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

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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.