Development of Novel High Energy Cluster Ion Beam Methodology for Molecular Analysis and Imaging

Abstract

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a sensitive surface analysis technique that has been used to study a large array of analytes. Two major limitations of this technique are low ionisation yields and matrix effects. The former is a limiting step in being able to analyse very small areas as well as specific analytes that do not ionise well under current methodologies. The latter issue (matrix effect) arises due to mutual interactions of compounds on the surface of interest and their ionisation enhancement/suppression. The unpredictable nature of matrix effects is what causes ToF-SIMS not to be a quantitative technique. Due to great dependence of matrix effects on the compounds being analysed as well as a range of instrument-related parameters it is a very elusive issue that has avoided simple solutions over the years. Both of these longstanding concerns have persisted in the field of ToF-SIMS, prompting the exploration of various approaches to address and resolve them. This thesis builds on previous work done to improve the ToF-SIMS instrumentation by changing the primary ion source. Large gas cluster ion beams (GCIBs) composed of water molecules had previously been shown to reduce matrix effects while also increasing yields for an assortment of organic compounds. Different attempts have been made to try to further improve these clusters but with varying degrees of success. Work presented in this thesis has shown that by doping reactive gas (CO2) into the water clusters it is possible to change their physical and chemical properties. This further resulted in significant changes in yields for tested pharmaceutical compounds as well as a reduction in matrix effects under certain conditions. Additionally, these findings also contribute to a fundamental understanding of the mechanism of cluster formation and composition, which will assist with further improvements in the field. The newly developed reactive water cluster ion beams were also applied to a range of different organic and biological samples with the aim of showing the applicability of these beams to be used to analyse more complex systems. Biological samples have been particularly difficult to work with due to the large number of interacting compounds which make the matrix effects far more difficult to address in a meaningful way. In this thesis analysis of murine brain samples was undertaken, with a specific focus on cholesterol detection and localisation. Results showed that the large reactive water clusters were very efficient at detecting cholesterol, a compound that a lot of other mass spectrometry techniques are not well suited for. Under specific condition it was also observed that using these novel ion beams also reduced matrix effects and provided a more quantitative analysis of the biological samples. In summary, this thesis demonstrates the successful development of a novel reactive cluster ion beam with the potential to increase yields and reduce matrix effects in ToF-SIMS. These findings also advance our understanding of cluster formation, a previously largely neglected area of experimental study.

Date of Award	2 Jan 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Nicholas Lockyer (Supervisor) & Katie Moore (Supervisor)