult operations. “For example, in the case of brain tumor operations, such a feature would make it easier for surgeons to tell the difference between healthy and diseased tissues,” says Fleischer.

With a normal surgical microscope, it is extremely difficult to make this distinction, which can have serious consequences. If the surgeon doesn’t remove enough tissue, the cancer can grow back. But if too much is removed, function could be compromised. According to Fleischer, better insight into tissue structure is important for other operations as well, such as those involving the throat, where the vocal chords could be at risk, or during prostate surgery, where a mistake could mean incontinence.

Help in achieving improved accuracy may come from a device developed by Siemens’ measurement technology center that is used in food quality control. The device can reveal how fresh a meat sample is, or what animal it came from. But it might also be used in the operating room. About the size of a ballpoint pen, the probe contains fiber optics that direct light from the near infrared spectrum onto a point of interest. Near infrared light penetrates the topmost millimeters of the tissue and, unlike X-rays, is completely harmless.

Information about tissue structure is provided by the light that is reflected back to the testing probe, which directs it to an infrared spectrometer. “Which wavelengths of the light are absorbed and which are reflected is, in part, determined by the molecular organization of the cell walls,” explains Fleischer. “Because tumor cells grow so fast, their cell walls are less uniform than those in healthy cells — a feature we can make visible with our method.” When light from the sensor reaches the edge of the tumor, the interface can be pinpointed with an accuracy of less than a millimeter.
The light sensor has already passed the acid test. With the help of this device, surgeons have been able to discern the difference between healthy and diseased tissue in throat cancer patients. What is more, tests on laboratory rats show how well the device can identify the boundaries of a brain tumor. However, the new method can not be tested on people with brain tumors because the laboratory device for this type of operation can not currently be adequately sterilized. “It has to be cleaned under high pressure and at high temperatures; the connections for the optical elements can’t survive that yet,” says Fleischer.
Should upcoming tests prove successful, scientists intend to build a version of the machine that can be sterilized quickly. Clinical trials could then begin. If everything goes as planned, the first models of the new surgical assistants could be available in a few years.

Andrea Hoferichter