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Breaking New Ground in Infection Diagnostics

21 Jun '17 | By Daniel Siegesmund
Breaking New Ground in Infection Diagnostics
Telltale Fingerprints: Every pathogen has a characteristic molecular fingerprint that can be measured by means of Raman spectroscopy. Doctoral candidate Björn Lorenz compares the spectra with the information stored in a database and in this way can identify the bacteria from the urine sample of a patient.
Image source: Sven Döring / Leibniz-IPHT

Sepsis begins with a localized infection caused by bacteria. Normally, the body is able to restrict the disease to its origin; however, in some cases, the pathogens and their toxins spread through the bloodstream to the entire body. The organism responds with an infection that spreads to all the organs in a short amount of time which can cause a serious multiple organ failure. The symptoms of sepsis are not always clear. Fever, increased pulse, and rapid breathing can also be signs of other serious diseases. Doctors, therefore, rely heavily on their experience when making a diagnosis so far.

Reliable information on the triggering pathogen and its resistance potential is provided via a biochemical analysis, such as a blood culture, after at least 24 hours. Every hour that passes without the administration of effective antibiotics worsens the patient’s chances of survival. Thus, if sepsis is suspected, a broad-spectrum antibiotic is given. To effectively treat the patient, it is important to quickly and reliably diagnose sepsis.

As part of the EU project HemoSpec, research scientists from six European countries are working on the development of a miniature laboratory to meet these medical needs.

Prof. Dr. Ute Neugebauer, a research scientist at Leibniz-IPHT and the Center for Sepsis Control and Care (CSCC) is participating in this project. Using light, she is researching one of three key technologies that this unit is designed to combine. With the help of Raman spectroscopy, Neugebauer is seeking molecular and biochemical information on white blood cells (i.e., leukocytes). They fight foreign organisms, such as bacteria and viruses, in the body. If the body has an infection, more leukocytes are present in the blood. If the leukocytes detect a pathogen, they are activated and begin to render these intruders harmless, for example, through phagocytosis (devouring) or the production and release of certain molecules, such as antibodies or chemical messengers. Thus, activated leukocytes differ from deactivated leukocytes. “We want to recognize this difference with the help of Raman spectroscopy. Our goal is to find out if we can determine whether the patient is suffering from sepsis based on the activation state of the leukocytes,” said Dr. Neugebauer. Her colleagues at Leibniz-IPHT are working on other elements of the miniature laboratory: holographic microscopy to count the cells and a microfluidic chip to separate and distribute the blood on the platform. These elements are supplemented by the research performed by the European project partners, who are working on reading biomarkers in the blood with the help of fluorescence-based methods, the development of miniaturized modules for the Raman and fluorescence analysis, and the development of software that controls everything.

By combining these technologies in a single unit, it should be possible to obtain reliable information from just a few drops of blood within a few hours. The miniature laboratory should be handy and user friendly so that it can be operated by both doctors and nurses. Therefore, the scientists are working closely with doctors to ensure that it meets clinical requirements. The first clinical studies are currently being run with eighty patients at Jena University Hospital.

Using Raman spectroscopy, it is not only possible to obtain molecular and biochemical information on white blood cells but on disease pathogens as well – directly in bodily fluids and without the need for a time-consuming cultivation step. The spectrum of a pathogen is very individual, much like a person’s fingerprint. Thus, compiling a “database of culprits” with the spectra of relevant pathogens is time consuming. Male and female scientists from Leibniz-IPHT and the Institute of Physical Chemistry (IPC) at the Friedrich Schiller University of Jena have been working on this database for a few years now. It is the basis for the fast and positive determination of pathogens and thus the basis for targeted treatment.

The fundamental technology was researched by Leibniz-IPHT in collaboration with IPC. The Berlin-based company ­rap.ID developed this technology further for commercial use. With the help of a spectroscopic measurement method and in combination with a statistical analysis method, the Bio Particle Explorer identifies whether or not, and if so, with which and with how many germs patients’ blood and urine samples or air and water samples are contaminated. By comparing these samples with the database, similar to a criminal database, the isolated pathogens can be detected within a matter of a few hours. Presently, Leibniz-IPHT is working with rap.ID to improve the quality and reproducibility of characterization and to optimize the manageability of the Bio Particle Explorer.

In addition to the identification of pathogens, the subject of resistances to antibiotics is an important area of research at Leibniz-IPHT. The young researchers’ group headed by Ute Neugebauer focuses on urinary tract infection pathogens. In medical microbiology, the identification of pathogens and their sensitivity to antibiotics using standard methods takes at least twenty-four hours. In this time, calculated treatment with antibiotics is often begun to counter the infection as quickly as possible. However, at a time of increasing resistances, this form of treatment is bound to fail.

With a combined dielectrophoresis Raman setup, the young researchers’ group developed an innovative method that makes it possible to detect pathogens much more quickly (in significantly less than twenty-four hours) and directly from patient material. The scientists capture the pathogens on a chip using electric fields (dielectrophoresis) in microstructured regions to subsequently identify the collected pathogens using Raman spectroscopy within a little more than half an hour.

In a second step, the pathogens that were incubated with antibiotics are applied to the chip. The interaction between the two is then monitored. From the Raman spectra obtained using this method, it is possible to draw conclusions about existing resistances. Unlike the preparation of an antibiogram, this method provides information on possible resistances to antibiotics within just 3.5 hours. This was verified with Vancomycin-resistant enterococci. Patient-specific treatment with antibiotics can be started much sooner.

Related user groups at Biophotonics.World:


Further information on the internet:

Clinical Spectroscopic Diagnostics Research Group (Leibniz-IPHT)

InfectoGnostics Research Campus Jena

HemoSpec - A European Research Alliance

Center for Sepsis Control and Care

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