Proceedings book workshop 1

Deliverable D8.1 Proceedings book workshop 1 This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP). This document reflects only the view of the author(s). The Agency is not responsible for any use that may be made of the information it contains. Deliverable D8.1 ii Project Acronym PRISMAP Project Title The European medical isotope programme: Production of high purity isotopes by mass separation Grant Agreement No. 101008571 Topic INFRAIA-02-2020: Integrating Activities for Starting Communities Project start date 01 May 2021 Nature Report Dissemination level Public Due date M24 Date of delivery M24 Lead partner INFN Contributing partner SCK CEN Authors M. Manzolaro, S. Corradetti, G. Pupillo (INFN), L. Popescu (SCK CEN) Reviewerx K. Leufgen (SCIPROM), L. Vermeeren (SCK CEN) Point of Contact Mattia Manzolaro Institution INFN, Laboratori Nazionali di Legnaro E-mail mattia.manzolar[email protected]n.it Phone +39 049 8068331 © PRISMAP 2021. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Deliverable D8.1 iii Revision History Version Date Author Comment 0.1 14.03.2023 M. Manzolaro, L. Popescu First draft, assembly of contributions 0.2 28.03.2023 L. Vermeeren General review: fixed figure numbering and referencing, corrected typing/grammar errors 0.3 02.04.2023 Kirsten Leufgen Review 0.4 24.04.2023 G. Pupillo, S. Corradetti, M. Manzolaro General review, revisions and completions 0.6 25.4.2023 Véronique Gobry, Kirsten Leufgen Final polishing 1.0 28.04.2023 Kirsten Leufgen Final version, approved by the coordinator Deliverable D8.1 iv Contents Abbreviations, Participant short names ix ... ix Abbreviations ix … ix Participant short names x Organizing committees xi Local Organizing Committee xi Programme Committee xi Summary xii ... xii // Keep this line in place. It is need to fix a Word-bug in the TOC. xii Workshop Programme xiii Day 1 –Monday, 21 November 2022 xiii Day 2 –Tuesday, 22 November 2022 xiv 1. PRISMAP: The goals 1 1.1 Introduction 1 1.2 PRISMAP consortium and integration of upcoming facilities 1 1.3 A dedicated work package and workshop on emerging infrastructures 2 1.4 Conclusions 3 2. Introduction to WP8 and the aim of the workshop 4 2.1 PRISMAP work package 8 - objectives 4 2.2 The tasks included in Work Package 8 4 2.2.1 Task 8.1: Workshops and facility visits 4 2.2.2 Task 8.2: Guidance and support of the PRISMAP operating and emerging infrastructures 5 2.3 Aim of the workshop 5 3. Promising radionuclides 6 3.1 Narrowing down on the list of promises 7 3.2 Promising alpha and Auger emitters 8 3.3 Final remarks 8 4. Production and distribution of radioisotopes at RIKEN RI Beam Factory 9 4.1 Introduction 9 4.2 Production and applications of 211At 10 4.3 Future RI Production with RI Beams 10 4.4 References 11 5. Supply Platform of Short-lived Radioisotopes in Japan 13 5.1 Introduction 13 5.2 Support from the platform 13 5.3 Outcomes of supported projects 14 Deliverable D8.1 v 5.4 Challenges and Prospects 14 6. Targeted Alpha Tumour Therapy and Other Oncological Solutions (TATTOOS) as part of Paul Scherrer Institute’s IMPACT Large Facilities project 16 6.1 Overview 16 6.2 Project introduction and brief description 16 6.3 Outlook 18 6.4 Acknowledgements 18 6.5 References 18 7. SCK CEN infrastructures for radiopharmaceuticals development 19 7.1 The BR2 reactor 19 7.2 R&D Radiochemistry labs – operational facilities 19 7.3 Animal facility for pre-clinical evaluation of radiopharmaceuticals 19 7.4 Radioisotopes production facilities 20 7.4.1 Centralised Radiochemistry Facility (CRF) 20 7.4.2 The emerging ISOL@MYRRHA facility 20 7.4.3 PANTERA 21 7.5 Conclusions 21 8. POLATOM – operational and emerging facilities 23 8.1 Operational facilities at NCBJ 23 8.1.1 Maria Research Reactor 23 8.1.2. Radioisotope Centre POLATOM 24 8.2 Emerging facilities at NCBJ - CERAD 24 9. JHR – Status report and development foreseen 26 10. Radionuclide production at Institut Laue-Langevin’s high flux reactor 29 10.1 Abstract 29 10.2 Introduction 29 10.3 Irradiations in the V4 beam tube 29 10.4 Transmutation in a high neutron flux 30 10.5 Conclusion 31 10.6 References 31 11. MEDICIS - mass separated radionuclides production (from target preparation to collection and shipment) 32 11.1 Introduction 32 11.2 Radionuclide production at CERN-MEDICIS 32 11.3 Organisation of operation at CERN-MEDICIS: budget and resources 34 11.4 Conclusions 35 12. Direct targets for the production of medical radionuclides: an update 155Tb as a case study 36 12.1 Introduction 36 Deliverable D8.1 vi 12.2 Preparation of enriched Gd targets 36 12.3 Cross section measurement 37 12.3.1 Determination of production cross sections of terbium-155 37 12.3.2 Determination of production cross sections of terbium-161 38 12.4 Thick target yields 38 12.5 How to improve chemical purity of produced terbium radionuclides 39 12.6 Conclusions 39 12.7 References 40 12.8 Acknowledgements 40 13. SPES: general overview, status and future plans 41 13.1 Introduction 41 13.2 The SPES Facility 41 13.2.1 Cyclotron 41 13.2.2 The Target Ion Source complex 42 13.2.3 The Low energy beam lines 43 13.3 LARAMED & ISOLPHARM Projects 45 13.3.1 LARAMED 45 13.3.2 ISOLPHARM 46 13.4 Conclusions 46 13.5 References 46 14. The Unites States Department of Energy Development of Radioactive and Stable Radionuclides 47 14.1 Abstract 47 14.2 Introduction 47 15. Innovative ISOL targets for the production of medical radionuclides 50 15.1 Abstract 50 15.2 Introduction 50 15.3 SPES Target production 51 15.4 SPES Target characterisation 51 15.5 ISOLPHARM secondary target production and characterisation 51 15.6 References 53 16. Direct targets for the production of medical radionuclides: an update 54 16.1 THE ARRONAX FACILITY 54 16.2 New radionuclide developments 54 16.2.1 Copper-64 54 16.2.2 Astatine-211 55 16.2.3 Titanium-44/Scandium-44 56 16.2.4 Ruthenium-97 56 16.3 Conclusion 57 16.4 References 57 16.5 Acknowledgements 57 Deliverable D8.1 vii 17. R&D Activities for alphatherapy at GANIL 58 18. Characterisation of target materials 60 18.1 Abstract 60 18.2 Introduction 60 18.3 Powder X-ray diffraction 60 18.4 Scanning Electron Microscopy/Energy Dispersive Spectroscopy 61 18.5 Laser-Heating 62 18.6 Raman spectroscopy 62 18.7 BET 63 18.8 Laser Flash method 63 18.9 References 63 19. High throughput ion sources for the production of medical radionuclides 64 19.1 Abstract 64 19.2 The ISOL method 64 19.3 The RILIS principle 64 19.4 MEDICIS 65 19.5 The ion source up-close 65 19.6 The ideal laser ion source for MEDICIS 67 19.7 Conclusions 67 19.8 References 67 20. Ion source developments at SCK CEN 68 20.1 References 71 21. DFT calculations of Ti-based molecules clustering with Ar for laser-based enrichment of stable isotopes 72 21.1 Introduction 72 21.2 SILARC 72 21.3 DFT calculations 73 21.3.1 Simple molecules 73 21.3.2 Complex molecules 74 21.3.3 Ar clustering 75 21.4 Conclusions 75 21.5 References 75 21.6 Acknowledgements 76 22. Characterisation of ion sources in terms of C-11 (isol production) capability 77 22.1 Abstract 77 22.2 Introduction 77 22.3 Ion source Requirements & Testing 78 22.4 References 79 Deliverable D8.1 viii 23. Poster. Target material research and hot materials characterisation infrastructure overview at SCK CEN 81 23.1 References 83 24. Poster. Impact of the laser ionisation and temperature on the Actinium production from UCx target 84 24.1 Production of 225Ac at the ISOLDE facility 84 24.1.1 Impact of laser ionisation 84 24.1.2 Impact of transfer line and ion source temperature 85 24.2 Conclusions 86 24.3 References 86 25. Poster. Additive Manufacturing of Refractory Metals: from material to product characterisation 87 25.1 Additive Manufacturing of Refractory Metals at DIAM lab 87 25.2 From Material Characterisation to Product Design and Manufacturing 88 25.2.1 Molybdenum and tungsten 88 25.2.2 Tantalum and niobium 89 25.2.3 Components production and validation 90 25.3 Conclusions and further development 90 25.4 References 91 26. Conclusion of the PRISMAP workshop 1 92 ... 92 // Keep this line in place. It is need to fix a Word-bug in the TOC. 92 Deliverable D8.1 ix Abbreviations, Participant short names ... Abbreviations … AM ATS Additive Manufacturing Active Thermal-Screen CA Consortium Agreement CRF Centralised Radiochemistry Facility DoA DFT DTA ECR EDS EDX FEBIAD FTE Description of Action Density Functional Theory Dufferential Thermal Analysis Electron Cyclotron Resonance Electron Dispersive Spectroscopy Energy Dispersive X-ray Forced Electron Beam Induced Ark Discharge Full Time Equivalent GA Grant Agreement GMP Good Manufacturing Practice GPS Global Purpose Separator HAF Hot Animal Facility HRS High-Resolution Separator IRE Institute National des Radioélément ISOL Isotope Separation On Line JRA LPBF Joint Research Activity Laser Powder Bed Fusion NIDC National Isotope Development Centre PET Positron Emission Tomography RILIS Resonance Ionisation Laser Ion Source RIB Radioactive Ion Beam RIBF RIKEN RI Beam Factory RIs Radioisotopes SEM SPECT Scanning Electron Microscopy Single-Photon Emission Computed Tomography PSB Proton Synchrotron Booster TAT targeted α-particle therapy TEM Transmission Electron Microscopy Deliverable D8.1 2 Figure 2. The SPES building, an isotope mass separation facility under construction The objectives of PRISMAP have been defined along five principal lines:  Provide access to new radionuclides and new purity grades for medical research  Create a common entry port and web interface for the starting research community  Enhance clarity and regulatory procedures to promote research with radiopharmaceuticals  Unlock the biomedical research through better data on radionuclides  Ensure the long-term sustainability of PRISMAP In this respect, the involvement of the future facilities in PRISMAP will accelerate their integration, providing them with the standardised procedures and new developments performed in PRISMAP. 1.3 A dedicated work package and workshop on emerging infrastructures PRISMAP has been organised into an infrastructure access project where work packages are defined along access provision, including the elaboration of the website prismap.eu and the organisation and the selection of the projects submitted by the users, networking activities to collect the clinical and industrial needs or involvement of futures facilities, and joint research activities, collaborative activities that aim at improving the services provided by PRISMAP, with for instance the development of the techniques related to the production by mass separation of the medical radionuclides or the generation of new nuclear data. The structure of the Work Packages and Tasks are described on https://www.prismap.eu/about/project/ The workshop that took place at INFN-Legnaro was therefore organised in the so-called Involvement of emerging infrastructures, and included invited presentations from the PRISMAP consortium, notably the infrastructures in operation, some future facilities at different stages of design and construction, and facilities and network from outside Europe such as USA, Canada or Japan. An effort was provided to understand what are the present and future radionuclides necessary to develop this field (Figure 3). This workshop and associated proceedings are part of a suite of deliverables that will edit a report on guidelines to follow for projects in construction, and with ultimately a white paper that will collect the needs of the PRISMAP users’ community. Deliverable D8.1 3 Figure 3. Growing user community soliciting PRISMAP services after the 2nd call for projects 1.4 Conclusions The early involvement of the next-generation facilities in PRISMAP will allow to maximize the flow of information between present-day facilities and future projects. The field of radiopharmaceuticals and their use both in diagnostics and treatments has been the subject of a recent market analysis, and is evaluated to follow a double-digit growth in billion Euros over the coming decade. This comes along with the expression of needs to continue integrating and structuring the research and radionuclides production European landscape in the coming years. It follows for instance the European Radionuclide Valley Initiative driven by the European Commission, where PRISMAP has been invited as one of the stakeholders identified, thus confirming the potential and interest to provide Europe with an integration of the major institutes able to provide non-conventional radionuclides for the biomedical research. Deliverable D8.1 4 2. Introduction to WP8 and the aim of the workshop Lucia Popescu (SCK CEN) 2.1 PRISMAP work package 8 - objectives The work package 8 within PRISMAP is focussed on increasing the involvement of the emerging infrastructures in the field of mass-separated radionuclides production and radiopharmaceutical development. Through a coherent effort, one aims to support implementation of mass-separated radionuclides production at multiple facilities in order to promote a good geographical coverage and sustainability of the PRISMAP research infrastructures. Through the activities developed in this work package, the community is updated with the progress registered at the different facilities, which are under development or under operation. The spectrum is very large, PRISMAP emerging infrastructures being in different stages, spanning from project consolidation (e.g., TATTOOS1 at PSI), or facility construction (e.g., ISOL@MYRRHA2 at SCK CEN), or under commissioning (e.g., SPES3 at INFN-LNL). Synergetic developments and sharing of lessons learned by these different partners represents a clear added value of the work package. Another important objective is to align the efforts for radionuclide production/development to user requests. This objective will be met not only through the activities included in this work package but also through the interlinks with the other work packages of PRISMAP (e.g. WP2: Production and dispatch of nonconventional radioisotopes, WP4: Harmonisation and Standardisation, WP9: Transport and shipping, WP10: Targets, ion sources and isotope separation techniques, WP12: Radiolanthanides). Last but not least, emerging infrastructures need the support of the user community which motivates their development. This is another important objective of WP8, which is addressed in a dedicated task (T8.2). 2.2 The tasks included in Work Package 8 2.2.1 Task 8.1: Workshops and facility visits Two workshops are being organised within this task. The objective is to favour information sharing and networking opportunities, enhancing interaction between PRISMAP partners. The programme of the workshops includes presentations from both operational and emerging infrastructures as well as technical presentations according to the selected topics of the workshop. In the current workshop, taking place at INFN-LNL, one focuses mostly on technical aspects related to the development of targets, ion sources and mass-separation techniques for the production of radionuclides with high specific activity. This is the topic of WP10-JRA2, led by INFN. The presence on INFN-LNL site, further gives the opportunity to visit the SPES facility, which is the first high-power Isotope mass Separation OnLine (ISOL) facility emerging in Europe, within PRISMAP. The period of the workshop is also ideal for the visit, because it marks the preparations for the start-up of SPES commissioning. A second workshop will be organised at SCK CEN, in 2024. Besides the presentations on the status of various related infrastructure-projects running at the facilities included in WP8-NA5, the technical topics addressed in the workshop will cover the entire chain of activities involved in the radiopharmaceutical development process: radionuclide production, chemical purification, radiolabelling, preclinical and clinical studies. The SCK CEN site is being selected for this workshop due to the presence of infrastructures covering all mentioned technical topics to be addressed in the workshop. Visits will be organised at those infrastructures: the BR2 1 Targeted Alpha Tumour Therapy and Other Oncological Solutions 2 Isotopes Separation On-Line at MYRRHA accelerator-driven system 3 Selective Production of Exotic Species Deliverable D8.1 5 reactor, ISOL@MYRRHA construction site and off-line laboratories, radiochemistry facilities, radiobiology and the Hot Animal Facility (HAF). Short contributions from the speakers will be collected in a Book of Proceedings for each of the two workshops, which also serves as input to the realisation of D8.3: a white paper summarizing the letters of interest from the user community. This task is connected to all Joint Research Activities (JRAs) of PRISMAP, presentations on technical developments performed within the JRAs are being included in the programme as well. The workshops therefore give an excellent opportunity to review the status of research and interaction between the various partners involved. 2.2.2 Task 8.2: Guidance and support of the PRISMAP operating and emerging infrastructures The goal of this task is to secure communication across the community for identifying radionuclides of interest for production at emerging facilities. One further needs to define strategic lines of development for future radionuclides production. The aim is to encourage and stimulate a strong participation of the user community into the networking activities of WP8-NA5 and involve the users in defining the strategic lines of development for future radionuclides production. Throughout the project, the goal is to formalise the input from the users into a white paper presenting letters of interest for guidance and in support of the PRISMAP operating and emerging infrastructures. Activities developed within T8.1 represent an important input to this activity. Therefore, besides sharing the information through the presentations included in the programme, active participation in the discussion sessions provides valuable input to this second task of WP8. 