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In this paper, we present the design, development, and characteristics of the novel aerosol mass spectrometer ERICA (ERC Instrument for Chemical composition of Aerosols; ERC – European Research Council) and selected results from the first airborne field deployment. The instrument combines two well-established methods of real-time in situ measurements of fine particle chemical composition. The first method is the laser desorption and ionization technique, or laser ablation technique, for single-particle mass spectrometry (here with a frequency-quadrupled Nd:YAG laser at λ = 266 nm). The second method is a combination of thermal particle desorption, also called flash vaporization, and electron impact ionization (like the Aerodyne aerosol mass spectrometer). The same aerosol sample flow is analyzed using both methods simultaneously, each using time-of-flight mass spectrometry. By means of the laser ablation, single particles are qualitatively analyzed (including the refractory components), while the flash vaporization and electron impact ionization technique provides quantitative information on the non-refractory components (i.e., particulate sulfate, nitrate, ammonia, organics, and chloride) of small particle ensembles. These techniques are implemented in two consecutive instrument stages within a common sample inlet and a common vacuum chamber. At its front end, the sample air containing the aerosol particles is continuously injected via an aerodynamic lens. All particles which are not ablated by the Nd:YAG laser in the first instrument stage continue their flight until they reach the second instrument stage and impact on the vaporizer surface (operated at 600 ∘C). The ERICA is capable of detecting single particles with vacuum aerodynamic diameters (dva) between ∼ 180 and 3170 nm (d50 cutoff). The chemical characterization of single particles is achieved by recording cations and anions with a bipolar time-of-flight mass spectrometer. For the measurement of non-refractory components, the particle size range extends from approximately 120 to 3500 nm (d50 cutoff; dva), and the cations are detected with a time-of-flight mass spectrometer. The compact dimensions of the instrument are such that the ERICA can be deployed on aircraft, at ground stations, or in mobile laboratories. To characterize the focused detection lasers, the ablation laser, and the particle beam, comprehensive laboratory experiments were conducted. During its first deployments the instrument was fully automated and operated during 11 research flights on the Russian high-altitude research aircraft M-55 Geophysica from ground pressure and temperature to 20 km altitude at 55 hPa and ambient temperatures as low as −86 ∘C. In this paper, we show that the ERICA is capable of measuring reliably under such conditions.

Biomechanical patient modeling incorporates physical knowledge of the human anatomy into the image processing that is required for tracking anatomical deformations during adaptive radiation therapy, especially particle therapy. In contrast to standard image registration, this enforces bio-fidelic image transformation. In this thesis, the potential of a kinematic skeleton model and soft tissue motion propagation are investigated for crucial image analysis steps in adaptive radiation therapy. The first application is the integration of the kinematic model in a deformable image registration process (KinematicDIR). For monomodal CT scan pairs, the median target registration error based on skeleton landmarks, is smaller than (1.6 ± 0.2) mm. In addition, the successful transferability of this concept to otherwise challenging multimodal registration between CT and CBCT as well as CT and MRI scan pairs is shown to result in median target registration error in the order of 2 mm. This meets the accuracy requirement for adaptive radiation therapy and is especially interesting for MR-guided approaches. Another aspect, emerging in radiotherapy, is the utilization of deep-learning-based organ segmentation. As radiotherapy-specific labeled data is scarce, the training of such methods relies heavily on augmentation techniques. In this work, the generation of synthetically but realistically deformed scans used as Bionic Augmentation in the training phase improved the predicted segmentations by up to 15% in the Dice similarity coefficient, depending on the training strategy. Finally, it is shown that the biomechanical model can be built-up from automatic segmentations without deterioration of the KinematicDIR application. This is essential for use in a clinical workflow.

Es werden neue Methoden zur automatischen Bestimmung und Optimierung von Bestrahlungsparametern für die perkutane Strahlentherapie mit hochenergetischen Photonen entwickelt. Die Methoden basieren auf einer Bestrahlungstechnik mit intensitätsmodulierten Strahlenfeldern. Das wesentliche Problem besteht daher in der Bestimmung der Form der Modulationsprofile für die einzelnen Felder, und zwar auf der Grundlage der vorgegebenen Solldosisverteilung. Dieses Problem wird als das inverse Problem der Strahlentherapieplanung bezeichnet. Es wird gezeigt, daß es sich dabei um die gespiegelte Version des Problems der Rekonstruktion eines Bildes aus seinen Projektionen handelt, wie es z.B. bei der Computer-Tomographie (CT) auftritt. Ausgehend von diesem Sachverhalt werden die aus der CT bekannten Methoden zur Bildrekonstruktion konsequent auf die Optimierung der Strahlentherapie übertragen. Durch entsprechende Modifikationen der Methoden werden besondere Merkmale, die für dieses neue Anwendungsgebiet charakteristisch sind, berücksichtigt. Dazu zählt insbesondere die Tatsache, daß keine negativen Strahlungsintensitäten realisiert werden können und daß man aus praktischen Gründen auf wenige Felder beschränkt ist. Es wird gezeigt, daß in den meisten Fällen sieben oder neun Strahlenfelder ausreichend sind und daß die Verwendung von mehr Feldern nicht zu klinisch signifikanten Verbesserungen führt. Die wichtigsten Methoden der Bildrekonstruktion, nämlich die gefilterte Rückprojektion und die iterative Rekonstruktionstechnik, werden in der CT alternativ eingesetzt. In der vorliegenden Anwendung werden diese Methoden dagegen quasi "symbiotisch" verwendet. Die gefilterte Rückprojektion, die hier als gefilterte Projektion bezeichnet wird, dient dabei zur schnellen Bestimmung eines Startwertes für die Modulationsprofile. Diese Startprofile werden durch ein iteratives Verfahren, das der iterativen Rekonstruktionstechnik entspricht, weiter optimiert. Durch die Einführung von Straffunktionen ist es erstmalig möglich, medizinisch indizierte Nebenbedingungen adäquat zu berücksichtigen. Das iterative Optimierungsverfahren basiert auf einem Algorithmus zur dreidimensionalen Dosisberechnung. Ein weiterer Schwerpunkt dieser Arbeit ist daher die Entwicklung eines solchen Algorithmus für intensitätsmodulierte Strahlenfelder. Mit konventionellen Dosisberechnungsalgorithmen können Modulationen nicht angemessen berücksichtigt werden. Zur Überprüfung des neu entwickelten Verfahrens wird ein erster Vergleich der damit berechneten Dosis mit gemessenen Daten durchgeführt. Die hier vorgestellten Methoden erlauben die direkte Bestimmung der Bestrahlungsparameter ohne das heute übliche "trial and error"-Verfahren. Darüber hinaus können Dosisverteilungen erzeugt werden, die auch mit den aufwendigsten konventionellen Bestrahlungstechniken kaum realisierbar sind. Dies sind insbesondere solche mit ausgedehnten konkaven Bereichen. Einige Beispiele dieser Art werden dargestellt.

Phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) enables non-invasive imaging of pH value and magnesium ion concentration, [Mg2+], in living tissue. Typically, the chemical shifts of 31P metabolites are translated to pH and [Mg2+] via calibration equations, which, however, are well-defined only for physiological conditions, thus limiting their reliability in pathologies. In this thesis, a novel approach for the in vivo determination of pH and [Mg2+] applicable for various chemical conditions, utilizing multiple 31P spectral properties in form of a look-up table, is proposed. To this end, the variability of spectral properties in vivo was investigated in high-quality human 31P MRSI data acquired at B0 = 7T, and reproduced in measurements of 114 model solutions prepared with physiologically relevant pH, [Mg2+] and ionic strengths, at B0 = 9.4T. The identified chemical shift changes of the adenosine-5’-triphosphate (ATP) resonances were translated into a multi-dimensional model, which was used for the implementation of a look-up algorithm, accounting also for measurement uncertainties. Application to in vivo data resulted in successful assignments of plausible pH and [Mg2+] values in healthy and tumorous tissue. The proposed approach is extendable by including further spectral properties, potentially allowing for more profound tissue characterizations, being particularly important for the application in pathologies.

Magnetic resonance imaging (MRI) employs time-varying magnetic gradient fields, which induce electric fields (E-fields) in the patient that can potentially stimulate the heart. The performance of novel gradient systems is increasingly restricted by regulatory safety limits, thus motivating a deeper understanding of cardiac stimulation (CS) in MRI. This thesis investigates the thresholds and mechanisms underlying CS using an integrative approach of modeling and measurements. First, a numerical modeling framework was developed that combines E-field simulations in computational body models with electrophysiological cardiac fiber models to predict stimulation thresholds and sites in the heart. The CS thresholds predicted for two commercial gradient systems were >10-fold higher than the regulatory limits. Second, cardiac magnetostimulation thresholds were measured in ten healthy pigs using magnetic field pulses created by capacitor discharges into a coil. The average threshold E-field in the porcine heart was 92.9 pm 13.5 V/m. CS thresholds predicted in individualized porcine models derived from MR images reproduced the measurements with deviations of

