1
Micro(fluidic) mass spectrometry
František Foret, Institute of Analytical Chemistry, Brno, Czech Republic Introduction – history
Instrumentation, ESI tip preparation
Applications
Miniaturized MS
Terry, S.C., Jerman, J.H., Angell, J.B. IEEE Transactions on Electron Devices, 1979, 26, 1880-86.
A Gas Chromatographic Air Analyzer Fabricated on a Silicon Wafer
Microfabrication at subdifraction-limit resolution
780 nm, 150 fsec, Ti-saphire
laser.
Raster scanning with
two photon absorbtion polymerization
of SCR500
resin.
Spatial resolution 120 nm.
Kawata, S., Sun, H.-B., Tanaka, T. & Takada, K. Finer features for functional microdevices.
Nature 412, 697 - 698 (2001).
2 mm
2 mm
Steven A. Soper, Univ. North Carolina, Chapel Hill Steven A. Soper, Univ. North Carolina, Chapel Hill
Adam T. Woolley And Richard A. Mathies Proc. Natl. Acad. Sci. USA, vol. 91, pp. 11348-11352, 1994
Ultra-high-speed DNA fragment separations using
microfabricated capillary array electrophoresis chips
Yining Shi, Peter C. Simpson, James R. Scherer, David Wexler, Christine Skibola,
Martyn T. Smith, and Richard A. Mathies. Anal. Chem. 1999, 71, 5354-5361
Radial Capillary Array Electrophoresis Microplate and Scanner
for High-Performance Nucleic Acid Analysis.
Karger, B.L., Foret, F., Qifeng, X., Dunayevski, Y., Zavracki, P., McGruer, N. U.S. Patent # 5,872,010, 1999.
What is claimed is: 1. A liquid handling system, comprising a microscale liquid handling substrate having one or more
channels integrally formed therein, for conducting a liquid sample in said substrate, said one or more channels
terminating in one or more exit ports in an outer surface of said substrate for transfer of a microscale quantity of a
liquid sample off said substrate by droplet, spray or stream;
Microscale Fluid Handling System
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Xue, Q., Foret, F., Dunayevskiy, Y.M., Zavracky, P.M., McGruer, N.E., Karger, B.L. Anal.Chem., 69, 1997, 426-430.
Multichannel Microchip Electrospray Mass Spectrometry
J. M. Ramsey, R. Ramsey Anal. Chem., 1997, 69, 1174-1178.
Generating Electrospray from Microchip Devices
Using Electroosmotic Pumping
Etching, pulling, …
Grinding
Original capillary
ESI tip (micro)fabrication ?
Electrospray tip preparation
• grinding
• pulling
• etching
Ryan T. Kelly , Jason S. Page, Quanzhou Luo et. all, Analytical Chemistry , 2006, 78 (22), 7786-7801Patrik Ek and Johan Roeraade, Analytical Chemistry , 2011, 83 (20), 7771-7777
ESI exit
spray fluid
BGE waste
sample
nebulizer gas
10 mm
Zhang, B. Liu, H. Karger, B. L. Foret, F. Anal. Chem., 1999, 71, 3258-3264.
CE Microdevice with a Pneumatic Nebulizer
0 2.0 4.0
Time (min)
0
20
40
60
80
100
RelativeAbundance
m/z
400 1200
591.6
1181.7
Angiotensin I
des-AspI
450.5
899.5
630.6
775.4
m/z
400 1200
m/z
400 1200
m/z
400 1200
Angiotensin III
1-7
Angiotensin I
Bullfrog
Angiotensin III
3-8
Base peak
441.1
880.8
m/z
400 1200
Angiotensinogen 1-14
Porcine
1
2
3
4
5
CE Microdevice with a Pneumatic Nebulizer
1. 2.
3. 4. 5.
Zhang, B. Liu, H. Karger, B. L. Foret, F. Anal. Chem., 1999, 71, 3258-3264.
Liquid junction with an external ESI tip
1cm
sample in
wasteinject
+ HV wash
liquid junction
(spray liquid)
ESI capillary in
B. Zhang, F. Foret, B.L. Karger High-Throughput Microfabricated CE/ESI-MS:
Automated Sampling from a Microwell Plate. Anal. Chem. 2001, 73, 2675-2681
V
V
+
V
wash - 5 s
Separation ~ 30-500 sinject sample - 2 s
load sample - 2 s
Scheme of the Operation
P
1
2
4
3
3
2 4 6 8 10
Time (min)
0
50
100
RelativeAbundance
100
2.0 4.0 6.0
Time (min)
0
50
RelativeAbundance
1.0 2.0 3.0 4.0
Time (min)
0
50
100
RelativeAbundance
1.0 2.0 3.0 4.0 5.0
Time (min)
0
50
100
RelativeAbundance
2.0 4.0 6.0
Time (min)
0
50
100
RelativeAbundance
1.0 2.0 3.0 4.0 5.0
Time (min)
0
50
100
RelativeAbundance
1.0 2.0 3.0
Time (min)
0
50
100
RelativeAbundance
2 4 6 8 10
Time (min)
0
50
100
RelativeAbundance
Fetuin BSA
Chymotrypsinogen
-Casein-LactoglobulinCytochrome cUbiquitin
Carbonic
Anhydrase
Protein Tryptic Digests High Throughput ESI/MS Analysis
pressure distribution
cover plate
MS sampling orifice extension
translation stage
96 ESI tips, 26 mm i.d.
flow ~ 200 nl/min
.
