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Precision Multi-Spectral Optoacoustic Tomography for Discovery Diagnosis and Intervention

Periodic Reporting for period 3 - PREMSOT (Precision Multi-Spectral Optoacoustic Tomography for Discovery Diagnosis and Intervention)

Okres sprawozdawczy: 2020-01-01 do 2021-06-30

In PREMSOT the clinical translation of multispectral optoacoustic tomography (MSOT) is catapulted to the next level, significantly advancing the accuracy of medical diagnosis and therapy monitoring for a variety of diseases. Precision medicine redefines diagnostic and interventional challenges and requires accurate, quantitative observation of pathophysiological tissue parameters and treatment effects. Radiology techniques play a central role in diagnosis and guiding therapy but they may be unavailable or inappropriate for some medical segments including ambulatory care or surgery, whereby a subset of imaging techniques (ultrasound, optical) is applied.

As we advance personalized medicine it becomes crucial to design tools for quantitative tissue readings that solve limitations of current technologies. MSOT measures light (photon) absorption, without being sensitive to photon scatter, as in conventional optical imaging, due to utilizing sound for detection (instead of light / cameras). Optical absorption relates to unique morphological and functional parameters, imaged by MSOT in a label-free mode (no contrast agents). Therefore, MSOT redefines optical imaging by making it cross-sectional, depth resolving and high-resolution within depths of millimetres to centimetres and offering unique imaging features not available to other radiology methods. Optoacoustic imaging is probably the most qualified method for non-invasive imaging oxygenated and deoxygenated haemoglobin (tissue oxygenation), haemoglobin concentration (blood volume / ischemia) and microvasculature in a portable format.

In PREMSOT a next-generation label-free imaging platform is developed that brings advances over existing MSOT technology by theoretical and hardware developments that solve critical current limitations in MSOT sensitivity, accuracy and quantitative capacity, which are then validated, relating the novel imaging features offered to quantitative pathophysiological parameters of tissue/disease. Furthermore, MSOT is applied to clinical discovery and care addressing unmet clinical needs requiring MSOT, particularly to vascular medicine but also to other diagnostic and theranostic settings.
A central aim within PREMSOT is to develop a handheld label-free video-rate multi-spectral optoacoustic system delivering unprecedented imaging features, with emphasis on imaging hemoglobin saturation / tissue oxygenation and vasculature. We designed an improved detector array with enhanced imaging capabilities deep in tissue based on a detailed analysis of the system sensitivity, the effect of a limited view geometry, and the interplay of system components and image reconstruction methods. The new detector will be operated with an MSOT prototype and a flexible software solution based on the experience with the current devices in the clinical setting. The software specifications allow for a great flexibility in tuning system parameters related to the illumination (laser power and trigger) and data acquisition. The prototype and flexible software are currently under development and will be validated in the next period of the project.

In parallel to advancing the hardware of the system, another aim within PREMSOT is to research and develop theory and algorithms that improve the sensitivity and the quantification accuracy of imaging tissue oxygenation, hypoxia, blood (haemoglobin) volume, vessel and micro-vessel morphology and flow, leading to label-free tissue readings appropriate for precision medicine. We improved the quantification of tissue properties from optoacoustic data by implementing advanced regularization schemes, engineering novel biomarkers, and designing novel data acquisition schemes. We exploited the advantages of the perfectly coregistered optoacoustic and ultrasound images of our system, achieving an improved molecular contrast in depth, thereby increasing the accessibility of medical information. In addition, the flexibility and efficiency of our tomographic reconstruction software was improved substantially, leading to more precise optoacoustic image data. Further, we improved the state-of-the-art method for oxygenation quantification in the preclinical setting by applying state-of-the-art machine learning methods. The transition of these eigenspectra methods to the clinical setting is challenging due to wavelength dependent fluence attenuation, which we address by developing a detailed model of the optical components of the handheld system to obtain a precise low-dimensional eigenspectra model of the fluence distribution in tissue.

We improved our mesoscopic raster scan system (RSOM) by developing a dynamic programming solution for skin surface detection, and a machine-learning approach to automatic skin morphology analysis. Together with a hardware-driven motion detection method, these advances lead to high-quality image data that contains a lot of medical information, as we could demonstrate in clinical cardiovascular and dermatology studies.

Furthermore , our optoacoustic systems have been applied in a variety of disease related studies on volunteers, patients, and in animal models. We investigated, for instance, brown fat metabolism based on optoacoustic imaging of hemoglobin gradients in brown adipose tissue (BAT). BAT works as a heater organ, utilizing the chemical energy extracted from carbohydrates and fat and is supposedly associated with human diseases such as obesity, diabetes, and atherosclerosis. As another example, we assessed flow-mediated dilatation (FMD) with MSOT by quantifying the dimensions and diameter changes of arteries, a technique used to characterize endothelial function which is supposed to influence risk of cardiovascular disease and to relate to atherosclerosis.
PREMSOT is establishing state of the art multispectral optoacoustic tomography systems on multiple imaging scales. The high-precision mesoscopy system allowed for gaining new insights into dermatology and microvascular function in the skin, while the macroscopic systems have been demonstrated to extract high-quality structural and functional information related to disease. The research within PREMSOT, in particular, new mathematical, programming and machine learning approaches, have already fundamentally advanced the technology and was helping to already overcome some of its limitations. These theoretical and technical improvements together with the experiences made in research and in MSOT application to human imaging with the existing technology, allowed us to design a new and significantly improved scanning system, which is currently under development. Together with advanced operating software recently designed within PREMSOT, allowing for manipulating the specifications of hardware settings in a highly flexible way, this prototype will be applied to address further open research questions in optoacoustic imaging and will further provide solutions to overcome its limitations, paving the way to make MSOT become a standard in clinics world-wide.

In addition, we were able to apply the system to measure several physiological and morphological attributes relating to human disease. In the upcoming period of PREMSOT we will strongly diversify our investigations of disease characterization and monitoring, demonstrating the suitability of optoacoustic readings to investigate a multitude of unmet clinical needs.

In conclusion, MSOT offers for the first time high-resolution quantitative images of tissue (Hb) oxygenation and Hb concentration, and opens new ways in video-rate visualizing and studying oxygenation/hypoxia, ischemia, vasculature and associated tissue features (inflammation, rarefaction or metabolism) without the need for optical chamber windows and small fields of view. By using portable, label-free imaging, such measurements can be made available to human investigation and clinical research and care for real-time feedback during intervention and longitudinally for in-human study of disease development and therapy effects. The new ability imparted with MSOT can become fundamental in basic discovery and clinical care. We will continue to deepen the research on the fundamentals of MSOT theory and improvement during the next period within PREMSOT and investigate its applications in vascular medicine and cardiology and in general surgery.