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Heft 2: Metrology in Medicine

PTB-Mitteilungen 2/2020


Metrology in Medicine

Tobias Schaeffter, Ulrike Ankerhold, Bernd Güttler, Christian Koch, Jörn Stenger

Healthcare is one of the major European challenges and a strategic cornerstone in almost all EU R&D programs. In the upcoming decades healthcare will remain a top priority politically as well as socio-economically, and its importance will even be intensified due to demographic change and increasing costs. This has been highlighted by the World Health Organization (WHO), European policy drivers and foresight studies with significant effort through research and technology development. The overall aim is to provide an early patient-specific diagnosis and to select the optimal individual therapy, thus making the healthcare system more efficient. This approach is based on the knowledge that individual biological predisposition, as well as lifestyle and the environmental factors, have an influence on the individual health. With this a new concept of stratified or personalized medicine has been established.

Metrology for Medical Acoustics and Audiology

Marion Bug, Elisa Burke, Thomas Fedtke, Christian Koch

Hearing plays an important role in shaping human life with high social and individual quality and comfortable wellbeing. Diagnosis, assessment and conservation of hearing is a key factor and plays an important role in health care also with respect to an increasingly elderly population. Considering a simultaneously rising anticipation of wellbeing by many individuals in European countries, meeting the requirements of quality of all processes involved represents a challenge for the heath care system of a country.

A comprehensive hearing assessment requires sophisticated measurements of a variety of variables. To ensure reliability and high or at least sufficient selectivity and specificity of a diagnosis, all measurements, but most importantly any quantitative measurements, should be underpinned by a quality management process to realise traceability to appropriate standards and references for all measurements. In this publication a short overview about PTB contributions to the metrological underpinning in the field of medical acoustics and audiology is presented. This includes the determination and distribution of important reference data describing the status of hearing. Novel methods will be developed as, for example the processing of transient stimuli which are preferentially applied in objective audiological techniques. Many activities are made in relation to the medical device regulation which currently became effective. In addition, research work is under way dealing with current topics as the measurement and perception of infrasound.

New Sensors for Biosignal Detection

Rainer Körber, Victor Lebedev, Thomas Middelmann, Jens Voigt, Tilmann Sander

The non-invasive measurement of magnetic fields generated by electrophysiological activities in the human body is an important method in clinical applications and basic research. This includes the measurement of electrical activity with high temporal resolution of the brain, heart, muscles, and nerves. All such magnetic biosignals are extremely small in comparison to the Earth magnetic field and technical magnetic fields in urban environments. Traditionally, highly sensitive superconducting quantum interference devices (SQUID) are used together with advanced magnetic shields. Recently they have been complemented in usability by a new class of sensors, optically pumped magnetometers (OPM). These quantum sensors offer high sensitivities without requiring cryogenic temperatures allowing the design of small and flexible sensors for clinical applications. The PTB has a track record in developing highly sensitive magnetic field measurement devices together with advanced magnetic shielding approaches. In this paper, new developments in the sensor types together with system design strategies will be presented. Potential applications in clinical practice and basic research will be discussed.

Electrolytes in Human Serum – Two Decades of SI Traceability

Olaf Rienitz, Karin Röhker, Carola Pape, Silvia Ulbrich, Ursula Schulz, Jessica Towara, Volker Görlitz, Reinhard Jährling, Anita Röthke, Detlef Schiel, Rainer Stosch

The ions lithium, sodium, potassium, magnesium, calcium, and chloride are important constituents of the electrolytes in human serum. Since electrolytes play an important role in the human body, the concentrations of the above-mentioned ions in human serum are meaningful markers for several diseases. For this reason, PTB has developed primary methods of measurement for the SI-traceable determination of these ions in the past more than two decades, as well as a routine method based on ion chromatography. The equivalence of the results of the primary method on the one hand and the routine method on the other hand as well as the international comparability of the results was demonstrated through successful participation in CCQM key comparisons. As a consequence, PTB holds eight serum-related CMC claims in the according BIPM database. The routine method was continuously improved over time resulting in relative measurement uncertainties of less than 0.5 % nearly on par with the ones obtained with the primary methods. Important improvements discussed in this work are the optimization of the serum digestion, the gravimetric preparation of reference solutions starting from primary monoelemental solutions, and the development of the exact matching one-point calibration as well as the combination of chemical and CO2-suppression.

Assuring SI Traceable Measurement Results in Germany for Organic, Peptide and Protein Biomarkers

Gavin O’Connor, André Henrion, Claudia Swart, Cristian Arsene, Rüdiger Ohlendorf, Christine Brauckmann, Claudia Frank, Rainer Stosch, Bernd Güttler

The international comparability of measurement results can be achieved by anchoring these measurements to the international System of Units (SI). Both the mechanisms and infrastructure for achieving this in the area of clinical chemistry are relatively new when compared to those for physical measurements. For the past two decades, PTB has been comparing the equivalence of its clinical measurement services with those of other NMIs. The development of high accuracy isotope dilution methods has enabled the provision of accurate results, whereby, all contributions to the measurement uncertainty can be appropriately estimated. These methods have been applied to priority clinical biomarkers, assuring the results provided by the German clinical reference laboratories are fully SI traceable. This, in turn, ensures the reference methods and routine clinical laboratories produce “fit for purpose” measurements as defined by RiLi-BÄK.

