Abstract

Flow cytometry is an ever-advancing high-throughput multivariate analysis tool that natively provides size and morphological information. To obtain molecular information, however, typically requires the addition of fluorophores, which are limited by spectral overlap, nonspecific binding, available conjugation chemistries, and cellular toxicity. A complementary or alternative, label-free approach to molecular information is through multiplex coherent anti-Stokes Raman scattering (MCARS), which is a coherent, nonlinear optical method that provides a wealth of molecular information by probing the Raman energies within a molecule. In this work, we demonstrate the unique capability of our MCARS flow cytometer to distinguish flowing particles and discuss system performance capabilities and possibilities.

© 2009 Optical Society of America

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2008 (6)

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

A. Y. Lau, L. P. Leeb, and J.W. Chan, "An integrated optofluidic platform for Raman-activated cell sorting," Lab on a Chip 8, 1116-1120 (2008).
[CrossRef] [PubMed]

H. Kano, "Molecular vibrational imaging of a human cell by multiplex coherent anti-Stokes Raman scattering microspectroscopy using a supercontinuum light source," J. Raman Spectrosc. 39, 1649-1652 (2008).
[CrossRef]

C. L. Evans and X. S. Xie, "Coherent anti-Stokes Raman scattering microscopy: chemical imaging for biology and medicine," Annu. Rev. Anal. Chem. 1, 883-909 (2008).
[CrossRef]

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

H. W. Wang, N. Bao, T. T. Le, C. Lu, and J. X. Cheng, "Microfluidic CARS cytometry," Opt. Express 16, 5782-5789 (2008).
[CrossRef] [PubMed]

2006 (4)

G. M. Whitesides, "The origins and the future of microfluidics," Nature 442, 368-373 (2006).
[CrossRef] [PubMed]

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

2005 (4)

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

T. M. Squires and S. R. Quake, "Microfluidics: fluid physics at the nanoliter scale," Rev. Mod. Phys. 77, 977-1026 (2005).
[CrossRef]

H. Kano and H. Hamaguchi, "Vibrationally resonant imaging of a single living cell by supercontinuum-based multiplex coherent anti-Stokes Raman scattering microspectroscopy," Opt. Express 13, 1322-1327 (2005).
[CrossRef] [PubMed]

E. R. Andresen, H. N. Paulsen, V. Birkedal, J. Thøgersen, and S. R. Keiding, "Broadband multiplex coherent anti-Stokes Raman scattering microscopy employing photonic-crystal fibers," J. Opt. Soc. Am. B 221934-1938 (2005).
[CrossRef]

2004 (2)

J. X. Cheng and X. S. Xie, "Coherent Anti-Stokes Raman Scattering Microscopy:Instrumentation, Theory, and Applications," J. Phys. Chem. B 108, 827-840 (2004).
[CrossRef]

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

2003 (2)

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

H. N. Paulsen, K. M. Hilligsøe, J. Thøgersen, S. R. Keiding, J. J. Larsen, "Coherent anti-Stokes Raman scattering microscopy with a photonic crystal fiber based light source," Opt. Lett.,  28, 1123-1125 (2003).
[CrossRef] [PubMed]

2002 (5)

J. X. Cheng, A. Volkmer, and X. S. Xie, "Theoretical and experimental characterization of coherent anti-Stokes Raman scattering microscopy," J. Opt. Soc. Am. B 19, 1363-1375 (2002).
[CrossRef]

G.W. H. Wurpel, J. M. Schins, and M. M¨uller, "Chemical specificity in three-dimensional imaging with multiplex coherent anti-Stokes Raman scattering microscopy," Opt. Lett. 27, 1093-1095 (2002).
[CrossRef]

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

M. M¨uller and J. M. Schins, "Imaging the Thermodynamic State of Lipid Membranes with Multiplex CARS Microscopy," J. Phys. Chem. B,  106, 3715-3723 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

2001 (2)

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

M. Roederer, "Spectral Compensation for Flow Cytometry: Visualization Artifacts, Limitations, and Caveats," Cytometry 45, 194-205 (2001).
[CrossRef] [PubMed]

2000 (1)

N. Baumgarth and M. Roederer, "A practical approach to multicolor flow cytometry for immunophenotyping," J. Immunological Methods 243, 77-97 (2000).
[CrossRef]

1996 (1)

A. D. Michelson, "Flow cytometry: a clinical test of platelet function," Blood 87, 4925-4936 (1996).
[PubMed]

1979 (1)

1972 (1)

M. L. Shuler, R. Aris, and H. M. Tsuchiya, "Hydrodynamic focusing and electronic cell-sizing techniques," Appl. Microbiol.,  24, 384-388 (1972).
[PubMed]

1956 (1)

W. H. Coulter, "High speed automatic blood cell counter and analyzer," inProceedings of the National Electronics Conference,  12, 1034-1040 (1956).