The advantages of carbon-ion pencil beam radiotherapy imply an increased sensitivity of the dose distribution in the patient to any changes in the patient geometry, such as internal anatomical changes or patient misalignment. This can lead to a deterioration of the dose distribution within the patient. Monitoring methods of the internal patient’s dose distribution for carbon-ion beam radiotherapy are therefore of great importance to early detect possible under- or over-dosage in the patient, eventually, reduce the tumor safety margins applied around targeted tumor volumes and thus decrease the delivered dose in healthy tissues. Up to now, several non-invasive in-vivo ion-beam monitoring methods have been developed. These are mostly based on the detection of different kinds of secondary radiation, such as annihilation-photons from β+ emitters, prompt photons, or prompt charged nuclear fragments, emitted from a patient during the treatment delivery. These secondary radiations are the results of nuclear interactions of the primary treatment beam with the irradiated tissue. They potentially carry valuable information about the primary treatment beam range, position, or intensity in the patient. However, so far none of the monitoring methods has reached sufficient maturity for a wide application in clinical routine. This thesis aimed to develop methods for detection and localization of therapy-relevant geometry variations of 2 mm in head models, mimicking possible inter-fractional changes on the surface or inside patients’ heads. In contrast to previous research which concentrated on single stationary pencil beams, this thesis was focused on entire therapy-like treatment plans composed of thousands of single pencil beams with low numbers of primary-ions and irradiated under clinic-like conditions in terms of dose, dose rate, and tumor volume. In this thesis, methods were based on the detection and tracking of charged secondary nuclear fragments (secondary ions) emitted from the patient during carbon ion radiotherapy delivery. Subsequently, methods for analysis and interpretation of the measured secondary-ion paths (tracks) were developed. The developed radiation detection methods exploited the capabilities of a novel mini-tracker, based on the Timepix3 technology developed at CERN and positioned behind the patient. The deadtime-free data acquisition enabled a gapless recording of all impacting secondary ion tracks. Moreover, it enabled synchronization of the data with the beam application monitoring system, and thus assign each measured secondary ion with its respective pencil beam, opening entirely new research possibilities. The experiments were performed at the Heidelberg Ion-Beam Therapy Center (HIT), closely mimicking clinic-like conditions. Single fields of carbon-ion treatment plans with a prescribed fraction dose of 3 Gy (RBE) were used to simulate treatments of spherical tumor volumes in the used head models. Two types of head models were used: a homogeneous plastic cylinder and an anthropomorphic head phantom composed of real bones and tissue-equivalent materials. Secondary ions exiting the head models during irradiation were detected with a mini-tracker composed of two small (2cm²) parallel Timepix3 detectors placed downstream of the head with a certain angle with respect to the beam axis. Inter-fractional changes were modeled by adding or removing 2-mm-thick slabs positioned in front or inside the targeted head models. Within the thesis, it was demonstrated that the developed method for the analysis of the measured track distributions, taking into account the actual time-dependent position of the pencil beam, approximated the measured position of the secondary ion creation in the head model significantly better than the methods developed up to now. By using this method, surface changes down to 1 mm were found to be detectable even for the anatomical head phantom. Internal changes of 2-mm-thickness extending over the whole lateral tumor dimension (wide changes) were found to be detectable for all investigated positions between the dose plateau and the distal end of the tumor. The significance was at least 3 standard deviations for a single mini-tracker and of at least 9 standard deviations when using 8 mini-trackers at 30°, as it is planned for the future. Correct localization of all the studied changes was achieved within 6.3 mm of their actual position. This is sufficient to provide information to the clinicians about the part of the dose distribution which is affected. The detection of 2-mm-thick changes affecting only a part of the tumor (narrow changes), required the development of a new method based on the additional information on the lateral pencil beam positions. With this technique, internal 2-mm-thick changes as small as 10 mm in diameter placed in front of the tumor, were demonstrated to be detectable with a significance of almost 2 standard deviations. This technique makes the developed monitoring method sensitive to the lateral position of the cavity and thus reaches the third dimension. Positions of the mini-tracker closer to the beam axis were found to provide higher detection efficiencies due to the larger amount of data, but also lead to larger geometrical uncertainties and lower localization accuracies. At larger angles, the accuracy of the change localization was found to be better. For future measurements, multi-angle detection systems are recommended to maximize both detectability and localization accuracy. Finally, the applicability of the monitoring of carbon-ion pencil beam delivery in a real patient treatment was demonstrated by designing a patient-friendly measurement system that was shown to be safely used in a clinical environment. After investigating the influence of the developed system on the beam delivery, and with the fulfillment of all clinical and safety requirements, the integration of this system into the clinical workflow of the HIT facility was achieved. With this detection system, the first measurement of a real patient irradiation fraction was performed. The amount of measured data was sufficient to determine a secondary-ion emission profile along the depth of the patient’s head. And a differentiation between pencil beams with a 1 cm range difference was demonstrated. In conclusion, this thesis presents novel methods for carbon ion treatment monitoring of external and internal patient geometry changes in the head based on secondary ion tracking, allowing detection changes down to the clinically desired 2 mm. The designed monitoring system was proven to be well incorporable into a clinical workflow. Thus, the presented work paves the way towards monitoring inter-fractional changes along the beam direction during carbon-ion beam therapy and builds the basis for the upcoming clinical trial at the HIT facility.

We report on the developments that enabled the field deployment of a fully-automated aerosol mass spectrometer, specially designed for high-altitude measurements on unpressurised aircraft. The merits of the two main categories of real-time aerosol mass spectrometry, i.e. (a) single particle laser desorption and ionization, and (b) continuous thermal desorption / electron impact ionization of aerosols, have been integrated into one compact apparatus with the aim to perform in-situ real-time analysis of aerosol chemical composition. The demonstrated instrument, named ERICA (European Research council Instrument for the Chemical composition of Aerosols), operated successfully aboard the high-altitude research aircraft M-55 Geophysica at altitudes up to 20 km, while being exposed to ambient conditions of very low atmospheric pressure and temperature. A primary goal of those field deployments was the in-situ study of the Asian Tropopause Aerosol Layer (ATAL). During 11 research flights, the instrument operated for more than 49 hours and collected chemical composition information of more than 150,000 single particles combined with quantitative chemical composition analysis of aerosol particle ensembles. This paper presents in detail the technical characteristics of the main constituent parts of the instrument, as well as the design considerations for its integration into the aircraft and its autonomous operation in the upper troposphere and lower stratosphere (UT/LS). Additionally, system performance data from the first field deployments of the instrument are presented and discussed, together with exemplary mass spectrometry data collected during those flights.

Biological systems are first of all physical systems whose function (or malfunction) is also determined by their response to external and internal forces as well as their physical properties. Therefore, measuring mechanical properties is not only essential for a complete understanding of cell function and organism development but also invaluable in disease diagnosis and treatment. Several techniques are available in the field of mechanobiology (an emerging field that focuses on the role of mechanical forces and properties in biology) to measure mechanical properties but they all virtually rely on analyzing the response of the sample to an external perturbation and have limited three-dimensional capabilities. Instead, Brillouin microscopy is a purely optical technique that requires no contact and no external mechanical perturbation of the sample and can provide 3D maps of viscoelastic properties with (sub)micron resolution. Its first demonstration for 3D imaging of biological samples was accomplished in 2007 and, since then, it has gained increasing interest among biologists for its potentialities. In this context, one of the aims of my PhD project was to facilitate the use of Brillouin microscopy for addressing biological questions. I did this by equipping a state-of-the-art Brillouin microscope with the add-ons necessary for studying living biological samples (confocal fluorescence and environment control) and by writing an intuitive software interface that would allow non-experts to use the microscope with minimal training. In collaboration with biologists, we investigated several biological questions, some of which produced interesting findings (that led to scientific publications) while others are still being explored. The second aim of my PhD was to tackle two issues that limit current implementations of Brillouin microscopy: limited speed (leading to imaging times in the excess of hours when whole organisms are imaged in 3D) and potential photodamage, especially in light-sensitive samples. I overcame this limitation by designing a line-scanning version of a Brillouin microscope, with particular attention to ensuring physiological mounting of the sample, low photodamage and high spatial resolution. The speed advantage is given by the parallel acquisition of about 100 Brillouin spectra in a single camera acquisition. This allowed us to image fast processes (gastrulation in Drosophila), large volumes (Phallusia embryos) and follow development of light-sensitive samples (mouse embryos) over two days.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) allows to non-invasively obtain information about the micromolecular environment of living tissues, particularly, intracellular pH (pHi). In this thesis, a method for quantitative CEST-based pHi mapping was developed enabling, for the first time, compensation of all concomitant effects on CEST signals in tumor tissues, such as unknown concentration changes and superimposing contributions. To this end, a novel model was established enabling direct translation of magnetization exchange rates between protons in proteins and water into pH. This model utilizes (i) the reliable extraction of exchange rates, accomplished by an optimized isolation of measured CEST signals at B0 = 9.4 T, and (ii) a calibration procedure exploiting a newly identified, distinct functional behavior of CEST signals. Porcine brain lysates mimicking in vivo conditions were employed for calibration and to demonstrate reliable pH mapping in the physiologically relevant range of 6.2–8.0. Application in vivo to lesions of tumorbearing mice showed a median pHi of approximately 7.2, further validating the developed method. This novel approach, now, allows to robustly assess the potential of pHi as imaging biomarker for cancer diagnosis or treatment monitoring in preclinical settings, representing an important milestone towards application in humans.

Magnetic resonance (MR)-guided radiotherapy (MRgRT) enables new treatment procedures such as online treatment plan adaption based on daily imaging of the patient. This allows for the delivery of high radiation doses to the tumor while optimally sparing surrounding healthy tissue. However, such complex workflows require thorough quality assurance including dedicated end-to-end tests to validate the feasibility and overall accuracy of each specific treatment workflow. In this thesis, end-to-end tests for online adaptive MRgRT in presence of inter-fractional anatomy changes were developed. For this, a standardized protocol for 3D polymer gel (PG) dosimetry and new anthropomorphic materials simulating the image contrast of real patients in computed tomography and MR imaging were developed. These methods were validated resulting in uncertainties < 5 % for PG dose measurements and < 3.5 % for the imaging parameters of the phantom materials. Finally, two end-to-end tests were developed and implemented at a 0.35 T MRgRT device using (i) a highly reproducible geometric phantom and (ii) an anthropomorphic and deformable pelvis phantom. These tests resulted in Gamma-index passing rates (3 %⁄ 3 mm) of 93.1 % (i) and 98.9 % (ii) for the PG-filled targets and demonstrated the feasibility of online adapted MRgRT in presence of inter-fractional anatomical changes.

