Learning how to look inside a body without having to cut it open is still an important part of medical research. One of the great challenges in imaging remains the visualization of oxygen in tissue. A team led by Prof. Vasilis Ntziachristos, Chair for Biological Imaging at the Technical University of Munich (TUM) and Director of the Institute for Biological and Medical Imaging at the Helmholtz Zentrum München , has developed a new approach to this task.
Imaging of tissue oxygenation is not straightforward; different techniques have been considered but each of them has their shortcomings. In recent years, research in this field has focused on optoacoustic methods. These, especially Multispectral optoacoustic tomography (MSOT), form one of the key areas of Vasilis Ntziachristos' research.
Put in simple terms, MSOT turns light into sound and then into visual information: First, a weak pulsed laser beam is directed at tissue. Absorbing molecules and cells respond with a minuscule vibration, which, in turn, creates sound signals. The sound signals are then picked up by sound sensors and translated into images. The way molecules and cells react to the laser beam offers insight into their optical and thus into their biochemical properties.
Complex tissue is an obstacle to optoacoustic imaging
While MSOT can, in theory, be used to tell how much oxygen can be found in blood, there is one major obstacle: The intensity of light changes with depth, not only because light has been filtered through all the tissue layers that it passed through, but also because different tissue structures may have different properties that affect how light is scattered and absorbed. In the past, there have been several attempts to solve this problem by calculating how the tissue will affect the propagation of light. "However, due to the high optical complexity of tissues, this approach so far could not be flexibly applied in optoacoustic images of tissues of living subjects," says Stratis Tzoumas, first author of a study published in Nature Communications, in which the scientists describe their new method.
A new description of light distribution in tissue
Ntziachristos, Tzoumas, and their colleagues came up with a completely different approach. Instead of describing the spatial distribution of light, their imaging method eMSOT – the e stands for "eigenspectra" – avoids simulating the path of light through complex tissue altogether. Instead the new method is based on the discovery that the spectrum of light propagating in tissue can be described by using a small number of basic spectra. eMSOT uses data from a conventional MSOT-device combined with a new algorithm that is based on this novel way of describing the light spectrum to correct for the effects of light propagation in tissue and obtain accurate images of blood oxygenation in tissue.
With eMSOT, the scientists were able to visualize the blood oxygenation level of living tissue up to one centimeter below the skin surface. "Theoretically, the imaging depth can be extended to more than that," says Stratis Tzoumas. "There is, however, a limit at about three because at some point, light cannot penetrate the tissue any further." The scientists observed a vastly improved accuracy in eMSOT over previous optical and optoacoustic approaches. Apart from being non-invasive and radiation-free, eMSOT also delivers comparable or higher resolution both spatially and temporally, than other optical imaging methods. "Information about the amount of oxygen in tissue is important when it comes to various fields in research and treatment – for example tumor growth or in measurements of metabolism" says Vasilis Ntziachristos. "It may be that eMSOT becomes the gold standard method, once it is ready for clinical use."
Dr. Barbara Schröder
Chair of Biological Imaging (CBI)
Technical University of Munich
S. Tzoumas S, A. Nunes, I. Olefir, S. Stangl, P. Symvoulidis, S. Glasl, C. Bayer, G. Multhoff, V. Ntziachristos. "Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues." Nature Communications (2016). DOI:10.1038/ncomms12121
Interview with Professor Vasilis Ntziachristos:
"An image is worth a thousand words"
Modern imaging methods greatly exceed the possibilities of X-rays. Vasilis Ntziachristos holds the Chair of Biological Imaging at the Technical University of Munich (TUM) and is Director of the Institute for Biological and Medical Imaging at Helmholtz Zentrum München. In this interview, he talks about the fascination of imaging techniques and about finding a common language for engineers and doctors.
Professor Ntziachristos, you have been working on imaging techniques for quite a while now. How did you end up in this field?
