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The present PhD project was carried out as part of an EPSRC Leadership Fellowship for the study of irradiation damage in zirconium alloys. The National Nuclear Laboratory (NNL) directly supported the project in terms of additional funding and insightful discussions regarding irradiation damage in zirconium alloys. The research carried out within the project aims to gain a better understanding of both a- and c-loops, formed during irradiation damage in zirconium alloys. A range of techniques have been utilised to assess the morphology and density of the dislocation loops after proton-irradiations. These techniques include transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS) and line profile analysis (LPA) using synchrotron X-ray diffraction (SXRD) profiles and analysing the data utilizing the extended convolutional multiple whole profile (CMWP) analysis software. The effect of experimental conditions on dislocation loop formation and stability of a-loops during post-irradiation annealing have also been investigated. Proton-irradiations were carried out on the commercial alloys Zircaloy-2, Optimized ZIRLOTM and also on binary Zr-0.1Fe and Zr-0.6Fe alloys. A mechanism has been proposed as to the effect of Fe redistribution on dislocation loop formation. By comparing proton-irradiated Zr-0.1Fe and Zircaloy-2 alloys it was possible to investigate the effect of increased amount of Fe redistribution, which occurs from secondary phase particle (SSP) dissolution, on the microstructural features that develop during irradiation. Zircaloy-2 has a higher density of SPPs and these are more homogenously distributed throughout the matrix in comparison to the Zr3Fe SPPs found in the Zr-0.1Fe alloy. It was found that Fe redistribution facilitates the formation of Fe-rich nano-precipitation. Bright-field STEM imaging has been used to image a- and c-loops and it was found that Zircaloy-2 had a lower dislocation line density compared to Zr-0.1Fe for both types of loops at similar damage levels. Therefore it has been proposed that Fe redistributed from SPPs precipitates in the matrix and the subsequent irradiation-induced precipitates act as annihilation sites for point defects; therefore preventing the formation of new dislocation loops and the growth of existing loops. In order to assess the effect of proton-irradiation temperature on a-loops, Zircaloy-2 and Optimized ZIRLOTM were proton irradiated to 2.3 dpa at 280°C, 350°C and 450°C. It was found that the a-loop density dropped in both alloys as irradiation temperature was increased and the a-loop diameter decreased. The changes in the density and size were more dramatic in Zircaloy-2 and this was explained by the presence of fine irradiation induced clustering of Nb seen in Optimized ZIRLOTM. These trends were calculated from both STEM imaging and CMWP, highlighting the suitability of using CMWP to investigate irradiation-induced dislocations. Finally the stability of the a-loops in proton-irradiated Zr-Fe binary alloys were investigated using novel in-situ SXRD and TEM annealing experiments. From CMWP analysis of the profiles generated during the in-situ annealing of a Zr-0.6Fe 3 dpa sample it was shown that the majority of the annealing takes place between 300°C-400°C. This was highlighted by a period of no change in the dislocation density up to 300°C, after which the density drops dramatically. In-situ annealing of a 1.5 dpa Zr-0.1Fe sample in the TEM allowed for the observation of a-loop gliding along prismatic planes enabling the annealing process taking place between 280°C-450°C, i.e. a similar temperature range at which SXRD analysis indicates the greatest level of annealing.

