Photochemical spin-hyperpolarization in confined environments

Lead Research Organisation: University of Warwick
Department Name: Physics


Nuclear Magnetic Resonance (NMR) is a tremendously powerful and versatile analytical technique for the investigation of the structure and dynamics of molecules from the simplest chemical species to complex biomolecules. The key limitation of NMR is that is suffers from low sensitivity because the obtainable nuclear spin polarization is small; lengthy signal averaging is therefore necessary making NMR slow which hinders new applications and because of finite equipment access even limits routine exploitation. This project will develop a new method for photochemically generating nuclear spin-hyperpolarization which by increasing sensitivity and reducing experiment times will provide the opportunity for a number of exciting new applications of NMR to be explored.

To observe a magnetic resonance signal spin-polarization is required, that is more nuclear spins (which act like tiny bar magnets) must line up with than against the applied magnetic field (or vice-versa). Even in strong magnetic fields, however, typically less than one in ten thousand nuclei do so at room temperature. The polarization of electron spins is higher than that of nuclear spins (by ~660 versus protons) making them more sensitive probes of molecular environment, but most molecules don't have the unpaired electron spins needed to use electrons as probes directly. However, a number of Dynamic Nuclear Polarization (DNP) techniques are under development which aim to generate nuclear hyperpolarization (greater than equilibrium polarization) by transfer of polarization from thermally polarized electrons to nuclear spins. However, these techniques rely on microwave pumping of the electron spins which causes problems with sample heating, and for liquid state NMR the biggest gains come when long pumping periods are combined with rapid heating and dissolution of molecules polarized at very low temperatures. Such approaches generate large nuclear hyperpolarizations but cannot be rapidly repeated hence little time-saving is achieved. Such methods will not make feasible the time-consuming multi-dimensional experiments needed to examine complex biological molecules, or speed-up NMR analysis to enable high throughput screening for medical diagnostics. The project will use a short pulse of laser light to hyperpolarize electron spins to hundreds of times their thermal polarization and then rapidly transfer this large hyperpolarization to the nuclei, achieving nuclear spin-hyperpolarizations far in excess of those possible when using thermally polarized electrons. This will provide a room temperature nuclear hyperpolarization method that can be combined with the high repetition rates conventionally employed in NMR when signal averaging or incrementing experimental parameters.

This project will exploit the as yet under-utilized Radical Triplet Pair Mechanism (RTPM) by which a stable radical interacts with a short-lived triplet state generated photochemically from a suitable precursor, resulting in electron spin-hyperpolarization of the radical. Such hyperpolarization can be conveniently observed by Electron Paramagnetic Resonance (EPR) spectroscopy. EPR will be used to investigate the key interactions giving rise to this effect, and in particular the effect of confining the radical and triplet molecules in cage-like structures on the size of the hyperpolarization generated. By restricting the relative separation of the radical and triplet molecules, and hence increasing their chances of encounter in solution, the electron hyperpolarization generated will be maximised. The effect of this encapsulation on the efficiency of the transfer to nuclear hyperpolarization will also be assessed. This project will test and further develop the underlying theory of the RTPM and provide a proof of principle that this method can be used as a new way to enhance sensitivity in NMR experiments, a result with potentially far reaching applications throughout analytical and medical science.

Planned Impact

Who will benefit from the research?

The proposed research will have both economic and societal impact. Magnetic resonance (MR) spectroscopy represents a multi-billion pound global market in which UK industry is a key player, with the future success of companies including Bruker, Oxford Instruments, Thomas Keating, Tesla Engineering and Cryogenic being dependent on continued innovation in this area. Bruker are supporting the project with an equipment loan and I will regularly discuss results and their potential exploitation with the Bruker UK team. Being a core technique within the analytical science arsenal the step-change in sensitivity of MR that this project aims to deliver will increase uptake of MR in industrial applications and further scientific understanding in a range of areas from catalysis to biochemistry. The project will therefore have long-term impact, maintaining the health of many other research areas by enhancing the analytical tools on which they rely. The wider public will also benefit through public engagement and outreach initiatives.

How will they benefit from the research?

