Combining cryo-DNP and rapid temperature jumps at high magnetic field for a dramatic increase of sensitivity in liquid state NMR spectroscopy

Lead Research Organisation: University of Nottingham
Department Name: Sch of Physics & Astronomy


Nuclear Magnetic Resonance (NMR) spectroscopy and Magnetic Resonance Imaging (MRI) are important tools in many scientific disciplines, including medical diagnostics, molecular biology, pharmaceutical and material sciences. However, due to the low energy of interaction between a strong magnetic field and the weak magnetic moment of certain nuclei such as hydrogen, the sensitivity of these techniques is usually low in comparison to other spectroscopic techniques.

We therefore propose in this project to design, construct and test an instrument which will enable us to generate a much stronger signal (10^4 -10^5 times) than is possible with current systems. The instrument relies on exploiting the interaction between unpaired electrons, which also possess a magnetic moment, and the nuclei. Since the magnetic moment of electrons is much stronger (660 times) than that of the nuclei, the energy of the interaction of electrons with a strong magnetic field is much higher. This means that at low temperatures it is possible to produce a frozen sample in which almost all the electron magnetic moments are aligned with a strong, applied magnetic field, corresponding to nearly 100 % polarisation. It is possible to transfer this very high degree of polarisation to the nuclei using millimetre wave irradiation (94GHz) at a well defined frequency in a process known as dynamic nuclear polarisation (DNP). Under certain conditions the high polarisation of the nuclei is conserved during rapid melting of the frozen sample. It can then be used in liquid state NMR experiments generating a signal that is dramatically enhanced in comparison to that obtainable using conventional NMR systems.
However, this approach is technically very challenging since it requires the generation of a very fast temperature jump within the sample space of the superconductive magnet. The manufacture of such an instrument requires the interaction of two different transmitters, with GHz and MHz frequencies, the development of a strategy to control the spatial distribution of the temperature within the sample during melting and the use of infrared lasers, microwave induced heating and the generation and control of extremely low cryogenic temperatures.
In addition, stable radical molecules are required that carry the unpaired electron. The dynamics of the transfer of polarisation from the electrons to the nuclear spin ensemble depends on several physico-chemical properties of the spin systems. We will optimise this process to achieve very fast build-up of the nuclear polarisation. A fast build-up is needed to make repetition of these experiments possible on a reasonable time scale.

The realisation of such a prototype instrument in conjuction with optimised dynamic nuclear polarisation will have strong impact on many applications of NMR spectroscopy since the generation of a much stronger NMR signal will enable a range of new and exciting experiments such as very fast spectroscopy of the interaction of different molecules during binding. The novel technology has a huge potential for applications in biomolecular NMR spectroscopy.

Planned Impact

NMR (Nuclear Magnetic Resonance) spectroscopy, microscopy and imaging techniques play a major role in numerous fields of science ranging from physics, chemistry, material sciences, biology to medicine. Development of multidimensional techniques in NMR allows obtaining structural and dynamic information with atomic resolution. Though the method is non-invasive its intrinsic low sensitivity has limited NMR in a number of applications, for instance in nanoscience, in the detection of fast dynamics on the molecular level or in acquiring signal from molecules in low concentration both in vitro and in vivo or from molecules bound to surfaces. Dynamic nuclear polarisation has the potential to overcome the sensitivity issue and to help open up new applications of NMR spectroscopy and imaging.
In this proposal a novel and challenging technology will be developed to generate dramatic signal enhancements for liquid state NMR experiments.
This includes the design of a large hardware component as part of the research to be carried out in this project.

There will be impact in several areas:
- academic impact will include the stimulation of the design of new experimental concepts that can be implemented with our new instrument
- commercial impact will be based on finding a mechanism for commercialisation of the technology. Commercialisation will contribute to make this technology available to end users
- general impact in many applications of NMR spectroscopy, including medical diagnostics, food quality control and environmental monitoring
- educational impact by providing training to a new generation of NMR scientist who will be experts in DNP enhancement strategies.


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Description We try to implement a fast temperautre jump using an infrared laser to change the temperature from 1K to 300K in less than a second. We have spent three years looking at various ways to achieve this and have now come up with an experimental setup which should work also within the environment of a superconductive magnet. This experimental setup required the development of a device that enables us to cool the sample to about 1.5K using liquid Helium. In this state the sample is irradiated with high frequency microwaves and we had to develop a special system to guide these microwaves into the cold environment. The most important experimental development was an arrangement that makes it possible to use a high power midrange infrared laser to bring enough energy into the sample so it melts rapidly and measurements can be carried out in liquid state before it is refrozen again. All components have been individually tested but our whole system was not assembled yet due to the lack of a dedicated postgraduate student or postdoc who could take on this project.
Exploitation Route We are aware of other research group abroad (The Netherlands, Israel) who are working on similar ideas.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

Description This project has During this project a collaboration with Thomas Keating LTD was initiated that resulted in the development of a dedicared microwavebridge and more importantly made it possible for the commercial partner to brach out into the development of cryogenic equipment. This was achieved by our commercial collaborator by also involving further external consultants. Therefore this project is a good example how medium sized enterprises can use their flexibility to quickly fill the gap in manufacturing highly specialied equipment.
First Year Of Impact 2015
Sector Chemicals
Impact Types Economic

Description DEvelopment of purpose desgined cryoinsert for temperature jump DNP 
Organisation Thomas Keating Ltd
Country United Kingdom 
Sector Private 
PI Contribution Design of an open ended cryinsert for temperature jump DNP. A PhD student (Ed Breeds) stayed at the company to help manufacturing the cryinsert
Collaborator Contribution The prototyp of the cryoinsert was made available to use at a discounted price.
Impact cnone
Start Year 2014