Photodetectors are used in many applications such as digital and thermal cameras or in solar panels. They can also be designed to detect the omnipresent high-energy radiation/particles, and for radiation imaging in biomedical applications. Novel nanostructures offer significant advantages compared to traditional designs for the realization of fast, sensitive, compact and cheap sensors and efficient solar cells. Examples of such nanostructures include quantum dots (QDs), quantum wells (QWs) and NW arrays. This thesis is devoted to experimental investigations of effects of high-energy (1 MeV) protons on the optical and electrical performance of InP/InAsP NW-based QDiscs-in wire photodetectors. The proton-induced degradation of the optical performance has been studied by means of Fourier Transform Infrared (FTIR) photocurrent spectroscopy. The spectrally resolved photocurrent (PC) and current-voltage (I-V) characteristics were measured at low temperature (5 K and 77K) and at room temperature (300K) before and after 1 MeV proton irradiation under vacuum conditions with fluences ranging from 1.0×1012–3.0×1013 cm-2. The particle radiation exposure has been done in the Ion Beam Accelerator at the Department of Nuclear Physics Department at Lund University. Considering both PC and I-V characteristics, it was found that the devices were sensitive to all proton irradiation at all fluences. In general, the PC intensity significantly increased after radiation for all fluences, however, a week after exposure the PC and dark current gradually recovered. At 3×1012 p/cm2 fluence level, it was figured out that photocurrent which attributed to QDiscs disappeared for a couple of days after exposure, however, over time and gradually, those started to manifest again even at low and room temperatures, causing radiation-induced changes in device parameters to be time-dependent; however, it was not recorded any signals related to QDiscs at fluence of 3×1013 p/cm2. Substantial changes in the dark I-V characteristics, as well as increases in the dark current, are observed after irradiation. The influence of proton irradiation on light and dark current characteristics also indicated that NW structures are a good potential candidate for radiation harsh-environment applications. It was also observed a significant increase in dark current after the radiation for all devices, however, by applying the voltage to the photodetectors, the PC and I-V characteristics gradually being to diminish, which may be attributed to an annealing process.

To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.

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Die Arbeit befasst sich mit der Untersuchung von weitbandlückigen Halbleitern über raumladungszonenspektroskopische Methoden. Dabei liegt der Schwerpunkt auf der Detektion von elektronisch und optisch aktiven Defektzuständen in solchen Materialien. Die Experimente wurden exemplarisch an dem II-VI Halbleiter Zinkoxid (ZnO) durchgeführt, welcher inform von Volumenkristallen, Mikronadeln und Dünnfilmen zur Verfügung stand. Raumladungszonen wurden über Schottky-Kontakte realisiert. Nach einer Einführung in die Theorie der Raumladungszonenspektroskopie wird ein Überblick über Defekte in verschiedenartig gezüchteten ZnO gegeben. Dazu werden die Standardverfahren Strom-Spannungs-Messung, Kapazitäts-Spannungs-Messung, Thermische Admittanz- Spektroskopie (TAS) und Deep Level Transient Spectroscopy (DLTS) verwendet. Ergänzend wurden die auf weitbandlückige Halbleiter ausgelegten Verfahren Low Rate Deep Level Transient Spectroscopy (LR-DLTS) und Deep Level Optical Spectroscopy (DLOS) eingesetzt, mit welchen es möglich ist Defektzustände in der gesamten Bandlücke von ZnO nachzuweisen. Für die untersuchten Störstellenniveaus konnten somit die thermische Aktivierungsenergie, Einfangquerschnitte freier Ladungsträger und Photoionisationsquerschnitte bestimmt werden. Typischerweise werden tiefe Defekte durch die Bestrahlung mit hochenergetischen Protonen erzeugt. Derartige Behandlungen wurden an binären ZnO- und ternären (Mg,Zn)ODünnfilmen durchgeführt, wobei die Generationsrate eines Defektes über Variation der verwendeten Strahlungsdosis bestimmt wurde. Ionenimplantationen spielen eine große Rolle im Herstellungsprozess von Bauelementen, sind jedoch für ZnO nicht etabliert. Die Auswirkung der Implantation von inerten Argon-Ionen, sowie die nachträgliche thermische Behandlung auf die Konzentration intrinsischer Defekte wurde untersucht. Zink- und Sauerstoff-Implantationen bewirken, neben der Generation von Defekten, eine lokale Änderung der Stöchiometrie. Durch einen Vergleich der Defektkonzentrationen nach Zn-, O-, Ne- und Ar-Implantation können Rückschlüsse auf die chemische Natur intrinsischer Defekte geschlossen werden.