UK industry will derive economic benefit from the research in two ways. In the first instance UK companies already at the forefront of MR technology will be well placed to exploit advances in this field. The development of a new technique for sensitivity enhancement will give rise to a need for commercial instruments offering this capability, and increased demand for MR equipment (of which the UK is a major exporter) as new applications become possible. Such increased demand could arise not only for high-end research instruments, but also for benchtop NMR (nuclear magnetic resonance) systems used for routine analysis (e.g. in the food industry) which could also benefit from improved sensitivity. The technique to be developed requires integration of optical excitation sources with magnetic resonance hardware and in the long term use of specific chemical polarizing agents, leading to further industrial opportunities within the optics and chemicals sectors. Furthermore, as sensitivity improvements are made, the routine exploitation of NMR in additional industrial settings will become plausible, with possibilities for use in quality control and real-time process monitoring. These benefits could be realised in the medium to long term, with necessary proof of principle work carried out within the 1 year time frame of this project, paving the way for the first applications to be demonstrated and commercialised in the following 3-5 years.

Low sensitivity currently makes NMR slow which hinders routine academic and industrial exploitation due to both limited equipment access and the low throughput of samples on high resolution machines. New applications such as certain multi-dimensional experiments needed to characterize complex biological macromolecules are unfeasibly time-consuming, while sensitivity is insufficient to allow NMR analysis of low concentration metabolites in clinical samples. Through sensitivity enhancement the speed of experiments can be increased, removing this research bottleneck. While the initial beneficiaries will be the research community, wider societal impact of the research will be achieved in the long term. Improvement of the underpinning technology enabling advances in biological NMR will contribute to improved understanding of countless biological systems and diseases, leading in future decades to new pharmaceutical targets and agents with eventual health benefits. In a clinical setting NMR detection of metabolites could be used for routine screening for disease biomarkers, and sensitivity of MR imaging scanners improved.

The project will also deliver benefits through public engagement work. Key research findings will be made publicly available through video podcasts, in order to interest the next generation of scientists in the development of analytical techniques that underpin scientific endeavour.


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Description Nuclear Magnetic Resonance (NMR) underpins research across the physical and biological sciences by providing atomic level detail on structure and dynamics. Development of new applications, or application to samples of limited volume, is however hindered by low sensitivity. Despite a recent surge in interest in techniques for boosting NMR sensitivity, and a method specific to solid samples becoming well established, there is no broadly applicable route to boost sensitivity for liquid samples and the microwave irradiation often used in these methods is technically demanding and beset with problems. This project proposed a new method to boost NMR sensitivity for liquids, adding a dye to the sample which absorbs high intensity visible light from a laser to make what is known as a triplet state, which then interacts with radicals in the solution to generate electron polarization. The end result is that the NMR signal intensity increases when the laser is switched on, and this project achieved its primary goal of obtaining the first proof of principle demonstration of this effect, and these results are now published in Chemical Communications.
Having validated the proposed mechanism a new research area is opened up to develop the method. Further investigation of the kinetics of the mechanism (optimal laser illumination times etc) have already begun, and future work will investigate the choice of dyes and radicals added to the solution, and how the efficiency of the method changes when scaled up to stronger magnetic fields conventionally used in NMR. A research visit to the Weber group (University of Freiburg, Germany) provided preliminary results regarding scale-up of the first step of the process (electron polarization), and visits to the Evans group (Aston University) began testing with higher-field benchtop NMR equipment. A local collaboration was also initiated during the project to investigate molecules in which the dye and radical are linked together, and it is expected that research in this area will grow as others become interested in the methodology.
A key result of the project was the finding that not only can NMR sensitivity be boosted by illumination of the sample with a laser (without the need for microwave irradiation) but this could be achieved using continuous rather than pulsed laser illumination. This is an unexpected result, with established theory suggesting effects to be too small to observe for continuous illumination, and hence informs future work in this area.
The project also investigated addition of structures called micelles to the solution to boost efficiency by holding the radical and dye in close proximity. Initial testing highlighted the difficulty in obtaining appropriate occupancy numbers, with too low a radical concentration giving too small a signal to allow detection, and higher radical concentrations giving too many radicals per micelle leading to a worse enhancement than without micelles as the radicals are held too close together. Significant further optimization with a different range of micelles is therefore needed to further improve gains by use of micelles.
Exploitation Route A symposium on hyperpolarization methodologies was held at the University of Huddersfield on 28th October 2016 with 18 participants drawn from various university research groups and industrial representatives. As described in the Pathways to Impact statement this meeting highlighted key results from the project, the demonstration of an entirely new hyperpolarization methodology, to others in the UK magnetic resonance and hyperpolarization communities. Developments in alternative hyperpolarization methodologies were also presented and the profile of hyperpolarization research in general was raised educating those participants having no prior knowledge of this field.