Carbon ion therapy is a promising treatment modality that is not widely accessible to patients due to limited resources and a high cost of treatment. Therefore, it is necessary to consider mixed modality treatments where carbon ions are utilized in combination with the more widely available and accessible, photon therapy. In contemporary clinical combined treatments, photon fractions and carbon ion fractions are separately optimized and simply accumulated based on the RBE weighted dose. Such a “naive” combination does not fully exploit physical and radiobiological advantages emerging from the interplay of both modalities. Carbon ions excel at delivering high RBE conformal dose to the target volume and avoid delivering dose to distal healthy tissue. Photons, besides generally larger integral dose, have a lower RBE and are desirable to irradiate target subvolumes that are adjacent to healthy tissue or have healthy tissue infiltrated by tumour tissue, due to the greater fractionation potential. This thesis presents a novel method to exploit these differences by simultaneously optimizing photon and carbon ion fluence contributions in order to answer the question: what is the ideal combined photon-carbon ion fluence distribution given a specific fraction allocation between photons and carbon ions? The joint optimization framework allows for the synergistic optimization of photon–carbon ion treatments based on the cumulative biological effect, incorporating both the variable RBE of carbon ions and the fractionation effect within the linear quadratic (LQ) model. As a part of this study, the joint optimization workflow was implemented within the open source treatment planning toolkit matRad. Joint optimization strategies yield individually non-conformal photon and carbon ion dose distributions that cumulatively deliver a homogeneous conformal biological effect distribution in the target volume. Compared to conventional combined treatments, joint optimized treatments exhibit better conformity and better sparing of critical structures through a spatial redistribution of dose between modalities and a non-uniform fractionation schedule within the target volume. Depending on the fraction allocation between modalities, there exists an optimized temporal distribution of biological effect where parts of the target volume are hypofractionated while areas around dose limiting critical structures are spared through fractionation. The additional degrees of freedom from the spatial and temporal redistribution of fluence enables the exploration of a new spectrum of plans that can better address physical and radiobiological treatment planning challenges. Apart from a proof of concept, the impact of key underlying treatment parameters were also investigated. With regards to fraction allocation for photon–carbon ion treatments, the joint optimized treatments were shown to benefit from a reduction in carbon ion fractions due to their limited fractionation capacity. The choice of LQ model parameters and an assumed fractionation benefit drives the biological motivation to fractionate dose, without it the joint optimization was purely driven by the physical characteristics and beam angles selected for treatment. Furthermore, the choice of LEM version for carbon ion RBE estimation predicts the fractionation capacity of carbon ions. The clinically used LEM I predicts a higher effectiveness of carbon ions in the entrance region and fragmentation tail as compared to LEM IV. Therefore, the use of LEM I in joint optimization results in a lowering of carbon ion contributions in order to spare healthy tissue located at the entrance channel and fragmentation tail. Finally, the method was demonstrated for six glioblastoma patients, where the CTV contains tumour infiltrated healthy tissue that would benefit from a fractionated treatment. In comparison to the current clinical standard of independently optimized photon–carbon ion plans, the optimal plan dose to CTV was primarily delivered by photons while carbon ions are restricted to the GTV with variations depending on tumour size and location. The joint optimization approach results in a targeted application of carbon ions that (1) reduces dose in normal tissues within the target volume which can only be protected through fractionation and (2) boosts central target volume regions in order to reduce integral dose. In conclusion, this thesis presents the first joint optimization framework that allows for an evidence based and mathematically optimal allocation of photons and carbon ions in mixed modality treatments.

During the development of an organism, chemokine signaling provides long range guidance for migrating cells and tissues. Using an intricate system of promiscuous receptor-ligand interactions, the embryo coordinates the robust positioning of its future organs in space and time. Cells both sense and actively shape a highly dynamical and diverse signaling environment, thus making it challenging to systematically study cell signaling regulation and function in vivo. To approach this problem, I combined novel methods from the fields of microscopy, cell biology and image analysis. Specifically, this includes multiple-view light sheet microscopy for imaging developmental processes simultaneously at the cell and organism scales and tandem fluorescent lifetime reporters as an emerging tool to visualize signaling receptor turnover in vivo. To quantitatively compare three dimensional embryo acquisitions across genetic conditions and multiplex fluorescent readouts, I used nonlinear image registration to perform spatial normalization. Further, the so obtained sample deformation maps were exploited to perform morphometric phenotype analysis. Together, these tools led to the development of a computational analysis framework enabling quantification of chemokine signaling activity and function during embryonic development. This framework was then applied to search for novel interactions between the chemokine scavenger CXCR7 (or ACKR3) and the signaling receptor CXCR4 in the early zebrafish embryo. In recent years, the competition of these receptors for their shared ligands has been shown to be implicated in several developmental processes as well as tumor progression. In my analysis, loss of the scavenger was revealed to exert a strong activating effect on CXCR4 expressing tissues across the entire embryo. The remarkable up-regulation of signaling activity in the absence of the scavenger was however found to be aphenotypic in many target tissues. Therefore, I proceeded to investigate at which level the phenotypic impact of this genetic perturbation is compensated for and found receptor desensitization to likely be dispensable in this context. In conclusion, this work provides an example of how spatial normalization and multiplexing of in toto light sheet images can be used to investigate the general logic and functional output of chemokine-scavenger interactions during embryonic development.

The extraordinary mechanical and charge transport properties of semiconducting single-walled carbon nanotubes (SWNTs) make them a promising material for solution-processable, flexible and stretchable electronics. Many of these remarkable features are even obtained in randomly-oriented SWNT networks that are compatible with established large-scale thin-film processes based on printing techniques or optical lithography. Given the enormous progress in the purification of solely semiconducting nanotubes as well as in the preparation of SWNT networks with a uniform and defined morphology in recent years, their widespread application as active layers in field-effect transistors (FETs) has become feasible. Likewise, this progress raised subsequent questions of what key parameters determine the charge transport processes across these networks and how they can further be optimized. This thesis investigates charge transport and its limitations in polymer-sorted semiconducting SWNT networks with a focus on the precise nanotube network composition. The employed FET geometry enabled a reproducible and undistorted analysis of composition- and temperature- dependent transport parameters such as the charge carrier mobility. A comparison between nanotube networks with various selected or even precisely defined SWNT species distributions and average tube diameters reveals that additional energy barriers created at the junctions of adjacent nanotubes with different diameters result in inferior transport properties. While the network charge transport was formerly considered to be solely limited by the charge transfer across these inter-nanotube junctions, the results of this work imply that also the transport within each individual SWNT is important. The specific diameter dependence of this intra-nanotube transport can rationalize the substantially higher carrier mobilities observed for large-diameter networks with a certain SWNT bandgap distribution compared to monochiral networks that contain only a single small-diameter nanotube species. These findings suggest that composition optimizations for SWNT network FETs with maximum carrier mobilities should aim at monochiral large-diameter nanotubes. Aside from insights into the underlying transport mechanisms, this work demonstrates a novel approach to intentionally modify charge transport in semiconducting SWNT network FETs by adding photochromic spiropyran compounds to the dielectric layer. The strong impact of the spiropyran and its photoinduced isomerization to merocyanine on the charge carrier mobilities give these transistors the properties of basic optical memory devices. Upon UV illumination the carrier mobilities are severely reduced until their recovery is induced by annealing or illumination with visible light. This implemented light responsiveness illustrates the fundamental suitability of SWNT network FETs for multifunctional applications beyond integrated circuits.

Particle therapy exploits the highly localized depth dose profile of protons and light ions to deliver a high dose to the target while largely sparing surrounding healthy tissue. The steep dose gradient at the end of the ions range, known as the Bragg peak, however, also makes particle therapy sensitive to range uncertainties. In current clinical practice, a major cause of range uncertainties resides in the conversion of the treatment planning x-ray CT to the patient specific relative stopping power (RSP) map that is crucial for accurate treatment planning. By measuring the energy loss of particles after traversing the patient, particle imaging enables a more direct reconstruction of the RSP. In this thesis, different aspects towards the clinical implementation of particle imaging are investigated. First, a theoretical description of the point-spread function for different particle radiography algorithms is developed in order to explain observed limitations. A novel filtering technique to remove nuclear interaction events in particle imaging is proposed and high quality experimental helium ion CTs are demonstrated. First results from an experimental comparison between particle and x-ray CT modalities for RSP prediction in animal tissue samples are presented. Furthermore, a novel technique for intra-treatment helium ion imaging based on a mixed helium/carbon beam is explored with that relative range changes in the millimeter regime were observable. Finally, novel particle imaging detector designs are investigated. The thesis highlights the potential of helium ion imaging for pre- and intra-treatment image guidance in particle therapy.

New methods for the automatic determination and optimization of irradiation parameters for percutaneous radiotherapy with high energy photons are developed. The methods are based on an irradiation technique with intensity-modulated radiation fields. The essential problem is therefore to determine the shape of the modulation profiles for the individual fields, based on the specified target dose distribution. This problem is called the inverse problem of radiotherapy planning. It is shown that this is the mirrored version of the problem of reconstructing an image from its projections, such as occurs in computed tomography (CT). Based on this fact, the methods for image reconstruction known from CT are consistently transferred to the optimization of radiotherapy. By appropriate modifications of the methods, special features characteristic for this new field of application are taken into account. This includes in particular the fact that no negative radiation intensities can be realized and that one is limited to a few fields for practical reasons. It is shown that in most cases seven or nine radiation fields are sufficient and that the use of more fields does not lead to clinically significant improvements. The main methods of image reconstruction, namely filtered back projection and iterative reconstruction technique, are used alternatively in CT. In the present application, on the other hand, these methods are used quasi “symbiotically”. The filtered back projection, referred to here as filtered projection is used to quickly determine a starting value for the modulation profiles. These initial profiles are further optimized by an iterative procedure corresponding to the iterative reconstruction technique. The introduction of penalty functions makes it possible for the first time to adequately consider medically indicated constraints. The iterative optimization procedure is based on an algorithm for three-dimensional dose calculation. Therefore, another focus of this work is the development of such an algorithm for intensity modulated radiation fields. Conventional dose calculation algorithms cannot adequately account for modulations. To verify the newly developed method, a first comparison of the dose calculated with it with measured data is carried out. The methods presented here allow the direct determination of the irradiation parameters without the trial and error procedure that is common today. In addition, dose distributions can be generated that are hardly feasible even with the most complex conventional irradiation techniques. These are especially those with extended concave areas. Some examples of this type are presented.

