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Clathrate nanostructures for mass spectrometry


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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Figure 1: Nanostructure-initiator mass spectrometry.
Figure 2: Laser-NIMS and fluorescent analysis of a single cancer cell.
Figure 3: Bi 3 + ion imaging of peptide array on ion-NIMS surface.
Figure 4: Tissue imaging by laser-NIMS.
Figure 5: Direct analysis of biofluids by laser-NIMS without sample preparation.


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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.

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Correspondence to Gary Siuzdak.

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Supplementary information

Supplementary Information

The file contains Supplementary Discussion, Supplementary Figures 1-11 with Legends, Supplementary Tables 1-2, Supplementary Methods (including illustrated step-by-step procedures) and Legends for Supplementary Videos 1-8. The Supplementary Discussion includes: in depth discussion of the single cell results by laser-NIMS and its comparison with MALDI, nanoESI and ion-NIMS. Supplementary Figure 1 is a schematic to the main findings and applications of NIMS to aid readers unfamiliar with the immediate discipline. The Supplementary Figures 2-11 and the 2 Supplementary Tables provide results to proof and better understand assertions made throughout the printed version of the paper. Supplementary Methods contains a detailed step-by-step protocol to make NIMS chips. Some images are provided, as well as 7 Supplementary Videos (2-8) to visualize and facilitate the performance of this protocol. Supplementary Video 1 concerns NIMS mechanism and shows the reversible migration of the initiator within the nanostructure surface. (PDF 1264 kb)

Supplementary Movie 1

The file contains Supplementary Movie 1 which shows perfluorinated initiator reversibly migrating out of the nanostructured surface in response to heating. (MOV 5241 kb)

Supplementary Movie 2

The file contains Supplementary Movie 2 which shows silicon wafer cutting with a diamond-tip scribe. (MOV 1885 kb)

Supplementary Movie 3

The file contains Supplementary Movie 3 which shows washing the wafer chip with methanol and blowing it off with UHP nitrogen. (MOV 1280 kb)

Supplementary Movie 4

The file contains Supplementary Movie 4 which shows assembling the teflon cell with the silicon wafer chip. (MOV 3096 kb)

Supplementary Movie 5

The file contains Supplementary Movie 5 which shows post-etching: teflon cell disassembling and washing. (MOV 3438 kb)

Supplementary Movie 6

The file contains Supplementary Movie 6 which shows washing and drying the chip with UHP nitrogen. (MOV 1834 kb)

Supplementary Movie 7

The file contains Supplementary Movie 7 which shows adding the initiator compound to the etched chip. (MOV 2606 kb)

Supplementary Movie 8

The file contains Supplementary Movie 8 which shows removing the excess of initiator compound with UHP nitrogen. (MOV 4132 kb)

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Northen, T., Yanes, O., Northen, M. et al. Clathrate nanostructures for mass spectrometry. Nature 449, 1033–1036 (2007).

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