As appropriate given the fundamental nature of the research program the outcomes at this stage are likely to be taken forward mainly via academic routes. Presentation at European conferences generated substantial interest from major contributors to the field, including requests for pre-prints of the first publication. Having provided the proof of principle demonstration of a new methodology this may now be explored by other researchers, and my own on-going research plan (which continues to receive industrial support from Bruker UK) will build towards applications on real-world rather than model samples, to enable the potential long-term benefits across a wide range of fields that were highlighted in the impact statement. Other key European researchers in the field have already seized upon the developments demonstrated and replicated them (albeit with lower efficiency) in other systems - see Phys. Chem. Chem. Phys., 2017,19, 31823-31829.
Sectors Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Other

Title Optically-generated Overhauser dynamic nuclear polarization: A numerical analysis - Data Set 
Description Dataset supporting publication J. Chem. Phys. 152, 034202 (2020); The publication reports the first numerical simulations of the optically generated hyperpolarization method demonstrated in the funded project, and while created outside of the funding period includes simulations fitting the experimental data created and published during the funded project. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact First reported simulation method for optically generated hyperpolarization which will become the benchmark for future experimental and theoretical studies by my research group and others working in the field. 
Description Bruker 
Organisation Bruker Corporation
Department Bruker BioSpin
Country Germany 
Sector Private 
PI Contribution Access was provided to results of development work on a novel hyperpolarization technique. This is of potential interest to the collaboration partner as a major manufacturer of magnetic resonance technology, who have previously commercialised other hyperpolarization techniques. Although early (pre-publication) access to results was provided discussions took place under the terms of a non-disclosure agreement and have not at this stage been licenced for commercial use.
Collaborator Contribution Significant equipment contributions were made, providing an NMR instrument (Bruker Avance console + HP4600) on long-term loan to enable the research work. This more advanced instrument provided greater functionality than the benchtop NMR device discussed in the original grant proposal. Additionally a tuning circuit (Bruker part no. H132224, B-MTU ENDOR TO NMR BOX SPOT, list price ~2800 EUR) that was not part of the initial agreement was gifted to the project and this resulted in a time saving in the early stages of the grant. In addition to provision of essential equipment staff time was devoted to supporting the project and reviewing progress, with both face-to-face meetings with the local Bruker representatives and Skype meetings with expert research staff based in Billerica, MA, USA. The latter staff member also provided insightful critique contributing to the first publication from the grant (detailed below).
Impact Publication 'Optically generated hyperpolarization for sensitivity enhancement in solution-state NMR spectroscopy' DOI: 10.1039/C6CC06651H
Start Year 2016
Description School Visit, Space Studio (Banbury) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School visit. Presentation to all year groups in school's morning assembly discussing what it is like to work as a science academic, variety of job roles undertaken, educational requirements and my route to academia from state-school background etc... followed by brief overview of my research interests.
This presentation as part of a series of careers talks the school was running was followed by a subject specific session for around a dozen sixth form students studying A-level science subjects. This second, more informal session, covered the aims of the research undertaken through the funded project and was supported with a number of demonstrations relating to the topics of magnetic induction and micellar solutions. These sparked a number of questions from students who were able to relate some of the work to topics they were studying, and all students and a staff member tried out the magnetic induction demonstration. A particular focus of discussion was the need for the continual development of new analytical techniques to underpin other research areas leading to more direct societal impact in the longer term
Year(s) Of Engagement Activity 2016
Description Science Evening, University of Huddersfield December 2019 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Outreach / public engagement talk with laboratory demonstration and exercise allowing participants to carry out their own nuclear magnetic resonance experiment and analysis using a research grade benchtop NMR instrument. The work and outcomes of the grant were presented as part of this session as details of ongoing research,
Main intended outcomes were to raise interest in science courses at the university and profile of ongoing research.
Two groups of around 10 students across a wide age range and their families attended for repeats of the 45 minute session, leading to questions from pupils and parents alike.
Year(s) Of Engagement Activity 2019