2.3 Aim of the workshop The aim of the current workshop was discussed in section 2.2.1 and the agenda was defined accordingly. In the first day, talks dedicated to infrastructures and radionuclides programmes have been included as well as a generic talk on the most promising radioisotopes on which the efforts of the community should focus. This topic represents a trigger as well as a back-bone for the round-up discussion foreseen in the last session of the first day of the workshop. Moreover, in order to place PRISMAP activities and infrastructures in a global perspective, invited speakers introduce similar initiatives in  Asia: see presentation by Hiromitsu Haba on Production and distribution of radionuclides at RIKEN RI Beam Factory and presentation by Takashi Nakano on Supply platform of short-lived radionuclides in Japan,  USA: see presentation by Cathy Cutler (BNL) on DOE programme for radionuclides production,  Canada: see presentation by Alexander Gottberg (TRIUMF) on TRIUMF’s programme for radionuclides production. In the second day of the workshop, which is also open to external participants, 9 technical talks are included in the programme, covering the major activities performed within WP10: on targets, ion sources and isotopes purification. The visit to SPES facility is also included in the programme of this second day. The ideas presented and discussed at this workshop are being collected in the Book of Proceedings, which represents as well the first deliverable of WP8, and which is published on the PRISMAP portal for the availability and benefit of the large public. Deliverable D8.1 6 3. Promising radionuclides Mikael Jensen (Hevesy Lab-DTU-Denmark) The ambition and goal for the PRISMAP programme is to provide a sustainable source of high purity grade new radionuclides for medicine. To fulfil the goals in a longer term and moving from translational research use into clinical trials, and eventually, clinical use, future input of radionuclides from the emerging facilities in Europe will be highly needed. This said, there might be good reasons to consider the full scope of such promises and plans. This talk primarily focuses on the meaning of the concepts of “new” and “novel” and “promising” radionuclides for medical use. By definition, these concepts reflect something that has not yet happened, but where we perhaps can project what will be important needs in the future. First of all, let us dryly conclude, that there are no truly “new” radionuclides within the reach of PRISMAP production. All nuclides of any use in medicine are already known and characterised by nuclear physics. Existing and new spallation/reverse kinematics/ISOL4 facilities (like ISOLDE, FRIB, ISOL at MYRRHA) can make and study truly new far-from-stability nuclides, but because of their now very-very short half-lives and long beta decay chains, they are uninteresting to nuclear medicine. However, at the same time, we can see that these facilities can produce signinficant amounts of radionuclides closer to the line of stability and that could be of interest to medicine, but that has not until now been available for either translational or radiopharmaceutical/medical research in quantities and in quality high enough to support proof-of-merit and clinical trial tests. At present, we well know the decay characteristics of such new nuclides, and we can from this dream or project their possible superiority to the existing, rather arcane arsenal of clinical nuclear medicine. It is these nuclides well within reach, where we know the elemental chemistry, the half-lives, decay chains and the emissions where we use the term “promising” radionuclides. In this term, I will also include less “exotic” nuclides that to some degrees have been used in translational or medical research, and that have been produced by our standard arsenal of reactors and low-to-medium energy accelerators, but where either purity or yield has been too low in practice to allow the transgression into medicine. In close connection with the development and maturation of the ISOL technique, it now becomes possible to build and use mass separators that can purify and refine radioactivity produced by more traditional ways and elsewhere. MEDICIS at CERN [Lambert et al 2022] has already demonstrated such capability. Broader scale access to such infrastructure can give us higher purity and high molar activity from both reactor and accelerator targets. To fulfil this promise, more off-line separators for highly radioactive materials will have to be built, and this can indeed be part of the PRISMAP sustainability roadmap. However, such facilities are expensive to build and very demanding in terms safety, licensing and maintenance. There is of course a “critical minimum mass”, below which such facilities will not be sustainable. In less scientific words, there must be users or “customers” willing to pay the investment and operational costs, before these facilities will be available on a future clinical scale. PRISMAP may provide the starting point for this, but the four-year funding scheme is not enough on its own. Without industrial stakeholders, a sufficient number of such off-line separators may never be established. With industrial stakeholders, the list of promising radionuclides could well be narrowed down to a small number of products for which there already is a perceived clinical market and probably also some kind of existing set of proprietary rights. Similarly, it should be remembered, that the costs of clinical trials necessary to get radioactive products into clinical routine are prohibitively large for single entity academia, let alone the PRISMAP consortium a such. PRISMAP promises should co-exist with these economic constraints. To be realistic about promises, it is worthwhile to remind that concepts of spallation production and off/online separators in production of medical radionuclides has been around for more than 30 years (Ravn and Beyer 1986), but with very limited commercial or routine impact. 4 ISOL = ” Isotope Separation On Line” Deliverable D8.1 7 3.1 Narrowing down on the list of promises The present boost in Nuclear Medicine is closely coupled to oncology and the fight against cancer. There may well be future developments in nuclear imaging and therapy in other clinical areas, but as for now, the focus is on cancer diagnosis, staging and therapy. This “tunnel-vision” of impact may reflect the same underlying mechanisms that has left modern nuclear medicine with the present rather narrow range of clinically used radionuclides. To be rough, the imaging field is still dominated only by arcane 99mTc (pushed to the medical field by National Laboratories and the research reactor community) and now 18F, narrowly distilled from the broad range of light element positron emitters. Similarly, radionuclide therapy is quantitatively concentrated on old fashion 131I and, more recently, 177Lu. It will take a long time and large effort to widen the clinical application to the realm of the PRISMAP promises. However, two developments in nuclear oncology may have implications for nuclides to be developed: a) The broader concept of individual dose planning for radionuclide therapy and the narrower implementation as theranostic pair usage b) The drive for more local action, normal tissue sparing radionuclide therapy, as reflected in the growth of alpha and Auger-electron emitter therapies. Both developments hold promises, but will require new and more radionuclide supply to translate and transgress into the clinic. Nuclear Medicine has its yearly fashions and favorite subjects (68Ga/177Lu peptides, 223 and later 225Ac therapy) but the quest for optimal radionuclide therapy is much broader and can be described as searching for optima in a 3dimensional landscape (Figure 4). When realising that each cancer, and probably each stage of such cancer will have its own optimum, it can be seen there is very much to be done for PRISMAP to fulfil even the initial research requirements. A very special obligation of PRISMAP is to support the possible clinical translation of the theranostics principles. If any research community can lift the obligation to supply relevant quantities of theranostic pairs, it must be PRISMAP. As first, but far from only examples of theranostics pairs already in the PRISMAP scope are 64Cu-67Cu and 43,44Sc47Sc as well as the terbium suite of radionuclides [Müller et al. 2012]. Figure 4. Phase space for optimal properties of therapeutic radionuclides Deliverable D8.1 8 The scope of the tools for individual radionuclide dose planning quest, the scope may be wider than just the above mentioned same-element pairs. Some or most of the radiolanthanides may form a multielement theranostics group. Likewise, it is possible that some of our best imaging/therapy biovectors have biodistributions that are insensitive to in example transition radiometal replacements deep in the core of the radiopharmaceuticals. In addition, there are needs for more research before the range of promising radionuclides can be narrowed down. As described in here, it is obvious that many “promises” still need exploration, and this will still take a “basic research” kind of approach to some of the uses of PRISMAP productions. 3.2 Promising alpha and Auger emitters Using the same line of arguments, the list of promising internal alpha emitters proposed for clinical use contains at several “day-1” PRISMAP radionuclides. Among these are 211At, 223Ra and 225Ac which are all already under commercial development by competing pathways and industrial partnerships or, like for 223Ra, has an already established commercial supply (223Ra, marketed as Xofigo). The development and supply of these established alpha emitters, that are all “hot topics” of nuclear medicine, is potentially only transitory until a mature commercial supply is established. Other of the alpha emitters are very far from the commercial domain (152Tb as example) and here PRISMAP may be the only resource for exploring if these less available radionuclides could have important medical benefits over the present commercial mainstay. Of course, PRISMAP is not a commercial source or a demonstration platform for single industry, but PRISMAP should be able to support the difficult supply chain for translational research. Among the alpha emitters, 152Tb holds a very special position as it is the only true-elemental-theranostic pair radionuclide among the alpha emitters. PRISMAP holds a special potential to support larger scale comparisons of betaversus alpha versus Auger cascade action on cancer. Auger emitter therapy has since long been proposed as a uniquely localised treatment, potentially sparing all healthy tissue. At the same time, some radiobiological aspects of the Auger cascade action on the cellular components of cancer cells point to a very potent local action, similar to the alpha emitters. However, despite many years of research, no universal proof-of-principle of the superiority of Auger therapy has yet been given, but if such proof does appear soon, it may well widen even further the list of promising radionuclides that PRISMAP partners must take on their shoulders during translation. 3.3 Final remarks The list of promises is far from complete, but of course, some restriction is needed to keep the consortium on track within the present time and finance restrictions of the existing grant. For demonstrating the need for an extension of the funding scheme beyond the four years, it is worth to mention that the broader group of platinum metal radionuclides contain some very interesting and potentially potent therapy nuclides, that can combine chemical action, biological chemistry and very localised radiotherapeutic effects. Many of the radionuclides can per se be produced already, but the radiochemistry still needs developments. Without access to supply of these exotic nuclides, this radiochemistry development may not happen. Deliverable D8.1 9 4. Production and distribution of radioisotopes at RIKEN RI Beam Factory Hiromitsu Haba (RIKEN) 4.1 Introduction At RIKEN RI Beam Factory (RIBF), Wako, Japan (see Figure 5), we have been developing production technologies of radioisotopes (RIs) for application studies using the AVF cyclotron (AVF), RIKEN Ring Cyclotron (RRC), and RIKEN Linear ACcelerator (RILAC) [1,2]. We are conducting RI application studies together with researchers in the world in various research fields, such as physics, chemistry, biology, engineering, medicine, pharmaceutical and environmental sciences [3]. Figure 5. A bird’s eye view of RIKEN RI Beam Factory With lightto heavy-ion beams from AVF, we produce more than 100 kinds of RIs from 7Be (atomic number Z = 4) to 262Db (Z = 105). Among them, 65Zn, 67Cu, 85Sr, 88Y, and 109Cd have been delivered to about 60 universities, research institutes, and companies through Japan Radioisotope Association. Short-lived RIs are also distributed to researchers in collaboration with the accelerator facilities at Osaka University, Tohoku University, and National Institutes for Quantum Science and Technology through the platform for short-lived RI distribution, supported by Grant-in-Aid for Scientific Research on Innovative Areas, The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. In this platform, RIBF has supplied 7Be, 28Mg, 44mSc, 67Cu, 88Zr, 95Nb, 111Ag, 121mTe, 124Sb, 141Ce, 175Hf, 179Ta, and 211At to the researchers since 2016. RIs of a large number of elements (multitracer) are simultaneously produced from metallic targets such as natTi, natAg, natHf, and 197Au irradiated with a 135-MeV/nucleon 14N beam from RRC [4]. The multitracer is useful to trace the behavior of many elements simultaneously under an identical experimental condition [1]. Recently, 225Ac was produced at RRC in the 232Th(14N,xnyp)225Ac reaction for targeted α-particle therapy (TAT) [5,6]. At RILAC, a gas-jet transport system was installed to the RIKEN gas-filled recoil ion separator (GARIS) as a novel technique for superheavy element (SHE) chemistry [7]. 261Rfa,b (Z = 104), 262Db, 265Sga,b (Z = 106), and 266Bh (Z = 107) were produced in the heavy-ion induced reactions on a 248Cm target and their decay properties were investigated in detail using a rotating wheel apparatus for α and SF (spontaneous fission) spectrometry [8-11]. The pre-separated RIs were used for chemistry studies of SHEs [12-14]. Deliverable D8.1 10 4.2 Production and applications of 211At RIs we have developed so far for medical and pharmaceutical research at RIBF are 24Na, 42,43K, 44m,gSc, 44Ti, 48V, 56,57,58Co, 52g,54Mn, 65Zn, 67Cu, 75Se, 88Y, 89Zr, 111Ag, 109Cd, 124I, 135mBa, 186Re, 188,189,191Pt, 203Pb, 206Bi, 211At, and 225Ac. Recently, the demand for 211At is rapidly increasing in Japan. Astatine-211 with the half-life of T1/2 = 7.214 h is one of the promising radionuclides for TAT [15]. The 5.87and 7.45-MeV α-particle emissions occur in intensities of 41.8% and 58.2%, respectively, associated with the 211At decay. Due to the proper ranges of these α-particles in tissue, the 211At-labeled medicine is effective in killing cancer cells. 211At is produced in the 209Bi(α,2n)211At reaction. Thus, we developed an 211At production system on the beam line of AVF (Figure 6 a and b) [16-19]. The metallic 209Bi target (20 mg/cm2) is irradiated by the 28-MeV α beam from AVF. The typical beam intensity is 20 particle μA (pμA). Under our current experimental condition, 1 GBq of 211At can be produced in 1-h irradiation. The irradiated 209Bi target is placed in a quartz tube and heated up to 850°C (Figure 6 c). 211At sublimated from the target is transported from the quartz tube to a cold PFA tube (–96°C) by O2 gas flow (10 mL/min). After the distillation, the PFA tube is washed with CHCl3 (300–400 μL) which is then dried up by N2 gas (100 mL/min). The typical chemical yield is 80%. Figure 6. (a) Layout of the 211At production chamber on the beam line of the AVF cyclotron, (b) Photo of the 211At production chamber, and (c) Photo of the dry distillation apparatus for 211At We are distributing 211At to about 20 universities, research institutes, and companies, where radiolabelling and animal experiments are ongoing to develop novel radiopharmaceuticals for cancer therapy [20-29]. RIKEN 211At has been supplied to Osaka University Hospital since 2016, and in 2022, the Japan's first clinical trial of TAT for refractory differentiated thyroid cancer has been initiated. In 2020, RILAC was upgraded as the superconducting RILAC (SRILAC) with a 28 GHz superconducting ECR ion source and a super-conducting quarter-wavelength resonator [30]. A large-scale production technology of 211At with a >100-puA α beam is under development in collaboration with Metal Technology Co. Ltd., Japan. 4.3 Future RI Production with RI Beams RIKEN Superconducting Ring Cyclotron (SRC) can accelerate light ions up to 440 MeV/nucleon and heavy ions up to 238U to 350 MeV/nucleon [31]. These energetic heavy-ion beams are converted into RI beams via projectile fragmentation or in-flight fission of 238U by the superconducting isotope separator, BigRIPS. RIBF can derive 3,000 kinds of RI beams with one of the world’s largest beam intensities. The beam intensities for RIs near the line of stability, which have relatively long half-lives (>1 min) and are practically available for applications, are over 1010 ions/s. One can catch the RI beams directly with suitable materials such as water, acids, physiological saline, and radiopharmaceuticals.1 One can select a radionuclide of interest with suitable decay properties for its application. Since they are mass-separated from other fragment isotopes, chemical Deliverable D8.1 11 separations may be simple or not be required. These RIs should be infinitely pure and carrier-free compared with those produced by conventional methods. As examples, RIBF generates the RI beams of 28Mg and 67Cu with intensities of 8.90×108 and 4.6×1010 ions/s, respectively. These result in 3.4 GBq for 28Mg and 0.5 GBq for 67Cu after 1-day irradiation. Thus, the RI beams derived from RIBF are expected to open new frontiers in RI applications as next-generation RI producers. 4.4 References [1] H. Haba et al., in Handbook of Nuclear Chemistry (2nd ed.), edited by A. Vértes, S. Nagy, Z. Klencsár, R. G. Lovas, and F. Roesch, Vol. 3, Springer, (2010) 1761–1792. [2] H. Haba, J. Part. Accel. Soc. Jpn. 12, 206 (2015) (in Japanese). [3] RIKEN Accel. Prog. Rep., each volume, Sect. Radiochemistry and Nuclear Chemistry, and the references cited in it (http://www.nishina.riken.jp/researcher/APR/index_e.html). [4] H. Haba et al., Radiochim. Acta 93, 539 (2005). [5] X. Yin et al., RIKEN Accel. Prog. Rep. 54, 162 (2021). [6] X. Yin et al., RIKEN Accel. Prog. Rep. 55, 147 (2022). [7] H. Haba et al., Chem. Lett. 38, 426 (2009). [8] H. Haba et al., Phys. Rev. C 83, 034602 (2011). [9] H. Haba et al., Phys. Rev. C 85, 024611 (2012). [10] H. Haba et al., Phys. Rev. C 89, 024618 (2014). [11] H. Haba et al., Phys. Rev. C 102, 024625 (2020). [12] J. Even et al., Science 345, 1491 (2014). [13] I. Usoltsev et al., Radiochim. Acta 104, 141 (2016). [14] Y. Wang et al., Phys. Chem. Chem. Phys. 21, 7147 (2019). [15] Y. Feng and M. R. Zalutsky, Nucl. Med. Biol. 100–101 12 (2021). [16] S. Yano et al., RIKEN Accel. Prog. Rep. 50, 261 (2017). [17] N. Sato et al., RIKEN Accel. Prog. Rep. 50, 262 (2017). [18] Y. Wang et al., RIKEN Accel. Prog. Rep. 53, 192 (2020). [19] H. Haba, Drug Deliv. Syst. 35, 114 (2020) (in Japanese). [20] K. Fujiki et al., Chem. Sci. 10, 1936 (2019). [21] Y. Ohshima et al., Nucl. Med. Biol. 90–91, 15 (2020). [22] H. Takashima et al., Cancer Sci. 112, 1975 (2021). [23] S. Manabe et al., ACS Omega 6, 14887 (2021). [24]. K. Kaneda-Nakashima et al., Int. J. Mol. Sci. 23, 15509 (2022). [25] K. Ohnuki et al., EJNMMI Phy. 9, 39 (2022). [26] T. Watabe et al., Int. J. Mol. Sci. 23, 9434 (2022). [27] A. Aso et al., Chem. Lett. 2022, 1091 (2022). [28] T. Watabe et al., Eur. J. Nucl. Med. Mol. Imaging. 50, 849 (2023). [29] H. Takashima et al., Mol. Pharmaceutics 20, 1156 (2023). Deliverable D8.1 18 6.3 Outlook A novel irradiation station with high-energy protons at PSI, in the view of enlarging the radionuclide production portfolio in Switzerland as well as Europe, was proposed to the Swiss ETH Council. The spallation process induced by high-energy protons, utilising various target material, will provide access to a plethora of exotic radionuclides not otherwise accessible with great scientific potential for nuclear physics, astrophysics and fundamental radiochemistry. The Swiss National Science Foundation reviewed the proposal for the science case, after which it was reviewed with regard to feasibility. IMPACT was recently recommended by the ETH council to be included for funding in the SERI’s Roadmap of Swiss Research Infrastructures 20252028 [10]. 6.4 Acknowledgements The authors are grateful to the vast team that contributed to the IMPACT Conceptual Design Report. 6.5 References [1] ISOLDE-CERN, https://isolde.cern/isolde-facility [2] Müller et al., EJNMMI Radiopharmacy and Chemistry, 2016, 1: 5. [3] Umbricht et al., Scientific Reports, 2019, 9: 17800. [4] Baum et al., Dalton Trans., 2017, 46: 14638. [5] Müller et al., EJNMMI Res., 2019, 9: 68. [6] IMPACT, https://www.psi.ch/en/impact [7] TATTOOS, https://www.psi.ch/en/impact/tattoos [8] Müller et al., J. Nucl. Med., 2017, 58: 91S. [9] van der Meulen & Talip, Nuclear Medicine and Molecular Imaging, 2022, 1: 133. [10] SERI https://www.sbfi.admin.ch/sbfi/en/home/services/publications/data-base-publications/s-n-20213/s-n-2021-3d.html Deliverable D8.1 19 7. SCK CEN infrastructures for radiopharmaceuticals development Lucia Popescu, Maarten Ooms and Dennis Elema (SCK CEN) The Belgian Nuclear Research Centre SCK CEN was founded in the 1950s to study the applications of nuclear energy, but since then it has expanded its knowledge to a wide range of research fields, with a strongly future-oriented and international focus. With its unique infrastructure – the BR2 reactor and soon ISOL@MYRRHA – SCK CEN has an unprecedented capacity to produce isotopes. Moreover, since 2016, SCK CEN integrated existing medical-related activities within radiochemistry, radiopharmacy, radiobiology and dosimetry into the NURA programme5 - a structure dedicated to radiopharmaceutical research and GMP production of therapeutic radioisotopes. 7.1 The BR2 reactor SCK CEN operates the BR2 high-flux reactor (Figure 11) which is the main European producer of medical radionuclides and key member of the worldwide production network of 99Mo and other radionuclides. Irradiation facilities with neutron flux up to 4×1014 n/cm2/s can be loaded and unloaded during reactor operation, i.e. enabling free choice of irradiation duration, and up to 1×1015 n/cm2/s neutron-flux is available in the pressure vessel for irradiations of 3 to 4 weeks duration. BR2 performs irradiations for commercial radionuclide suppliers and produces novel radionuclides for inhouse researchers from SCK CEN as well as for Belgian and international researchers via bilateral collaborations. Two radioisotopes take up the largest part of the production: 99Mo and 177Lu, but also other isotopes are being produced, like: 161Tb, 188Re, 153Sm and many more. Figure 11. A picture of the BR2 high-flux reactor (left) and the R&D Radiochemistry labs (right) 7.2 R&D Radiochemistry labs – operational facilities SCK CEN has dedicated radiopharmacy labs for the development of new radiopharmaceuticals (Figure 11). These facilities cover domains as radiolabelling, organic synthesis, or chelator design. To these, one has to add the R&D radioisotope laboratory for the development/upscaling of radiochemical processes towards GMP radioisotope production. In 2023 the current laboratories will be upgraded with new hot cells. 