Novel ion beams to enhance ionization in molecular secondary ion mass spectrometry

Lead Research Organisation: University of Manchester
Department Name: Chem Eng and Analytical Science

Abstract

Secondary ion mass spectrometry (SIMS) is an analytical technique with unique potential to probe the chemistry of complex materials in 2D and 3D on the micron level without the need for chemical modification or tagging. Surface chemistry is desorbed (sputtered) using a focused high energy (keV) 'primary' ion beam and the ionised fraction is subjected to mass spectrometric analysis. Our research over the last several years has focused on developing the application of SIMS to the study of biological cells and tissue, although the outcomes are equally applicable to other complex systems such as organic electronic materials.

Sensitivity is the central issue in mass spectrometry particularly in the imaging mode because the desire for increasing levels of spatial resolution means that the sample to be analysed gets smaller and smaller and there can never be enough ion yield. With EPSRC's support we have very successfully introduced and demonstrated the power of new primary ion beams for SIMS, first based on gold clusters and then on C60, that have greatly increased the ion yield of the large molecular species that are chemically significant. Despite these advances spatially resolved analysis below 1 micron is problematical because the current ionisation probability in organic SIMS (and indeed in other desorption mass spectrometries such as MALDI and DESI) is less than 10-5 in most cases. Related to this problem is the operation of the matrix effect. The secondary ion formation mechanism for compound A is influenced by the chemistry of the other molecules surrounding it in the emission zone. The ion yield of A may be enhanced, reduced or even entirely suppressed dependent on the identity of the surrounding molecules. This makes analysis uncertain and quantification very difficult. In the case of organic materials there is a considerable SIMS and MALDI literature that demonstrates the influence of the relative basicity of compound A compared to its molecular neighbours on the formation of the (A+H)+ species. Thus a significant contributor to the matrix effect is probably due to competition for protons in the ion emission zone. Thus in the case of organic analysis where the majority of molecular related ions are formed by proton transfer, greatly increasing the density of proton source molecules in the emission zone is expected to increase the M+H or M-H yields.

In a collaboration with a small ion beam manufacturer, Ionoptika Ltd, this project will develop a water ion beam system capable of delivering a high density of either H3O+ or giant water cluster ions (H2O)nH+ (N=50 to 10000), that on impact with the sample surface will generate a high density of proton related species to enhance the secondary ion yield of (A+H)+ by at least a factor of 10, and is expected to have the added benefit of relieving the matrix effect. The project will be a mix of instrument development and water beam characterisation followed by research into its operation. The water beam system will be built refined and interfaced with an ion optical column developed previously for a giant argon cluster beam. The optimum operational conditions for the water beam will be researched and then using model compound systems the fundamentals of the degree and mechanism of proton assisted ion yield enhancement will be researched. This will then be followed by studies of multi-component model materials to investigate the influence of the water beam on the matrix effect and the improvement of quantitative analysis in imaging mass spectrometry.

Time permitting we hope to carry out proof of principle studies into the beneficial effects of the water beam in MALDI MS.

The successful outcome of this project will very significantly enhance the capabilities and wide uptake of SIMS, enabling molecular sub-micron analysis and imaging, greatly ameliorating the interference of the matrix effect and significantly improving quantitative measurements.

Planned Impact

The successful outcome of this project to develop a method to significantly increase the secondary ion yield from organic and bio-organic systems will have major impacts in two related directions. The first impact will that a major expansion of the utility and application of SIMS can be envisaged in the following and many other areas: medical materials and clinical diagnosis; single cell bio-studies; studies of the mechanism of drug operation at the cellular and tissue level; R&D of organic electronic devices; forensic science; cultural artefact studies. Highly focussed primary ion beams give SIMS the potential ability to probe materials with spatial resolution below the 1 micron level. In principle mass spectrometry enables very precise chemical state analysis. As explained in this proposal the low secondary ion yields mean that sensitivities very much limit the spatial resolution from which useful information can be obtained to no more than 1 micron and frequently worse than this. In addition the matrix effect introduces very real uncertainties into the validity of the analysis. A significant increase in the ion yield and the alleviation of the matrix effect will dramatically expand the range of systems that will benefit from SIMS analysis. Despite the present challenges of the technique there is strong evidence of the benefits of the spatially resolved analysis that SIMS offers in the life sciences, pharmaceutical and electronics industries. There is no doubt that with a successful outcome of our project the application of SIMS will expand dramatically and within 5 years it will become an extremely valuable tool in the R&D laboratories of many research intensive companies. Furthermore it may be envisaged that, as with the case of inorganic SIMS in the semiconductor industry, within a few year the incorporation of molecular SIMS monitoring on the production line will rapidly develop.