I began working with imaging very early on. Back in 1993, I received my diploma for a thesis on Magnetic Resonance Imaging electronics and sequences. Since then, I looked into several different ways of making biological information visible – optical techniques, radio frequency imaging, combinations with X-ray, CT, MRI and ultrasound – but it has always been imaging.
What is it about imaging that got you?
Images are a fundamental way of understanding the world. They say an image is worth a thousand words, and it's true. Take biology: There is a lot of information to be found in the spatial relation of biological contrast and interworking of cell populations. It is fascinating when you visualize processes that are usually hidden. Using technology, we can for instance see what happens functionally in tissues. Not just the anatomy, but also the distribution of cells or molecular information, such as the concentration of oxygen within different tissues.
You received praise, awards, and research grants for several research projects. How many different imaging techniques are you and your colleagues working on?
We have three major directions: fluorescence imaging, thermoacoustics, and optoacoustics. Within these fields, we work on different devices and different applications. In optoacoustics, for example, we have three microscope implementations with very different abilities; we have developed three different mesoscopes for skin and subsurface tissue visualization and several other optoacoustic devices. Overall, there are at least ten different implementations of the technology, probably more, depending on how you count.
Your optoacoustic devices are in various stages of development. How long will it be until the first one of them will be in everyday use in hospitals?
In biomedical technology, this is always a long process. There actually are optoacoustic systems in hospitals today for research purposes but not for everyday routine use. We believe, however, that it won't be long until these methods are used in cardiology, in cancer, dermatology, and other fields. Through research and through tests in clinical environments we should be able to find the key diagnostic and theranostic applications in the next two to three years.
What are the typical problems if you want to adapt a technology you developed for practical use?
You need to be able to bridge the gap between engineering and medicine. Engineers tend to develop technologies because they can be developed and because it is scientifically interesting to develop them. Everyday use, however, comes from not only having a good technology but from solving an unmet clinical need. You have to find a common language to understand the needs of medical doctors.
How do you address this in your projects?
When we developed the proposal for Innoderm – a handheld device for dermatologists that we are currently working on – we sat down and talked to several dermatologists at Klinikum rechts der Isar. It turned out that there are several unmet needs. One of them, for example is to assess treatment of the skin accurately and quantitatively. It is important to quickly understand if a certain treatment works or if a different therapeutic approach must be followed. As a next step, we go into the clinic to do pilot studies to show the feasibility of our techniques and then a more extensive study to show the clinical value. The Innoderm project, which started in March, is going to last for five years. In the first two years we are going to improve the technology and adapt it to solving particular problems. Then, we are going to apply it to further clinical tests.
Apart from Innoderm, where are your goals right now?
We want to identify where we can really have an impact on society and health care with our technology. We have many ideas about how to further evolve ways of sensing and visualizing information that is invisible as of yet and can lead to earlier and more accurate diagnosis. You could say that half of our activity is dedicated to this goal. The other half will remain on the technical development of devices.
Prof. Dr. Vasilis Ntziachristos
Vasilis Ntziachristos as assistant professor and Director of the Laboratory for Bio-Optics and Molecular Imaging at Harvard University and Massachusetts General Hospital, before being appointed to the Chair of Biological Imaging at TUM. The Chair is closely linked with the Institute for Biological and Medical Imaging at Helmholtz Zentrum München, of which Prof. Ntziachristos is Director. Among other honors, Prof. Ntziachristos received the Gottfried Wilhelm Leibniz Prize of the Deutsche Forschungsgemeinschaft (DFG) and several grants by the European Research Council (ERC).
With "Innoderm" TUM is heading a European research project, where engineers and physicians together develop a new optoacoustic handheld instrument for early diagnosis of skin cancer. The goal is to provide the physicians with a tool that allows on site-assessment of morphological, physiological and cellular changes of the skin area examined not only by inspecting the skin surface, but also sub-surface features within several millimeters of depth. The project combines the expertise of engineers, scientists and clinicians in a consortium comprising five partners from four European countries. The project has been awarded a grant of 3,8 million € from Horizon 2020, the EU framework program for research and innovation.