7.3 Animal facility for pre-clinical evaluation of radiopharmaceuticals Moreover, SCK CEN is building infrastructure for pre-clinical evaluation of radiopharmaceuticals. The animal facility (currently only used for research concerning effects of external radiation) is being extended to be able to use open sources of radioactive material in animal experiments. The facility will contain an imaging platform with autoradiography and a microSPECT/CT scanner allowing in vivo and ex vivo animal studies. The 5 https://www.sckcen.be/en/our-scientific-projects/nura Deliverable D8.1 20 Hot Animal Facility (HAF) will be equipped also for in vitro studies on cells and it will become operational in 2023. Figure 12. Scheme of the The Hot Animal Facility (HAF) and the Centralised Radiochemistry Facility (CRF) 7.4 Radioisotopes production facilities 7.4.1 Centralised Radiochemistry Facility (CRF) At the same time, SCK CEN in collaboration with the Institute National des Radioéléments (IRE) is setting-up the production of 177Lu and building a GMP-compliant production facility CRF on the site of SCK CEN6. Thanks to the CRF, the supply of medical isotopes, both for research into new radiopharmaceuticals in clinical trials and for therapy in hospitals, can be ensured. The supply of 177Lu is expected from 2025 on. The facility is also equipped to process promising next-generation radionuclides such as 161Tb, also used to treat prostate cancer and neuroendocrine cancers. Besides the supply of radionuclides, the CRF will act as a pilot facility in which new production processes developed at lab scale can be scaled up to reliable commercial processes according to 'good manufacturing practice' (GMP). A step towards pharmaceuticals, in other words. 7.4.2 The emerging ISOL@MYRRHA facility The SCK CEN’s radionuclides-production facilities will be further extended through the implementation of MYRRHA: a Multipurpose hYbrid Research Reactor for High-tech Applications. The primary design of MYRRHA7 envisages to combine a linear accelerator, providing high-intensity proton beams with a subcritical reactor core, of which operation is strictly dependent on the proton beam. Furthermore, a fraction of the protons feeds a Radioactive Ion Beam (RIB) facility, ISOL@MYRRHA, where the Isotope Separation OnLine (ISOL) technique is implemented for the production of high-purity and high-intensity RIBs. ISOL@MYRRHA is constructed in MYRRHA phase 1 Implementation, and will be using proton beams of 100 MeV. Next to a target station dedicated to fusion-materials irradiation (the Full-Power Facility operated with p-beams up to 4 mA), the ISOL target station is limited in terms of proton-beam intensity to 500 µA. The initial licensing envelope imposes a second limitation level for operation: 500 µA on non-actinide targets and 200 µA on actinide targets. In an effort to realize a state-of-the-art facility, ISOL@MYRRHA is developed on the basis of the technology from ARIEL8 at TRIUMF. The design of ARIEL combines return of experience from two major ISOL facilities: ISAC, under operation at TRIUMF, and ISOLDE, under operation at CERN. Moreover, the technical challenges associated to high power-density deposition given the rather low-energy and high-intensity primary beam at 6 https://www.sckcen.be/en/news/new-pilot-production-targeted-cancer-treatments 7 https://www.myrrha.be/ 8 https://www.triumf.ca/ariel Deliverable D8.1 21 ISOL@MYRRHA, are similar to the challenges that ARIEL faces in the development of its electron-beam target station. Ground-breaking is expected in 2023, while the first proton beams delivered to the target station for the generation of RIBs are presently expected in 2028. Moreover, apart from simultaneous irradiation and extraction (online extraction), ISOL@MYRRHA will also allow the production and extraction of isotopes from the target/sample at different moments in time (off-line extraction and separation). This enables:  the use of sources produced in other installations with higher cross sections (e.g. irradiations in BR2 and BR1 research reactors on the SCK CEN site, MYRRHA accelerator (full-power target station) or external accelerator facilities),  the decay of unwanted short-lived species,  the addition of an intermediate radiochemistry step for more efficient extraction of the isotopes. Figure 13. Layout of the ISOL@MYRRHA facility (left) and of the PANTERA spin-off (right). 7.4.3 PANTERA In 2021, SCK CEN and IBA (Ion Beam Applications S.A., EURONEXT), the world leader in particle accelerator technology, established an R&D strategic partnership for the development of a radionuclides-production facility9. A spin-off was launched10: Pantera SA/NV which aims to secure the large-scale production of 225Ac. The selected production route is photo transmutation of 226Ra, followed by chemical purification for the extraction of 225Ac from the decaying 225Ra generator. Pantera is now completing the technical feasibility studies while working on the conceptual design, before working on the final design and construction of its first facility in Mol, Belgium. Groundbreaking is expected to take place in 2024, with production starting in 2027. 7.5 Conclusions SCK CEN positions itself at the fore-front of radiopharmaceuticals research & production. SCK CEN’s dedicated cancer research programme NURA is constantly developing new knowledge in the field of nuclear medicine – both independently and as a Contract Research Organisation. At the core of NURA is the aim to facilitate the development of new radiopharmaceuticals for cancer treatment and GMP production of therapeutic radionuclides. SCK CEN acts as a pre-clinical research partner and manufacturer of medical radionuclides specialising in the field of radiopharmaceuticals. The operational BR2 reactor performs irradiations for commercial radionuclide suppliers and produces novel radionuclides for in-house researchers from SCK CEN as well as for Belgian and international researchers via bilateral collaborations. Moreover, SCK CEN offers state-of-the-art radiolabelling services to support preclinical studies or scientific research. 9 https://www.sckcen.be/en/highlights-2021/belgian-partnerships/joining-forces-makes-treatment-cancer-patients-more-effective 10 https://www.sckcen.be/en/news/iba-and-sck-cen-launch-pantera Deliverable D8.1 22 The existing infrastructure is currently expanded with a Hot Animal Facility (HAF – 2023). Also, in collaboration with IRE, SCK CEN is setting-up the production of 177Lu and building a GMP compliant production facility (CRF – 2024). The on-site infrastructure is further expanded with the first MYRRHA facilities for the production of Radioactive Isotope Beams (ISOL@MYRRHA – 2027). At the same time, plans for the construction of an 225Ac-production facility are put in place in collaboration with IBA (PANTERA – 2027). Deliverable D8.1 23 8. POLATOM – operational and emerging facilities Renata Mikolajczak (NCBJ) National Centre for Nuclear Research, NCBJ, is the largest research institute in Poland. It is located near Otwock, Poland, at around 30 km south from of the centre of Warsaw. The nuclear research reactor MARIA (nominal power of 30 MW, and max neutron flux of 3x1014 n/cm²s, suitable for production of radioactive isotopes, material science and neutron irradiation investigations) constitutes the large research infrastructure of NCBJ. It is supported by an IT Centre with specialist software for in silico simulations and dosimetry calculations. Within NCBJ the infrastructure of the radioisotope centre POLATOM is focused on research programmes related to the processing of radioisotopes and to the design of radiopharmaceuticals. Developed technologies can be then implemented into the routine production under GMP. POLATOM is also GMP certified for preparation of radiopharmaceuticals for clinical trials. The new emerging facility CERAD is under construction which will host 30 MeV cyclotron (accelerating protons, deuterons and alpha ions), production lines for medical radioisotopes and research laboratories. 8.1 Operational facilities at NCBJ 8.1.1 Maria Research Reactor The high flux research reactor MARIA is a water and beryllium moderated reactor of a pool type. Neutron irradiation services provided at the MARIA research reactor are mainly related to the radioisotope production, other research activities such as testing of fuel and structural materials for nuclear power engineering, neutron radiography, neutron activation analysis, neutron transmutation doping are also carried out. MARIA is also involved in education and training of young researchers. The neutron-thermal characteristics for the research channels:  fast neutron flux 1.0 – 1.5 × 1014 n cm-2 s-1  thermal neutron flux 1.0 × 1014 n cm-2 s-1  heat generation 3 – 4 W g-1 Figure 14. Vertical cross-section of the MARIA research reactor pools. The core of the MARIA reactor has a modular structure, each time adapted to the production or research programme. Figure 14 presents the cross section of MARIA research reactor. The fuel channels are situated in a matrix containing beryllium blocks and enclosed by lateral reflector made of graphite blocks in aluminum cans. In the outer part of the basket there are graphite reflector blocks, devices for the irradiation of largevolume materials, such as silicon or minerals, and other experimental devices, such as an epithermal neutron beam converter. Directly behind the core basket there are channels for ionisation chambers used for Deliverable D8.1 24 monitoring and controlling the reactor. MARIA is equipped with vertical channels for irradiation of target materials, a rabbit system for short irradiations and six horizontal neutron beam channels. MARIA research reactor reached its first criticality in 1974. Then it was modernised significantly in the ‘80s of the 20th century and is continuously upgraded, keeping up with the regulatory requirements. In 2010 MARIA started the irradiation of uranium targets for production of molybdenum-99, the parent radionuclide of technetium-99m, providing up to 18% of the global demand for molybdenum-99. Today MARIA belongs to the busiest research reactors worldwide and the radioisotopes produced here serve millions of patients. As the TNA2 facility MARIA will produce Tb-161 for PRISMAP users, other radioisotopes of potential interest are Lu-177, Ho-166, Sm-153, I-131, Sc-47 and more. 8.1.2. Radioisotope Centre POLATOM NCBJ’s Radioisotope Centre POLATOM is GMP certified for radiopharmaceutical manufacture and provides radiopharmaceuticals for both diagnostics and therapy. The research activities of POLATOM include new technologies for production of radioisotopes via reactor and accelerator routes, design of novel radiopharmaceuticals and methods for assessing their quality, with full range of pre-clinical studies as well as pharmaceutical formulations for clinical studies. Figure 15. Radiopharmaceutical laboratories at NCBJ/Polatom For these investigations the laboratories are equipped in high-tech analytical instruments: HPLC systems with UV, MS and radiometric detectors, ICP-Optical Emission Spectrometry, autoradiography systems, optical microscopes, gamma-spectrometry and LSC counters. Pre-clinical Laboratory with animal facility is certified for safety evaluation (acute toxicity), imaging and organ distribution of locally manufactured radiopharmaceuticals and investigational drugs. Laboratory of Radioactivity Standards at POLATOM is accredited for measurements of radioactivity by absolute methods (accreditation number: AP 120). POLATOM has specialised transport and logistics licensed for handling radioactive products. 8.2 Emerging facilities at NCBJ - CERAD 8.2.1. CERAD, Centre of Design and Synthesis of Radiopharmaceuticals for Molecular Targeting In order to meet the high demand for radiometals with potential for medical applications, with a particular focus on their theranostic value, the new research facility is being built at NCBJ/POLATOM, named “Centre of Design and Synthesis of Radiopharmaceuticals for Molecular Targeting, CERAD”. Its main component is the 30 MeV cyclotron which will accelerate protons and alpha particles to 30 MeV and deuterons to 15 MeV. It will be a powerful tool for production of novel radioisotopes for medical use, which were not available in Poland up today. Among them the radioisotopes such as 18F, 44/43Sc, 64Cu, 67Cu, Ge68, 89Zr, 123I and 211At will be produced. Installation of a new high-current cyclotron at NCBJ, with an equipment and infrastructure, combined with already existing scientific base, creates the unique and pro-development research capabilities. The cyclotron of CERAD, Cyclone 30XP, has been already built by Belgian company Ion Beam Applications. Next to protons and deuterons it will also accelerate alpha particles. For that it is equipped with the alpha ion source, the alpha particles will be accelerated to 30 MeV. The cyclotron will be soon transported and Deliverable D8.1 25 installed in the new building which will not only host the cyclotron but also a number of dedicated labs with hot-cells for radioisotope processing, with the QC and research laboratories. The entire facility offers a space of 2500 m2. The upcoming infrastructure will be open to PRISMAP user projects. Figure 16. Cyclone 30XP during assembling at IBA The infrastructure of CERAD can be used for both research and commercial activities, it creates the platform for comprehensive studies oriented at research and design of new medicinal products, in particular radiopharmaceuticals, and at implementing diagnostic and therapeutic procedures for diseases, which are currently treated ineffectively. The CERAD project has found its place on the Polish Roadmap of Large Research Infrastructure because it will not only offer new radioisotopes but also a possibility to design innovative radiopharmaceuticals. The research potential of NCBJ as consortium leader is supported by partner institutions: University of Warsaw, Warsaw Medical University, Institute of Nuclear Chemistry and Technology, Jagiellonian University Medical College and Medical University of Bialystok. The CERAD project is co-funded under the Smart Growth Operational Programme 2014-2020, Priority IV: INCREASING THE RESEARCH POTENTIAL, Measure 4.2. Development of modern research infrastructure of the science sector. www.polatom.pl, www.ncbj.gov.pl Deliverable D8.1 26 9. JHR – Status report and development foreseen Fabrice Carle, JHR Clients and Consortium Director, CEA Marion Libessart, JHR Business Development Manager, CEA The JHR Material Test Reactor is a project led by the CEA and sponsored by several international partners (15 members). It is currently under construction in France at the CEA Cadarache centre. The JHR Material Test Reactor is developed to:  test the behaviour of materials and fuels under irradiation in order to support current and future nuclear reactors,  produce the radioelements needed in nuclear medicine, to secure a just-in-time production for medical purposes in France and Europe.  The JHR Material Test Reactor will also be able to produce radioelements for other applications. Figure 17. The JHR Material Test Reactor Some key figures The JHR Material Test Reactor is a 70 up to 100 thermal MegaWatt power (high density of power concentrated into a small reactor of 60cm*60cm), with a neutron flux of about 5.1014 neutron/cm2/sec and in operation during about 6 cycles/year, from 25 to 35 days each. The reactor building is about 43 m to 35 m high and 37 m of perimeter, the overall facility being comparable to a 900 MWe French power plant. Indeed, the building is huge compared to the size of the core vessel. This JHR Material Test Reactor is a pool type reactor, all experiments and radioisotope targets are planned to be loaded and unloaded under water. There are 7 hot cells:  4 big hot cells to host the experimental devices, to prepare the experiments in the reactor and to introduce or remove the irradiation containers,  3 small hot cells to make some non-destructive examinations on fuel and material samples. Deliverable D8.1 27 A dual activity The JHR Material Test Reactor objective is twofold:  To perform tests on material and fuel elements. There are two types of experiments:  “easy to handle” capsule-type irradiation, i.e. a protective casing that contains the sample to irradiate,  ‘Loop’ irradiation in which the samples can be more instrumented so measurements can be recorded and temperature, water circulation and pressure levels can be monitored to reproduce the environment of Nuclear Power Plants  To produce radioisotope for nuclear medicine:  Between 25% to 50% of the yearly European molybdenum 99 requirements for diagnostic  Therapeutic radioelements to foster future medical progress. Figure 18. Detailed pictures of the JHR Material Test Reactor Dedicated radionuclide equipments To achieve its radionuclide mission, the Material Test Reactor project is developing:  4 displacement systems (installed into the reflector of the core and positioned near by the core vessel) dedicated to load and unload the molybdenum 99 (12 targets at the maximum) during the reactor cycles (about 7 days are needed for the molybdenum irradiation). These systems could also be used for the production of other radioisotopes of interest, depending on the market demand.  2 in core irradiation devices:  1 device with 4 containers,  1 device with 12 containers.  2 long reflector irradiation devices with 5 containers each.  2 short reflector irradiation devices with 5 containers each. Business model and loading Considering that the JHR Material Test Reactor is planned to be in operation at the beginning of the next decade, the business model communicated to the French state this year takes into account the production of the three main radioisotopes of the moment: Molybdenum, Iridium and Lutetium. Deliverable D8.1 34 2021 CERN PSB Beam External Sources Sc-44,47, Ba-128/Cs-128, Sm-153, Tb-155. Tm-167, Pt-191. Yb-175, Ac-225 25 1300 KU Leuven (BE), SCK CEN (BE), PSI (CH), CHUV (CH), NPL (UK), PAEC (PK) 2022 CERN PSB Beam External Sources Sc-44,47, Ba-128/Cs-128, Sm-153, Tb-155, Tm-165, Tm-167 Pt-195m, Ac-225 26 840 KU Leuven (BE) SCK CEN (BE), PSI (CH), CHUV (CH) 11.3 Organisation of operation at CERN-MEDICIS: budget and resources Such facility has been financed by getting « seed money » for the project financed by CERN at an amount of 7 MCHF. After 4 years of operation, it has been concluded that the average operation costs are between 500 to 650 kCHF per year, including material and personnel, covered by contributions from the partner institutes, by donations & by CERN (see Figure 23). A lower cost of operation has been recorded during the Long Shutdown 2 (LS2) since there was no beam operation at CERN. Moreover, during that time, the irradiation and production of radioactive sources at partner institutes were not invoiced to CERN-MEDICIS. Some examples of in-kind contribution not included in the total costs include:  Irradiation and production at partner institutes;  Some hardware such as separator magnet, laser;  Support of radiochemistry experts for several months, associate scientists and students. It should be noted that the protons provided by CERN are considered as for free for the MEDICIS collaboration, since the CERN-MEDICIS facility profits from the beam that is not used by ISOLDE and would otherwise be lost into the beam dump. The yearly cost above-mentioned include a budget of about 15 kCHF per target built which can go up to 30 kCHF depending on the complexity and developments required for a specific target. About 10 new targets are being built per operational year. On top of that, CERN-MEDICIS recycles and re-uses targets from previous collections performed as much as it is possible. The yearly costs include a budget of about 50 kCHF for isotope shipping and reception as well as for services cost on the CERN site such as maintenance work, repair work, technical support, electrical supplies etc. It covers 1 FTE (Full Time Equivalent) CERN Staff for Radiation Protection services as well as 0.8 FTE for scientific support (associate/student). Figure 23. MEDICIS budget and resources Deliverable D8.1 35 11.4 Conclusions Since the end of 2017, MEDICIS has been providing innovative radioisotopes with high specific activity to research facilities and hospitals. Within the CERN-MEDICIS collaboration and the PRISMAP European project, the list of isotopes will continue to be extended according to the needs of the community. By gaining experience during every year of operation, progressively larger activities will be produced and delivered to the research institute. CERN-MEDICIS is continuously working on research and development to increase the outcome of the facility. More information on the facility can be found on the CERN-MEDICIS website (medicis.cern) as well as at this reference: Duchemin C et al. on behalf of the MEDICIS collaboration, CERN-MEDICIS: a review since commissioning in 2017. Frontiers in Medicine - Research Topic MEDICIS-Promed: Advances in Radioactive Ion Beams for Nuclear Medicine (2021) https://www.frontiersin.org/articles/10.3389/fmed.2021.693682/full Deliverable D8.1 36 12. Direct targets for the production of medical radionuclides: an update 155Tb as a case study Yizheng Wang2, Thomas Sounalet2, Nadia Audouin1, Arnaud Guertin2, Férid Haddad1,2, Nathalie Michel1,2, Etienne Nigron1 1GIP Arronax, 1 rue Aronnax, 44817 Saint-Herblain cedex, France. 