Die Kombination eines Magnetresonanztomographen mit einem Linearbeschleuniger zu einem Hybridsystem (MR-Linac) ermöglicht die Verfolgung der Tumorposition in Echtzeit während einer Strahlentherapieanwendung. Hierdurch kann die Bestrahlung unterbrochen werden, sobald sich ein Tumor aus seinem Zielvolumen herausbewegt, und folglich gesundes Gewebe geschont werden. In der klinischen Anwendung wird hierzu eine kartesische Bildgebung mit 4 Bildern pro Sekunde (fps) verwendet. Ziele dieser Arbeit waren die Erhöhung der Bildrate bei gleichzeitig robustem Tumortracking sowie eine möglichst große räumliche Abdeckung des zu trackenden Objektes. Dabei wurden radiale Aufnahmen, mit kleinen Goldenen Winkelinkrementen, und kartesische Aufnahmen miteinander verglichen. Die Bilder wurden mit einer iterativen SENSE- bzw. GRAPPA-Rekonstruktion berechnet. Eine deformierbare Bildregistrierung (B-spline) bzw. ein neuronales Netzwerk (U-net) detektierten Tumorkonturen für das Tumortracking. Bildartefakte aufgrund von Unterabtastung wurden optional mit einer Rauschunterdrückung durch ein weiteres U-net minimiert. Die beste Tracking-Performance zeigte das U-net. Bei zwei Lebertumoren betrug der mittlere Konturenabstand zwischen computergenerierter und manueller Segmentierung bei ansteigenden Bildraten bis zu 10,6 fps im Durchschnitt jeweils maximal 0,5 Pixel. Nach Anwendung der Rauschunterdrückung konnte bei gleichbleibender Performance die Bildrate deutlich erhöht werden (31,8 fps). Des Weiteren konnte eine große räumliche Abdeckung eines Organs durch eine spezielle bSSFP-Sequenz für Mehrschicht-Aufnahmen erzielt werden. Diese ermöglicht 3D-Bewegungstracking bei 6,0 fps in zwei zeitgleich aufgenommenen Schichten.

Accelerated mixed-signal neuromorphic hardware refers to electronic systems that emulate electrophysiological aspects of biological nervous systems in analog voltages and currents in an accelerated manner. While the functional spectrum of these systems already includes many observed neuronal capabilities, such as learning or classification, some areas remain largely unexplored. In particular, this concerns cybernetic scenarios in which nervous systems engage in closed interaction with their bodies and environments. Since the control of behavior and movement in animals is both the purpose and the cause of the development of nervous systems, such processes are, however, of essential importance in nature. Besides the design of neuromorphic circuit- and system components, the main focus of this work is therefore the construction and analysis of accelerated neuromorphic agents that are integrated into cybernetic chains of action. These agents are, on the one hand, an accelerated mechanical robot, on the other hand, an accelerated virtual insect. In both cases, the sensory organs and actuators of their artificial bodies are derived from the neurophysiology of the biological prototypes and are reproduced as faithfully as possible. In addition, each of the two biomimetic organisms is subjected to evolutionary optimization, which illustrates the advantages of accelerated neuromorphic nervous systems through significant time savings.

Magnetic resonance (MR)-guided radiotherapy involves complex irradiation- and imaging devices (MR-Linacs), as well as complex treatment procedures. To assure accurate patient treatments, both have to be tested for proper functioning. Here, new methods to simultane-ously measure the isocenter alignment accuracy and the geometric image distortions of clin-ical MR-Linacs were developed. A new phantom was designed, which includes a polymer dosimetry gel-container to visualize the beams from a star shot and to identify the radiation isocenter position in MR as well as a regular grid used to visualize the MR image distortions in 3D. It was found that the gel can be evaluated immediately after irradiation with a geo-metric accuracy comparable to that of radiochromic films. The method was applied on a clinical 0.35 T MR-Linac and the isocenter alignment accuracy in 3D was found to be (0.8 ± 0.9) mm. The spatial image distortions after machine-specific correction were (0.60 ± 0.28) mm and 99.82% of the 1330 evaluated control points within a 140 mm sphere had devi-ations below 1.5 mm. Finally, a 3D printing materials and printing technique, compatible with the polymer dosimetry gel, was identified for future designs of anthropomorphic phantoms to be used in end-to-end tests in MR-guided radiotherapy.

Chemical exchange saturation transfer (CEST) is an emerging magnetic resonance imaging (MRI) technique enabling indirect detection of low-concentration cellular compounds in living tissue by their magnetization transfer with water. In particular, protein-attributed CEST signals have been shown to provide valuable diagnostic information for various diseases. While conventional CEST approaches suffer from confounding signals from metabolites and macromolecules, the novel dual-frequency irradiation CEST (dualCEST) technique enables increased protein specificity by selectively detecting the intramolecular spin-diffusion. However, application of this technique has so far been limited to spectroscopic investigations of model solutions at ultrahigh magnetic field strengths. In this thesis, dualCEST was translated to a clinical whole-body MR scanner, enabling protein imaging of the human brain. To this end, several methodological developments were implemented and optimized: (i) improved dual-frequency pulses for signal preparation, (ii) a fast and robust volumetric image readout, (iii) a weighted acquisition scheme, and (iv) an adaptive denoising technique. The resulting improvements are not limited to dualCEST but are relevant for the research field of CEST-MRI in general. Extensive measurements of biochemical model solutions and volunteers demonstrated the protein specificity and reproducibility of dualCEST-MRI. The clinical applicability was verified in pilot studies with tumor and Alzheimer’s patients.

Intensity-modulated scanned particle therapy in combination with the characteristic depth dose deposition of carbon ions entail a higher sensitivity to physical changes of the patient geometry as compared to photons. As a result, carbon ions may stop at different spatial locations than predicted during treatment planning. But also the patient's response to radiation is uncertain thereby further compromising the quality of the radiation treatment plan. The unknown level of uncertainty in the carbon ion dose requires a patient specific uncertainty analysis and uncertainty mitigation. For this reason the thesis at hand presents a novel method to assess and quantify carbon ion treatment plan uncertainties considering physical uncertainties, biological uncertainties as well as fractionation effects. Second, the manuscript demonstrated how uncertainties were in a subsequent probabilistic optimization mitigated. The proposed methodology was applied to multiple clinical scenarios and its advantageous impact on the carbon ion treatment plan robustness was demonstrated. Unlike protons, carbon ion treatment planning needs to account for the increased nonlinear cell killing of carbon ions in a mixed radiation field which increases the treatment planning complexity. With respect to uncertainties, not only the location of dose deposition is uncertain for carbon ions but also their effectiveness which consequently introduces biological uncertainties to treatment planning. Different to scenario based approaches, this work presents exact and approximated nonlinear closed-form calculations of the expectation value and covariance of the RBE weighted dose accounting for setup-, range- and biological-uncertainties in fractionated carbon ion therapy. The developed analytical pipeline allows propagating linearly correlated Gaussian input uncertainties through the carbon ion pencil beam dose calculation algorithm to obtain uncertainties in dose. With I and J being the number of voxels and pencil beams, respectively, low-rank tensor approximations were derived for the expectation value and standard deviation reducing the computational complexity from O(I x J^2) to O(I x J) and from O(I x J^4) to O(I x J^2) with minimal loss in accuracy. The consideration of biological errors introduces a new uncertainty structure in the analytical pipeline without increasing the computational complexity. The calculation of expected dose and variance influence information via APM allows performing a subsequent probabilistic optimization. A proof of concept and several aspects such as accuracy, fractionation and the impact of different probability densities to model input uncertainties were studied in detail on a one-dimensional phantom case. Further, basic three-dimensional dose calculation and optimization functionalities were implemented in the open-source treatment planning system matRad. A subsequent validation against a clinical reference system revealed excellent agreement for elementary pencil beams and patient cases as indicated by γ-pass rates above 99.67%. Theoretical APM derivations were implemented on top and were then applied to clinical carbon ion patient cases. The expectation value and standard deviation of the RBE weighted dose were compared to estimated analogs stemming from 5000 random samples. The γ-pass rate exceeded 94.95% in all patient cases thereby proving the validity of the proposed analytical pipeline. A subsequent probabilistic optimization avoided underdosage of the target volume, reduced the integral dose and resulted in carbon ion treatment plans with a minimized standard deviation of RBE weighted dose. Thus the developed Analytical Probabilistic Model facilitates a flexible, effective and accurate probabilistic description of the radiation treatment plan and generalizes to probabilistic optimization. In conclusion, the manuscript presents an analytical method to quantify and minimize the uncertainty in the delivery of carbon ion treatment plans. As a result, treatment plans became more robust against the involved uncertainties as demonstrated for a number of clinical scenarios.

