Preliminary finite element analysis of the stainless-steel liner of the maintainable test cell concept of IFMIF-DONES

The main purpose of IFMIF-DONES facility is to provide a neutron source for irradiating small specimens and producing experimental data of material properties for the construction of DEMO fusion power plant. The Test Cell (TC) of the DONES is a confined and well-shielded room, where the strong irradiation environment is created. The biological shielding of the TC mainly consists of several meters thick concrete walls and shielding plugs, and a stainless-steel liner. The TC liner and the concrete walls are actively cooled by water because of the high volumetric heating coming from nuclear reactions. Although, the TC is designed to be fully functional for the complete life span of the facility, still there is a very low probability of defect of the TC biological shielding due to their exposure of intense neutron and gamma irradiation. Therefore, the original TC configuration, which was a monolithic approach, had to be revised. Due to this reason, at the end of 2019 the project team has changed the TC concept from the monolithic design to the so-called Maintainable TC Concept (MTCC) design, which allows a maintenance possibility in case of unexpected damage

Target Identification for Stereotactic Thalamotomy Using Diffusion Tractography

BACKGROUND: Stereotactic targets for thalamotomy are usually derived from population-based coordinates. Individual anatomy is used only to scale the coordinates based on the location of some internal guide points. While on conventional MR imaging the thalamic nuclei are indistinguishable, recently it has become possible to identify individual thalamic nuclei using different connectivity profiles, as defined by MR diffusion tractography. METHODOLOGY AND PRINCIPAL FINDINGS: Here we investigated the inter-individual variation of the location of target nuclei for thalamotomy: the putative ventralis oralis posterior (Vop) and the ventral intermedius (Vim) nucleus as defined by probabilistic tractography. We showed that the mean inter-individual distance of the peak Vop location is 7.33 mm and 7.42 mm for Vim. The mean overlap between individual Vop nuclei was 40.2% and it was 31.8% for Vim nuclei. As a proof of concept, we also present a patient who underwent Vop thalamotomy for untreatable tremor caused by traumatic brain injury and another patient who underwent Vim thalamotomy for essential tremor. The probabilistic tractography indicated that the successful tremor control was achieved with lesions in the Vop and Vim respectively. CONCLUSIONS: Our data call attention to the need for a better appreciation of the individual anatomy when planning stereotactic functional neurosurgery

On Predicting Mössbauer Parameters of Iron-Containing Molecules with Density-Functional Theory

The performance of six frequently used density functional theory (DFT) methods (RPBE, OLYP, TPSS, B3LYP, B3LYP*, and TPSSh) in the prediction of Mössbauer isomer shifts(δ) and quadrupole splittings (ΔEQ) is studied for an extended and diverse set of Fe complexes. In addition to the influence of the applied density functional and the type of the basis set, the effect of the environment of the molecule, approximated with the conducting-like screening solvation model (COSMO) on the computed Mössbauer parameters, is also investigated. For the isomer shifts the COSMO-B3LYP method is found to provide accurate δ values for all 66 investigated complexes, with a mean absolute error (MAE) of 0.05 mm s–1 and a maximum deviation of 0.12 mm s–1. Obtaining accurate ΔEQ values presents a bigger challenge; however, with the selection of an appropriate DFT method, a reasonable agreement can be achieved between experiment and theory. Identifying the various chemical classes of compounds that need different treatment allowed us to construct a recipe for ΔEQ calculations; the application of this approach yields a MAE of 0.12 mm s–1 (7% error) and a maximum deviation of 0.55 mm s–1 (17% error). This accuracy should be sufficient for most chemical problems that concern Fe complexes. Furthermore, the reliability of the DFT approach is verified by extending the investigation to chemically relevant case studies which include geometric isomerism, phase transitions induced by variations of the electronic structure (e.g., spin crossover and inversion of the orbital ground state), and the description of electronically degenerate triplet and quintet states. Finally, the immense and often unexploited potential of utilizing the sign of the ΔEQ in characterizing distortions or in identifying the appropriate electronic state at the assignment of the spectral lines is also shown

Dextran-coated superparamagnetic iron oxide nanoparticles for magnetic resonance imaging: evaluation of size-dependent imaging properties, storage stability and safety