Previously simple protein biomarkers were considered too complex for the application of the high accuracy methods developed by NMIs. Improvements in analytical technology combined with simpler protein expression systems that enabled the production of isotopically labelled peptides and proteins enabled these methods to be applied to this group of analytes for the first time. The developed methods enabled full traceability to the SI through a stepwise approach, whereby, protein-specific peptides can be used to determine the amount of protein present in a biological sample. These methods can be easily applied to simple proteins but alternative approaches using protein metal complexes, that could infer a protein’s structural integrity are currently been investigated.

The metrology community has developed and compared their measurement services at the highest level for several important clinical markers. Greater effort is required to further disseminate these services, with the final goal of improving the comparability of patient measurement results on a continuous and global basis, for a broader range of biomarkers. If this is to become a reality much greater collaboration is required between the NMIs, reference laboratories, IVDD manufactures, and routine laboratories. This collaboration is essential if the benefits of metrological traceability are to be realised in full.

Quantitative Magnetic Resonance Imaging

Christoph Kolbitsch, Sebastian Schmitter, Tobias Schaeffter

Magnetic Resonance Imaging (MRI) is a widely used medical imaging modality. Due to its excellent soft tissue contrast, it is often used in brain imaging but also for many other applications such as cardiovascular imaging or tumour diagnosis. The majority of MRI scans provide qualitative images, where the contrast (i.e. the difference in signal intensity) between healthy and diseased tissue is used for diagnosis. Quantitative MRI on the other hand provides physical (e.g. relaxation times) and biophysical parameters (e.g. blood flow velocities, blood perfusion), which can be used for an objective assessment of pathologies. Quantitative MRI does not depend on hardware or acquisition related parameters, making it much easier to combine data from multiple hospitals in multi-centre studies and allowing for monitoring of disease progression or treatment outcome.

PTB is working on novel techniques in order to ensure that the full potential of quantitative MRI can be utilised for patient care. We have developed novel signal models to provide more accurate measurements and ensure negative effects during data acquisition (e.g. breathing motion of the organs) are taken into consideration to minimize measurement errors. In addition, we have combined quantitative parameter estimation with statistical approaches in order to be able to assess not just the biophysical quantities but also their uncertainty. Finally, we are also working on novel hardware designs to ensure best possible measurement quality.

Metrology for RF Safety in Magnetic Resonance Imaging

Frank Seifert

Magnetic Resonance Imaging (MRI) is a noninvasive medical imaging technique to obtain three-dimensional images with up to submillimeter resolution. Because of the remarkably high soft-tissue contrast and the avoidance of ionizing radiation, MRI is widely applied in clinic and research. Nevertheless, there are hazards that are particularly related to tissue heating due to the absorption of radiofrequency (RF) energy expressed by the Specific Absorption Rate (SAR). The distribution of local SAR in the human body is very inhomogeneous and can only be derived from numerical simulations using a variety of human voxel models. Validation of these simulations by measurements of RF field quantities is necessary to create confidence in this computational approach. Thus, the metrological concept to assess the SAR hazards of MRI is based on instrumentation for traceable in situ measurements of RF electromagnetic fields and other RF related quantities which can be operated within the MR environment. PTB developed unique measurement methods which are suitable for MRI equipment at 1.5 tesla to 7 tesla together with parallel transmission (pTx) capability. This measurement infrastructure was developed for RF safety in MRI and is independent from MR vendor specific solutions. In addition to this, it can be operated independently from the MR equipment allowing measurements in specific exposure scenarios. The measurement infrastructure allows research on future technologies in the field of sensor equipped implants which are capable to to monitor and mitigate the RF related hazards during MRI examinations.

Dosimetry in Medical X-ray Imaging

Ludwig Büermann

X-ray computed tomography is by far the largest contributor to the radiation burden of patients. Therefore, good clinical practice in medical X-ray imaging requires the quantification of radiation exposure to optimize the image quality in relation to the absorbed dose ratio. This article covers the dosimetry part but not the quantification of image quality. Dose measurements in X-ray imaging are fundamental for two purposes: First, to set and check standards of good practice and second, to assist in assessing detriment or harm. Different application specific dose quantities are defined for general radiography and fluoroscopy, mammography and computed tomography. These provide the basis for quality assurance in X-ray imaging – for example, for acceptance testing, or for application-specific diagnostic reference levels. Non-invasive X-ray multimeters are used for quality control measurements in the beams of diagnostic X-ray devices. The patient dose is usually evaluated as the absorbed dose in organs and tissues from which the risk-related quantity “effective dose” is estimated. The latter quantity allows an estimate of the patient’s risk to suffer from stochastic radiation effects. The effective dose is estimated from the measured applicationspecific dose quantities by use of dose conversion coefficients. These cannot be measured directly. Instead, they are calculated by means of Monte- Carlo simulations using computational reference models of the human body. Alternatively, they can be determined by dose measurements in adequate physical (anthropomorphic) phantoms. Simulations and dose measurements are important requirements for the development of personalized dosimetry in computed tomography.