.
stationary gas
pressure nozzle
stationary HV electrode
N2
gas distribution channels
Microtiter well plate
with 96 ESI tips
96 Tip Plastic Microdevice
electrode array
25 mm
Fused silica tips (25 mm id)
Liu, H., Felten, C., Xue, Q., Zhang, B., Jedrzejewski, P., Karger, B.L., Foret, F.
Anal. Chem., 2000, 72, 3303-3310.
A
B
C
D
E
F
G
H
1 2 3 4 5 6 7 8 9 10 11 12
High Throughput Analysis with 96 ESI Tips Microdevice
Total analysis time = 480 s
Chip
Separation channels
Deposition
probe
Vacuum chamber
MALDI target
Infusion capillaries
384 microtiter plate
Vacuum Deposition MALDI With
Multichannel CE Chip
Liquid junction
Rejtar, T., et al., unpublished
Rejtar, T., et al., unpublished
Parallel sample loading and injection device
for multichannel microfluidic devices
Foret; F., Rejtar; T., Zhang; B., Karger; B. L.
US Patent 6,939,452
A. G. Chambers and J. M. Ramsey, Anal. Chem., 2012, 84, 1446.
Microfluidic dual emitter electrospray ionization
source for accurate mass measurements
1 mm
Si wafer
SU-8
Le Gac S., Arscott S., Rolando C. ELECTROPHORESIS 2003 , 24, 3640-3647.
Micro-nib electrospray source
(SU-8 on a silicon wafer)
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Sjödahl, J., Melin, J., Griss, P., Emmer, A., Stemme, G., Roeraade, J. Rapid Commun. Mass Spectrom. 2003, 17, 337—341.
ESI tips produced by DRIE in silicon Infusion ESI Tip Array
www.advion.com
www.gyros.com
The CD microdevice concept
100 mm
Integrated Au tips
99.0 479.2 859.4 1239.6 1619.8 2000.0
Mass (m/z)
10
20
30
40
50
60
70
80
90
100
%Intensity
Mariner Spec #55
942.3776
1060.0493
997.7748
892.8873
1130.6530
848.2501
1211.3672
1304.4031
615.9114
807.8893
1413.1471
1550.2806
99.0 479.2 859.4 1239.6
Mass (m/z)
10
20
30
40
50
60
70
80
90
100
%Intensity
Mariner Spec #475
432.8174
558.2133
530.6894354.1298
649.2124 836.7822
10-5 M Bradykinin, Angiotensin, Neurotensin in 50% ACN, 1% HAc10-6 M myoglobin in 50% IPA, 1% HAc
HV
MS
external pump
Aerodynamic mass spectrometry interfacing
of microdevices without electrospray tips
J. Grym, M. Otevrel, F. Foret Lab Chip, 2006, 6, 1306–1314
ESI tip fabrication
www.advion.com
DRIE in silicone
Plasma etched in polyimide
www.diagnoswiss.com www.phoenix-st.com
www.agilent.com
Injection molding in polypropylene
Applications
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Microfabricated Monolith Columns for Liquid Chromatography
Sculpting Supports for Liquid Chromatography
Fred E. Regnier J. High Resol. Chromatogr.
2000, 23, (1) 19–26
De Malsche W., Op de Beeck J., De Bruyne
S., Gardeniers H., Desmet G.
Analytical chemistry 2012, 84(3), 1214-1219
De Malsche W., De Bruyne S., Op de Beeck J.,
Eeltink S., Detobel F., Gardeniers H., Desmet G.
Journal of Separation Science 2012, 35, 2010-17
Porous-shell pillar array column separations on
a capillary LC instrument
Gradient LC separation of albumin digest
(4ml/min, 1 mg/ml, UV detection)
De Malsche W., De Bruyne S., Op de Beeck J., Eeltink S., Detobel F., Gardeniers H., Desmet G.
Journal of Separation Science 2012, 35, 2010-2017
A microfabricated micropillar liquid chromatographic chip
Monolithically integrated with an electrospray ionization tip
Lauri Sainiemi, Teemu Nissilä, Risto Kostiainen, Sami Franssila and Raimo A. Ketola
Lab Chip, 2012, 12, 325
Mao, P; Gomez-Sjoberg, R; Wang, DJ. Anal. Chem. 2013, 85, 816-819.
Multinozzle Emitter Array Chips for Small-Volume Proteomics
Multinozzle Emitter Array Chips for Small-Volume Proteomics
Mao, P; Gomez-Sjoberg, R; Wang, DJ. Anal. Chem. 2013, 85, 816-819.
