New Developments in Quantitative 3D Chemical Imaging

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is an outstanding method of chemical analysis, used extensively in academia and industry to characterise complex samples in 2D/3D. Application areas include materials science, biology, healthcare, energy etc. In the analysis the high-energy 'primary' ion projectile impact on a sample surface, causes ejection of 'secondary' molecular ions which are analysed by a mass spectrometer to provide chemically-rich material characterisation. Scanning the primary beam across the sample provides 2D surface imaging (>100 nm lateral resolution) and by sequentially collecting images while the sample is eroded, 3D sub-surface imaging (>3 nm depth resolution). This unique combination of analytical capabilities means ToF-SIMS is unmatched in its potential to determine, in a single analysis, the composition and detailed distribution of multiple, chemicals in complex samples. Importantly, this technology supports 'discovery mode' research, where the analysis is not biased towards pre-selected, labelled compounds, and therefore leads to hypothesis generation. The analysis is highly-multiplexed and comprehensive - hundreds of species can be potentially detected in a single measurement, limited only by the sensitivity of the process, which here we seek to enhance 100-fold.

This proposal addresses critical challenges from next-generation samples demanding greater sensitivity, broader chemical coverage and reliable quantification to address issues including sub-cellular drug localisation and nanoscale molecular materials. It builds on our internationally-leading reputation for innovative ToF-SIMS instrumentation. The characteristics of the primary ion are fundamental in determining impact dynamics at the sample surface and the success of the resulting measurement. The challenge of producing intact secondary molecules from the sample has been largely solved using polyatomic cluster projectiles e.g. C60 and Ar2000 which produce ~100 sputtered molecules per impact. However, only ~0.001-0.1% of these molecules are produced as charged ions, which is necessary for their detection. Clearly there is huge room for improvement in the ionisation efficiency. The principle of projectile-initiated chemical reactions promoting ionisation of sputtered species has recently been firmly established by our work and that of others. We must now build on this knowledge and develop complementary approaches to meet the ionisation challenge and deliver quantitative compositional information.

We have assembled a multidisciplinary team of international experts from academia and industry, which is uniquely positioned to pursue this important project. Building on >20 years' experience in innovation of SIMS instrumentation, enabled through EPSRC support and close collaboration with UK Industry, we will develop next-generation reactive ion beams and analytical methodology. This will deliver further transformative gains in performance which are critical to meet future application needs. Our novel results will be framed within the context of emerging theory to understand mechanisms of enhanced ionisation and to underpin the optimisation of projectile parameters. They will stimulate further development of theoretical models of the physical processes underlying SIMS and related techniques.

The project is highly-adventurous, providing beyond state-of-the-art analytical capability underpinned with new fundamental understanding. We are ideally placed to exploit this through the interdisciplinary research collaborations at the Manchester Institute of Biotechnology and the Sir Henry Royce Institute for Advanced Materials. The vastly increased quality of data will result in new understanding in a wide range of applications spanning many areas of science and technology.

EPSRC's Review of Analytical Sciences (May 2015) acknowledges its 'vastly interdisciplinary' nature, 'affecting science, society and the economy'. This proposal promises significant impact leverage in the following areas:

Knowledge. Discoveries across many disciplines are underpinned by cutting-edge analytical science. The unparalleled capabilities delivered through this research will promote new understanding of structure-function relationships in technological and biological materials, providing many new opportunities for control or intervention. For example, cellular level molecular pathology promises new insights into disease mechanisms and drug targets. This is exemplified through the CRUK Grand Challenge #5 "Find a way of mapping tumours at the molecular and cellular level" supporting a £10m MS imaging programme led by project partners at NPL. This proposal will impact directly on the vital contribution that SIMS can make to this programme, significantly extending quantitative imaging capabilities.

Society. MS imaging is adopted widely in healthcare, manufacturing and consumer products, developing innovative products to enhance the quality of life and promote well-being. Examples include the development of antimicrobial resistant surfaces and new drugs, stratified medicine and precision drug delivery. The project will accelerate and extend this impact through enhanced capability. Outreach activities will engage with schools and public and promote scientific discussion and inspire the next generation of UK scientists.

People. The PDRA and student-users will benefit from interdisciplinary training and personal development, engaging with academic and industrial collaborators and project partners. Close collaboration with Ionoptika Ltd will foster innovation skills and entrepreneurship. Students exposed to this research will contribute to human capacity-building in cross-disciplinary scientific research. Recent PhD alumni have gained tenure at Gothenburg, Salford and Strathclyde, post-docs in leading UK and US labs, and UK research positions with Waters Corp, Millbrook Instruments, MKS, Nu Instruments, DSTL, SAI Ltd, and Intertek Ltd.

Economy. The global market for MS is estimated to be $7.3bn by 2020, with compound annual growth rate >8% (www.marketsandmarkets.com). Single cell analysis and MS imaging are cited as among the fastest growing markets. As a critical enabler of innovation there is significant stakeholder pull from industry for enhanced capability. Economic impact will be derived from the accelerated development of new protocols and products with the associated additional income generation. Enhanced sensitivity will deliver cost-saving through increased sample throughput. Relevant industries span healthcare, biotechnology, automotive, organic electronics and agrichem. The international competitiveness of UK instrumentation manufacturing will be enhanced, stimulating financial growth and securing employment. Maintaining the highly successful collaboration between the Manchester group and Ionoptika Ltd will keep the UK at the forefront of the expanding international ToF-SIMS field. Our previous EPSRC-funded research has led directly to a number of ground-breaking technological advances contributing to the UK economy through Ionoptika's growth and the widespread adoption of cluster beams for ToF-SIMS. Sales of five J105 instruments (>£1m each) has stimulated significant expansion at Ionoptika Ltd. Our REF2014 Impact Case based on the C60 ion beam, highlights job-creation within UK SME, >£4.5m sales (>150 C60 guns sold) and 3 patents. ULVAC-Phi's early adoption of this technology gained them a competitive advantage (sales of several £10m). Our track record of driving commercial success through scientific innovation with UK SME is well-established and the scientific and technological developments achieved through this project will ensure greater access to a growing worldwide instrumentation market.