2Subatech, EMN-IN2P3/CNRS-Nantes Université, 4 rue Alfred Kastler, La Chantrerie, BP 20722, 44307 Nantes cedex 3, France. 12.1 Introduction Nuclear medicine uses radionuclides or radiopharmaceuticals to diagnose and treat cancer cells for decades. In recent years, a new paradigm called theranostics has emerged. It consists of coupling a given vector with different isotopes (one for imaging, another one for treatment) to personalize radiopharmaceutical treatment to each patient and to monitor the early results of the treatment [1]. Ideally, theranostics should use radionuclides from the same chemical element to keep identical behaviour and properties in the body. The terbium element is of particular interest to this end as four of its radioactive isotopes have properties compatible with medical applications: 149Tb can be used for alpha targeted therapy, 152Tb as a positron emitter can be used for positron emission tomography (PET), 155Tb can be used for single photon emission tomography (SPECT) and for Auger therapy and finally 161Tb can be used for beta targeted therapy. Despite 161Tb for which the production route is well defined and based on neutron capture on 160Gd, other terbium radionuclides availability is rather scarce and mostly based on the use of spallation reaction followed by mass separation [2]. At our facility [3], to help the scientific community to overcome this, we are looking to different production routes using cyclotrons in order to define the best ones by working on methods to produce enriched Gd targets with different thicknesses and on chemical methods to extract and purify terbium from a large amount of gadolinium. We use 155Tb as a case study. 12.2 Preparation of enriched Gd targets To prepare thin targets, electroplating if often used as it is a low-cost method with high efficiency. In the case of Gd target preparation, the redox potential of Gd3+/Gd is very low (E = -2.28 V/SHE) in acid solutions and a strong competition with water decomposition is occurring leading to bad deposit quality. We decide to go for an alternative way called the co-deposition method. The basic principle of this method is to mechanically transport and physically embed target particles (here insoluble Gd2O3 particles) mixed in a bath to the growing deposited layer made of nickel. The main advantages are more simple experimental conditions (aqueous solution) and a shorter target manufacturing duration (30-60 min). Using this method and after an extensive impact study of several parameters as temperature, stirring speed, Gd2O3 concentration [4], we were able to manufacture Ni-Gd2O3 composite target with a thickness of 10-20 µm containing few mg of Gd on a gold backing. Figure 24 presents one example of such deposit. In this case, the obtained deposit has a thickness of 13 µm and contains 3mg of Gd according to EDX measurements performed on site. This is consistent with later analysis made on dissolved target using our ICP-OES. Figure 24. Ni-Gd2O3 deposit on a gold backing obtained by co-deposition. Deliverable D8.1 37 As the main purpose of our work was to study cross section for deuteron induced reaction on enriched 155Gd target, we purchased enriched material to Trace Sciences International. The composition of the enriched gadolinium oxide, noted *Gd2O3, is presented in Table 2. As can be seen in the table, the major contaminant is 156Gd which represents almost 6% of the Gd content. Table 2. Composition of the enriched *Gd2O3 purchased from Trace Sciences international Isotopes Gd-155 Gd-156 Gd-157 Gd-158 Gd-160 Abundance (%) 92.8 5.7 0.8 0.5 0.2 From 1 g of enriched *Gd2O3 powder, 10 targets were made leaving 0.6 g of powder that was used to make a *Gd2O3 pressed pellet. 12.3 Cross section measurement Cross section measurements have been done using the well-known stacked foils technique [5]. All nuclear data used were extracted from the NUDAT database [6]. 12.3.1 Determination of production cross sections of terbium-155 To measure the 155Tb excitation function, enriched *Gd2O3 (see Table 2) material was irradiated with a deuteron beam. For each experiment, two *Gd2O3 co-deposited foils were irradiated along with monitor (Ti and Ni) and degrader foils (Al). The deuteron beam intensity was 50 nA and the irradiation duration was 30 min. After each irradiation, the deposit was dissolved and separated from the gold substrate for data acquisition. Figure 25. Cross section of the *Gd(d,x)155Tb nuclear reaction The *Gd(d,x)155Tb reaction cross section is presented on Figure 25. The measured values show a maximum of 797.9 ± 77.8 mbarn for 14.2 ± 0.3 MeV. Uncertainties are between 9.3 - 13.5% and are strongly linked to the gadolinium content in the target. During experiments, other terbium contaminants were also measured. 155Tb production cross sections are almost twice higher for deuterons than for protons. However, the purity of the final product is lower with deuterons mostly due to the co-production of 156Tb. Increasing the enrichment level of 155Gd would help to reduce the amount of 156Tb, nevertheless, this purity stays lower than what is achievable with protons (this work will be submitted soon to a scientific journal). Deliverable D8.1 38 12.3.2 Determination of production cross sections of terbium-161 Production cross sections of 161Tb from deuteron irradiated natGd targets were investigated in order to extract 160Gd(d,n)161Tb. Indeed, this nuclear reaction is the only one allowing the production of 161Tb from stable Gd isotopes and natural Gd target can be used for such measurement without interferences. In each experiment, two natGd target foils with titanium monitor and aluminium degrader foils were used. Typical irradiation time was 30 minutes with 50 nA beam current. The results are presented in Figure 26 for the cumulative production of 161Tb. The results are in good agreement with those of Tarkanyi (2014) [7], however, higher than Szelecsenyi (2016) [8]. Long-lived contaminant 160Tb (T1/2=72.3d) is co-produced over a wide range of incident energy leading to limited radionuclidic purity. Unless a highly efficient mass separation method is found and added to the chemical process to separate Tb from Gd, this production method is less interesting than the neutron-induced reaction. Measured values for 161Tb, 160Tb and other contaminants can be found in [9]. Figure 26. Excitation function of 161cumTb for deuteron irradiated natGd targets 12.4 Thick target yields To validate our cross-section measurements, we have performed a thick target yield experiment using an enriched *Gd2O3 pressed pellet. The incident deuteron energy was 15.1 MeV, the beam intensity was 500 nA and the irradiation duration 1h. Considering the target thickness, the output energy was determined to be 8.6 MeV using the SRIM software [10]. After irradiation, terbium radionuclides were measured and the thick target yield was determined for 155Tb (156Tb) to be 10.2 ± 0.7 MBq/µAh (1.3 ± 0.1 MBq/µAh). These values are in good agreement with calculated thick target yields using the measured cross sections (see Figure 27). This leads to a 155Tb purity of 89% determined 10 days after EOB. Figure 27. Production yield of 155Tb (orange curve) and 156Tb (blue). The red box is use to ease the reading on the curves to compare to the experimental values reported in the text. Deliverable D8.1 39 12.5 How to improve chemical purity of produced terbium radionuclides As discussed in the previous paragraph, the final purity of terbium radionuclides is not optimal due to the coproduction of other terbium radionuclides. In the case of 155Tb production, 156Tb and 154Tb are the main contaminants. To improve the final purity, a mass separation step can be set. In order to not be overloaded with the target element (in our case gadolinium) and improve the efficiency of this mass separation step, it is important to perform previously a chemical separation step to remove most of the target element (see Figure 28). Such a chemical procedure has been developed and several experiments have been performed to optimize the mass separation step. Three sources of 155Tb were produced at the ARRONAX cyclotron in Nantes (France) from the irradiation of natural gadolinium foil targets (~300 mg, 25 µm thickness, 99.9% Gd purity) with 34 MeV protons. Before being shipped to CERN-MEDICIS, the irradiated gadolinium foils were first dissolved in HNO3 and chemically processed at ARRONAX using a LN resin method to reach a Tb:Gd ratio of 1:100 from an initial ratio greater than 1:1000000. The final solution was transferred to a dedicated sample holder and evaporated. This sample holder developed at CERN allowed for rapid and secure transfer of the radioactive source into the empty target tantalum oven from a standard ISOLDE target. Figure 28. Description of all sequences made to manage mass separation at MEDICIS-CERN of a target irradiated at Arronax. Once at CERN-MEDICIS, the sample holder was inserted in the target container connected to a rhenium ion source via a transfer line. Terbium-155 was extracted from targets that were heated up to 2200 °C. Laser resonance ionisation was applied with MEDICIS’s Laser Ion Source for Separator Assembly (MELISSA) to selectively enhance the ionisation of 155Tb, using a two-step resonant excitation scheme. Separation efficiencies ranging between 1 and 6% were achieved during the different Tb-155 collections performed in 2021 with activities up to 20 MBq available [2]. 12.6 Conclusions Terbium radionuclides have a high potential in nuclear medicine and we are looking on different methods to produce them using accelerators. As everything starts with a target, an original method has been developed to make thin targets containing enriched Gd isotopes for cross section measurements. Production of 155Tb and other contaminants have been measured using these targets as proof of concept. In parallel, Deliverable D8.1 40 measurements on the possibility to make 161Tb from deuteron irradiations have been done. In both cases, it has been shown that terbium contaminants are co-produced and in most cases a mass separation step will be beneficial to improve the final purity. Finally, to prepare for large production batches works have been also done on pelletizing gadolinium oxide. 12.7 References [1] Qaim, S.M., Scholten, B., Neumaier, B., 2018. New developments in the production of theranostic pairs of radionuclides. J Radioanal Nucl Chem 318, 1493–1509. https://doi.org/10.1007/s10967-018-6238-x [2] C. Duchemin et al, CERN-MEDICIS: A Review Since Commissioning in 2017, Front. Med., 15 July 2021. https://doi.org/10.3389/fmed.2021.693682 [3] Haddad, F., et al, ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine, Eur. J. Med. Mol. Imaging 35, 2008,1377-1387. [4] Yizheng Wang et al, Electrochemical co-deposition of Ni-Gd2O3 for composite thin targets preparation: production of 155Tb as a case study, Applied Radiation and Isotopes 186 (2022) 110287. doi: https://doi.org/10.1016/j.apradiso.2022.110287 [5] F. Szelecsényi, G. Blessing and S.M. Qaim, "Excitation functions of proton induced nuclear reactions on enriched 61Ni and 64Ni: Possibility of production of no-carrier-added 61Cu and 64Cu at a small cyclotron", Appl. radiat. Isot. vol. 44, No.3, pp.575-580, 1993. [6] Kinsey R.R., et al., The NUDAT/PCNUDAT Programme for Nuclear Data, paper submitted to the 9th International Symposium of Capture Gamma-Ray Spectroscopy and Related Topics, Budapest, Hungary, October 1996. [7] F. Tárkányi, S. Takács, F. Ditrói, J. Csikai, A. Hermanne, et A. V. Ignatyuk, « Activation cross-sections of deuteron induced reactions on natGd up to 50MeV », Appl. Radiat. Isot., vol. 83, p. 25‑35, janv. 2014, doi: 10.1016/j.apradiso.2013.10.010. [8] F. Szelecsényi, Z. Kovács, K. Nagatsu, M.-R. Zhang, et K. Suzuki, « Investigation of deuteron-induced reactions on natGd up to 30 MeV: possibility of production of medically relevant 155Tb and 161Tb radioisotopes », J. Radioanal. Nucl. Chem., vol. 307, no 3, p. 1877‑1881, mars 2016, doi: 10.1007/s10967015-4528-0. [9] E. Nigron et al, “Can we reach suitable purity for accelerator produced 161Tb through 160Gd(d,x) reaction? “, submitted to Applied radiation and isotopes (2023) [10] JF Ziegler, MD Ziegler, JP Biersack, “SRIM – The stopping and range of ions in matter” (2010). NIMB, 19th International Conference on Ion Beam Analysis 268, 1818–1823. https://doi.org/10.1016/j.nimb.2010.02.091 12.8 Acknowledgements The cyclotron Arronax is supported by CNRS, Inserm, INCa, the Nantes University, the Regional Council of Pays de la Loire, local authorities, the French government and the European Union. This work has been, in part, supported by a grant from the French National Agency for Research called “Investissements d’Avenir”, Equipex Arronax-Plus ANR-11-EQPX-0004, Labex IRON ANR-11-LABX-18-01 and ISITE NExT ANR-16-IDEX-007. It has been also supported partly through a funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP). Deliverable D8.1 41 13. SPES: general overview, status and future plans Daniele Scarpa (INFN) 13.1 Introduction Modern nuclear research relies heavily on the availability of radioactive isotopes as a vehicle both for fundamental studies and for many applications in various fields of science. A large number of facilities for the production of radioactive ion beams (RIBs) already in operation or under construction employ the socalled ISOL (Isotope Separation On-Line) technique. Legnaro National Laboratories of INFN (Istituto Nazionale di Fisica Nucleare) are now engaged in the advanced construction phase of a second-generation nuclear facility known as SPES, or Selective Production of Exotic Species [0]. 13.2 The SPES Facility In SPES the Radioactive Beam Production (RIB) production method is based on a proton beam of about 40MeV energy and 200 μA current, produced by a high intensity cyclotron, which interacts with a Uranium Carbide (UCx) target. Radioactive neutron-rich isotopes are produced by nuclear fission induced on uranium at a rate of about 1013 fission/s. The primary driver is a commercial cyclotron produced by the Best Cyclotron Systems Inc. The proton beam can be delivered in the 35-70 MeV energy range with a maximum of 750 μA total current. The machine accelerates Hions provided by an external multi-cusp ion source via an axial injection line and an electrostatic inflector. Protons are extracted by stripping the electrons in a thin graphite foil. The layout of the facility complex is shown in Figure 29, together with the existing accelerator complex, PiaveTandem – Alpi, which, at present, delivers stable beams at LNL. Figure 29. The whole accelerator SPES complex. 13.2.1 Cyclotron The primary driver of SPES is a commercial cyclotron manufactured by Best Cyclotron Systems Inc®. The proton beam can be delivered with an energy range of 35-70 MeV and a total current of up to 750 µA. Two Deliverable D8.1 42 exit ports on opposite sides of the machine provide simultaneous double extraction. An axial injection line and an electrostatic inflector are used by to accelerate Hions coming from an external multi-cusp ion source. Protons are extracted by stripping electrons in a thin graphite foil. Transport, setup, and successful commissioning were completed in recent years, driving the beam towards a high-power beam dump designed and built by LNL. Stability and reliability testing have been performed with an average beam current of about 200 µA. The system has then been verified in a 70 MeV - 500 µA configuration, showing good reproducibility and stability. Dual extraction was finally demonstrated. The Best® P70 Cyclotron installed at SPES is visible in Figure 30. Figure 30. View of the Best® P70 cyclotron. 13.2.2 The Target Ion Source complex The SPES Target and Ion Source (TIS) unit has been developed at Legnaro National Laboratories since 2006. In particular, the SPES Uranium Carbide target is designed to dissipate the important amount of power deposited by the 40 MeV 200 μA primary proton beam, and to release in an efficient way the produced radioisotopes [1]. A surface ionisation source [2] can be coupled with the target, with the possibility to implement resonant laser ionisation in its tubular hot-cavity. 13.2.2.1 Surface and Laser Ion Source The resonant laser ionisation is an adaptable method, applicable to many elements in the periodic table, for very selective ion production. Ions of a chosen element are ionised via stepwise atomic resonant excitations using, mainly, two or three laser beams tuned to the transition energies of the element of interest. Furthermore, the activities on element laser ionisation are still in progress and future development is the extension of its range with the study of new ionisation schemes with new laser systems such as TiSa tunable lasers. In LNL recently a new laser laboratory with an all-solid state laser system installed (Figure 31) will be active to provide laser resonant ionisation on the SPES project ISOL ion source prepared for lasers [3]. Deliverable D8.1 43 Figure 31. SPES Laser Laboratory @ LNL and Plasma ion source 13.2.2.2 Plasma Ion Source As an alternative, a plasma ion source (FEBIAD type) can be used, as reported in [4]. As specified in the following paragraph, a SiC target will be used for the SPES facility commissioning. In this phase the proton beam intensity will be consistently reduced (5-10 μA) and a scaled target version will be adopted (13 mm disks in diameter instead of the nominal 40 mm). The scaled SiC target coupled with a FEBIAD source has been tested at high temperature, together with all its auxiliary components such as type C thermocouples and gas injection tubes for the ion source. A lot of constructive details have been consolidated during the last years and the TIS unit is now ready for the first irradiation at the SPES facility. The research activities on target materials have been focused in recent years on three different materials [5], representing three different stages of the SPES facility operation: silicon carbide, uranium carbide and titanium carbide. 13.2.2.3 TIS Remote handling The TIS unit is planned to be irradiated on the SPES Front-End for a two-week period. It is then left at rest within the ISOL hall for a first steep radioactive decay in the following two weeks. The significant expected gamma dose rate, mainly due to the TIS unit activation, extraction electrode surface isotope deposition, and residual activation of the SPES Front-End promoted the development of a set of automated systems, referred to as the SPES Remote Handling framework [6]. 13.2.3 The Low energy beam lines The very first part of the Front-End is constituted by an axial movable extractor electrode which can apply a difference of potential of about 40 kV. Subsequently the accelerator includes two couple of steerers for each transversal plane, followed by a triplet for beam focusing. A preliminary separation stage is provided by a Wien Filter that was installed in the SPES bunker, able to reject more than 99% of the contaminants into the vertical plane. Finally, a triplet focuses the beam out of the SPES bunker. The current status of the SPES target bunker hall is presented in Figure 32. The ground plants are now being installed and the completion of the bunker is expected soon. Deliverable D8.1 50 15. Innovative ISOL targets for the production of medical radionuclides Stefano Corradetti1, Alberto Andrighetto1, Alberto Arzenton1,2, Michele Ballan1, Sara Maria Carturan1,3, Lisa Centofante1, Paolo Colombo4, Giorgia Franchin4, Mattia Manzolaro1, Giordano Lilli1, Alberto Monetti1, Daniele Scarpa1, Davide Serafini1,2, Alice Zanini4 1INFN-Laboratori Nazionali di Legnaro, Viale dell’Università 2, 35020 Legnaro (PD), Italy 2Università degli Studi di Siena, Dipartimento di Scienze Fisiche, della Terra e dell’Ambiente, Via Roma 56, 53100 Siena, Italy 3Università degli Studi di Padova, Dipartimento di Fisica e Astronomia, Via Marzolo 8, 35131 Padova, Italy 4Università degli Studi di Padova, Dipartimento di Ingegneria Industriale, Via Marzolo 9, 35131 Padova, Italy 15.1 Abstract The target is the core of each facility for the production of radioactive ion beams for nuclear physics and medicine research. The materials which constitute it must work in extremes conditions of temperature and pressure, being bombarded by energetic beams of light particles for several days. For this reason, accurate choice and design of materials is of extreme importance. On recent years, several studies were carried out in the framework of target production and characterisation. In this work, recent results on primary and secondary targets for medical radionuclides production are presented. 