A new dynamic in mass spectral imaging for biological systems

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

Abstract

A collaborative project is proposed with the Penn State SIMS Group to capitalise on the dramatic advances in ToF-SIMS resulting from the development of routine C60 primary ion beam technology by the Manchester SIMS Group in 2000. ToF-SIMS (Time of Flight Secondary Ion Mass Spectrometry) analyses the surface chemistry of materials by bombarding the surface with moderate energy particles and thereby removing and detecting molecular and atomic fragments in the form of charged particles (or ions). C60 beams remove molecules rather gently ensuring that the analyte materials are much less damaged in the removal process than under the atomic ion beam bombardment technology previously used. C60 also delivers a much larger molecular removal rate (sputtering) resulting in enhanced sensitivity and analytical efficiency. The Penn State Group under Professor Winograd, rapidly recognised the importance of this development and in parallel with the Manchester group has been exploring C60 sputtering and developing applications. The most exciting advance is that because C60 is able to remove surface layers with little damage to underlying layers, molecular depth profiling is possible and, of even more significance, 3D molecular imaging with good 2D and 3D spatial resolution. The potential applications in biological research alone are legion.Both groups have realized that to exploit this new capability requires new instrument concepts. The Manchester group has been funded by EPSRC to develop a new instrument design with two small UK companies. This is close to completion and initial results show that it will more than meet expectations. The Penn State group has been funded to adapt a current commercial mass spectrometer of somewhat different geometry with a C60 source to the same end. The outputs from their system are also beyond expectations. Through discussions at international meetings it is clear that the research and development requirements to fully realise the potential of this SIMS analysis approach are almost identical, but exceed the level envisaged when each groups' work was originally funded. A coordinated programme of work at PSU and UoM is proposed to realise the full power of the new technologies. This will involve the exchange of doctoral and post-graduate student researchers to harness the expertise of the two groups on two focused areas of work. The first will be concerned with fundamental sputtering studies and analysis protocol development to fully enable the potential for reliable 2 and 3 D analysis and imaging. Fundamental studies will seek to unravel and define the degree to which ion/material interactions and instrumental parameters influence the acquisition of reliable and understandable 2D and 3D chemical images. Parallel studies on the two instruments will be vital for this work. The other important operational parameter is that both instruments deliver vast amounts of information very rapidly and the outputs are potentially very complex. Computational methods will be researched to handle the outputs and deliver understandable information quickly, for example using the latest 3D visualisation methods and the use of MVA analysis techniques to extract real chemical information.Sensitivity is the central issue in mass spectrometry in the imaging mode because the desire for increasing levels of spatial resolution means there can never be enough ion yield. 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. Increasing secondary ion yield by at least a factor 10 would be an enormous benefit to this and other mass spectrometries. The second area of research will therefore investigate mechanisms and develop equipment to implement enhanced cationisation and particularly protonation of bio-molecules to seek to obtain a more than 10-fold increase.

Publications

10 25 50

publication icon
Fletcher JS (2011) Label free biochemical 2D and 3D imaging using secondary ion mass spectrometry. in Current opinion in chemical biology

publication icon
Fletcher JS (2009) Cellular imaging with secondary ion mass spectrometry. in The Analyst

 
Description The research performed during this project has contributed to understanding the new physics associated with bombarding molecular materials with high-energy massive clusters comprising upto several thousand atoms. This has led to new protocols for the chemical analysis and 2D/3D imaging of organic materials and biological systems. Using these protocols researchers are able to study detailed chemical composition and distributions within complex molecular samples in sectors including advanced materials and healthcare.
Exploitation Route This research will drive further understanding of how materials perform and how healthy/diseased biological systems are organized and respond to therapeutic intervention.
Sectors Aerospace, Defence and Marine,Agriculture, Food and Drink,Electronics,Energy,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy

URL http://www.sarc.manchester.ac.uk/index.php/publications/
 
Description The research was directed towards exploiting new ion beam technologies using a new concept ToF-SIMS instrument funded in a previous EPSRC supported project. Our developments in primary beam technology have shown up the weaknesses of the conventional pulsed reflectron ToF analysers. They are ill-suited to the demands imposed by the analysis of complex chemistry. The C60 and argon cluster beams with their low damage capability suggested the application of a dc analysis mode akin to that used in ortho-ToFs. In collaboration with Ionoptika Ltd Manchester the group developed a similar concept instrument that has a buncher-ToF configuration. In the present project our results have demonstrated the unique capabilities and versatility of this instrument for analysis and 2D and 3D imaging of biological cells and tissue using both C60+ and Arn+ primary beams. As a consequence of this work two instruments (costing £1m each) have been installed at Penn State University and Gothenburg University. A further 2 are under construction in late 2014 for installation in the University of Washington and Newcastle University.
First Year Of Impact 2012
Sector Agriculture, Food and Drink,Chemicals,Energy,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy,Other
Impact Types Economic

 
Description BBSRC Grouped
Amount £600,000 (GBP)
Funding ID BB/K011170/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2013 
End 01/2016
 
Description BBSRC Grouped
Amount £600,000 (GBP)
Funding ID BB/K011170/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2013 
End 01/2016
 
Description EPSRC
Amount £260,893 (GBP)
Funding ID EP/K01353X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2012 
End 12/2014
 
Title 3D ToF-SIMS imaging 
Description The J105 3D ToF-SIMS developed under EP/C008251/1 is a completely novel instrument design for surface chemical analysis and imaging on the micron scale. The instrument uses a novel linear buncher/time-of-flight mass spectrometer combination to allow the use of quasi-continuous ion beams. Under EP/G045623/1 the potential of this instrument is realised for 3D analysis of complex chemical systems including biological cells/tissue and organic electronics. Rapid and sensitive sample analysis using polyatomic cluster primary ion beams is realised, together with capabilities for enhanced structural identification using tandem mass spectrometry. 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact The further demonstration of the state-of-the-art capabilities of J105 instrument resulting from this project led to sales of four subsequent instruments by the UK SME and project collaborator Ionoptika Ltd. 
URL http://www.ionoptika.com/tof-sims/products/tofsims/j105-sims