Background: A highly desmoplasmic microenvironment, the mutational landscape, and intra-tumoral heterogeneity contribute to the therapy resistance in pancreatic ductal adenocarcino-ma (PDAC). Due to higher precision, proton beam therapy is regarded beneficial compared to standard photon radiotherapy, although the role of radiotherapy is still ambiguous in PDAC. Cellular adhesion to the extracellular matrix (ECM) via integrins is well-known to mediate radi-ochemoresistance in various tumor entities. In PDAC, β1 integrins are associated with tumor progression. However, their role in radiochemoresistance is yet to be unraveled. Consequently, a comparative evaluation of cell survival and therapy sensitization after inhibition of β1 integ-rins or other survival-promoting protein kinases combined with either photon or proton irradia-tion and the underlying molecular mechanisms was carried out in this work. Materials and Methods: The expression of β1 integrins in PDAC and the correlation with pa-tient survival were assessed using publicly available patient data. The effect of β1 integrin inhi-bition by inhibitory antibodies or depletion on PDAC cell survival upon photon and proton irra-diation was explored using the tumoroid formation assay in three therapy-naïve and one radio-resistant PDAC cell lines grown in more physiological 3D laminin-rich ECM. Protein expression and cellular localization of β1 integrins were analyzed applying Western blot and immunofluo-rescence in the cell line panel. Basal molecular differences and those upon β1 integrin inhibi-tion were determined by a broad-spectrum kinome profiling in therapy-naïve and radioresistant 3D PDAC cultures. A potential interrelation of specific kinases with β1 integrin signaling in re-sponse to radiation was investigated in a single and double knockdown screen. The effects of photon and proton irradiation on PDAC cell survival of five 3D cultured PDAC cell lines were comparatively assessed using the 3D tumoroid formation assay. Molecular alterations upon both radiation types were identified by a broad-spectrum phosphoproteome analysis and Western blot. The exploitation of uniquely altered molecules and other signal transduction and DNA repair molecules for specific sensitization to photon and proton radiation was evaluated using specific biologicals in 3D cultured PDAC cell lines. Results: β1 integrins are overexpressed in PDAC compared to the normal pancreas, and the expression correlates with poorer patient survival. β1 integrin expression and localization var-ied cell line-dependently in the PDAC cell line panel. β1 integrin inhibition elicited an increase in radiosensitivity in all analyzed therapy-naïve and radioresistant 3D PDAC cultures, although less prominent in the latter. In line, the extent of kinase deregulation induced by AIIB2 was lower in the radioresistant 3D PDAC cultures. Double targeting of specific kinases with β1 in-tegrins further increased the radiosensitization in the therapy-naïve 3D PDAC cell cultures, whereas in the radioresistant counterpart, the effect was weak. Further, Erk2, PKD1, and CK1δ were revealed as potential interactors in the β1 integrin-mediated response to radiation. Proton irradiation showed a higher efficacy in the reduction of PDAC cell survival than photon irradia-tion. On the molecular level, irradiation with protons induced more phosphoproteomic altera-tions than photon radiation. Targeting of molecules uniquely altered upon irradiation failed to sensitize 3D PDAC cultures radiation type-specifically. However, a similar degree of radiosen-sitization for proton and photon irradiation in 3D PDAC cultures was observed upon targeting signal transduction and DNA repair proteins. Targeting non-homologous end joining (NHEJ)-specific proteins increased cellular radiosensitivity exceedingly for both radiation types in all 3D PDAC cell cultures. Conclusion: This work revealed a fundamental role of β1 integrins in intrinsic and acquired radioresistance of PDAC. However, to substantially overcome acquired radioresistance, further investigation is needed. Furthermore, a similar efficacy of proton