15.2 Introduction The target represents the heart of an ISOL (Isotope Separation On-Line) facility for the production of radioactive ion beams [1]. In the target, nuclear reactions take place for several days of continuous operation. In this work, the SPES (Selective Production of Exotic Species) target [2] is described, but in principle its production and characterisation have a lot in common with those of other high-power ISOL facilities. In this case, the target is designed to absorb nearly all the power coming from the primary proton beam, to maximize the isotopes production. In this work, this production target will be referred to as the primary target. Deposited power of up to 10 kW must be dissipated mostly by means of thermal radiation, being the target operated in high vacuum at extremely high temperature, more than 2000 ◦C in most cases. This condition helps to speed up the release of isotopes towards the ion source through diffusion and effusion mechanisms, but the set of materials which can withstand these extreme conditions is limited. Recent studies have highlighted the importance of designing the ISOL target materials microstructural properties to achieve high-yield and stable productions of isotopes [3]. Three different aspects currently considered to be related to good target performances are:  Low grain size and nanostructured materials provide high yields of selected isotopes and constant yields in time.  Open interconnected porosity is important to facilitate the isotopes release. The presence of permeable pores and high specific surface areas (SSA) are also considered positive properties.  High thermal and thermo-mechanical properties. In high-power facilities, thermal conductivity and emissivity are important for maintaining the target structural stability through heat dissipation. To balance this set of requisites, porous carbides or carbide/carbon nanocomposites have emerged as the most promising class of materials for this application. Other important targets, especially in the case of the ISOLPHARM project (ISOL technique for radioPHARMaceuticals) are the so-called secondary targets [4], in which the radioactive beam coming from the primary target is collected, to then extract medically relevant radionuclides. The working conditions of these secondary targets are milder than those of the primary ones, since the energy of the impinging beam is low, in the order of tens of keV. In any case, research and development is necessary also in this case, to come up with solutions to have a target which is able to absorb nuclides present in the radioactive ion beam and at the same time to achieve a fast release of the deposited atoms when needed. Deliverable D8.1 51 15.3 SPES Target production The standard SPES target production technique is based on the carbothermal reduction of oxides in high vacuum at high temperature, which leads to porous carbides in the form of thin disks. This approach was carried out in the last fifteen years for the production of lanthanum, uranium, thorium and titanium carbides. This technique is useful for producing porous materials with high reproducibility, but usually porosity is not optimised. A target indeed, to be efficient in terms of isotopes release, must have porosity at the nanoscale and associated high specific surface area. In order to improve the control of porosity and thermal properties in SPES targets, other innovative production techniques are being used in recent years, such as sol-gel and the use of new carbon sources for the carbothermal reduction. The sol-gel method is based on the development of an interconnected metal-oxygen-carbon network which is then converted to a carbide. It can be exploited to obtain porous carbides with micro and mesoporosity (d < 50 nm) and high specific surface area, as recently proved for titanium carbide. Nanostructured carbon sources such as nanotubes or graphene can be used in place of graphite to improve thermal properties of SPES targets, as recently demonstrated for uranium carbide. Among the new production techniques for SPES targets, the use of fibers seems very promising. The use of carbon fibers has very recently proven to be a successful way of improving thermal and mechanical properties of porous materials. For example, silicon carbide/carbon fibers composites with a porous matrix have proven to possess higher thermal properties than porous SiC (without fibers) and at the same time do not undergo catastrophic fragile failure common in fully dense SiC under thermal stress. Usually, the use of fibers is designed to obtain dense ultra-high temperature ceramic matrix composites for aerospace but the method is also effective to produce porous ceramic matrix composites. 15.4 SPES Target characterisation Several techniques can be used to characterize porosity: helium pycnometry is used to distinguish open from closed porosity, because the latter does not help isotopes release due to the necessity of re-diffusion. Gas permeability can be seen as another useful tool to investigate the presence of permeable pores (directly connecting two sides of a sample), very effective to release isotopes. Electron microscopy, in scanning or transmission mode, gives useful information on the micro and/or nanostructure of the material. Nitrogen physisorption is useful for characterizing the amount and size of nanopores and to calculate specific surface area. As for thermo-mechanical characterisation, an experimental setup has recently been developed at INFN-LNL with the aim of measuring thermal and structural properties of SPES target disks (Figure 38). It works by creating a strong thermal gradient on the surface of a disk and at the same time measuring temperatures in centre and periphery. By combining experimental measurements of temperature and emissivity with numerical data obtained by simulations it is possible to calculate thermal conductivity. Moreover, pushing the gradient to high values it is possible to destroy the samples and at the same time to measure critical stresses, which must not be exceeded during target operation. In this way, it is possible to estimate the survival probability of a target under a thermal load during operation [5]. 15.5 ISOLPHARM secondary target production and characterisation ISOLPHARM will make use of the SPES beam with the aim of collecting innovative radionuclides as a base for the development and test of novel radiopharmaceuticals [6]. For this purpose, it is necessary to have a secondary target placed at the end of the beamline to collect the isotopes coming from the mass separator. The implantation of radioactive beams on solid substrates is a common technique in solid-state physics applications of ISOL beams, but the use of such technology for medical radionuclides is more challenging. The existing ISOL facilities indeed generally employ metallic foils as collection substrates, but metallic impurities act as competitors of the radionuclide of interest during the labeling of the radiopharmaceutical. Alternative implantation target materials are then under consideration to tackle this problem. Self-sustaining soluble non-metallic or salt-based deposition targets were recently investigated as potential alternative collection substrates for radioisotope harvesting in ISOL-type facilities. As the development of automatised Deliverable D8.1 52 target handling systems requires the use of targets resistant to impacts and/or friction, the use of pharmaceutical grade powders has also been proposed. In a recent work, different materials such as NaCl, NaNO3, cellulose and dextrates were cold pressed into disks and then characterised (Figure 40). Their morphology, density, porosity, mechanical strength and impact resistance were evaluated. Moreover, a correlation between the mechanical strength and the dissolution or disaggregation time was obtained, suggesting that excessive resistance is generally not desirable, unless the target substrate can release the implanted ions independently from its actual disaggregation. The result of simulation of implantation depth show that very thin targets can be used, provided that they are not too brittle to be remotely handled. Proofof-concept deposition tests of Ag+ ions were also carried out, obtaining two different scenarios. In the case of NaNO3, the collected Ag+ reacted with the substrate, but it was still possible to dissolve and quantify the implanted metal, whereas in the case of dextrates, the deposited silver formed a thin metallic layer that detached from the substrate and dissolved independently (Figure 41). The latter finding is particularly relevant, because if a similar occurrence can be observed with insoluble substrates, their use as collection targets could be done as well. Figure 40. a) The device for thermal and structural characterisation; b) CAD view; c) a heated sample. Deliverable D8.1 53 Figure 41. A dextrates substrate during target disaggregation after Ag deposition, with visible detached Ag layer. 15.6 References [1] S. Corradetti et al., Nuclear Instruments and Methods in Physics Research B 488 (2021) 12. [2] A. Monetti et al., European Physical Journal A 51 (2015) 128. [3] J.P. Ramos, Nuclear Instruments and Methods in Physics Research B 463 (2020) 201. [4] M. Ballan et al., Applied Radiation and Isotopes 175 (2021) 109795. [5] M. Manzolaro et al., Materials 14 (2021) 2689. [6] A. Andrighetto et al., Journal of Radioanalytical and Nuclear Chemistry 322 (2019) 73. Deliverable D8.1 54 16. Direct targets for the production of medical radionuclides: an update Ferid Haddad GIP Arronax, 1 rue Aronnax, 44817 Saint-Herblain cedex, France. Subatech, EMN-IN2P3/CNRS-Nantes Université, 4 rue Alfred Kastler, La Chantrerie, BP 20722, 44307 Nantes cedex 3, France. 16.1 THE ARRONAX FACILITY ARRONAX (Accelerator for Research in Radiochemistry and Oncology in Nantes Atlantique) [1] host a multiparticle, high energy and high intensity cyclotron (C70XP from the IBA company). The accelerator has turned into operation in February 2011 and is able to accelerate both positive (HH+, He++) and negative ions (H-, D-) up to 70 MeV. It can deliver proton beams up to 750 µAe in dual mode (two beams of 375 µAe each) and alpha-particle beams up to 70 µAe. The main characteristics of the beam available on our accelerator are summarised in Table 3. Recent developments on the accelerators have consisted to develop a very low intensity platform for radiobiology [2] and to design and operate a beam pulsing device that allows to provide very intense and short beam pulses (down to few µs duration and up tu 70kGy/s on sample) [3]. Table 3. ARRONAX beam characteristics Beam Accelerated particles Energy range (MeV) Intensity (µAe) Number of simultaneous extracted beams Protons H - 30-70 < 375 2 HH + Fixed 17 < 50 1 Deuterons D - 15-35 < 50 2 α-particles He ++ Fixed 68 < 70 1 Beam can be sent in 6 experimental vaults: four are dedicated to radionuclide production for nuclear medicine and are equipped with irradiation stations and remote pneumatic transfer systems from the vault to the hot cells while the two others are devoted to research in associated fields (physics, radiochemistry and radiobiology). In addition, several laboratories (radiochemistry, biochemistry, hot cells, radiolabelling, chemical analysis, nuclear metrology…) are available allowing radiopharmaceuticals development and quality control of final products. In 2018, an in-house radiopharmacy has opened to produce radiopharmaceuticals for clinical trials [4] using either radionuclides produced at our site (64Cu, 211At) or bought on the market (177Lu, 225Ac, 111In). Last November 2022, we have passed 100 manufactured doses on site. 16.2 New radionuclide developments A great advantage of our facility is the ability to select the best combination of “incident energy/ particle type/ target element” to have access to a very large body of radionuclides of potential medical interest. This is illustrated by the new developments that have been performed that are presented below. All nuclear data used were extracted from the NUDAT database [5]. 16.2.1 Copper-64 Copper-64 has a half-life of 12.7004 h. It decays through electron capture in 44.00% of the case, by bin 38.48 % with a maximum energy of 579.4 keV and finally by b+ emission in 17.52 % of the case with a maximum Deliverable D8.1 55 energy of 653 keV. Associated to these emissions, there is a high energy gamma ray at 1345.75 keV with a low probability of occurrence (0.4749 %). Considering the emitted radiations, it can be used for both therapy and PET imaging. Figure 42. Production cross section as a function of the projectile energy for Ni-64(p,n)Cu-64 (left) and Ni64(d,2n)Cu-64 (right). Data have been extracted from [6]. Several routes to produce 64Cu have been reported in the literature among which the irradiation of enriched Ni-64 with protons is the most often used. As most (p,n) reactions, production cross sections are high (see left plot on Figure 42). Looking at the deuteron production route, it is found that the maximum cross section value for (d,2n) reaction is higher than for (p,n), reaching 800 mb at 14 MeV and the curve evolves more slowly around the maximum for (d,2n) in comparison to (p,n) [6]. At Arronax, we produce every other week Cu-64 using 16 MeV deuteron beam impinging on an enriched Ni-64 target to take full advantage of the maximum cross section. This allows us to reach a production yield comparable to that obtained with proton but using a 25% thinner target thickness. The purity of the final product is comparable to that obtained using the proton route as demonstrated by the preliminary results obtained in the intercomparison currently under way within the PRISMAP project [7]. With the 64Cu produced on site, we have started a clinical trial that uses the 64Cu-ATSM radiopharmaceutical to evaluate 64Cu-ATSM PET-CT as a predictor of response to neoadjuvant therapy in locally advanced rectal cancers. This clinical trial is a multicentric study conducted in 5 clinical centres of the west part of France (Nantes, Angers, Rennes, Brest, Rouen) and 29 patients have been included to date. 16.2.2 Astatine-211 Astatine-211 has a half-life of 7.214 h. It decays through α decay in 41.80% and by electron capture in 58.20%. In this latter case, the short-lived daughter nucleus (211Po – T1/2=0.516 s) decays by α decay in 100.00%. Ultimately, there is one α-particle emitted for each 211At decay making 211At a very good candidate for targeted alpha therapy [8]. At ARRONAX, the α-beam has a fixed energy of 68 MeV which is not suitable for 211At production. It is necessary to reduce the beam energy down to 28.6 MeV, the threshold energy of 210At. This radionuclide is the main contaminant to take care of as it will behave the same way as 211At, it has a similar half-life and it decays to 210Po which is a toxic bone seeker. To this end, we have developed a beam energy degrader made of graphite. This system is placed just in front the target position and can allow 15 µAe on target. After irradiation, a dry chemistry method is used to extract astatine from the bismuth target in chloroform (see Figure 43). Deliverable D8.1 56 Figure 43. Production scheme at Arronax. The production yield of 211At is strongly correlated to the ratio 210At/211At. A higher value corresponding to a higher yield. It is then important to have a good knowledge of the evolution of the production cross section as a function of the energy near the 210At threshold energy. To that purpose, an experiment has been made last September at NFS (GANIL) by the REPARE collaboration and with our colleagues from NPI, Rez, Czech Republic. Analysis is under way. In parallel, we are studying different designs of liquid bismuth and eutectic Pb/Bi targets for 211At production [9]. At the moment, the main conclusion is that the complexity of such design (high thermal and mechanical stress, unknow behaviour of astatine at the interface with metallic surfaces …) do not justify to move to liquid targets and it seems more interesting to have a network of dedicated machine using solid bismuth targets to spread the availability of 211At. 16.2.3 Titanium-44/Scandium-44 Scandium-44g has a half-life of 3.97 h. It decays through electron capture in 5.73 % of the cases and by b+ emission in 94.27 % of the cases with a mean kinetic energy of 632 keV. It can be used for PET imaging and will be complementary to the shorter half-life 68Ga (T1/2= 67.71 min). It is possible to produce it directly by irradiation on calcium or titanium targets. However, is also possible to make it available through a generator system, the so-called 44Ti/44Sc generator. To produce 44Ti (T1/2 = 60.0 y), long irradiation time is required making this generator expensive to produce. To overcome this issue, it is possible to use spared particles after irradiation of another radionuclide that requires high energy protons like 82Sr [10]. This is the dual target concept. We have modified our targetry system to be able to accommodate a 45Sc (purity > 99.9%) target in order to produce 44Ti through the (p,2n) reaction. Two irradiations were conducted. The first one for a duration of 3 days (24/24) whereas the duration of the second one was 8 consecutive days (24/24). Measurements shown that unexpected 46Sc is produced coming from the interaction of secondary neutrons created in the Rb target placed in front of the scandium through the (n,ɣ) reaction. In order to be able to handle the target more easily, few months of cooling time are required. Next step will be to perform the chemical work necessary to fabricate the generator and study it to better understand how to use it efficiently and in particular to study breakthrough. 16.2.4 Ruthenium-97 Ruthenium-97 has a half-life of 2.83 d. It decays 100% through electron capture. Associated to these decay, 215.70 keV (85.62%) and 324.49 keV (10.79%) gamma rays are emitted. These gamma rays are suitable for single photon emission computed tomography (SPECT imaging). These imaging capabilities can be useful for imaging new Ru based chemotherapy drugs under development and also for the theranostics approach associated with 103Ru, a βemitter with a T1/2=39.249 d. As technetium is a radioelement, ruthenium isotopes are produced by using an α-particle beam interacting on a molybdenum target. Recent cross section measurements performed at our facilities confirm that the cross section on natMo is quite flat at 200 mb from 20 MeV up to 70 MeV [11]. Typical irradiation conditions are a natMo target thickness of 75µm (250mg), an integrated current of 150 µAe.h on target and a beam energy around 27 MeV obtained using the beam energy degrader developed for astatine-211 production. In Deliverable D8.1 57 these conditions, the 97Ru production yield reaches 2 MBq/µA.h at EOB. Major impurities are 103Ru and 95mTc. A purification process using a chromatographic method have been developed leading to 70-80% yield and a stable Mo versus Ru ratio equal to 10 to 1. Monthly productions are now scheduled to support chemistry and preclinical works. 16.3 Conclusion A multi-particle, high energy and high intensity machine is a very versatile tool for isotope production. The C70XP machine in house allows us to use high energy proton beam to produce 44Ti, high intensity deuteron beam for 64Cu and alpha beam for 211At and 97Ru. 16.4 References [1] Haddad, F., et al, ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine, Eur. J. Med. Mol. Imaging 35, 2008,1377-1387. [2] Koumeir et al, the radiobiological platform at Arronax, Rad. Prot. Dos., ncy301, https://doi.org/10.1093/rpd/ncy301 [3] Poirier F. et al, The Injection and Chopper-Based System at Arronax C70XP Cyclotron, Proc. Cyclotrons'19, Cape Town, South Africa, Sep. 2019, pp. 160--162. doi:10.18429/JACoW - Cyclotrons2019-TUP006 [4] Vidal A. et al, ARRONAX Cyclotron: Setting up of In-House Hospital RadiopharmacyBioMed Research International 2020, 2020: 1572841 [5] Kinsey R.R., et al., The NUDAT/PCNUDAT Program for Nuclear Data, paper submitted to the 9th International Symposium of Capture Gamma-Ray Spectroscopy and Related Topics, Budapest, Hungary, October 1996. [6] Aslam M.N. et al, charged particle induced reaction cross section data for production of the emerging medically important positron emitter 64Cu: A comprehensive evaluation, Radiochim. Acta 97, 2009, 669 [7] PRISMAP EU project – under No 101008571 [8] Eychenne, R et al, Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The Hopeful Eight. Pharmaceutics 2021, 13 (6), 906 [9] T. Bigourdan, Discussions on liquid bismuth targets use as an alternative for astatine-211 production. Proceedings of the 30th World Conference of the INTDS, Villigen, Switzerland. [10] T. Sounalet et al, Strontium-82 and Future Germanium-68 Production at the ARRONAX Facility. Nuclear Data Sheets, Volume 119, May 2014, Pages 261-266 [11] Sitarz M. et al, New cross-sections for natMo(α,x) reactions and medical 97Ru production estimations with Radionuclide Yield Calculator, Instruments 2019, 3(1), 7; doi:10.3390/instruments3010007. 