Aufgrund ihrer physikalischen Hauptwirkung ist die HIT-Anlage ein Medizinprodukt, das aus einer Industrieanlage (Beschleuniger, HOAI-Leistung der GSI), einem Medizinprodukt (PT-System, Siemens AG) und einer Maschine (Gantry, MT Mechatronics) zusammengesetzt ist. Da sie vom Universitätsklinikum Heidelberg herstellt, betrieben und angewendet wird, und keine Abgabe an Dritte (Inverkehrbringen) erfolgt, gilt die HIT-Anlage als Eigenherstellung gemäß § 3 Nr. 21 MPG und muss keine CE-Kennzeichnung tragen. Gemäß § 12 Abs. 1 MPG ist die Inbetriebnahme einer Eigenherstellung nur zulässig, wenn deren Hersteller die auf sie anwendbaren Grundlegenden Anforderungen des Anhangs I der Richtlinie 93/42/EWG über Medizinprodukte erfüllt und das für sie vorgesehene Konformitätsbewertungsverfahren gemäß § 7 Abs. 9 MPV durchgeführt hat. Die erstgenannte und somit zentrale Grundlegende Anforderung ist der Nachweis eines positiven Nutzen-/Risiko-Verhältnisses für den Patienten sowie die Gewährleistung der Sicherheit von Patienten, Anwendern und ggf. Dritten bei zweckbestimmungsgemäßer Anwendung des Medizinprodukts, was eine Risikoanalyse, bewertung und beherrschung während seines gesamten Lebenszyklus und somit ein auf objektiven Nachweisen basierendes Risikomanagement impliziert. Artikel 5 Abs. 1 der o.g. Richtlinie enthält ebenso wie § 8 Abs. 1 MPG einen Verweis auf harmonisierte Normen und die mit ihrer Anwendung einhergehende Konformitätsvermutung. Die harmonisierte Norm für das Risikomanagement von Medizinprodukten ist die EN ISO 14971. Im Rahmen meiner Tätigkeit als Risikomanagement-Beauftragte war es meine Aufgabe, die DIN EN ISO 14971 auf die HIT-Anlage anzuwenden, als Dreh- und Angelpunkt der aufgrund der raum- und versionsweisen Übergabe des PT-Systems zwischen 06/2006 und 10/2012 durchgeführten vier Konformitätsbewertungsverfahren und zur Gewährleistung der Nachhaltigkeit des dadurch erzielten Sicherheitsniveaus für Patienten, Anwender und Dritte während der erwarteten Lebensdauer von 25 Jahren. Durch Entwicklung eines Risikomanagementplans und eines sog. RA Gesamtdokuments wurde zunächst der formale Rahmen für die Planung und Erstellung von Risikoanalysen geschaffen. Aufgrund der Größe und Komplexität der HIT-Anlage wurden die Gebäude Infrastruktur und der Beschleuniger hierfür in 9 Gewerke unterteilt, für Zubehör, Arbeitsabläufe und MPG-technische Aspekte der Gantry wurden weitere Risikoanalysen aufgesetzt. Auf Grundlage von Funktionsanalysen wurden diese 12 Risikoanalysen von mit Experten besetzten RA-Teams durchgeführt, wobei systematisch gelistet wurde, welche Ursachen zu welchen Fehlern und welche Fehler zu welchen Gefährdungen führen können, und wie die daraus resultierenden Risiken – Auswirkungen und Wahrscheinlichkeiten – bewertet werden (Risiken vor Maßnahmen). Falls aufgrund der im o.g. Risikomanagementplan festgelegten Akzeptanzkriterien eine Risikominderung erforderlich war, wurden eine oder mehrere Maßnahmen zur Risikobeherrschung spezifiziert, die geeignet waren, das jeweilige Risiko auf ein akzeptables Maß zu mindern. Anschließend wurden die Restrisiken unter der Prämisse bewertet, dass diese Maßnahmen implementiert und wirksam sind (Risiken nach Maßnahmen). Nach vorläufigem Abschluss einer Risikoanalyse wurden die Maßnahmen thematisch zusammengefasst in sog Maßnahmenblätter exportiert, wobei jede Maßnahme einem Maßnahmen- und einem Prüfverantwortlichen zugeordnet wurde (4-Augen-Prinzip), deren Aufgabe es war, die Implementierung der Anforderung(en) durch Bereitstellung eines oder mehrerer objektiver Nachweise zu bestätigen. Danach wurde jede Maßnahme von einem Audit-Team verifiziert, das sie in ein Nachaudit verwies, falls die Anforderung(en) nicht vollumfänglich erfüllt war(en). Am Ende jedes Konformitätsbewertungsverfahrens wurden die Ergebnisse aller Audits des ihm zugeordneten Maßnahmenpakets RA-weise zusammengefasst und den RA-Teams zur Überprüfung vorgelegt, um evtl. Änderungen zu bestätigen, die o.g. Restrisiken zu überprüfen und ggf. zu korrigieren oder durch weitere Maßnahmen zu mindern. Ein übergeordnetes Kern-Team entschied abschließend über die Akzeptanz evtl. Restrisiken oberhalb der Akzeptanzgrenze und die Akzeptanz des Gesamt-Restrisikos. Die Ergebnisse des Risikomanagement-Prozesses wurden in einem Risikomanagementbericht aufgezeichnet. Aus den o.g. von 42 Personen in 3959,85 Stunden erstellten Risikoanalysen wurden 1387 Maßnahmen abgeleitet, die zu 681 Kombi-Maßnahmen zusammengefasst und von 45 Maßnahmen- und Prüfverantwortlichen implementiert wurden. Im Rahmen der vier Konformitätsbewertungsverfahren wurden in 80 Audits in 734,15 Personenstunden aufgrund von Nachaudits und Wiederholungen (bei raum- und/oder versionsspezifischen Anforderungen) insgesamt 1187 Kombi-Maßnahmen verifiziert. Durch aus der Gap Analyse anlässlich eines Normenwechsels (EN ISO 14971:2009 → EN ISO 14971:2012) abgeleitete Aktivitäten konnte die Anzahl der Restrisiken oberhalb der Akzeptanzgrenze von initial 25 bzw. (ohne Mehrfachnennungen) 16 auf 15 bzw. (ohne Mehrfachnennungen) 9 gesenkt werden, wobei es sich z.T. um nicht Ionenstrahl-Therapiespezifische Restrisiken handelt, wie die Bestrahlung von Patienten mit aktiven (z.B. Herzschrittmacher) und nicht-aktiven (z.B. Endoprothesen) Implantaten. Das Gesamt-Restrisiko wurde jedoch stets als akzeptabel bewertet. Um die mit der Anwendung der HIT-Anlage verbundenen Risiken für Patienten, Anwender und Dritte dauerhaft zu beherrschen muss der Risikomanagement-Prozess während ihres gesamten Lebenszyklus aufrechterhalten werden. Nur durch regelmäßige Überprüfung der Wirksamkeit des Maßnahmenbestands, strukturierte Aufarbeitung potentiell sicherheitsrelevanter Informationen und bedarfsorientierte Anpassung der Risikoanalyse(n) bei geplanten Änderungen kann der Regelkreis des Risikomanagements geschlossen und die Sicherheit, Eignung und Leistung der HIT-Anlage auch langfristig gewährleistet werden. Ein Teil des o.g. Maßnahmenvolumens ist auf Wiederholung ausgelegt und wird i.d.R. jährlich und/oder bedarfsorientiert durchlaufen. Die Sammlung und Überprüfung von Informationen aus der Herstellung nachgelagerten Phasen erfolgt sowohl produkt- als auch prozessbezogen: Ersteres geschieht regelmäßig im Rahmen der Marktbeobachtung, bei der HIT-interne und öffentlich zugängliche Informationen auf evtl. Handlungsbedarf bewertet werden. Letzteres findet bedarfsorientiert mittels eines Critical Incident Reporting Systems statt, mit dem Meldungen über kritische Ereignisse bei der Vorbereitung und Durchführung der Ionenstrahl-Therapie aufgearbeitet werden. Unwesentliche Änderungen der HIT-Anlage werden über ein Änderungsverfahren abgewickelt, in dem u.a. eine Klärung der risikotechnischen Implikationen – Neudurchlauf von Maßnahmen und/oder Aktualisierung der Risikoanalyse(n) – enthalten ist. Bei wesentlichen Änderungen ist jeweils ein Konformitätsbewertungsverfahren erforderlich. Darüber hinaus wird die Entwicklung der für die HIT-Anlage relevanten regulatorischen Anforderungen mittels eines Rechtskatasters verfolgt, um darauf ggf. fristgerecht reagieren zu können. Der Vorstand des Universitätsklinikums erhält Jahresberichte, in denen das aktuelle Risikoprofil der HIT-Anlage und die geplanten risikorelevanten Aktivitäten dargestellt werden. Das für die HIT-Anlage etablierte Risikomanagement gemäß DIN EN ISO 14971 erfüllt alle normativen Anforderungen und wird seit Aufnahme des Patientenbetriebs am 15. November 2009 vom gesamten an der Ionenstrahl-Therapie beteiligten Team erfolgreich gelebt. Bisher wurden mehr als 5000 Patienten bestrahlt, wobei die Anzahl der applizierten Fraktionen ca. 14000 pro Jahr beträgt. Verglichen damit ist die Anzahl von 19 gemeldeten CIRS-Fällen in einem Zeitraum von 6 Jahren äußerst gering, zumal es sich bei keinem dieser Ereignisse um ein meldepflichtiges Vorkommnis gemäß § 2 Nr. 1 MPSV handelte. Die Risikomanagementakte umfasst derzeit (u.a. aus Gründen der Transparenz und Nachvollziehbarkeit) mehr als 35000 Anforderungs- und Nachweisdokumente, davon ca. 500 DIN A3 Seiten Risikoanalysen, und wächst aufgrund o.g. Aktivitäten zur Nachhaltigkeit stetig weiter. Unabhängig von geplanten administrativen Vereinfachungen ist das Risikomanagement der HIT-Anlage auch für künftige Weiterentwicklungen der Technologie und ihrer Verwendung gut aufgestellt.