Image Quality Assessment for CT and Mammography

Mathias Anton, Tobias Kretz, Marcel Reginatto, Clemens Elster

Mammography and computed tomography are modalities of medical imaging involving ionizing radiation. The choice of applied dose is determined by a tradeoff between the quality of the images and possible risks to the patient. Established measures of image quality assume linearity and shift-invariance of the imaging system, but the application of these measures is problematic due to the development of improved imaging systems that violate these assumptions.

Task-specific image quality assessment using model observers provides a promising alternative which has become increasingly popular. This approach assesses image quality based on the ability of a mathematical or human observer to successfully solve a clinically relevant task using images which can be obtained by means of technical phantoms. Current questions of research in this field include the design of appropriate technical phantoms, the development of efficient mathematical observers, and the evaluation of the uncertainty of the mathematical observers.

In 2016, PTB started research in this field, which may be viewed as being in between medical research and classical metrology. One of the goals is to include uncertainty evaluation in the mathematical model observers in line with current standards in metrology, and to foster current efforts in reaching standardized procedures for the application of task-based image quality assessment in computed tomography and mammography. Another aim of this research is to apply modern techniques of data analysis, including deep learning, to improve image quality assessments. This paper presents some of the results of this research.


Doping mit Wachstumshormon – zuverlässig nachgewiesen durch Massenspektrometrie

Höher, schneller, weiter … Dieses Motto ist Ansporn vieler Leistungssportler, um noch größere Höchstleistungen zu erbringen. Leider beschränken sich manche Athleten dabei nicht bloß auf präzise abgestimmtes Training und Ernährung, sondern greifen zu unerlaubten leistungssteigernden Substanzen. Die neue massenspektrometrische Analysemethode der PTB verspricht mehr Zuverlässigkeit im Nachweis von Doping mit Wachstumshormon.

Selektive Charakterisierung magnetischer Nanopartikel

Die Magnetpartikelspektroskopie (MPS) ist ein hochempfindliches und schnelles magnetisches Messverfahren zur Quantifizierung und Charakterisierung magnetischer Nanopartikel. Erstmals wurde die MPS mit einem chromatografischen Trennverfahren kombiniert, um MNP direkt während ihrer größenselektiven Fraktionierung magnetisch zu charakterisieren.

Label- und hämolysefreie Vollblut- Differenzierung in mikrofluidischen Sensoren mittels AC-Impedanz

Die quantitative Untersuchung von Zellen im Blut mittels Durchflusszytometrie ist ein routinediagnostisches Verfahren in der Hämatologie. Durch die neue PTB-Technologie kann jetzt die zuverlässige Messung der Konzentration der Subpopulationen von Leukozyten mittels AC-Impedanz ohne Hämolyse durchgeführt werden. Somit ist erstmalig eine zuverlässige Vollblut-Differenzierung unter anderem auch bei Leukämiepatienten möglich.


Die Zahl der deutschen Arbeitsplätze, an denen mit Ultraschall gearbeitet wird, ist durch den zunehmenden Einsatz von Ultraschallreinigungsanlagen, Schweiß- und Schneidemaschinen stetig steigend. Um zu der gesetzlich geforderten Gefährdungsbeurteilung dieser Arbeitsplätze zu gelangen ist es erforderlich den Lärm an diesen Arbeitsplätzen zu messen und zu beurteilen. Derzeitige Messmethoden sind hier ungenügend. Das Ultraschallpegelmesssystem ist für den mobilen Einsatz ausgelegt und entspricht den Bedingungen an den praktischen Einsatz an Arbeitsplätzen und ermöglicht gleichzeitig eine rückführbare Messung.

Mobiler Messstand für Röntgenstrahlerprüfungen

Röntgenstrahler müssen während der Entwicklung, der Zertifizierung und zur Qualitätskontrolle auf ihre Gehäusedurchlassstrahlung überprüft werden, wobei der unerwünschte Austritt von Strahlung (bei abgedecktem Nutzstrahl) der entscheidende Parameter ist. Für ihre eigene, gesetzliche Aufgabe der Bauartprüfung hat die PTB einen mobilen Messstand für die Prüfung von Röntgenstrahlern aufgebaut. Mit diesem Messstand können vor Ort zuverlässige Dosisleistungsmessungen in einem festen Abstand von 1 m vom Brennfleck einer Röntgenröhre durchgeführt werden.


Dr. Bernhard Smandek
Telefon: +49 531 592-8303
Telefax: +49 531 592-69-8303
E-Mail: bernhard.smandek(at)ptb.de