Pump-priming capacity development for translational medical research

Lead Research Organisation: University of Nottingham
Department Name: Inst of Infections and Immunity

Abstract

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Publications

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Hughes-Riley T (2013) Cryogenics free production of hyperpolarized 129Xe and 83Kr for biomedical MRI applications. in Journal of magnetic resonance (San Diego, Calif. : 1997)

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Lilburn DM (2013) Perspectives of hyperpolarized noble gas MRI beyond 3He. in Journal of magnetic resonance (San Diego, Calif. : 1997)

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Pavlovskaya G (2018) Fluid flow in a porous medium with transverse permeability discontinuity in Physical Review Fluids

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Pavlovskaya G (2018) Fluid flow in a porous medium with transverse permeability discontinuity in Physical Review Fluids

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Rogers NJ (2016) Molecular hydrogen and catalytic combustion in the production of hyperpolarized 83Kr and 129Xe MRI contrast agents. in Proceedings of the National Academy of Sciences of the United States of America

 
Description BBSRC Tools and Resources Development
Amount £160,000 (GBP)
Funding ID BB/N021460/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2017
 
Description Development of cryogen-free 129Xe and 83Kr hyperpolarizer to enable and facilitate pre-clinical MRI of lungs'
Amount £75,000 (GBP)
Funding ID Paul Instrument Fund 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2012 
End 10/2014
 
Description Discovery Award
Amount £1,200,000 (GBP)
Funding ID MP_PCP15074 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2016 
End 12/2017
 
Description EPSRC DTP Studentship "Development of hyperpolarisation MRI"
Amount £100,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 08/2021
 
Description EPSRC Global Challenges Research Fund pump-priming for Beacons of Excellence
Amount £8,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 03/2018
 
Description MRC Confidence in Concepts.
Amount £101,744 (GBP)
Funding ID CiC2016041 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 02/2018
 
Description Paul Instrument Fund
Amount £75,000 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 10/2014
 
Description Project Grant
Amount £553,341 (GBP)
Funding ID G1100564/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 04/2015
 
Description project grant
Amount £55,000 (GBP)
Funding ID G1100564/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 09/2014
 
Title Build up of MRI methodology development laboratory for translational imaging research. 
Description In order to allow for an expedite research activities at the Nottingham Translational Imaging Center, the following infrastructural work was accomplished: 1.) Instruments and devises for the production of hyperpolarized gases have been developed and assembled. The technology is based on previous research at Colorado State University (CSU) and on recent developments in Nottingham. Almost the complete previous laboratory was relocated (free of charge except transportation) from Colorado to the University of Nottingham. Major items include: a.) one already assembled hyperpolarization devise and parts for a partially assembled second system, b.) a gas delivery system including vacuum unit, gas mixing, peristaltic pumps, high purity filtration. c.) a 9.4 T superconducting magnet (89 mm vertical bore) for micro imaging and NMR spectroscopy d.) A microimaging gradient system including amplifiers and gradient coils. e.) 0 - 3 T superconducting magnet (89 mm vertical bore) for field cycling (i.e. field dependent noble gas relaxation measurements), including charging system to allow for the field ramping. f.) Various glassware specifically designed for the experiments. g.) Various NMR/MRI probe heads for work with hyperpolarized noble gases. The the laboratory equipment from Colorado was moved to the UK, temporarily stored, refitted where needed (different electrical, and gas delivery requirement, different usage compared to previous) and further assembled. New develpments have been made in improving the hyperpolarization of the MRI contrast agents. 2.) Acquisition of new equipment. The following major items have been purchased: a.) a state-of-the-art 9.4T Microimaging system from Bruker with 'ultrashielded' magnet . This system will be a primary research instrumentation in the translational imaging laboratory. It will also allow for flow (blood flow) measurements in model systems and for rheological NMR experiments. The system includes a variety of radio frequency coils for detection. The system is currently been tested and a number of items have been returned for modification b.) A low cost console for the second 9.4 T MRI system and existing microimaging system (both transfers from Colorado). The magnet has been energized to 9.4 T initially but can be ramped to any field below this value if needed. The system will also allow for optical pumping in the stray-field of the unshielded magnet. c.) A Rheo-meter to complement the Bruker Rheological NMR system (still in purchasing the processes). 3.) Development and construction of MRI Coils for hyperpolarized xenon-129 and krypton-83 for 7.4 T small animal imaging system at the University of Nottingham Brain and Body Centre and for 3 T whole body Philips MRI system (still in process). 4.) Hiring of personnel: one post-graduate student has joined in January 2010 and a second post graduate student has joined in September 2010. A post doctoral researcher has joined in April 2010. A lecturer has joined University of Nottingham who will be crucial for the Rheological and blood flow work. A further post graduate student (with medical doctorate degee) has joined the group in April 2011. 5.) Planning of major reconstruction of Lab space at the Sir Peter Mansfield Magnetic Resonance Centre to accommodate the vertical bore microimaging systems. Although the actual construction is not part of this grant, planning from the on-set because this work is crucial from the infrastructure point of view. Because of too low ceiling height at the centre major reconstruction within the existing building was necessary. The planning allowed for significant extra laboratory space within the existing building. Work was completed in early April 2010. 6.) A new hyperpolarizer system has been successfully developed in 2011 that allows for the production of hp xenon-129 and krypton-83 without cryogenic separation. A publication is currently pending and the system is in used of work with excised lungs where it has produced first pulmonary MR images of excised rodent lungs. A second system is currently been revised to produce larger quantities of hp gas for pulmonary MRI. 7.) Transverse relaxation measurements of hp xenon-129 and krypton-83 have produced new insights in the relaxation behavior of the gases in confined porous models systems and lungs. The work is currently ongoing. 
Type Of Material Improvements to research infrastructure 
Year Produced 2011 
Provided To Others? Yes  
Impact Using the hyperpolarizer system described in 6.) lung studies have been initiated in animal models of pulmonary disease. This work is performed in collaboration with researchers at the respiratory biomedical research unit in Nottingham. First results have been obtained (see other out puts and knowledge section). Added in 2016: The instrument has made a number of breakthrough developments possible. In particular it has enabled us do provide the first demonstration of hyperpolarized krypton as a novel pulmonary MRI contrast agent that is sensitive to an animal model of emphysema. Building on this development, hyperpolarized 83Kr MRI will now be implemented at Nottingham's 7T whole body MRI to prepare for a future phase 1 trail. The necessary 7T upgrade was supported as part of the MRC funded 'Enhancing UK's clinical research infrastructure' awarded to Nottingham in 2015. 
 