Quantitative Dynamic Contrast-Enhanced Perfusion MRI - A Phantom and in Vivo Study The quantification of tissue perfusion with magnetic resonance imaging (MRI) is of great medical value for tumor diagnosis, treatment planning and therapy control. The aim of this work was to evaluate the feasibility as well as to find limitations and improvements of perfusion quantification using dynamic contrast-enhanced (DCE) MRI in combination with pharmacokinetic modeling. In the first part, a multimodal perfusion phantom mimicking human physiology at capillary level and simulating intra- and extravascular space was developed. This enables the application of a dual compartment model leading to perfusion parameters of which among others the Plasma Flow PF shows reproducible values both within a series of measurements (PF = (91 ± 7) ml/100 ml/min) and in the repetition after one week (PF = (91 ± 26) ml/100 ml/min). A reliable comparison not only between MRI and DCE computer tomography (CT) (PF = (94 ± 53) ml/100 ml/min), but also to the alternative MRI perfusion technique Arterial Spin Labeling (ASL) (PF = (99 ± 36) ml/100 ml/min) is applicable. Fast temporal resolution through a high sampling rate, indispensable for exact modeling, was achieved by the implementation of parallel imaging and led to a significant reduction of the intra measurement deviation by 30%. In the second part, an in vivo perfusion study of rectal carcinomas showed that the bilateral selection of the arterial input function and the use of dual compartment models have a significant influence on the quantification of perfusion parameters with deviations of the PF of up to 30 ml/100 ml/min. The importance of tissue ROI selection in heterogeneous tumors has been shown, as the parameters within a tumor differ by up to 36%. The combination of the findings of the phantom and the patient study reveals new and promising strategies for quantifying DCE-MRI in the future.

Magnetic resonance imaging (MRI) provides a versatile tool to determine a variety of fluid mechanical properties, but similarly the quantification is biased by the acquisition itself and the technique has limitations among which are limited spatial resolution and low signal-to-noise-ratio. To overcome such issues, phase contrast MRI methods have been investigated at 7 T. At this field strength variations of the transmit field pose a substantial problem. Additionally, so-called displacement artifacts become important, since they scale with spatial resolution. Transmit field variations are addressed in this work by multi-spoke RF pulses, which are not straightforwardly applicable to velocity quantification. They require a detailed investigation of displacement artifacts that arise due to differences in the encoding time points of velocity and space. This work investigates three different encoding schemes, for conventional excitation as well as for multi-spoke excitation, which yield different displacement artifacts. Their impact on derived haemodynamic parameters, such as wall shear stress, which had been unknown so far, are investigated. Moreover, spoke pulses are further fine-tuned by using asymmetric pulse shapes. Besides the correct determination of the velocity at 7 T, the precise quantification of acceleration is another important factor, which is solved in this work by developing an acceleration-encoded sequence free of artifacts. Furthermore, another confounding factor in MRI-based velocitmetry, the intravoxel velocity distributions, affect the velocity encoding process. This effect has been investigated and, based on measured velocity spectra, noise-optimized velocity encoding sensitivity (VENC) values have been proposed. Finally, the potential of precise MR-based velocity measurements is demonstrated for a well-known fluid dynamic test case (flow over periodic hills) with a Reynolds number of 60,000. For this case, the Reynolds stress tensor has been quantified. In conclusion, the presented techniques improve the precision at which fluid mechanical properties can be quantified by means of MRI.

In 2011, stereotactic body radiotherapy was introduced for the treatment of hepatocellular carcinoma at the Heidelberg Ion-Beam Therapy Center (HIT). Initially, thirteen patients were treated, including the first patient treated using respiratory beam gating. This thesis presents the work flow and data acquisition for the treatment of moving organs. Based on the acquired patient data, simulated and reconstructed 4D dose distributions are now available. Simulations of 4D dose distributions require precise knowledge of the organ motion and accelerator timing. To improve the prediction, the properties of the HIT synchrotron cycle were investigated, revealing energy-dependent and stochastic aspects and day-to-day beam intensity fluctuations. A simulation was implemented based on a realistic model of the accelerator. The accuracy of calculated irradiation sequences was verified using treatment records. Experimental verification using a patient treatment plan was performed in a moving water phantom, where a total dose deviation of (1.0±7.3)% was determined. Since 2012, the HIT heavy-ion gantry offers new treatment options. In a treatment planning study, optimal plan geometries for the treatment of esophageal carcinoma were determined. Effects of intrafractional organ motion were accounted for in a quasi-static dose calculation. Results can potentially be used for margin and gating window definition.

ALICE is one of the four major experiments at the Large Hadron Collider (LHC). It is the dedicated heavy-ion experiment and therefore primarily examines the Quark–Gluon Plasma. In order to prepare for the running conditions of 50 kHz lead-lead interactions at the LHC after the Long Shutdown 2 (2018–2021), an extensive upgrade program is carried out. The goal of the upgrade is a continuous readout of the TPC without the need of a trigger. It is essential to reduce the enormous data rate of 3.7 TB/s, generated by the upgraded detector, already during the data taking by a factor of about 60. Otherwise the data volume would exceed the expected available bandwidth and storage capabilities. In this thesis, an online Cluster Finder (CF) was developed and implemented for FPGAs which processes the whole data volume in real-time during the read out. This is the first step in the data reduction sequence which achieves already a factor of about 5 by keeping only physically relevant information and making use of a better suited data format. In addition to the CF, also the whole data preparation chain was designed and implemented to decode the input data stream, to resort the individual channels to allow for cluster finding and to correct the detector effects in the input signals. All modules which were implemented were extensively simulated to verify their proper functionality. With this, the complete processing chain within the FPGAs was prepared and validated.

Magnetic resonance imaging (MRI)-based mapping of the tissue oxygenation would be highly beneficial for the treatment of patients with brain tumours. Hence, the purpose of this thesis was to incorporate quantitative susceptibility mapping (QSM) into a reconstruction of the oxygen extraction fraction (OEF), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2). In the first part, a joint QSM and quantitative blood oxygenation level-dependent (qBOLD) approach from two different MRI sequences, gradient echo sampling of spin echo (GESSE) and multi-gradient echo (GRE), was compared in seven healthy subjects and simulations. GESSE yielded higher parameter accuracy in simulated grey matter but produced unphysiological grey–white matter contrast in OEF in vivo. GRE is more efficient and generated uniform OEF maps in vivo but revealed biases in simulation. In the second part, an artificial neural network (ANN) was trained for QSM+qBOLD analysis and compared to the initial quasi-Newton (QN) reconstruction. The ANN allowed a faster and more robust reconstruction of OEF maps with lower intersubject variation (OEF_ANN = 43.5 +- 0.8% vs OEF_QN = 43.8 +- 5.2 %). In the third part, machine learning-based clustering was incorporated into the QN QSM+qBOLD analysis and applied to eight patients with high-grade gliomas. The OEF was significantly lower inside the tumour compared to the contralateral side in grade III (OEF_tum = 12.5 +- 0.5% vs OEF_con = 24.5 +- 2.3 %) and grade IV (OEF_tum = 17.2 +- 6.1% vs OEF_con = 24.8 +- 4.5 %) gliomas. The CBF was significantly higher; yet, only in grade IV gliomas (CBF_tum = 108.1 +- 83.3 ml/100 g/min vs CBF_con = 29.1 +- 21.0 ml/100 g/min). The CMRO2 revealed no significant differences. Exploiting the phase and magnitude of the acquired MRI signal and including machine learning for reconstruction of the OEF with QSM+qBOLD is promising and might facilitate the implementation of a robust quantification of the tissue oxygenation in the clinical routine in the future.

Adaptive Cone-Beam Scan-Trajektorien für interventionelle Anwendungen Die interventionelle Röntgenbildgebung stellt Ärzten während minimalinvasiven Eingriffen Informationen über die Patientenmorphologie bereit. Sie muss aber aufgrund der gewebeschädigenden Wirkung mit Bedacht eingesetzt werden. Derzeit können Ärzte nur zwischen dosisarmen Röntgenprojektionen ohne Tiefeninformation und strahlungsintensiven Cone-Beam- Computertomografien mit Tiefeninformation wählen. Viele medizinische Anwendungen wie Positionskontrollen erfordern zwar Tiefeninformation, aber keinen vollständigen 3D-Datensatz. Adaptive Scan-Trajektorien können diese Lücke schließen, indem sie Objekte gezielt unterabtasten und die relevanten Informationen so dosiseffizient in Erfahrung bringen. In dieser Arbeit wird eine Methode präsentiert, die eine Implementierung von neuen adaptiven Scan-Trajektorien an einem C-Bogen-System erlaubt. Am Beispiel einer Klasse von Scan-Trajektorien, der zirkulären Tomosynthese (ZT), wurde die Realisierbarkeit der Methode demonstriert. Streustrahlenmessungen ergaben, dass die ZT eine vorteilhaftere Streustrahlenverteilung als die klassischen 3D-Trajektorien aufweist. In kritischen Körperpartien wie oberer Torso und Gesicht, wurde eine geringere relative Dosis von 75% und 46% (ZT) als bei klassischen Trajektorien (100% und 63%) gemessen. Die Scan-Trajektorien wurden mit einer Kalibrierung kombiniert, die auch eine retrospektive Kalibrierung an beliebigen Positionen im Interventionsraum erlaubt. In Streßtests konnten die Positionen von Metallkugeln eines Evaluierungsphantoms mit einer mittleren Genauigkeit von (0,01 ± 0,08) mm und einer mittleren Radiusabweichung von (0,13 ± 0,07) mm bestimmt werden. Bei einer Voxelgröße von 0,48 mm sind die Abweichungen kleiner als die Messgenauigkeit des bildgebenden Systems. Die untersuchten Trajektorien verwenden nur ein Viertel bis ein Fünftel der Projektionen herkömmlicher 3D-Trajektorien. Die Unterabtastung des Objekts und die Dosiseinsparung verursachen Artefakte in den Bilddaten. Mithilfe eines vorwissenbasierten Ansatzes konnten diese Artefakte minimiert und die Bildqualität auf die eines konventionellen 3D-Datensatzes verbessert werden. Die Ergebnisse dieser Arbeit zeigen, dass adaptive Scan-Trajektorien die interventionelle Röntgenbildgebung um einen neuen Bildgebungsmodus erweitern können, der gegenüber derzeitigen Bildgebungsmodi relevante Bildinformationen bei reduzierter Dosis akquiriert.

