The ability of mass spectrometry to generate intact biomolecular ions efficiently in the gas phase has led to its widespread application in metabolomics1, proteomics2, biological imaging3, biomarker discovery4 and clinical assays (namely neonatal screens5). Matrix-assisted laser desorption/ionization6,7 (MALDI) and electrospray ionization8 have been at the forefront of these developments. However, matrix application complicates the use of MALDI for cellular, tissue, biofluid and microarray analysis and can limit the spatial resolution because of the matrix crystal size9 (typically more than 10 μm), sensitivity and detection of small compounds (less than 500 Da). Secondary-ion mass spectrometry10 has extremely high lateral resolution (100 nm) and has found biological applications11,12 although the energetic desorption/ionization is a limitation owing to molecular fragmentation. Here we introduce nanostructure-initiator mass spectrometry (NIMS), a tool for spatially defined mass analysis. NIMS uses ‘initiator’ molecules trapped in nanostructured surfaces or ‘clathrates’ to release and ionize intact molecules adsorbed on the surface. This surface responds to both ion and laser irradiation. The lateral resolution (ion-NIMS about 150 nm), sensitivity, matrix-free and reduced fragmentation of NIMS allows direct characterization of peptide microarrays, direct mass analysis of single cells, tissue imaging, and direct characterization of blood and urine.
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We thank K. J. Wu and L. Wu for initial TOF–SIMS analysis; N. Winograd, A. Brock, B. Bothner, P. Kuhn and B. F. Cravatt for comments; J. Hoffmann and S. Head for peptide array preparation; the Kuhn laboratory for cell culture and imaging; B. Bowen for software development; D. Herr and J. Chun for tissue sections; the K. L. Turner laboratory for SEM imaging; and S. A. Trauger for nanospray ESI analysis. A.N. was supported by a postdoctoral fellowship from the Swedish Research Council (VR). We gratefully acknowledge financial support from the Department of Energy, the National Science Foundation, the National Cancer Institute and the National Institutes of Health.
Author Contributions T.R.N. and O.Y. contributed equally to this work. T.R.N. and G.S. conceived of NIMS, developed and applied NIMS, designed experiments, analysed data, and wrote the manuscript. O.Y. developed and applied NIMS, designed experiments, analysed data, and wrote the manuscript. M.T.N. performed SEM studies. D.M. prepared cell cultures and performed fluorescent imaging. A.N. and W.U. developed and applied NIMS. J.A. used NIMS to image mouse embryo. S.L.G. performed ion-NIMS.
The file contains Supplementary Movie 1 which shows perfluorinated initiator reversibly migrating out of the nanostructured surface in response to heating.
The file contains Supplementary Movie 2 which shows silicon wafer cutting with a diamond-tip scribe.
The file contains Supplementary Movie 3 which shows washing the wafer chip with methanol and blowing it off with UHP nitrogen.
The file contains Supplementary Movie 4 which shows assembling the teflon cell with the silicon wafer chip.
The file contains Supplementary Movie 5 which shows post-etching: teflon cell disassembling and washing.
The file contains Supplementary Movie 6 which shows washing and drying the chip with UHP nitrogen.
The file contains Supplementary Movie 7 which shows adding the initiator compound to the etched chip.
The file contains Supplementary Movie 8 which shows removing the excess of initiator compound with UHP nitrogen.