TOF-SIMS Imagingof Intact Lipids in Biological Tissuewith Enhanced Ion Intensity by Ionic Liquid

Abstract Mass spectrometry imaging (MSI) is a powerful technique for visualizing the spatial distribution of chemical species in biological samples. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) enables high-spatial-resolution imaging and the detection of a broad range of molecular ions, including intact lipids. However, the observation of high-mass components remains challenging due to limitations in ionization efficiency and sample degradation. In this study, we present a novel sample preparation method for TOF-SIMS using an ionic liquid (IL) pretreatment to enhance the ionization efficiency of high-mass lipid ions. This approach increases the ionization efficiency of lipid molecules by achieving an appropriate distribution of ionic liquid to the surface of the sample. By reducing fragmentation, this method exceeds the static limit and increases the lipid ion signal by nearly 3 orders of magnitude. Furthermore, this method enabled static TOF-SIMS imaging of lipid-related ions and ion-induced electron imaging beyond the conventional static limit. These advancements significantly improve TOF-SIMS-based MSI applications, offering new opportunities for lipidomics and biological research.