Description Development of krypton-83 MRI 
Organisation University of Colorado Denver
Department School of Medicine Colorado
Country United States 
Sector Academic/University 
PI Contribution Developed 83Kr MRI using excised rat lungs. This collaboration originally commenced in 2006. However, under the pump-priming capacity development grant, we explored the relaxation behavior of the hyperpolarized krypton-83 contrast agent as a function of lung inhalation. It was found that the contrast agent is very little effected by small fluctuations in inhalation of healthy lungs, making it very robust for the detection of pathological changes. This set the ground for later development of this contrast agent for an elastase induced emphysema model.
Collaborator Contribution provided excised rat lungs of healthy animals for initial work.
Impact Karl F. Stupic, Nancy D. Elkins, Galina E. Pavlovskaya, John E. Repine and T. Meersmann, "Effects of Pulmonary Inflation on Hyperpolarized Krypton-83 Magnetic Resonance T1 Relaxation.", Physics in Medicine and Biology, 56 (2011) 3731-3748.
Start Year 2009
 
Description Hyperpolarization collaboration with Ningbo, China 
Organisation University of Nottingham Ningbo China
Country China 
Sector Academic/University 
PI Contribution To develop and construct a hpXe129 production system for The Univeristy of Nottingham, Ningbo Campus (UNNC) trough iterative process between the two campuses. Construction of fully functional first generation Xe hyperpolarizer designed and build at SPMIC-UP for SPMIC-UNNC is almost complete. Two UNNC students have been send for training and research to the lab of the PI in Nottingham. Progress in the catalytic production / purification of hyperpolarized noble gases.
Collaborator Contribution 1.5 Tesla whole body MRI scanner for pulmonary imaging with hp 129Xe has been installed and is currently been tested.
Impact Publication in ACS Catalysis: Dudari B. Burueva, Ekaterina V. Pokochueva, Xinpei Wang, Max Filkins, Alexandra I. Svyatova, Sean P. Rigby, Chengbo Wang, Galina E. Pavlovskaya, Kirill V. Kovtunov,* Thomas Meersmann,* and Igor V. Koptyug, In Situ Monitoring of Heretogeneous Catalytic Hydrogenation Via 129Xe NMR Spectroscopy and Proton MRI', ACS Catalysis Letter, 10, (2020) 1417-1422; DOI: 10.1021/acscatal.9b05000.
Start Year 2019
 
Description Hyperpolarized noble gas MRI contrast agents through catalytic hydrogen combustion 
Organisation University of Nottingham
Department Department of Chemical and Environmental Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution My group has utilized catalytic hydrogen combustion, a process that is typically associated with clean energy related sciences, for the production of inhalable contrast agents for magnetic resonance imaging (MRI). The proof-of-concept work, now published in the Proceedings of the National Academy of Sciences, produced purified laser-pumped krypton gas that may serve as a promising new contrast agent for pulmonary MRI. Pulmonary MRI with laser-pumped krypton had previously been demonstrated conceptually but its application had been hampered by limitations in the production process of this contrast agent.
Collaborator Contribution There are a number of chemical engineering related problems that need expert input, for example how to best remove the buffer gas. The collaborator have helped with the planning of the project. Furthermore, I co-supervising a student with the collaborators and this student has participated in the project. Further input is required to move this project beyond the proof of concept stage and the collaborations are therefore continuing.
Impact The collaboration has resulted in in a paper, accepted in the Proceedings of the National Academy of Sciences of the USA (PNAS) entiteled: Molecular hydrogen and catalytic combustion in the production of hyperpolarized 83Kr and 129Xe MRI contrast agents. We are currently applying for funding to move this project beyond the proof of principle stage. `
Start Year 2013
 