and photon irradiation when combined with targeted therapies was demonstrated. These results suggest that multitargeting approaches based on targeting of β1 integrins or NHEJ-specific molecules combined with pho-ton or proton irradiation may turn out particularly promising. The strong radiosensitizing poten-tial of targeting these molecules may enable a more frequent use of radiotherapy for PDAC patient treatment. / Hintergrund: Ein stark desmoplasmatisches Mikromilieu, das Mutationsprofil und die intra-tumorale Heterogenität tragen zur Therapieresistenz des Pankreaskarzinoms bei. Aufgrund der höheren Präzision wird die Protonentherapie als vorteilhaft gegenüber der Standard Pho-tonentherapie angesehen, obwohl ihre Wirksamkeit im Pankreaskarzinom noch ungewiss ist. Es ist bekannt, dass die zelluläre Adhäsion an die extrazelluläre Matrix (EZM) über Integrine die Radiochemoresistenz in verschiedenen Tumorentitäten vermittelt. Hierbei stehen β1 In-tegrine in Zusammenhang mit dem Fortschreiten der Erkrankung. Welche Rolle die β1 Integri-ne in der Radiochemoresistenz im Pankreaskarzinom spielen ist jedoch noch nicht bekannt. In dieser Arbeit wurde daher eine vergleichende Analyse des Zellüberlebens und der Therapie-empfindlichkeit nach Hemmung von β1 Integrinen oder anderen überlebensfördernden Pro-teinkinasen in Kombination mit Photonen- oder Protonenbestrahlung sowie der zugrundelie-genden molekularen Mechanismen durchgeführt. Material und Methoden: Die Expression von β1 Integrinen im Pankreaskarzinom und die Kor-relation mit dem Patientenüberleben wurden mittels öffentlich verfügbarer Patientendaten be-stimmt. Die Wirkung der β1-Integrin-Hemmung durch inhibitorische Antikörper oder mittels knockdown auf das Überleben von Pankreaskarzinomzellen bei Bestrahlung mit Photonen und Protonen wurde durch den Tumoroidbildungsassay in drei therapienaiven und einer strahlen-resistenten Pankreaskarzinomzelllinien untersucht. Diese wurden in physiologischer, 3D Lami-nin-reicher EZM kultiviert. Die Proteinexpression und die zelluläre Lokalisation von β1 Integri-nen wurden in allen Zelllinien mittels Western Blot und Immunfluoreszenz analysiert. Basale molekulare Unterschiede und solche nach Hemmung von β1 Integrinen wurden durch eine Breitspektrum-Kinomanalyse in therapienaiven und strahlenresistenten 3D-Pankreaskarzinomkulturen bestimmt. Eine mögliche Wechselbeziehung spezifischer Kinasen mit der β1 Integrin-vermittelten Strahlenantwort wurde in einem Einzel- und Doppel-knockdown Screen untersucht. Die Effekte der Bestrahlung mit Photonen und Protonen auf das Überleben von Pankreaskarzinomzellen wurden vergleichend anhand des Tumoroidbildungsassays in fünf 3D-kultivierten Pankreaskarzinomzelllinien bewertet. Durch beide Strahlungstypen indu-zierte molekulare Veränderungen wurden durch eine Breitspektrum-Phosphoproteomanalyse und mittels Western Blot identifiziert. Die Nutzung einzigartig veränderter Moleküle sowie an-derer Signaltransduktions- und DNA-Reparaturmoleküle zur spezifischen Sensibilisierung für Photonen- und Protonenstrahlung wurde untersucht. Dies erfolgte durch eine gezielte Hem-mung dieser Moleküle durch spezifische Biologika in 3D-kultivierten Pankreaskarzinomzellli-nien. Ergebnisse: β1 Integrine sind im Pankreaskarzinom im Vergleich zum gesunden Pankreas überexprimiert und ihre Expression korreliert negativ mit dem Patientenüberleben. Die Expres-sion und Lokalisierung der β1 Integrine variierte zelllinienabhängig in den Pankreaskarzinom-zelllinien. Die Hemmung der β1 Integrine führte zu einer Erhöhung der Strahlenempfindlichkeit in allen analysierten therapienaiven und strahlenresistenten 3D kultivierten Pankreaskarzinom-zelllinien, auch wenn diese in den letzteren weniger stark ausfiel. Auch der Grad der durch die Hemmung induzierten Deregulierung von Kinasen in den strahlenresistenten 3D Pankreaskar-zinomzellkulturen war geringer. Der gleichzeitige knockdown spezifischer Kinasen mit β1 In-tegrinen potenzierte die Strahlenempfindlichkeit in den therapienaiven 3D Pankreaskarzinom-zellkulturen, während diese im strahlenresistenten Pendant nur wenig beeinflusst wurde. Fer-ner