A transmission geometry optical configuration allows for smaller laser spot size to facilitate high-resolution matrix-assisted laser/desorption ionization (MALDI) mass spectrometry. This increase in spatial resolution (ie, smaller laser spot size) is often associated with a decrease in analyte signal. MALDI-2 is a post-ionization technique, which irradiates ions and neutrals generated in the initial MALDI plume with a second orthogonal laser pulse, and has been shown to improve sensitivity. Herein, we have modified a commercial Orbitrap mass spectrometer to incorporate a transmission geometry MALDI source with MALDI-2 capabilities to improve sensitivity at higher spatial resolutions.
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