Development of a Novel MALDI Mass Spectrometer and Technology for the Generation of Multiply Charged Ions at High Sensitivity

Modern mass spectrometry (MS) can be compared to microscopy with its impact on analysing nature and materials down to the molecular (individual molecule) level, including the analysis of the cellular processes of life and the structure of molecules. These analytical tools have frequently been the key to major breakthroughs in science. MS in particular, has been at the forefront of recent advances in areas like biomedicine and healthcare. In this project we will develop a new instrument and the associated methodologies for another major step forward in MS and its application.

MS requires the production of gas phase ions. The two major ionisation techniques in modern MS are electrospray ionisation (ESI) and matrix-assisted laser desorption/ionisation (MALDI). There are fundamental differences between these two techniques. ESI enables ion formation exclusively out of a liquid while MALDI uses predominantly solid samples. Another significant difference can be found in their ability to produce multiply charged ions. For peptides, MALDI typically generates singly charged while ESI easily provides multiply charged ions.

Importantly, the production of highly charged ions is desirable as it allows the use of high-performance mass spectrometers, which typically cannot analyse the larger singly charged ions. It also facilitates more informative controlled fragmentation of the ions, thus helping to obtain further information such as their molecular structure. Consequently, there is a clear advantage of using ESI. Nonetheless, MALDI with its higher tolerance to contaminants, ease-of-operation, potential for high-speed automated analysis as well as its MS imaging capabilities makes it an ionisation technique that can cover (bio)analytical areas where ESI is less suitable. If these strengths could be combined with the analytical power of multiply charged ions, new instrumental configurations and new large-scale (bio)analyses using MALDI MS would become feasible.

The proposed instrument and method development will lead to a new technology that will enable the production of stable and high yields of multiply charged MALDI ions at high sensitivity, i.e. low analyte concentration and low sample consumption. It is based on a new ion source design, using a heated ion transfer tube to transfer the produced ions into the analyser of the mass spectrometer, and novel liquid sample preparation methods, ensuring stable and high yields of ESI-like multiply charged ions. Thus, the two main disadvantages of MALDI (no/low yield of multiply charged ions and highly variable ion yield and signal quality) will be addressed within this project. Ultimately, the newly developed technology should not only become a real competitor for ESI but also open up new areas of analysis that have previously been inaccessible.

In short, this project will develop a new MS technology that will significantly widen the application range of MALDI MS and thus MS in general, enabling new and more powerful analytical strategies. The project will result in a prototype instrument and methodology that can easily be commercialised. As MALDI MS is already making great strides within the (bio)analytical field it can be anticipated that this project will have significant impact in many areas from academia and industry to the public health sector and thus society at large.

Novel and improved analytical tools have frequently been the key to major breakthroughs in science.
Mass spectrometry (MS) in particular, has been at the forefront of recent advances in areas like biomedicine and healthcare. The MALDI mass spectrometer and technology that will be developed in this project will significantly widen the application range of MALDI, enabling new and more powerful analytical strategies. As MALDI MS is already making great strides within the bioanalytical arena it can be anticipated that this project will have significant impact in many areas from academia and industry to the public health sector and society at large.

Who might benefit from this research?

- Academia: MS researchers and all researchers applying MS as an analytical tool, from physicists and chemists to biomedical and clinical scientists. As MS is employed in molecular analysis, post-genomic research and increasingly in clinical research, this new technology has the potential to accelerate the work of an enormously wide research community.
How might they benefit? MS is often compared to microscopy. Similarly to microscopy that has enabled us to 'look' at cellular processes and molecular structure and interaction, MS is one of the modern analytical techniques that has the sensitivity and capability to reveal and investigate molecular processes further, from synthetic chemistry to systems biology and medicine. This new MALDI-based technique can combine the advantages of the competitor technique ESI (electrospray ionisation) with the advantages of MALDI and overcome some of the restrictive disadvantages of ESI, making it a technique that will be immensely powerful in modern MS. One project outcome will be the implementation of this new technology, resulting in a semi-commercial instrument. Thus, this project will provide the means and evidence for the technology's direct impact on studies and set-ups using modern mass spectrometers.

- Business/Industry: MS manufacturers and industry applying modern MS in research and analysis.
How might they benefit? New innovations in MS have been a major driver for the analytical sciences industry. MS is a multi billion dollar business and thus new technology in this field will have a major impact on the manufacturing industry, particular if it is a fundamental advance. In industry where MS is applied this new technology has the potential to enable the analysis of new substance classes under conditions previously impossible to employ. In combination with its speed and automation capabilities, major steps towards large-scale and rapid analysis in important areas such as diagnostics and screening can be foreseen, potentially leading to the next step for MS to be firmly established in areas such as healthcare (clinical labs), food security/testing, and other environmental analyses where modern MS is required.

- General Public: Various sections of the world population (e.g. patients)
How might they benefit? In general, there is great potential for advances in areas where organic macromolecules and their analysis play a major role, from the polymer sciences (new materials) to biomedicine, and society at large will benefit from these advances through better living conditions, economic advances and health, to name but a few. One specific example is the healthcare system where patients will indirectly benefit through new research and data in the life and biomedical sciences as well as through new diagnostic capabilities, all made possible with improved analytical methods such as the presented one.

- Public/Third Sector/Policy Makers/Governments: Research sponsors/funders, Science Advisors, (public) analytical laboratories
How might they benefit? Through new possibilities in funding research and savings from employing this new technology and its capabilities in providing deeper and more effective analyses.