Gegenstand der Untersuchungen sind Kavernenvorgänge und Werkstofftransfer beim Unterpulverschweißen unter besonderer Berücksichtigung des Zu- und Abbrandes von Legierungselementen und Eisenbegleitern. Dabei wurde der Einfluss von Schweißparametervariationen, insbesondere die Wirkung durch Verschiebung des Zeitanteils der Wechselstromhalbwellen, untersucht. Die Untersuchungen wurden an Massiv- und Fülldrähten mit unterschiedlichen Legierungskonzepten durchgeführt. Die Übertragbarkeit der Erkenntnisse auf UP-Mehrdrahtschweißungen wurde durch begleitende chemische Untersuchungen dargestellt.

In clinical routine, a case-adapted CT examination is usually conducted for each medical indication in order to allow for a comprehensive high-quality diagnosis of a patient. Therefore, image reading requires the transition between various image stacks, since each medical question implicitly requires organ-dependent reconstructions, display settings, multi planar reformations and image analysis tools. In particular, if dual or multi energy CT data are available, various spectral evaluation methods yield material-specific or functional information. However, the interpretation of this large amount of data is a time-consuming and tedious task. Hence, the purpose of this thesis is to evaluate the potential benefit of the incorporation of patient-specific anatomical priors, which are gained from an automatic multi-organ segmentation, in order to discover novel opportunities to improve the clinical workflow. In this thesis, a new paradigm is proposed which combines competing image properties resulting from different reconstruction algorithms and display settings into a context-sensitive CT imaging by means of anatomical prior information. With the incorporation of anatomical prior knowledge, which is obtained using an automatic multi-organ segmentation approach, various desired image characteristics are combined into a single context-sensitive CT image formation and presentation. The comparison with conventional CT images reveals an improved spatial resolution in highly attenuating materials as well as in air-filled body regions. Simultaneously, the compound image maintains a low noise level in soft tissue resulting in a superior soft tissue contrast compared to conventional images. Furthermore, the novel CT imaging framework allows for the combination of mutually exclusive display settings for the presentation of context-sensitive images to the radiologists. By exploiting anatomical prior information, numerous DECT applications can be integrated into one single DE analysis tool. Moreover, the tools can be chosen and applied to different organs simultaneously without any user interaction. The prior-based DE scheme performs all organ-specific feasible methods instantaneously without the need of a manual selection. Exploiting the anatomical priors, DECT analysis and evaluations are automated and standardized. The iodine quantification accuracy is significantly improved using patient-specific calibrations. The evaluation method and the presentation of the data to the radiologist can be realized via color overlays, pop up menus, volume rendering etc. Furthermore, the method can readily be generalized to the cases of multi energy CT data as it is not limited to the processing of DECT data. The principle of incorporation anatomical prior knowledge is then extended to provide a novel pseudo material decomposition that decomposes dual energy data into more than three basis materials. The method consists of multiple three-material decompositions, where the basis materials are automatically adjusted to the organ of interest based on the automatic segmentation. Moreover, a patient-specific calibration is introduced to improve the volume fraction and material quantification accuracy. An organ-adapted basis material triplet is automatically assigned to each anatomical region resulting in overlapping triangles in the dual energy space. The basis materials are calibrated by evaluating ROIs to improve the volume fraction accuracy. Besides presenting evermore increasing material images to the radiologists, the volume fractions are rescaled to organ-dependent material scores and visualized via pie charts to be later correlated with different diagnoses. The prior-based pseudo multi material decomposition is evaluated using phantom and patient data. The materials are quantified according to the anatomical structure they belong to. Overall, the proposed method provides physically plausible volume fractions that bear the potential to improve the material quantification for diagnosis and e.g. tumor treatment monitoring. In addition, the iodine quantification accuracy and the volume fraction accuracy are evaluated depending on different material calibration methods in conventional DECT applications as well as in the novel pseudo multi material decomposition. The accuracy using default parameters or simulation-based calibrations is compared against the accuracy obtained using patient-specific ROIs. All patient-specific calibrations can be performed directly from the patient data itself, such that almost no user interaction is required. It turns out that a patient-specific calibration is superior compared to a default or simulation based calibration. The new paradigm offers the possibility to display evermore complex information in CT imaging in order to significantly improve the workflow of radiologists. In the clinical routine, e.g. during case presentations and discussions, the fast switching between different image stacks is time-consuming and can be avoided in the future since the CS images merge advantageous image properties resulting from various reconstructions and display settings. The results of the DE evaluation can be dynamically superimposed by color overlays. This superposition provides a comprehensive quantitative analysis of the patient data that can be interpreted as an additional image dimension. By means of the combined DECT evaluation scheme, the radiologists might be assisted in finding a precise diagnosis. In summary, diagnostic accuracy could be increased with the CS imaging by improving the sensitivity for incidental findings: e.g. small nodules can be diagnosed in the lung parenchyma, even if the radiologist is mainly focused on assessing soft tissue. The possibility to robustly decompose DECT data into more than three basis materials opens up for novel clinical evaluation to quantify e.g. fat content and iodine content in the liver simultaneously and to assess long term material scores using pie chart visualizations.

Thanks to their extremely high mobilities, semiconducting carbon nanotubes (CNTs) are a promising material for high speed electronics. Beyond that, CNT networks are inherently flexible and stretchable and can be processed from dispersions resulting in devices with still remarkable electronic properties. They can fulfill many of the various requirements for novel applications including fast switching speeds and high currents at low drive voltages. Depending on the intended use, one or another device property might be more important. CNT networks, processes, and architectures can be tailored to yield devices that can serve the respective purpose. Highly purified semiconducting CNTs are, however, still rather expensive and direct-write techniques are thus preferred to enable variable designs and reduce manufacturing costs. In this work, aerosol-jet printing is investigated as a deposition technique for CNTs that works with small ink volumes but can also be upscaled by parallelization and integrated into high-throughput roll-to-roll printing processes. After the development of printable inks, it is shown that the printing process itself has no influence on the quality of the CNTs although sonication is used to transfer the ink into an aerosol. The electronic properties of CNT networks incorporated in an established transistor structure exhibit reproducibility comparable to other deposition techniques. Moreover, additive manufacturing enables the deposition of several layers on top of each other to increase the overall film thickness up to optically dense films visible to the naked eye. Field-effect mobilities and on-conductances increase and the hysteresis decreases for thicker films compared to dense but thin networks. Based on these findings, CNT films are printed with a thickness of 50–600 nm and vertical charge transport is demonstrated. These films are subsequently sandwiched between electrodes and electrolyte-gating results in doping of CNT films throughout electrode overlap areas of several hundred µm2. The vertical device architecture decouples the printing accuracy from the critical device dimensions while supporting high currents for a small footprint. A comparison of different printed electrode materials reveals the superior properties of printed metals over mixed (metallic and semiconducting) CNTs. Electrodes based on inkjet-printed gold nanoparticles are additionally used on flexible substrates and stable device performance even after several hundred bending cycles is demonstrated for vertical and lateral CNT network transistors. These all-printed devices are promising for further development of electronic circuits that do not require high operating frequencies but rather flexibility, high-currents, and small footprints.

In this work, novel algorithms in the field of retrospective intrinsic respiratory and cardiac gating and moving metal artifact reduction (MMAR) for cone-beam CT (CBCT) scans that are used in image-guided radiation therapy (IGRT) were developed. The added difficulty for CBCT scans is the relatively long acquisition time of up to 60 s compared to 0.25 s for clinical CT scans. The occuring respiratory and cardiac motion in combination with metal inserts cannot be handled with classical metal artifact reduction (MAR) methods. The proposed MMAR algorithms utilize an approach that combines the fields of motion compensation (MoCo) with classical MAR methods. In order for the MMAR methods to work, the motion state has to be known for every projection angle. A novel intrinsic gating approach, that automatically generates a list of potential motion surrogate candidates and identifies the best, was developed and used as a basis for the MMAR algorithms, so they can be applied for patients where no externally recorded motion signal is available. Whereas classical approaches for intrinsic gating are not designed for a laterally shifted detector, that is commonly used in IGRT with a CBCT, the novel algorithm works on scans with or without a shifted detector. It can also be used as a basis for 4D (3D + respiratory) or 5D (3D + respiratory + cardiac) MoCo algorithms.

In this thesis, the development of a novel magnetic resonance imaging (MRI) pulse sequence based on magnetic resonance fingerprinting (MRF) is presented. The proposed technique, termed “Flow-MRF”, allows time-resolved velocities and relaxation constants to be quantified simultaneously, in shorter acquisition times than conventional MR-based velocimetry. The simultaneous quantification of both sets of parameters was achieved by formulating the combined problem in the MRF framework. An MRF pattern was designed to create minimal coupling between the relaxometric and velocimetric parameter encoding. Flow-MRF was validated and tested in simulations, phantom experiments, and an in vivo study targeting the popliteal artery and the gastrocnemius muscle. In each investigation, Flow-MRF quantified relaxation constants and flow velocities in strong agreement with literature and reference measurements. Furthermore, the use of high velocity encoding moments (Δm1 = 60 mT/m·ms^2) was demonstrated while maintaining a range of correctly quantifiable velocities beyond 800 cm/s. In the volunteer study, Flow-MRF determined an average longitudinal relaxation time of (1384±75) ms and a transverse relaxation time of (26±4) ms in the gastrocnemius muscle. The average velocity deviation over all three volunteers between Flow-MRF and the reference was (-2.6±5.2) cm/s. Lastly, the potential to quantify the complete Reynolds stress tensor with Flow-MRF was investigated and shown in a stenotic flow phantom experiment. Flow‐MRF presents a novel method of quantifying velocities in up to fourfold shorter measurement times than conventional velocity mapping techniques, while simultaneously providing relaxometric maps of static tissue. These improvements can potentially be helpful in the assessment of pathologies such as arteriosclerosis.