Description Molecular imaging with hyperpolarized xenon using switchable chemical exchange relaxation transfer. 
Organisation University of Nottingham
Department Children’s Brain Tumour Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Devised the new relaxation based concept for molecular imaging with hyperpolarized biosensors, supervised (still ongoing) hyperpolarized xenon NMR experiments. The idea is that a new type of biosensor molecule will destroy the hyperpolarized state of xenon thereby making it undetectable for MRI. However, upon the presence of particular biomarker molecules (such as MMP9) that are upregulated in certain diseases, the biosensor molecule gets deactivated. In regions where this happens, the hyperpolarized xenon will be observable thereby enabling the (molecular) imaging of the regions with upregulated biomarkers. Most of the developmental work utilized the microimaging / NMR spectrometer in my group.
Collaborator Contribution Department of Chemistry synthesizes the required biosensor molecules that (a) interact with xenon through molecular cages, (b) contain a relaxation agent, and (c) can be cleaved by the biomarker molecules (MMP) thereby separating the cage from the relaxation agent. The collaboration uses an iterative process, i.e. chemistry synthesizes the biosensor and we characterize and test the sensor with hyperpolarized xenon NMR and microimaging. The results lead to modification in the molecular design for the chemistry department.
Impact 1 publication: DOI: 10.1002/cphc.201500367
Start Year 2014
 
Description Refining Modles of Fibrotic Lung Disease 
Organisation University of Nottingham
Department School of Biomedical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided preliminary ventilation Lung MRI for animal model of disease
Collaborator Contribution Help in development of excised lung for MRI applications
Impact NC3R Funding obtained (Co-I) PI Dr. Gisli Jenkins
Start Year 2011
 
Title PRODUCTION OF HYPERPOLARIZED GAS 
Description A method of removing buffer gas from a mixture comprising the buffer gas and hyperpolarized noble gas is described. The method includes reacting the buffer gas to produce a reaction product different to the buffer gas. The buffer gas may be reactively removed by one or more of oxidation, reduction, polymerization and binding reactions with solid surfaces. The buffer gas may be molecular hydrogen and/or molecular nitrogen. Apparatus for carrying out the method are also disclosed. 
IP Reference US2018244523 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact Ongoing research - further funding applied for
 
Title New production method for hyperpolarized noble gas contrast agents 
Description A new addition to the laser-pumped noble gas MRI contrast agent family is krypton-83. My team in Nottingham has demonstrated the sensitivity of this contrast agent for emphysema (model) related changes in the lung surface. However, this distinct sensitivity also leads to complications in the production of this novel contrast agent for clinical applications. The success of the laser pumping process is measured by the enhancement factor in the MRI sensitivity that is many orders of magnitude above the pre-pumped state. In order to reach this enhancement, xenon-129 or krypton-83 are usually diluted by other gases during laser pumping. For MRI usage, these additional gases are usually removed after the pumping process. However, the gas removal from laser pumped krypton-83 mixture was previously not possible because conventional "cleaning up" methods lead to the complete loss of the hyperpolarized state, rendering the contrast agent useless for MRI. We have now solved this problem by diluting krypton-83 in molecular hydrogen gas (H2) for the laser pumping process. After successful laser pumping, the hydrogen gas is removed in a safe and controlled fashion through a catalysed combustion reaction. Water vapour, the sole product of the 'clean' hydrogen reaction, is easily removed through condensation, leaving behind the purified laser-polarized krypton-83 gas diluted only by small remaining quantities of harmless water vapour. This development significantly improves the potential usefulness of laser-pumped krypton-83 as MRI contrast agent for clinical applications. The novel methodology can also be utilized for laser polarized xenon-129 and may lead to a cheaper and more accessible production of this contrast agent. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2016 
Impact Has just been completed - no output yet. 
 
Description British Council funded UK-Russia meeting on 'Perspectives of Hyperpolarized MRI in Precision Medicine' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact British Council funded UK-Russia meeting on 'Perspectives of Hyperpolarized MRI in Precision Medicine
This lead to the host term exchange of 8 postgraduate students from Moscow, St. Petersburg, and Novosibirsk to the UK and inititated further collaborations
Year(s) Of Engagement Activity 2018
URL http://hp-mri-workshop.com
 
Description COST 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact presented: 'New methods and recent advances in hp 83Kr and hp 129Xe MRI'

Student exchange with German research group (University of Leibzig)
Year(s) Of Engagement Activity 2013
URL http://www.cost.eu/domains_actions/mpns/Actions/TD1103
 
Description COST LEiden 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact presented 'Polarization transfer in SEOP for spin I = ½ noble gas isotopes'

COST workshop: 'Hot Topics in Spin Hyperpolarization', Lorentz Centre, Leiden,
Year(s) Of Engagement Activity 2012
URL http://www.lorentzcenter.nl/lc/web/2012/477/info.php3?wsid=477