wurden Erk2, PKD1 und CK1δ als potenziell beteiligte Kinasen in der durch β1 Integrine vermittelten Strahlenantwort entdeckt. Die Bestrahlung mit Protonen zeigte eine höhere Wirk-samkeit bei der Verringerung des Pankreaskarzinomzellüberlebens als die Photonenbestrah-lung. Auf molekularer Ebene induzierte die Protonenbestrahlung mehr Veränderungen im Phosphoproteom als die Photonenbestrahlung. Die gezielte Hemmung von einzigartig verän-derten Molekülen sensibilisierte die 3D Pankreaskarzinomzellkulturen nicht Strahlungsart-spezifisch. Jedoch konnte eine ähnliche Effizienz der beiden Strahlungstypen nach Hemmung gewisser Signaltransduktions- und DNA-Reparaturproteine in 3D Pankreaskarzinomzellkultu-ren gezeigt werden. Die zelluläre Strahlenempfindlichkeit gegenüber beiden Strahlungsarten wurde hierbei besonders durch die Hemmung spezifischer Proteine des non-homologous end joining (NHEJ) in allen 3D Pankreaskarzinomzellkulturen erhöht. Schlussfolgerung: Diese Arbeit konnte eine wesentliche Rolle von β1 Integrinen bei der intrinsischen und erworbenen Strahlenresistenz im Pankreaskarzinom ermitteln. Um die Strah-lenresistenz jedoch gänzlich zu überwinden, sind weitere Untersuchungen erforderlich. Des Weiteren wurde eine ähnliche Wirksamkeit von Protonen- und Photonenbestrahlung in Kombi-nation mit gezielten Therapien gezeigt. Diese Ergebnisse legen nahe, dass Multi-Targeting-Ansätze, die auf der Hemmung von β1 Integrinen oder NHEJ-spezifischen Molekülen in Kom-bination mit Photonen- oder Protonenbestrahlung basieren, ausgesprochen vielversprechend sein können. Angesichts des enormen Potentials zur Steigerung der Strahlenempfindlichkeit durch die Hemmung dieser Moleküle könnte eine häufigere Anwendung der Strahlentherapie bei Pankreaskarzinompatienten ermöglicht werden.

To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.

Thermal control in spacecraft will be increasingly important as the spacecraft grows smaller and more compact. Such spacecraft with low thermal mass will have to be designed to retain or reject heat more efficiently. The passive smart radiation device (SRD) is a new type of thermal control material for spacecraft. Current space thermal control systems require heaters with an additional power penalty to maintain spacecraft temperatures during cold swings. Because its emissivity can be changed without electrical instruments or mechanical part, the use of SRD decreases the request of spacecraft power budget. The (SRD) based on VO2 films is one of the most important structures of the functional thermal control surface, being lighter, more advanced and without a moving devices. A large portion of the heat exchange between an object in space and the environment is performed throughout radiation, which is in turn determined by the object surface properties. The modulation device is coated on the spacecraft surface and thus provides a thermal window that can adapt to the changing conditions in orbit. VO2 is well known to have a temperature driven metal to insulator transition ≈ 68ᴼC accompanying a transformation of crystallographic structure, from monoclinic (M-phase, semiconductor) at temperature below 68ᴼC to tetragonal (R-phase, metal) at temperature above 68ᴼC. This transition temperature is accompanied by an increase of infrared reflectivity and a decrease of infrared emissivity with increasing temperature. This flexibility makes VO2 potentially interesting for optical, electrical, and electro-optical switches devices, and as window for energy efficiency buildings applications. This study reports on effect of thickness on VO2 as well as the effect of proton irradiation on VO2 for active smart radiation device (SRD) application. VO2 was deposited on mica by Pulsed laser deposition techniques. The thickness of the film was varied by varying the deposition time. To characterize VO2 the following techniques were performed: XRD, AFM, SEM, TEM, XPS, RBS, RAMAN and transport measurements for optical properties. The effect of proton irradiation was observed using the SEM, where the change in structure, from crystal grains to rods, was observed. / Physics / M.Sc. (Physics)