16.5 Acknowledgements The cyclotron Arronax is supported by CNRS, Inserm, INCa, the Nantes University, the Regional Council of Pays de la Loire, local authorities, the French government and the European Union. This work has been, in part, supported by a grant from the French National Agency for Research called “Investissements d’Avenir”, Equipex Arronax-Plus ANR-11-EQPX-0004, Labex IRON ANR-11-LABX-18-01 and ISITE NExT ANR-16-IDEX-007. It has been also supported partly through a funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP). Deliverable D8.1 58 17. R&D Activities for alphatherapy at GANIL Gilles de France (GANIL), for the REPARE collaboration With the advent of high intensity, light beams delivered by the superconducting LINAC at GANIL-SPIRAL2, new opportunities arose with a focus on research and development activities associated to Targeted Alpha Therapy. More precisely, and to start with, the emphasis has been put on the synthesis of 211At, in close connection with ARRONAX. Today, several factors prohibitively limit the production and use of 211At:  The maximum intensity of the beam available from the accelerators. The most efficient reaction is 4He(209Bi,2n)211At.  The energy loss of the particles in the bismuth target (90 mm is enough to absorb the 8.3 MeV of a particle between the 29 MeV of incident energy for the production of 211At, which is the optimal energy, at 20.7 MeV, which is the production threshold below which 211At is no longer produced). This can cause the temperature to rise rapidly and the bismuth to melt as the beam current to the target increases.  The production of 210At decaying to 210Po which concentrates in the bones (for patients) and the presence of high energy gamma rays in the decay of 210At (a potential radiation protection problem for personnel).  The half-life of 7.2 h which limits the delivery zone. The REPARE project, funded by the ANR and PRISMAP, and led by GANIL, is underway and aims to remove the scientific and technical barriers linked to these limitations. To do this, we plan to:  Use the high-intensity beam of alpha particles from SPIRAL2: the expected intensity is around one mAe, about 20 times more than at ARRONAX.  Develop dedicated high-power targets capable of handling the available beam intensity. One option is a rotating system while an even more complex but potentially more efficient design would be a liquid target.  Accurately measure the production of contaminants and in particular 210At and 210Po.  Study of radon chemistry and possibly design of a 211At generator. This would make it possible to use the decay of 211Rn (T1/2 = 14.5 h) to produce 211At, thus very significantly increasing the delivery zone. For this, the 6,7Li(209Bi,xn)211Rn reaction must be used and precisely characterised (in particular contaminants such as 210,211Po which are weakly produced but which have never been measured in these reactions). In the presentation, the status of these developments has been shown. The first experiment to measure cross sections at SPIRAL2 has been performed in September 2022. The analysis is ongoing and will bring new measurements in particular in the critical energy region of 210Po production threshold. One major goal of REPARE is to design and build a target station able to produce ~1GBq/h, which implies a system able to dissipate 10 kW of beam power. The proposed design consists in a rotating wheel hosting 12 targets, cooled with water (see Figure 44). Fluidic CFD (Computational Fluid Dynamics) calculations have been performed in order to determine inlet water temperature, pressure and wheel rotation velocity. Several off-beam tests have been performed to check cooling, beam current reading system, absence of water leak, reliability of the target extraction system, etc. In July 2023, the target station will be further tested in-beam. Deliverable D8.1 59 Figure 44. Wheel of the target station hosting 12 targets and showing the water flow (left). Picture of the actual target station. The horizontal compartment hosts the lead container in which the irradiated targets are stored at the end of beam time (Right) Another concept of high-power target system involving liquid bismuth or Lead-Bismuth Eutectic (LBE) mixture is also being studied. Various options are considered: a sealed capsule with liquid bismuth inside, an LBE loop with a window cooled by the LBE itself and including heating resistances and thermal exchanger. The 211At might be extracted online. In this design, the LBE has a triple role: target material, coolant and 211At carrier. The third, more ambitious, design is a windowless circuit. A comparison of the three designs shows that the capsule option has a very efficient activity production with the advantages of simplicity, easyness of installation, exploitation and integration as well as being cost effective. To summarize, the development of R&D activities for Targeted Alpha Therapy at GANIL is progressing well. Cross section measurements have been performed and a high-power solid bismuth target station has been designed, built and is currently under test. Several designs of liquid targets are being evaluated within the REPARE collaboration. The capsule option seems promising. This work is also supported by the French Research National Agency under the contract ANR-19-CE31-0013-01. Deliverable D8.1 66 Figure 49. A schematic overview of a typical ion source used by ISOLDE and MEDICIS. Alongside the surface and laser ionisation mechanisms discussed above, the figure also shows the thermionic emission of electrons from the walls induced by the heating of the ion source. This emission is known to enhance ionisation efficiency due to the longitudinal plasma potential created in the centre of the source which confines the ions and thus reduces the probability for recombination through wall collisions [4]. Figure 1 also shows the extraction which penetrates inside the source at a distance proportional to the aperture of the source (shown in blue). The atoms ionised within the extraction field get immediately extracted, but exhibit a large energy spread since they are not created in a field-free region. A way to "see" inside the source is by looking at the time structure of the ions within one laser pulse (100𝜇𝜇s) which shows the time-of-flight of the extracted ions (Figure 50). Figure 50. Three-time courses taken for low, medium and high ion loads at the same ion source temperature. The ions created in the extraction field have a large energy spread and can be seen in Figure 2 as a prompt peak. The intensity of the peak should be more or less constant since it depends primarily on the atomic distribution in the source. The main, broad peak represents the ions created along the length of the source and it can be clearly seen that at high ion loads, the ratio between the constant prompt peak and the main Deliverable D8.1 67 peak changes and the ions created at the back of the source are no longer efficiently extracted (the region between 0 and 20𝜇𝜇s on the figure). 19.6 The ideal laser ion source for MEDICIS In order to better extract the ions at high ion loads, all of the effects described above should be considered which can be difficult since these effects are coupled. The requirements for such an ion source design can be described in the following way. An optimal design for the MEDICIS ion source should include:  A low work function material. This has a two-fold advantage - on the one hand it promotes thermionic emission which confines the ions better and on the other hand it suppresses surface ionisation.  Improved ion survival. This effect depends on the thermionic emission but can also be decoupled by creating this potential externally - for example via a magnet around the source.  Improved ion extraction. Fast ion extraction is favoured as it is coupled to ion survival. The drift potential which guides the ions to the extraction electrode can be increased by changing the thickness and/or the resistivity of the source material.  Homogeneous temperature distribution. The ISOLDE ion source, which is typically used for MEDICIS, does not have active heating of the back of the transfer line. This can lead to cold spots in the source where atoms condense and since the thermionic emission is an effect prompted by heating, it could additionally lead to a non-homogeneous confining potential in order to improve our understanding of the various effects playing a role in the ion creation, confinement and extraction. 19.7 Conclusions Fast extraction and collection of radioactive samples can decrease losses through decay in medical radioisotope production for MEDICIS and other medical radionuclide collection facilities. A laser ion source specifically designed for MEDICIS can improve collection times. The ion source material, temperature distribution as well as ion survival and ion extraction are important parameters which are studied in order to design a new ion source which has proven to be challenging as these parameters are coupled. Time course measurements are a useful way to probe the ion source. 19.8 References [1] М. Borge B. Jonson. ISOLDE past, present and future. Journal of Physics G: Nuclear and Particle Physics (2017). 44. 044011. 10.1088/1361-6471/aa5f03. [2] V.N. Fedosseev et al. Ion beam production and study of radioactive isotopes with the laser ion source at ISOLDE. J. Phys. G: Nucl. Part. Phys. 44084006, 2017 [3] C. Duchemin, et al. CERN-MEDICIS: A Review Since Commissioning in 2017. Frontiers in Medicine 8 (2021) 693682. 10.3389/fmed.2021.693682 [4] R. Kirchner. On the thermoionisation in hot cavities. Nuclear Instruments and Methods in Physics Research A292 (1990) 203-208, North-Holland Deliverable D8.1 68 20. Ion source developments at SCK CEN Kim Rijpstra1, Sophie Hurier1,2, Thomas Elias Cocolios2, Philip Creemers1, Marc Dierckx1, Donald Houngbo1, João Pedro Ramos1, Lucia Popescu1. 1 Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium 2 KU Leuven, Institute for Nuclear and Radiation Physics (IKS), Leuven, Belgium Given the increased demand for the production of Radioactive Ion Beams (RIBs) using the Isotope Separation On-Line (ISOL) technique, a new ISOL facility is currently being built at SCK CEN, as part of the MYRRHA project [1](Figure 51). The intense 100 MeV driver beam (up to 0.5 mA) will lead to a high production rate of isotopes from a target which operates under up to 50 kW of proton beam power. The aim is to efficiently produce RIBs from these isotopes, running a single target-ion-source unit for up to 4 weeks in a row. A crucial process in the formation of RIBs is the ionisation and extraction of isotopes. The requirements for 1a long lifetime of ion source, 2an increased overall production (up to one order of magnitude higher than at ISOLDE, depending on the isotope), combined with requirements to produce all known RIBs, to serve different applications and to achieve as high efficiencies as achievable, triggers the study and further development of existing ion sources early on. Figure 51. Overview of the MYRRHA project. To this end, the design of the ISOL@MYRRHA front-end foresees connections for the implementation of several types of ion sources in its Target-Ion Source assemblies: a hot cavity for surface ionisation, a plasma ion source (a Forced Electron Beam Induced Arc Discharge FEBIAD and evolutions [2]) or sources with ion guides (LIST [3], IGLIS [4]) for in-source spectroscopy. The target-ion source assembly is a transportable vacuum vessel that contains the target and the ion source and allows swift installation and removal of these from the ISOL system in the target station. Resonant Ionisation Laser Ion Source (RILIS) operation is foreseen, to be applied in any requesting ion source. A hybrid laser system [5], composed of multiple tunable dye and Ti:Sa lasers and fixed-wavelength solid state lasers will be installed in a dedicated laser lab to produce the laser beams for any specific elemental ionisation scheme. Through a system of mirrors, of which some dichroic (to merge the multiple laser beams) and prisms, the laser light will be aimed into the ion source through the mass separator and the front-end of the ISOL System, similar to TRILIS [6]. To this end, a small laser laboratory with two dye lasers and two Nd:YAG pumplasers has been realised close to the offline ISOL system that is currently under construction at SCK CEN. Coupled to this offline setup, the laser system can be used to evaluate future ion source developments inhouse. The laboratory is also equipped with a so-called Atomic Beam Unit (ABU), based on a design from the Deliverable D8.1 69 KU Leuven Institute for Nuclear and Radiation Physics (IKS) [7], to allow, within the limit of 2 tunable lasers, the development of new ionisation schemes using a vapor of a stable element. Because of its reliability and simple design, a surface ion source (SIS) or hot cavity was chosen for implementation as first type of ion-source in ISOL@MYRRHA. The reference model is the SIS from SPES, INFN [8], which itself is an evolution from ISOLDE’s (CERN) standard hot cavity, ISOLDE MK1. This source will most likely be saturated (stagnant production of RIB with increasing primary beam) under these operating conditions as this efficiency reduction is already encountered in today’s facilities, during operation as a surface ion source, but even more explicitly in RILIS mode. In a SIS, an isotope, with low to moderate ionisation potential, can ionize when it interacts with a hot surface usually tube or cavity made of refractory metal with a high work function like tungsten (W) or tantalum (Ta). This metal is ohmically heated with a high current (> 250 A), which heats the ionizer tube to temperatures above 1500°C. However, this temperature is not constant along the ionizer tube. A cold spot at the cavity’s end leads to local loss in ionisation efficiency at that position and more critically, it could lead to reduced confinement of ions. The lower capacity of thermionic electron emission at lower temperature [9] limits how strong the negative confinement potential in the centre of the cavity can be. It also limits how fast the confining electron sheet can reinforce itself in case of a sudden burst of positive ions (for example after a laser pulse). Therefore, this cold spot potentially, gives rise to the aforementioned saturation issues, especially if it is already strong before the extraction field from the extraction electrode takes effect in the cavity. Figure 52. Overview of an ion source mounted onto a base plate, with a view of the current flow through the cavity and the 'active thermal screen'. In a publication by Hurier et al. [10], a modification to the hot cavity heating was studied through thermoelectric simulations using the finite elements package ANSYS, in order to reduce this cold spot. This resulted in the ’Active Thermal-Screen’ (ATS) concept, see Figure 52. In this ATS design, the hot cavity is electrically isolated from its base plate with insulating washers. As such, current is no longer directly fed to the back plate, but one uses two separate feedthroughs for the input and the output current. This allows eventually to put the target-ion source at a different electrical potential, creating options for a second extraction electrode. The current will flow through a thermal screen around the cavity. Normally, this screen, or heat shield, passively reflects the radiative heat back to the source. This is the case in the SPES design, but, in the ATS design, it becomes an actively heated part. This improves the temperature profile: the cold spot at the cavity’s end diminishes, which should improve ion confinement and extraction. Additionally [10] shows how the length of this heat shield affects the peak temperature and the position of that peak temperature along the cavity. Deliverable D8.1 70 Not only the design but also the production method plays a key role in the operation and reliability of ion sources. For this concept, several methods have been considered of which two are under investigation: assembly through press-fitting and 3D-printing. The former is made in tantalum with conventional manufacturing methods. This design focuses on simplicity and with a play of press fittings, it removes all welding steps from the assembly. The advantages are simplicity as only cutting, simple bending and press-fitting are required, the use of well-known tantalum with its refractory nature, good mechanical and thermal-electric properties. On the other hand, it might be less reliable and less reproducible, due to many manual manufacturing steps and potentially deficient/nonuniform contacts between the pieces. This manufacturing process will be evaluated during the in-house construction of a prototype. Furthermore, there are some differences between this assembled design and the earlier concept, which makes it advisable to repeat the thermal-electric simulations that were done in [10] for this final design. Figure 53 shows the hot cavity temperature (between 0 and 33 mm) of our assembled design. The temperatures are significantly higher along the cavity compared to the SPES design. Furthermore, when compared to the results presented in [10], higher temperatures are achieved for this design. This is due the direct fitting of the thermal screen into the support plate, rather than sliding it in/over a thin ring welded on the support. This latter was the case for the passive thermal screen in the reference design, but for the active heat shield it created a cold spot in the heat shield as the electrical resistance was locally halved. In all simulations perfect contacts were assumed, which is, as mentioned, not necessarily the case. When the prototype is successfully manufactured, its heating response will be tested on our thermal test bench, during which also the temperature profile will be measured and long-term mechanical stability will be tested. In a final stage, the prototype will be installed in an offline ISOL setup, either at CERN or at KU Leuven, to characterize its operation as ion source. Figure 53. Temperature profile for different currents along the cavity, both for the assembled design in this work and the reference SPES design. The drawing shows a cut through the ion source axis viewed from the top. The second fabrication-route under investigation is that of 3D-printing, using the Laser Beam Melting on Powder Bed (LBM-PB) method. Through collaboration with a commercial partner, this currently focuses on the potential printing of an ion source in tungsten. The technique and the design are still under development. Deliverable D8.1 71 Nonetheless, we deem 3D-printing a potential manufacturing method in the future, giving opportunity to implement innovative design-concepts and geometries that are hardly possible today. To conclude, in this contribution we underlined that ISOL@MYRRHA infrastructure foresees sufficient services to operate state-of-the-art ion sources running in operational facilities today, as well as future sources. The current in-house development focuses on the design of an improved hot cavity by means of thermo-electric engineering and implementation novel manufacturing techniques, while for resonant laser ionisation a hybrid (Dye & Ti:Sa) laser system is foreseen. To guide the on-line facility design and support further ISOL development, a laser laboratory has been constructed to be coupled to the offline ISOL system of SCK CEN. 20.1 References [1] L. Popescu, "Nuclear-physics applications of MYRRHA," in EPJ Web of Conferences, 2014, vol. 66: EDP Sciences, p. 10011. [2] T. D. Goodacre et al., "Blurring the boundaries between ion sources: The application of the RILIS inside a FEBIAD type ion source at ISOLDE," Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 376, pp. 39-45, 2016. [3] R. Heinke, "In-source high-resolution spectroscopy of holmium radioisotopes-On-line tailored perpendicular laser interaction at ISOLDE's Laser Ion Source and Trap LIST," Mainz U., Inst. Phys., 2019. [4] M. Mostamand et al., "Production of clean rare isotope beams at TRIUMF Ion guide laser ion source," Hyperfine Interactions, vol. 241, no. 1, pp. 1-9, 2020. [5] B. A. Marsh, "Resonance ionisation laser ion sources for on-line isotope separators (invited)," Rev Sci Instrum, vol. 85, no. 2, p. 02B923, Feb 2014, doi: 10.1063/1.4858015. [6] J. Lassen, P. Bricault, M. Dombsky, J. P. Lavoie, C. Geppert, and K. Wendt, "Resonant Ionisation Laser Ion Source Project at TRIUMF," Hyperfine Interactions, vol. 162, no. 1-4, pp. 69-75, 2006, doi: 10.1007/s10751-005-9212-2. [7] K. Dockx et al., "A new control system for high-precision in-gas laser ionisation and spectroscopy experiments at KU Leuven," Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 463, pp. 297-301, 2020. [8] M. Manzolaro, F. D'Agostini, A. Monetti, and A. Andrighetto, "The SPES surface ionisation source," Rev Sci Instrum, vol. 88, no. 9, p. 093302, Sep 2017, doi: 10.1063/1.4998246. [9] R. Kirchner, "On the thermoionisation in hot cavities," Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, vol. 292, no. 2, pp. 203-208, 1990. [10] S. Hurier, K. Rijpstra, P. Creemers, J. P. Ramos, L. Popescu, and T. E. Cocolios, "Design and thermal simulations towards a high intensity radioactive ion source for ISOL@MYRRHA," Journal of Physics: Conference Series, vol. 2244, 19th International Conference on Ion Sources – ICIS2021 20/09/2021 - 24/09/2021 Online, p. 012065, apr 2022, doi: 10.1088/1742-6596/2244/1/012065. Deliverable D8.1 72 21. DFT calculations of Ti-based molecules clustering with Ar for laserbased enrichment of stable isotopes Thomas Elias Cocolios1, Cyril Bernerd1,2, Lucas Dooms3, Piero Ferrari4,5, Oliver Payne3 1KU Leuven, Institute for Nuclear and Radiation Physics, Celestijnenlaan 200D, 3001 Leuven, Belgium 2SY Department, CERN, 1 Esplanade des Particules, 1311 Geneva, Switzerland 3KU Leuven, Department of Physics and Astronomy, Celestijnenlaan 200D, 3001 Leuven, Belgium 4KU Leuven, Quantum Solid State Physics, Celestijnenlaan 200D, 3001 Leuven, Belgium 5FELIX Laboratory, Radboud Universiteit, 6525 ED Nijmegen, Netherlands Disclaimer: this text was submitted for peer-review to Nuclear Instruments and Methods in Physics Research B as part of the proceedings to the EMIS 2022 conference, held in Daejeon, South Korea. 