Harald Unterweger,1 László Dézsi,2,3 Jasmin Matuszak,1 Christina Janko,1 Marina Poettler,1 Jutta Jordan,4 Tobias Bäuerle,4 János Szebeni,2,3 Tobias Fey,5 Aldo R Boccaccini,6 Christoph Alexiou,1 Iwona Cicha1 1ENT Department, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, Universitätsklinikum Erlangen, Erlangen, Germany; 2Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; 3SeroScience Ltd., Budapest, Hungary; 4Institute of Radiology, Preclinical Imaging Platform Erlangen, Universitätsklinikum Erlangen, Erlangen, Germany; 5Institute of Glass and Ceramics, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, Germany; 6Institute of Biomaterials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, Germany Background: Rising criticism of currently available contrast agents for magnetic resonance imaging, either due to their side effects or limited possibilities in terms of functional imaging, evoked the need for safer and more versatile agents. We previously demonstrated the suitability of novel dextran-coated superparamagnetic iron oxide nanoparticles (SPIONDex) for biomedical applications in terms of safety and biocompatibility. Methods: In the present study, we investigated the size-dependent cross-linking process of these particles as well as the size dependency of their imaging properties. For the latter purpose, we adopted a simple and easy-to-perform experiment to estimate the relaxivity of the particles. Furthermore, we performed an extensive analysis of the particles’ storage stability under different temperature conditions, showing their superb stability and the lack of any signs of agglomeration or sedimentation during a 12 week period. Results: Independent of their size, SPIONDex displayed no irritation potential in a chick chorioallantoic membrane assay. Cell uptake studies of ultra-small (30 nm) SPIONDex confirmed their internalization by macrophages, but not by non-phagocytic cells. Additionally, complement activation-related pseudoallergy (CARPA) experiments in pigs treated with ultra-small SPIONDex indicated the absence of hypersensitivity reactions. Conclusion: These results emphasize the exceptional safety of SPIONDex, setting them apart from the existing SPION-based contrast agents and making them a very promising candidate for further clinical development. Keywords: CARPA, cross-linking, irritation potential, MRI, SPION, storage stabilit

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Harald Unterweger,1,* Christina Janko,1,* Marc Schwarz,2 László Dézsi,3 Rudolf Urbanics,4 Jasmin Matuszak,1 Erik Őrfi,3 Tamás Fülöp,3 Tobias Bäuerle,2 János Szebeni,3,4 Clément Journé,5 Aldo R Boccaccini,6 Christoph Alexiou,1 Stefan Lyer,1 Iwona Cicha1 1Cardiovascular Nanomedicine Unit, Section of Experimental Oncology und Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, ENT Department, University Hospital Erlangen, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 2Preclinical Imaging Platform Erlangen (PIPE), Institute of Radiology, University Hospital Erlangen, Erlangen, Germany; 3Nanomedicine Research and Education Center, Semmelweis University, 4SeroScience Ltd., Budapest, Hungary; 5Inserm U1148, Fédération de Recherche en Imagerie Multimodalités (FRIM), X Bichat Hospital, Paris Diderot University, Paris, France; 6Institute of Biomaterials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, Germany *These authors contributed equally to this work Abstract: Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent. Keywords: superparamagnetic iron oxide nanoparticles, MRI, hypersensitivity reaction, SPION uptake, hemocompatibilit

Comparative in vitro and in vivo Evaluation of Different Iron Oxide-Based Contrast Agents to Promote Clinical Translation in Compliance with Patient Safety

Harald Unterweger,1,* Christina Janko,1,* Tamara Folk,1 Iwona Cicha,1 Noémi Kovács,2 Gyula Gyebnár,3 Ildikó Horváth,4 Domokos Máthé,2,3 Kang H Zheng,5 Bram F Coolen,6 Erik Stroes,5 János Szebeni,7,8 Christoph Alexiou,1 László Dézsi,7,8,* Stefan Lyer1,* 1ENT-Department, Section of Experimental Oncology und Nanomedicine (SEON), Universitätsklinikum Erlangen, Erlangen, Germany; 2Hungarian Centre of Excellence for Molecular Medicine, Semmelweis University, Budapest, Hungary; 3Medical Imaging Centre, Semmelweis University, Budapest, Hungary; 4Department Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary; 5Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, the Netherlands; 6Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, the Netherlands; 7Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; 8SeroScience Ltd, Budapest, Hungary*These authors contributed equally to this workCorrespondence: Harald Unterweger, Universitätsklinikum Erlangen, Glueckstr. 10a, Erlangen, 91054, Germany, Tel +49 9131 85-33142, Fax +49 9131 85-34828, Email [email protected]: One of the major challenges in the clinical translation of nanoparticles is the development of formulations combining favorable efficacy and optimal safety. In the past, iron oxide nanoparticles have been introduced as an alternative for gadolinium-containing contrast agents; however, candidates available at the time were not free from adverse effects.Methods: Following the development of a potent iron oxide-based contrast agent SPIONDex, we now performed a systematic comparison of this formulation with the conventional contrast agent ferucarbotran and with ferumoxytol, taking into consideration their physicochemical characteristics, bio- and hemocompatibility in vitro and in vivo, as well as their liver imaging properties in rats.Results: The results demonstrated superior in vitro cyto-, hemo- and immunocompatibility of SPIONDex in comparison to the other two formulations. Intravenous administration of ferucarbotran or ferumoxytol induced strong complement activation-related pseudoallergy in pigs. In contrast, SPIONDex did not elicit any hypersensitivity reactions in the experimental animals. In a rat model, comparable liver imaging properties, but a faster clearance was demonstrated for SPIONDex.Conclusion: The results indicate that SPIONDex possess an exceptional safety compared to the other two formulations, making them a promising candidate for further clinical translation.Keywords: magnetic resonance imaging, MRI, nanomedicine, nanoparticles, complement activation, CARP