The Mu3e experiment is a proposed experiment to probe for new physics by searching for the charged lepton-flavour violating decay μ+ → e+e+e− with a branching ratio sensitivity of 10^−16 , improving the current limit by four orders of magnitude. To search for such rare events, extremely high muon decay rate, good background suppression and high detector efficiencies are required. This demands an excellent momentum, vertex and timing resolution from the detector systems. Furthermore, the experiment will be running at a muon stopping rate of more than 10^9 Hz in order to observe enough muon decays in a reasonable experiment running time. This poses another challenge to the detectors and readout electronics, which have to be designed to cope with the present event rate. This thesis presents the development of a dedicated Silicon Photomultiplier (SiPM) readout Application-Specific Integrated Circuit (ASIC) for the Mu3e timing detectors. It provides the precise timing measurement while being capable of working with the high event rates. Fully differential analog front-end channel and 50 ps time binning TDC are utilized to achieve excellent timing resolution. The customized Low-Voltage Differential Signaling (LVDS) transmitter cell and double data rate serializer provides gigabit data rate to transfer data out of the chip. Detailed measurements have been preformed to characterize the timing performance and to verify the digital functionalities of the chip.

Electro-optical deflectors provide a very attractive means of laser scanning in coordinate-targeted super-resolution microscopy due to their high scanning precision and high scanning velocity. Setups equipped with electro-optical deflectors demonstrate especially high resolving powers, fast imaging and reduced photobleaching. Two major shortcomings limit a widespread application of such devices. Their polarizing properties prevent de-scanning causing either a loss in signal or an increased background signal and the restricted deflection angles severely narrow the field of view. Herein, I report solutions to both of these problems. The polarization issue is evaded via a passive polarization rectifier that allows unpolarized light to pass the laser scanner. The field of view is nearly doubled through a digital light deflector composed of a Pockels cell and a Wollaston prism. This principle could be extended by N stages of the same kind yielding a field of view enlargement by a factor of 2^N. Thus, the work at hand paves the way for ultrafast electro-optical laser scanning with a large field of view.

In vielen Organismen nimmt die Verstoffwechselung von molekularem Sauerstoff eine zentrale Rolle im Energiestoffwechsel ein. Ziel dieser Arbeit war es, die dynamische Magnetresonanztomographie (MRT) des Sauerstoffisotops 17O zur quantitativen und lokalen Bestimmung des zerebralen Sauerstoffumsatzes (CMRO2) mittels eines Inhalationsexperimentes bei einer Magnetfeldstärke von B0=7T weiterzuentwickeln sowie in ihrer Robustheit und Genauigkeit zu evaluieren. Die physikalischen Eigenschaften des 17O-Atomkerns verlangen spezielle radiale Auslesetechniken und erlauben nur geringe räumliche Auflösungen. Die daraus resultierenden Partialvolumeneffekte(PVE) verfälschen die Signalwertbestimmung und vermindern die erreichbare Präzision bei der funktionellen Quantifizierung. Daher wurde ein PVE-Korrekturalgorithmus etabliert, der eine verbesserte Konzentrations- sowie T2*-Bestimmung erlaubt. Für Inhalationsexperimente wurde ein Aufbau bestehend aus einem Gasapplikationssystem und optimierter Hochfrequenz-Sende- und Empfangsantenne konzipiert. Des Weiteren wurde für die 17O-MRT die Korrekturstabilität und erreichbare zeitliche sowie nominelle räumliche Auflösung von (4,5mm)3 verifiziert: eine temporäre Abtastrate von 1:00 min erlaubt eine Genauigkeit der Konzentrationsbestimmung innerhalb von 5–9% des Literaturwertes. Die Analyse des dynamischen Signal- und Korrekturverhaltens mittels Simulationen führte zum Protokoll eines In-vivo-Inhalationsexperiments. Die quantifizierten funktionellen Parameter einer Probandenstudie waren CMRO2,GM=(2,03–2,52)±0,14μmol/g min (graue Substanz, GM) sowie CMRO2,WM=(0,61–0,74)±0,08μmol/g min (weiße Substanz, WM) und lagen damit im GM-Kompartiment höher als in vorherigen Studien. Die Ergebnisse zeigten eine geringe Variation über alle Messungen und demonstrierten dadurch die Reproduzierbarkeit der vorgeschlagenen Methode der dynamischen 17O-MRT.

Das Ziel dieser Arbeit war es, die In-vivo-23Na-Magnetresonanz(MR)-Bildgebung des Körperstamms bei B0 = 7 Tesla zu ermöglichen. Zur Anregung der 23Na-Kernspins sowie zur Detektion der 23Na-Magnetisierung wurde eine 23Na-HF-Körperspule entwickelt, aufgebaut und optimiert. Drei Spulenkonfigurationen der ovalen, eng anliegenden Birdcage-Spule wurden untersucht: Zur Erhöhung der Homogenität des Sende- und Empfangsfeldes wurde im ersten Optimierungsschritt die herkömmliche Zweikanal-Einspeisung zu einer Vierkanal-Einspeisung erweitert. Im zweiten Optimierungsschritt wurde durch eine Anpassung der Sendephasen der relative Flipwinkelfehler in einem Bereich der Größe (23×13×10) cm³ von 8,6 % auf 4,9 % reduziert. Die 23Na-HF-Körperspule mit vier Empfangskanälen stellt ein relativ homogenes Sendefeld ((11,97 ± 0,59) μT, HF-Sendeleistung 2,4 kW) sowie Empfangsfeld zur Verfügung, welche einen großen Bereich des Körperstamms abdecken. Daher ermöglicht die HF-Körperspule erstmalig die Aufnahme von In-vivo-23Na-MR-Bildern der gesamten Breite des Körperstamms eines Erwachsenen mit einer großen Abdeckung in Längsrichtung bei B0 = 7 Tesla (Sichtfeld FOV = (40 cm)³). In den rekonstruierten 23Na-MR-Bildern treten Verschmierungen aufgrund der Atembewegung auf. Daher wurde das intrinsische Atemsignal retrospektiv aus den 23Na-MR-Daten bestimmt. Basierend auf diesem Atemsignal wurden die aufgenommenen MR-Daten in zwei Atemzustände (eingeatmet, ausgeatmet) aufgeteilt, was zu einer Reduktion der Verschmierungen führt. Die Zuordnung basierend auf dem intrinsischen und dem extrinsischen Atemsignal (Atemgurt) zeigte für drei Probanden eine gute Übereinstimmung von (90,6 ± 2,8) % bei der 23Na-Lungen-MR-Bildgebung und von (82,3 ± 3,8) % bei der 23Na-MR-Bildgebung des Abdomens.

Light-sheet fluorescence microscopy, also recognised as selective plane illumination microscopy, or SPIM, has paved a new road towards imaging of entire specimens for long periods of time, in vivo. Nevertheless, as in any other microscopy technique, light-sheet fluorescence microscopy also heavily depends on the scattering and absorption properties of the imaged sample in order to generate 3D datasets with high signal to noise even at larger tissue depths. This thesis focuses on the development and implementation of new strategies and methods which target the minimization of scattering and absorption effects stemming from living specimens. Combined, the three methods provide the ability to perform gentle, high contrast deep tissue imaging and photomanipulation. Additionally, it allows easier handling and fusion of 3D multiview light-sheet images.

Clinical implementation of novel advanced treatment techniques in adaptive radiation therapy requires proper workflow verification. However, this subject is not satisfactorily solved yet as current experimental validation techniques do not reflect the complexity of real patient treatments. In this thesis, several methods for patient-specific end-to-end tests were developed and applied to clinical workflows especially including treatments of moving tumors. End-to-end-tests were performed with geometrically well-defined phantoms as well as with an anthropomorphic dynamic ex-vivo porcine lung phantom in combination with a 3-dimensional (3D) polymer gel dosimeter (PGD). Different experimental settings of increasing complexity were tested in terms of (i) accuracy, (ii) feasibility of clinical workflows testing, (iii) validation of clinical concepts for motion-compensated treatments, (iv) additional integration of real-time markerless fluoroscopic imaging, and (v) validation of 4D dose calculation algorithms. Phantom irradiations were performed under static and dynamic conditions with and without beam gating. PGD evaluation revealed good tumor coverage for all treatment concepts and beam gating significantly reduced normal tissue exposure. In all cases, good agreement with the calculated dose distribution was obtained. As a conclusion, the established experimental workflow provides a versatile and valuable tool for geometrical and dosimetrical validation of advanced motion-compensated treatment techniques in adaptive radiation therapy.

Chemical Exchange Saturation Transfer (CEST) experiments enable the indirect detection of small metabolites, e.g. creatine, and proteins in living tissue by means of magnetic resonance imaging. Selective RF saturation of solute protons in chemical exchange with water leads to an accumulation of saturation in the water magnetization. The resulting reduction of the water signal depends on physiological properties, e.g. pH, temperature and solute concentration, but also on the saturation scheme. In a clinical setup, the latter is limited to a series of short RF-pulses to obey safety regulations. Pulsed saturation is diffcult to describe theoretically, thus, the quantitative determination of physiological parameters via CEST experiments is a challenging task. In this thesis, a new analytical model for CEST is proposed, which extends a former interleaved saturation-relaxation approach. This model enables the analytical calculation of Z-spectra yielding deeper insight into the physics of pulsed CEST experiments. Furthermore, it enables for the first time in the case of pulsed saturation the separate and independent determination of the exchange rate k and the relative proton concentration f. The validity of this approach was tested by simulations and verified in measurements of model solutions containing creatine on a 7-Tesla whole-body MR tomograph. Finally, the obtained knowledge was used to quantitatively investigate pH and absolute creatine concentration in the human calf muscle under resting conditions and during exercise.