21.1 Introduction The selective production of radioisotopes with low-energy particle accelerators based on fusion-evaporation reactions, or in nuclear reactors with neutron capture, partially relies on the availability of isotopically pure target material. Isotopes of calcium (Z=20) and titanium (Z=22) are promising for the production of the medically relevant isotopes 43Sc, 44Sc, and 47Sc [1, 2] - see Table 4. However, both elements have a fragmented natural distribution across 6 and 5 stable isotopes, respectively. Moreover, 48Ca (natural abundance 0.185%) is the most neutron-rich stable isotope that can be used as a beam to synthesize superheavy elements [3]. Table 4. Scandium radioisotopes employed in nuclear medicine, their half-life, and their production routes Isotope Half-life Production reactions 43Sc 3.89 h 40Ca(α,p)43Sc, 42Ca(d,n)43Sc, 43Ca(p,n)43Sc, natCa(α,n)43Ti→43Sc, 46Ti(p,α)43Sc 44Sc 3.97 h 44Ca(p,n)44Sc/44mSc, 44Ca(d,2n)44Sc/44mSc, natCa(p,xn)44Sc, 45Sc(p,2n)44Ti→44Sc, 47Ti(p,α)44Sc 44mSc 58.6 h 44Ca(p,n)44Sc/44mSc, 44Ca(d,2n)44Sc/44mSc 47Sc 3.35 d 46Ca(n,γ)47Ca→47Sc, 48Ca(p,2n)47Sc, 47Ti(n,p)47Sc, 48Ti(γ,p)47Sc, 50Ti(p,α)47Sc Calcium and titanium are metals, which enrichment is currently only available through physical mass separation with large magnetic dipoles, the so-called calutrons. Such facilities are not available in Europe, and have extremely limited access in the USA; the main supplier is the Russian Federation. This poses substantial constrains on the reliable supply of such material due to limited competition and high dependence upon geopolitical situation, as the supply of such material becomes a subject of political strategies. In order to diversify the supply of enriched calcium and titanium, a research programme on the Separation of Isotopes by Laser-Assisted Retardation of Condensation (SILARC) is currently ongoing within PRISMAP - The European medical radioisotope programme. Here, we report here on preliminary calculations aimed at identifying the most promising molecules containing calcium or titanium with which to perform SILARC. 21.2 SILARC The Separation of Isotopes by Laser-Assisted Retardation of Condensation (SILARC) is a method by which an element can be enriched by selective laser ionisation of molecules in a gas jet [4]. A molecule containing the element of interest – here calcium or titanium – is introduced in a buffer gas cell. The mixture is released through an aperture and the expanding gas jet becomes supersonic, resulting in sudden cooling down to ∼ 15 K [5]. Deliverable D8.1 73 The buffer gas condensates on the molecules and forms clusters. Isotope-selective infrared (IR) excitations of the molecules selectively heat up one isotopomer (molecule containing a specific isotope), preventing clusterisation. The heavy clusters and clean isotopomer experience different drag forces and can be separated by a skimmer. Recycling the material allows for multiple passages for improved enrichment of the isotope of interest. As a precursor to this technique, it is essential to identify a molecule that contains a single element of interest, to ensure that the isotopomer is pure, and that the molecule is sensitive to IR excitation in a range accessible by high-power lasers. 21.3 DFT calculations An initial assessment was performed on the simplest Ti-containing molecules that may be produced and investigated, namely titanium fluoride TiFx (x = 1 − 4), and then extended to more complex molecules. Density Functional Theory (DFT) calculations were performed with the ORCA 5.0 software package [6] using the Def2TZVPP basis set and D3BJ dispersion corrections. Five functionals were initially tested: PBE, TPSS, PBE0, B3LYP and CAM-B3LYP, against experimental data available on TiF4 (bond length and harmonic vibrational frequencies) [7, 8]. For each molecule, the geometry is first optimised at different spin multiplicities. The harmonic vibrational frequencies are then determined, which are all positive, thus confirming that the optimised geometries correspond to true minima in the potential energy surface. Finally, the binding of buffer gas atoms to the molecules is explored at different temperatures to assess the clustering effect. For all the calculations, the tight convergence criterion was selected for the geometry and the SCF optimisation cycles, as implemented in ORCA. 21.3.1 Simple molecules Figure 54. Shape and bond lengths of TiFx (x = 1 − 4) from DFT calculations using the hybrid PBE0 exchange-correlation functional. The large, grey spheres represent Ti atoms and the small, turquoise spheres represent F atoms. The numbers correspond to the different bond lengths in Å. TiF2 also shows the angle between the two fluorine atoms. The lowest-energy spin multiplicity is shown at the bottom of each panel. The simplest molecules for which DFT calculations were performed were titanium fluorides, TiFx (x = 1 − 4), as they are only made of two elements, and also as there exists data on TiF4 for comparison [7, 8]. The different configurations are shown in Figure 54. TiF4 was first computed to compare the calculations against experimental data: the Ti-F bond length of 1.754 Å [7] and a vibrational frequency of 712 cm−1 [8]. In general, all functionals perform well, deviating less than 0.015 Å for the bond length and less than 20 cm−1 for the vibrational frequency. The hybrid PBE0 exchangecorrelation functional is best to reproduce both properties at once and is thus used further in these calculations. The obtained vibrational frequencies for the different isotopomers are listed in Table 5. Most of the vibrational frequencies show an isotope shift, though one vibrational frequency in TiF3 and TiF4 are Deliverable D8.1 74 independent of the titanium isotope. Those vibrations are associated with the motion of the fluorine atoms only with minor or no involvement of the titanium atom. All identified resonances are found in the 700 − 820 cm−1 range, which corresponds to wavelengths in the 11.75 − 14.25 μm range. Those are challenging to reach with commercial laser systems, prompting the idea to explore more complex molecules, with potentially more accessible IR transitions. Table 5. Selected vibration frequencies (in cm−1) of titanium fluoride isotopomers and more complex molecules of interest calculated with DFT. Molecule 46Ti 47Ti 48Ti 49Ti 50Ti TiF 721.05 718.80 716.64 714.56 712.56 TiF 2 752.99 749.62 746.37 743.24 740.22 TiF 3 662.29 779.71 780.00 662.28 776.30 776.65 662.28 773.01 773.43 662.27 769.84 770.32 662.27 766.78 767.34 TiF 4 727.72 815.51 818.56 819.36 727.72 812.07 815.09 815.88 727.72 808.77 811.74 812.52 727.72 805.59 808.52 809.30 727.72 802.53 805.42 806.19 Ti[OEt] 4 642.71 649.07 650.07 3159.8 3160.3 3160.7 639.52 645.76 646.70 3159.8 3160.3 3160.7 636.44 642.56 643.45 3159.8 3160.3 3160.7 633.47 639.48 640.32 3159.8 3160.3 3160.7 630.60 636.50 637.29 3159.8 3160.3 3160.7 Ti[OPr] 4 629.91 632.39 641.17 3136.8 3138.5 3138.8 627.12 629.65 638.98 3136.8 3138.5 3138.8 624.42 627.03 636.89 3136.8 3138.5 3138.8 621.83 624.50 634.89 3136.8 3138.5 3138.8 619.33 622.06 632.98 3136.8 3138.5 3138.8 C 10 H 2 TiF 12 O 4 670.18 670.44 3175.9 3176.1 669.51 669.78 3175.9 3176.1 668.87 669.13 3175.9 3176.1 668.26 668.52 3175.9 3176.1 667.67 667.92 3175.9 3176.1 21.3.2 Complex molecules Experimental investigations of titanium (IV) ethoxide, Ti[OEt]4, have shown IR vibrational resonances at much more accessible frequencies [9]. By analogy, titanium (IV) isopropoxide, Ti[OPr]4, was also investigated, as it should possess accessible frequencies too. As shown in Table 2, there are indeed many more vibrations around 3138 cm−1, corresponding to 3.2 μm. Those higher frequency vibrations, however, are all independent of the titanium isotope since they arise from stretching of the C−H bond. In contrast, the vibrations involving the titanium isotope, and thus presenting an isotope shift, remain at much lower frequencies. There is thus no improvement in selectivity opportunity from those molecules. A final computation was performed on titanium (IV) hexafluoroacetyl acetonate, C10H2TiF12O4, as the synthesis of this molecule could allow the scalability of the process in the future. Similarly, to the other species, the only vibration frequencies presenting any isotope shift are in the range 600 − 650 nm, corresponding to wavelengths in the range 15.33 − 16.66 μm. Deliverable D8.1 75 21.3.3 Ar clustering Figure 55. TiF4 loosely bound to 20 Ar atoms, represented by the large cyan spheres, at low temperature (15 K). As part of demonstrating the feasibility of the SILARC approach for these molecules, we applied the formalism developed above to the binding of argon atoms. The binding energy Eb of adding an Ar atom to a TiF4 molecule was determined at temperature T = 15 K and 300 K. This value is computed as the difference between the Gibbs free energy F of the cluster to that of the two separate components: Eb = F(TiF4) + F(Ar) − F(TiF4 − Ar). At 15 K, a positive value Eb = 0.04 eV is found, while at 300 K, the same gives a negative value Eb = −0.22 eV. From this, it can be concluded that an Ar atom may indeed attach to this molecule at low temperature to form a cluster. This approach was repeated incrementally up to 20 Ar atoms, each step confirming that the additional Ar atom binds to the cluster at low temperature. This suggests that very large clusters may thus form in the supersonic gas jet, providing substantial differences in condensation between the cold molecules and those excited by the IR laser. An illustration of the [TiF4]Ar20 cluster is shown in Figure 55. 21.4 Conclusions Titanium and calcium enrichment is being researched by the SILARC method in the framework of medical radioisotope production, with potential to also support radioactive ion beam production. As premise to this technique, DFT calculations have been performed on Ti-containing molecules, first to validate the method with TiF4, and then to explore the most appropriate molecule with accessible, isotope-dependent, IR excitations. The excitation frequencies displaying an isotope shift are all located at low frequencies, with wavelength >12 μm. Higher vibration frequencies may be found, but are not sensitive to the different Ti isotopes. This means that besides the chemical developments to produce the molecules of interest, and the technical developments to produce a SILARC facility, it is necessary to develop a laser system that may supply such IR light. It is proposed to explore frequency mixing of near-IR light to investigate these transitions [10], although the scalability of this approach remains uncertain. In the future, it will be essential to validate fully those calculations experimentally by investigating the vibrations within the molecule of interest using enriched isotopomers. Such measurements may be performed, e.g., at a free-electron laser facility that provides access to such frequencies. 21.5 References [1] S. Huclier-Markai et al., Cancer Biotheraphy & Radiopharma. 33, 316 (2018). [2] C. M¨uller et al., The Brit. J. of Radiology 91, 1091 (2018). [3] S.A. Giuliani et al., Rev. Mod. Phys. 91, 011001 (2019). [4] J.-M. Zellweger et al., Phys. Rev. Lett. 52, 522 (1984). [5] R. Ferrer et al., Phys. Rev. Res. 3, 043041 (2021). [6] F. Neese et al., J. of Chem. Phys. 152, 224108 (2020). [7] S.P. Webb et al., J. of the Am. Chem. Soc. 121, 2552 (1999). Deliverable D8.1 82  Dilatometer (<1600 °C) in either air, inert or reductive atmosphere;  Differential Thermal Analysis/Thermal Gravimetric Analysis (DTA/TGA) (<1750 °C) under controlled atmosphere;  Eddy current measurements – oxide thickness layers;  Gamma spectrometry;  Optical microscopy (microhardness and etching);  Scanning Electron Microscopy, with  Secondary electron (SE) and back scattered electron (BSE) detectors,  Energy dispersive X-ray (EDS/EDX),  Electron backscattered diffraction (EBSD);  Focused Ion Beam (FIB) with Scanning Electron Microscopy (SEM),  Also used for sample preparation together and alternatively to Precision Ion Polishing System – PIPS (also available at SCK CEN);  Electron MicroProbe Analysis (EPMA);  Transmission Electron Microscopy (TEM);  High resolution imaging,  Scanning transmission electron microscopy (STEM);  X-ray radiography;  and X-Ray diffraction (XRD)  with in situ high temperature XRD (<1600 °C in air, >2000 °C possible in vacuum). Using the mentioned characterisation infrastructure, through a collaboration, 6 samples were shipped in a special container to SCK CEN from TRIUMF’s irradiated and non-irradiated uranium carbide target materials (Figure 61a shows the non-irradiated TRIUMF’s target UCx disks). As can be seen in Figure 61b, a very small sample was extracted in the TRIUMF’s hot cell from the irradiated UCx target, to a SEM stub before shipping. The samples were then extracted from the shipping container and prepared for microscopy. Using SEM, the surface morphology of uranium carbide before and after irradiation was fully characterised as well as the elemental composition by EDS. Additionally FIB was used to look into the bulk of the UCx materials and to prepare lamella’s (see Figure 61c) for in-depth TEM characterisation. This target material due to its pyrophoricity, has seldomly been characterised in the literature [4, 5] and especially after irradiation, as it is extremely radioactive. A relatively large amount of data and information about this material and its evolution at the end of irradiation has been obtained and will be published elsewhere. Figure 61. (a) Pristine UCx target material composite (0.36 mm thick) casted in 0.13 mm thick graphite foil disks of 12.7 mm diameter; (b) Up - sample extraction tool, bottom – irradiated UCx sample retrieved from the hot cell; (c) TEM lamella of irradiated UCx sample prepared by FIB. Following the study on TaCx-based materials, the target material research for ISOL@MYRRHA is at this moment focused on Th-based materials within an SCK CEN funded PhD framework, in collaboration with Deliverable D8.1 83 ISOLDE at CERN. Additional focus is also being given, in the same collaboration, to the development of the “day-1” target(s), which are consisted of other (non-actinide) materials. In the target materials research, apart from the mentioned active collaborations with TRIUMF and CERN, SCK CEN is also involved in the PRISMAP consortium [6] and has future prospects for a collaboration with SPES [7]. With the currently emerging ISOL Facility which will also include dedicated actinide target material research laboratories, SCK CEN is creating a unique environment to potentiate innovative target material research including also post-irradiation characterisation studies, using the already existing in-house techniques. 23.1 References [1] L. Popescu, D. Houngbo, and M. Dierckx, "High-power target development for the next-generation ISOL facilities," Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 463, pp. 262-268, 2020, doi: 10.1016/j.nimb.2019.05.023. [2] M. Griseri et al., "Synthesis, properties and thermal decomposition of the Ta4AlC3 MAX phase," Journal of the European Ceramic Society, vol. 39, no. 10, pp. 2973-2981, 2019, doi: 10.1016/j.jeurceramsoc.2019.04.021. [3] M. Griseri et al., "Porous TaCx ISOL target materials from mould-casted Ta4AlC3," Journal of the European Ceramic Society, vol. 41, no. 7, pp. 3947-3959, 2021, doi: 10.1016/j.jeurceramsoc.2021.02.022. [4] J. P. Ramos, "Thick solid targets for the production and online release of radioisotopes: The importance of the material characteristics – A review," Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 463, pp. 201-210, 2020, doi: 10.1016/j.nimb.2019.05.045. [5] A. Gottberg, "Target materials for exotic ISOL beams," Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, vol. 376, pp. 8-15, 2016, doi: 10.1016/j.nimb.2016.01.020. [6] "PRISMAP Consortium Webpage." https://www.prismap.eu/ (accessed 31/01/2023). [7] M. Ballan et al., "Nuclear Physics Midterm Plan at LNL," To be submitted to a peer reviewed journal, 2023. Deliverable D8.1 84 24. Poster. Impact of the laser ionisation and temperature on the Actinium production from UCx target E. Jajčišinová1,2, K. Dockx1, T. E. Cocolios1, B. Cooper3, K. Chrysalidis4, D. V. Fedorov5, V. N. Fedosseev4, K. T. Flanagan3, M. Griseri1,6, D. Houngbo6, A. Kellerbauer2, S. Kraemer1, B. A. Marsh4, L. Popescu6, J.P. Ramos1,4,6, S. Rothe4, M. D. Seliverstov5, S. Sels1, G.J.F. Smith1, S. Stegemann1, M. Stryjczyk1,7, V. Verelst1 1KU Leuven, Instituut voor Kernen Stralingsfysica, B-3000 Leuven, Belgium, 2JRC Karlsruhe, 76125 Karlsruhe, Germany, 3The University of Manchester, M13 9PL Manchester, United Kingdom, 4CERN, CH-1211 Geneva, Switzerland, 5PNPI, 188300 Gatchina, Russia, 6SCK CEN, 2400 Mol, Belgium, 7University of Jyväskylä, Accelerator Laboratory, FI-40014 Jyväskylä, Finland The applications of nuclear physics in daily life can go from energy production to medicine. In recent years the research of radionuclides suitable for medicine is evolving. For example, they can be used for diagnostic purposes or cancer treatment. The choice of radionuclide is determined by its properties such as type of decay, half-life etc. The most potent option for cancer treatment is the use of alpha-decaying radionuclides as they provide deposition of a large amount of energy in a short range, sparing the healthy tissue. Based on these criteria, a new radionuclide 225Ac (T1/2=9.92 days) was introduced and proven as very efficient candidate for targeted alpha therapy (TAT) [1]. This isotope decays via 4 alpha decays with energies between 5-8.4 MeV and has high linear energy transfer (LET). Promising results in medical applications of this radionuclide [2] have led to an increased demand which cannot be fulfilled by the existing production methods. As a result, new production methods are under investigation. Various production routes appeared promising and one of them is production from the spallation reaction of protons with heavy long-lived targets like natural thorium or uranium. The difficulty of this route, however, is especially in the separation of 225Ac from 227Ac, both isotopes being produced in the spallation reactions. For this reason, chemical separation techniques can be complemented by mass-separation techniques. In this study, we investigate the potential of the Isotope Separation On-Line (ISOL) technique for ensuring the requested mass separation at the CERN-ISOLDE facility. 