Mellors, JS; Black, WA; Chambers, AG; Starkey, JA; Lacher, NA; Ramsey, JM. Anal. Chem. 2013, 85, 4100-4106
Hybrid Capillary/Microfluidic System for Comprehensive Online
Liquid Chromatography-Capillary Electrophoresis-ESI-MS
Hybrid Capillary/Microfluidic System for Comprehensive Online
Liquid Chromatography-Capillary Electrophoresis-ESI-MS
Mellors, JS; Black, WA; Chambers, AG; Starkey, JA; Lacher, NA; Ramsey, JM. Anal. Chem. 2013, 85, 4100-4106
S. Fritzsche, S. Ohla, P. Glaser, D. S. Giera, M. Sickert, C. Schneider and D. Belder
Angew. Chem., Int. Ed., 2011, 50, 9467-9470.
Asymmetric Organocatalysis and Analysis on
a Single Microfluidic Nanospray Chip
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B
Enzymatic microreactor with magnetic nanoparticles
Jean-Louis Viovy, InstitutCurie
Self assembly of magnetic nanoparticles
667 nL/min
417 nL/min
167 nL/min
On-chip tryptic digest with direct coupling
to ESI-MS using magnetic particles
A. Le Nel, J. Krenkova, K. Kleparnik, C. Smadja, M. Taverna, J.-L. Viovy, F. Foret Electrophoresis 2008, 29, 4944–4947
cytochrome c
J. Ji, L. Nie, L. Qiao, Y. Li, L. Guo, B. Liu, P. Yang and H. H.
Girault, Lab Chip, 2012, 12, 2625-2629.
Proteolysis in microfluidic droplets: an approach to interface
protein separation and peptide mass spectrometry
Proteolysis in microfluidic droplets: an approach to interface
protein separation and peptide mass spectrometry
J. Ji, L. Nie, L. Qiao, Y. Li, L. Guo, B. Liu, P. Yang and H. H. Girault, Lab Chip, 2012, 12, 2625-2629.
Nanoliter Segmented-Flow Sampling Mass Spectrometry
with On-Line Compartmentalization
M. Volný, J. Rolfs, B. Hakimi, P. Fryčák, T. Schneider, D. Liu, G. Yen, D.T. Chiu, F. Tureček
Anal. Chem., 2014, 86, 3647–3652
Commercialization
Microfluidic Chip for Peptide Analysis with an Integrated HPLC Column,
Sample Enrichment Column, and Nanoelectrospray Tip
H. Yin, K. Killeen, R. Brennen, D. Sobek, M. Werlich, T. van de GoorAnal. Chem. 2005, 77, 527-533
Polyimide HPLC-chip, integrating an enrichment column, frits, a
laser ablated ESI tip and trapazoidal separation column
www.agilent.com
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Segmented column HPLC/chip
www.agilent.com
Three LC columns – length 130 mm
Each segment individually packed.
BSA digest separated with a 30min gradient on a 2 column segmented chip,
packed with 3.5μm particles
Segmented column HPLC/chip
www.agilent.com
TRIZAIC nanoTile - Waters Enolase digest
70 fmol, 2 mm particles
nanoACQUITY
TRIZAIC nanoTile
Green tape
Al2O3–MgO–SiO2 glass particles mixed with organic binders and
solvents to form glass ceramic
Product Description
951 Green Tape is a low-temperature cofired ceramic tape.
The 951 system comprises a complete cofireable family of Au and Ag metallizations,
buried passives, and encapsulants.
951 is available in multiple thicknesses for use as an insulating layer in:
•Multichip modules
•Single chip packages
•Ceramic printed wiring boards
•RF modules
http://www.dupont.com/mcm
Cut Ceramic Material Fired Wafer
Ceramic Microfluidic Fabrication
Final Diced Part
Channel Geometries and Packing
1.7mm particles
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Channel shape effect
connections
Packed glass LC chip
Eksigent, part of AB SCIEX, www.eksigent.com
Miniaturized (microfabricated) mass spectrometers?
Miniaturized (microfabricated) mass spectrometers Miniature Mass Spectrometers
Ouyang Z., Cooks, G.R., Annu.Rev.Anal.Chem. 2009, 2, 187-214.
Ouyang Z., Cooks, G.R., Annual Rev.Anal.Chem. 2009, 2, 187-214.
Miniature Mass Spectrometer Systems based on
a Microengineered Quadrupole Filter
A. Malcolm, S.Wright, R. R. A. Syms,
N. Dash, M.-A. Schwab, A. Finlay
Anal. Chem. 2010, 82, 1751–1758
A miniature mass spectrometer for liquid
chromatography applications
Rapid Communications in Mass Spectrometry
Volume 25, Issue 21, pages 3281-3288, 3 OCT 2011 DOI: 10.1002/rcm.5230
http://onlinelibrary.wiley.com/doi/10.1002/rcm.5230/full#rcm5230-fig-0002
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Mass Analyzer ionchip® quadrupole mass spectrometer
Mass Range m/z 50-800 with ionchip®150
Mass Accuracy ± m/z 0.3 in full scan
Mass Resolution m/z 0.7±0.1 FWHM
Sensitivity 10pg of reserpine in SIM mode S/N ratio of 10:1 (RMS)
www.microsaic.com
Advion expression Compact Mass Spectrometer
www.advion.com
www.ce-ce.org
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