The second related area of major impact will be that the sales of SIMS instruments for molecular analysis from organic based materials will rapidly expand. At present there are about 400 ToF-SIMS instruments world-wide of which approximately 150 have implemented the C60 ion beam system mainly for organic materials analysis since the production version became available in after our announcement in 2003. The argon-cluster beam that was introduced last year is also beginning to be taken up in significant numbers. There is a growing realisation that the use of the cluster beams offers the possibility of using the new types of SIMS instrumentation of the type we have developed that offer the possibility of using the mass spectral tools of MSMS that are required for proper mass spectral analysis. Success in our project will add a significant increase in sensitivity to these developments, and with it sales of many more instruments can be envisaged to the benefit of the manufacturers. Although SIMS is capable of higher spatial resolution, and in many ways is a more controllable technique than MALDI because it does not use a matrix that can complicate the analyte in uncertain ways, to date MALDI has had the more rapid take up in the imaging MS field. Success in increasing ion yield and reversing the matrix effect should help to highlight the benefits of SIMS, particularly for imaging complex materials with sub-micron resolution. Such a development would bring SIMS into the main-stream of mass spectrometry and make it a very much more saleable instrumental platform. This might have the knock on benefit of reducing the cost of SIMS instruments relative to other MS instruments as economies of scale take hold.

Imaging MS by MALDI despite its intrinsic uncertainties has already made a significant impact. If ion yields can be enhanced and matrix effects relieved in MALDI using our proposed beam system, the impact of our work may spread out to the major MS manufacturers with enormous commercial benefits.

Publications

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Description The aim of the research was to find ways to increase the secondary ion yield in time of flight secondary ion mass spectrometry from the current level of less than 1E-5 by 100 to 100 times. The purpose is to increase the analytical sensitivity of ToFSIMS particularly when it is used in high spatial resolution mode where the number of molecules accessible for analysis is very small.

We have demonstrated that high energy (20 keV) cluster ion beams composed of 6000 to 7000 water molecules enhance the yield of protonated analyse ions from arrange of standard bio-related compounds by 10 to more than 100 times over against the yield observed using argon cluster beams of the similar size.

We have shown that the energy per water molecule in the cluster beam (e.g. 20 keV/6000 = 3.3 eV) is critical in optimising the conditions for high analyte ion yield. This is very new observation. We have also shown that the larger the number of water molecules in the cluster for a given energy per molecule, the greater the ion yield. This implies that if a higher energy beam can built, very much larger clusters can be used to give even high ion yields.

The beams have been applied to high spatial resolution imaging of mouse brain tissue. This work has demonstrated that the increased ion yield seen for the standard compounds is replicated in the real analysis such that higher sensitivity is attained. Furthermore the ion suppression effects frequently seen as a consequence of interfering chemistry in analyse sample is greatly ameliorated. This is highlighted by the fact using argon or C60 primary beams cholesterol is observed in the white matter of the brain but not in the grey matter (even though it is actually present), using the water cluster beams cholesterol can be observed.

We have also shown that water incorporated into argon cluster beams can result in ion yield enhancement at roughly 30 to 50% of the level seen with pure water beams.
Exploitation Route It is expected that the ion beam system will be used by other researchers in bio-imaging or organic electronics applications.

The possibilities for higher energy beams and beams incorporating other molecules could be area of further fruitful research.
Sectors Chemicals,Electronics,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology

 
Description The research was carried out using a prototype beam system developed with Ionoptika Ltd of Chandlers Ford. The beam system has been refined and and offered as an add-on ion beam system for ToF-SIMS systems. At the end date of the grant one sale had already been made. In subsequent work in collaboration in 2019 with a group at Penn State University in the US extending the ion energy range to 70 keV has resulted in even higher ion yields and a more highly focused beam capable of sub-micron imaging. Since the end of the grant in 2014, water cluster beams whose development arose from this grant have been suppled and incorporated on two J105 ToFSIMS systems in the USA, one in Sweden, one in Japan, one in the UK and the latest one, on a new J105 system in Prof Lockyer's lab at The University of Manchester.
First Year Of Impact 2014
Sector Chemicals,Electronics,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Title Enhancement of secondary ionisation using proton-containing cluster beams 
Description A massive water cluster ion beam source has been developed that increases the level of ionisation observed during molecular ToF-SIMS analysis by x10-100. This provides associated levels of increased sensitivity in the 2D and 3D characterisation of molecular surfaces. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2013 
Impact Commercialization of a water cluster primary ion beam system by UK SME Ionoptika Ltd.