24.1 Production of 225Ac at the ISOLDE facility Radioactive ion beams (RIBs) generated by ISOLDE may contain a wide range of radionuclides, including the aforementioned 225Ac [3]. The protons are accelerated up to 1.4 GeV and then delivered to the target unit. In our study, the target consisted of a depleted Uranium Carbide (UCx) material surrounded by a graphite insert inside a tantalum container (#638). Highly energetic protons induce nuclear reactions, mostly fission, fragmentation, and spallation. The reaction products diffuse from the target, effuse from the surface to the ion source where they are ionised (e.g., surface, laser, plasma). This process is very complex, and all the steps impact the release efficiency and therefore overall production. After the RIB is created, another part of the ISOL method follows: with the use of a dipole magnet the mass of interest is filtered from the rest with respect to the ion mass-to-charge ratio. As well as the leading release step, the ionisation step has been identified as a bottleneck in RIB production. Some elements, such as Fr and Ra can be efficiently ionised on a hot surface, Ac beams cannot be produced in that fashion and require a different approach to ensure the extraction of the radionuclides of interest. In this work, we used element-selective laser ionisation to produce Ac beams [4]. 24.1.1 Impact of laser ionisation One of the ways to optimise the production of Ac is by using laser ionisation: a series of lasers are tuned to the energy of transitions between atomic states of the element of interest, namely Ac-I. These energies form Deliverable D8.1 85 a unique fingerprint of the element. The atom is ionised by stepwise exciting of the electron to different atomic states, where the last step lifts the electron beyond the ionisation threshold. In this work, we report on the results of Ac production test performed at ISOLDE in November 2018. The used ionisation scheme promoted the ground state electron from the 2D3/2 to the 4P5/2° level with a laser at 438.58 nm and then subsequently to an autoionising state with a laser at 424.69 nm [5], provided by the RILIS [6]. The beam production was monitored using a Faraday cup (FC) by measuring mass 227, with a beam composed of surface-ionised Fr and Ra, and laser-ionised Ac. By comparing the rate in so-called ‘Laser On’ and ‘Laser Off’ (first step laser blocked) modes, we proved that laser ionisation significantly enhances the Ac production, see Figure 62. Figure 62. Impact of the laser ionisation and transfer line temperature on the production. Data measured by FC at mass A=227. 24.1.2 Impact of transfer line and ion source temperature Another studied parameter, for suppression of Fr and Ra contamination, is the transfer line and ion source temperature. All the measurements were performed with the target at a stable temperature of 2000˚C and only the temperature of the transfer line and ion source (see Figure 62) varied between 1700-2350˚C. The impact of the transfer line and ions source heating temperature is observable (see Figure 63) but not as significant as the laser ionisation. Furthermore, Figure 62 shows that beyond 2000˚C, we observe a saturation beyond which no more increase in beam intensity is seen with a further increase in temperature. After observing this impact, a comparison between the pure actinium that was released and ionised (difference between laser on and laser off) and the total production consisting of surface ionised contaminants + Ac (laser on) was plotted. The behaviour of this ratio is presented in Figure 64. The fact that the ratio is almost constant indicates that even if we enhance the production of Ac, we also enhance the production of other isotopes as well. Additionally, reduction of transfer line and ion source temperature did not suppress the yield of surface ionised contaminants. One can conclude that transfer line and ionizer temperature do not have an impact on the relative ionisation efficiencies of the elements but rather on the survival efficiency from the ion source. Figure 63: Schematic layout of standard ISOLDE target -ion source unit. Figure adapted from [7]. Deliverable D8.1 86 Figure 64. Dependence of the line heating temperature on the enhanced production of the ²²⁷Ac relative to the total RIB production. 24.2 Conclusions The production process of RIB is very complex and can be influenced by many variables. In this work, we presented results of the first laser ionisation of Ac at the ISOLDE facility at CERN, opening the way to further opportunities in the production of 225Ac for TAT. Furthermore, we observed a small impact of transfer line and ion source temperature on the yield of Ac and contaminants. To conclude, the effect of these variables is observable but shows that when one enhances the yield of Ac, the yield of other isobars is enhanced as well. As a result, the relative population of Ac to surface ionised contaminants in the RIB cannot be changed only based on the ion source alone. We proved that producing 225Ac with this method is possible. This initial test shows that there are more options to boost the production of Ac RIBs to meet demand. Further work on the details of the laser ionisation of Ac is presented in follow-up work at CERN MEDICIS [8]. 24.3 References [1] Radchenko, V. et al., Production and supply of α -particle–emitting radionuclides for targeted α-therapy, J. Nucl. Med. (2021), 62:1495–1503, https://doi.org/10.2967/jnumed.120.261016 [2] Kratochwil, C. et al., 225Ac-PSMA-617 for PSMA-Targeted α -radiation therapy of metastatic castrationresistant prostate cancer, JNM (2016), https://doi.org/10.2967/jnumed.116.178673 [3] Catherall, R. et al., The ISOLDE facility, Journal of Physics G: Nuclear and Particle Physics (2017), 44:094002, https://doi.org/10.1088/1361-6471/aa7eba [4] Fedossev, V. N., Kudryavtsev, Yu., Mishin, V. I., Resonance laser ionisation of atoms for nuclear physics, Phys. Scr. (2012), 85:058104, http://stacks.iop.org/PhysScr/85/058104 [5] Raeder, S. et al., In-source laser spectroscopy developments at TRILIS – towards spectroscopy on actinium and scandium, Hyperfine Interac. (2013), 216:33-39, https://doi.org/10.1007/s10751-013-0832-7 [6] Chrysalidis, K. et al., Developments towards the delivery of selenium ion beams at ISOLDE, Eur. Phys. J. A (2019), 55:173, https://doi.org/10.1140/epja/i2019-12873-4 [7] Bouquerel et al., Atomic beam merging and suppression of alkali contaminants in multi body high power targets: design and test of target and ion source prototypes at ISOLDE, Université Paris XI Orsay, Doctoral dissertation, CERN-THESIS-2010-057 (2009) [8] Johnson, J. D. et al., Resonant laser ionisation and mass separation of 225Ac, Scientific Reports (2023), 13:1347, https://doi.org/10.1038/s41598-023-28299-4 Deliverable D8.1 87 25. Poster. Additive Manufacturing of Refractory Metals: from material to product characterisation P. Rebesan on behalf of the DIAM1 and SPES2 workgroup 1 National Institute for Nuclear Physics (INFN) – Padova Division, via Marzolo 8, 35131, Padova, Italy 2 National Institute for Nuclear Physics – Legnaro National Laboratories (INFN-LNL), Viale dell'Università 2, 35020 Legnaro (Pd), Italy 25.1 Additive Manufacturing of Refractory Metals at DIAM lab Additive Manufacturing (AM), also known as 3D printing, is considered the complementary technology to the conventional subtractive process. Metal Additive Manufacturing (MAM) is a production technology that fabricates metallic parts with layer-by-layer procedures, starting from different possible raw material forms (i.e., powder, wire, or sheets). Even though the way to implement the "layer by layer" process can be different (i.e., direct melting, joining, or binder jetting and sintering), as well as the energy source adopted, the main idea behind this technology is that a model made using a three-dimensional computer-aided design (3D CAD) system may be directly built in only one or a few steps. The manufacture of complicated geometries is made possible by AM technology. On the other hand, AM requires a thorough understanding of the limitations and qualities of the materials used to construct the additively manufactured part [1]. In fact, not all metallic materials are suitable to be produced using additive manufacturing production processes. For instance, this contribution illustrates some peculiar characteristics of different refractory metals produced by the Laser Powder Bed Fusion (LPBF) process. In the LPBF process, common research subjects include density measurements, surface morphology analysis, mechanical properties evaluation, and residual stresses analysis [2]. Despite the fact that the LPBF process manufactures functional components with peculiar characteristics and microstructure, more research is required to optimize the process parameters and building strategies to achieve the desired features [3]. Refractory metals belong to the group of "transition metals." Differently from the other elements of the group, they have physical, chemical, and mechanical properties specifically useful for high-temperature applications in extreme operating conditions. One of the most important characteristics is the high density (i.e., Os = 22.5 g/cm3; W = 19.25 g/cm3), which is combined with outstanding thermal shock resistance (W) and great resistance to electrochemical corrosion (Ta). These metals are therefore suitable for uses related to nuclear energy. Future nuclear fusion devices, like the tokamak at ITER, may use W as a material for their plasma-facing components (PFC) [4]. Mo is an excellent candidate for fusion reactor components due to its high thermal conductivity and temperature strength [5]. Niobium and its alloys are widely used in aerospace industry but also in high-energy and nuclear physics field, especially for the fabrication of next-generation superconducting radiofrequency (SRF) accelerating cavities [6]. One of the research activities conducted at the Development and Innovation on Additive Manufacturing (DIAM) laboratory of the National Institute for Nuclear Physics (INFN) aims to develop and characterize these exotic materials produced with the LPBF process. The materials chosen were determined by the projects and experiments carried out by INFN. Refractory metals, are employed frequently, for instance, in the construction of isotope separation on line (ISOL) facilities that generate radioactive ion beams for nuclear physics research [7]. Ta, Mo, and W semifinished materials are particularly used in the manufacturing of some of the most crucial and significant ISOL components, such as the high-temperature production targets and ion sources. Depending on the intended uses and performance requirements, refractory metal components are frequently produced using conventional manufacturing techniques. When the intended geometries are complex, as in the case of the aforementioned ISOL targets and ion sources, standard subtractive and joining procedures become troublesome and expensive [9], [10]. Normal production processes are challenging when Ta, Mo, or W are handled at high temperatures, such as in the heat affected zone (HAZ) of welding [10]. In addition, the hardness of Mo and W makes their production even more expensive due to material waste and Deliverable D8.1 88 higher machining tool costs. Sintering is an alternative powder metallurgy-based manufacturing technique that has been investigated and proven for refractory metals components production. As aforementioned, the most advanced manufacturing techniques in the powder metallurgy industry in order to obtain complex geometries and light-weight structures is Additive Manufacturing. The LPBF process provides a variety of advantages that deal with the main problems in the production of refractory metals. For instance, considering the high cost of powders like Ta, Nb, W, and Mo, the recycle of the unmelted particles is essential. Furthermore, the production process is carried out in a controlled environment chamber, which is an advantage required when producing refractory metals with high density due to their strong tendency to oxidize at high temperatures [11]. 25.2 From Material Characterisation to Product Design and Manufacturing The first step in order to obtain almost fully-dense AM refractory metals parts is the process parameters tuning. The fine-tuning of the latest starts from the Single Scan Tracks (SSTs) analysis. Thanks to the first screening of the parameters given by the SSTs analysis it is possible to narrow the parameter window in order to obtain volumetric samples that have densities close to fully-dense. High-density specimens are then characterised at roomand high-temperature. The main goal of high-temperature thermal characterisation is to measure emissivity (ε) and thermal conductivity (k) in a temperature range as near as possible to 2000°C, the usual higher operating temperature of ISOL ion sources [12]. Assuming that thermal convection is negligible due to the high vacuum environment required for the functioning of ISOL high-temperature devices, these two parameters are in fact sufficient under steady-state conditions to define the temperature field within the ion source. A customised experimental set-up coupling with a consolidate electro-thermal numerical model, both developed at the National Laboratories of Legnaro (LNL) of the INFN, is used to evaluate the thermal properties in the 600÷1600 °C range [13]. Specifically, sample emissivity is determined using a ratio pyrometer during the radiative and conductive heating, whereas thermal conductivity is calculated using a steady-state high temperature method based on pyrometric temperature observations and the inverse parameter estimation technique [14]. Tensile or compressive tests, according to the brittleness of the refractory metals tested, are performed at room temperature in order to evaluate the mechanical properties of additively manufactured specimens. Both for thermal and mechanical properties measurement, standard refractory metals are also tested, in order to compared AM with conventionally manufactured samples. The effect of building direction and post-processing machining of AM specimens was also investigated for tensile tests at room temperature. Last but not least, "secondary" process parameters that are related to geometrical performances of the additively manufactured parts were analysed to fine-tune the production process. This characterisation stage enables the investigation of the overhang angles and the evaluation of geometrical integrity as thickness changes, leading to the fabrication of complex geometry. 25.2.1 Molybdenum and tungsten Thanks to the fine-tuning of the process parameters, samples of both Mo and W were successfully produced. The best specimens have a high density, which is close to the bulk material produced with conventional production techniques. In the Mo characterisation study published by Rebesan et al. [15], the density of the samples was particularly affected by the laser power parameter, reaching its maximum value at 150 W (99.9%). On the other hand, in the W production, Rebesan et al. [16] has demonstrated how the parameter involving the distance between consecutive laser passes is decisive in order to raise the density of the manufactured articles. In fact, using a low h (0.04 mm) in conjunction with scan speed values in the 400-600 mm/s range allows for density values greater than 99%, with a maximum of 99.61 0.5% for a scan speed of 600 mm/s. Deliverable D8.1 89 Figure 65. The crack network homogenously distributed on W [16] (a) and Mo [15] (b) manufactured by LPBF The common feature of both additively produced Mo and W is the tendency to crack during the manufacturing process. This phenomenon is widely described in the literature [15], [16]. The extensive presence of a homogeneously distributed network of cracks leads to a strong reduction of the thermal and mechanical properties, as demonstrated in the results highlighted by the characterisation of AM Mo, both at room temperature and at high temperature [15]. This result leads to the final consideration that pure W and Mo are not suitable to be produced with this production process, guaranteeing the absence of defects and with properties close to standard W and Mo produced with traditional technologies. Kaserer et al. [17], [18], demonstrated that for Mo the only possible solution to eliminate the presence of cracks and to obtain material properties comparable to standard Mo consists of using Mo alloys and a building platform heated up to 800 °C. However, their use for the production of non-structural components is currently under investigation in order to verify whether the degree of freedom given by AM in the production of more performing geometries can equally guarantee a functional improvement at high temperatures. 25.2.2 Tantalum and niobium A completely different behavior with respect to Mo and W is shown by the Ta and Nb produced with the LPBF process. Indeed, as shown in Figure 64(b) there are no specific surface defects, such as cracks or lacks of fusion, and the melt pools appear to be continuous and homogeneous. This suitability to be produced by laser melting is confirmed by the high-density value we obtain in the samples, 99.8% for Ta and 99.7% for Nb. Figure 66 (a) the additively manufactured tantalum sample for process parameters tuning; (b) top surface morphology of the tantalum tag. The preliminary results of the characterisation of Ta AM performed so far have shown that the thermal and electrical properties at room temperature and at high temperature are close to those of the reference standard material, whose properties have been measured by the same method. The measurements of the mechanical properties of the horizontally produced as-built specimens show an increase in strength and a decrease in elongation compared to the conventionally produced standard material. The characterisation of the electro-thermal-structural properties of Nb is now under development. Deliverable D8.1 90 25.2.3 Components production and validation As a result of the material characterisation phase, from the physical, thermal, and mechanical properties measurements to the evaluation of geometrical performances of the additively manufactured and analysed refractory metals, the first AM molybdenum and tantalum components, shown respectively in Figure 65 (a) and (b), were successfully produced. Figure 67 (a) the additively manufactured molydenum anode and (b) the additively manufactuerd tantalum cathode. These components are the anode (Mo) and the cathode (Ta) of the FEBIAD (Forced Electron Beam-Induced Arc Discharge) Ion Source used in the production of extremely pure radioactive ion beams in the context of the Selective Production of Exotic Species (SPES) project. Currently, both the anode and the cathode of the traditional FEBIAD type ion source are made of three components, which are subsequently joined by TIG. This welding process strongly compromises the alignment of the components and compliance with the required tolerances, in particular for the distance between the anode and the cathode, a fundamental parameter for the correct functioning of the beam ionisation process. Firstly, the main ion source components, produced entirely by AM, do not show the aforementioned issues caused by the welding process; secondly, AM allows for the investigation of new forms of anode-cathode interface and therefore for the evaluation of their effect on the variation of the physical performance of the source. The physical performance of the traditional geometry of the anode and the cathode reproduced by the LPBF process is now under investigation in preliminary high-temperature and off-line tests carried out at the SPES and ISOLDE facility systems at INFN-LNL and CERN. 25.3 Conclusions and further development This study described the production process and the main characterisations performed by the INFN DIAM laboratory in order to be able to produce refractory metal components using Additive Manufacturing technology. Recent research has confirmed that pure W and Mo are not suitable for processing with LPBF technology on commercially available machines. The widespread presence of cracks in manufactured articles leads to a strong reduction in the thermal and mechanical properties of the material. In the near future, the presence of alloy elements that make them processable will be investigated. On the other hand, the LPBF technology is particularly suitable for additively producing Ta and Nb. These metals, even if pure, have densities close to Ta and Nb bulk. The next step is to finalize the evaluation of tantalum and niobium electrical, mechanical, and thermal properties. Finally, following all the steps reported, two components of the ionisation source for the SPES project were produced: the anode, a non-structural component made in Mo, and the cathode, a structural component made in Ta. Both samples are currently undergoing hightemperature characterisation and non-radioactive beam production in order to be able to compare these additively manufactured components with the traditional anode and cathode used historically. Deliverable D8.1 91 25.4 References [1] J. O. Milewski, Additive Manufacturing of Metals, vol. 258. Gewerbestrasse 11, 6330 Cham, Switzerland: Springer International Publishing, 2017. [2] W. E. Frazier, “Metal additive manufacturing: A review,” J. Mater. 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