1901 (1)

K. Pearson, "On lines and planes of closest fit to systems of points in space," Philosoph. Mag. 2, 559-572 (1901).

Andresen, E. R.

Aris, R.

M. L. Shuler, R. Aris, and H. M. Tsuchiya, "Hydrodynamic focusing and electronic cell-sizing techniques," Appl. Microbiol.,  24, 384-388 (1972).
[PubMed]

Bao, N.

Baumgarth, N.

N. Baumgarth and M. Roederer, "A practical approach to multicolor flow cytometry for immunophenotyping," J. Immunological Methods 243, 77-97 (2000).
[CrossRef]

Birkedal, V.

Bonn, D.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

Bonn, M.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

Book, L. D.

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

Brock, R. S.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Brown, L. O.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

Chan, J. W.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Chan, J.W.

A. Y. Lau, L. P. Leeb, and J.W. Chan, "An integrated optofluidic platform for Raman-activated cell sorting," Lab on a Chip 8, 1116-1120 (2008).
[CrossRef] [PubMed]

Cheng, J. X.

H. W. Wang, N. Bao, T. T. Le, C. Lu, and J. X. Cheng, "Microfluidic CARS cytometry," Opt. Express 16, 5782-5789 (2008).
[CrossRef] [PubMed]

J. X. Cheng and X. S. Xie, "Coherent Anti-Stokes Raman Scattering Microscopy:Instrumentation, Theory, and Applications," J. Phys. Chem. B 108, 827-840 (2004).
[CrossRef]

J. X. Cheng, A. Volkmer, and X. S. Xie, "Theoretical and experimental characterization of coherent anti-Stokes Raman scattering microscopy," J. Opt. Soc. Am. B 19, 1363-1375 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

Cote, D.

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Coulter, W. H.

W. H. Coulter, "High speed automatic blood cell counter and analyzer," inProceedings of the National Electronics Conference,  12, 1034-1040 (1956).

Doorn, S. K.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

Evans, C. L.

C. L. Evans and X. S. Xie, "Coherent anti-Stokes Raman scattering microscopy: chemical imaging for biology and medicine," Annu. Rev. Anal. Chem. 1, 883-909 (2008).
[CrossRef]

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Feldman, A.

Gaskill, D. F.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

Goddard, G.

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Goodwin, P. M.

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Graves, S. W.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Griebner, U.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Habbersett, R.

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Hamaguchi, H.

Herrmann, J.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Hilligsøe, K. M.

Horowitz, D.

Hu, X. H.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Husakou, A.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Huser, T.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Ihara, K.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Jacobs, K. M.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Jett, J. H.

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Johnson, J. C.

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Kano, H.

H. Kano, "Molecular vibrational imaging of a human cell by multiplex coherent anti-Stokes Raman scattering microspectroscopy using a supercontinuum light source," J. Raman Spectrosc. 39, 1649-1652 (2008).
[CrossRef]

H. Kano and H. Hamaguchi, "Vibrationally resonant imaging of a single living cell by supercontinuum-based multiplex coherent anti-Stokes Raman scattering microspectroscopy," Opt. Express 13, 1322-1327 (2005).
[CrossRef] [PubMed]

Keiding, S. R.

Knight, J. C.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Knutsen, K. P.

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Korn, G.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Lane, S. M.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Larsen, J. J.

Lau, A. Y.

A. Y. Lau, L. P. Leeb, and J.W. Chan, "An integrated optofluidic platform for Raman-activated cell sorting," Lab on a Chip 8, 1116-1120 (2008).
[CrossRef] [PubMed]

Le, T. T.

Leeb, L. P.

A. Y. Lau, L. P. Leeb, and J.W. Chan, "An integrated optofluidic platform for Raman-activated cell sorting," Lab on a Chip 8, 1116-1120 (2008).
[CrossRef] [PubMed]

Lin, C. P.

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Lu, C.

Lu, J. Q.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

M¨uller, M.

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

M. M¨uller and J. M. Schins, "Imaging the Thermodynamic State of Lipid Membranes with Multiplex CARS Microscopy," J. Phys. Chem. B,  106, 3715-3723 (2002).
[CrossRef]

G.W. H. Wurpel, J. M. Schins, and M. M¨uller, "Chemical specificity in three-dimensional imaging with multiplex coherent anti-Stokes Raman scattering microscopy," Opt. Lett. 27, 1093-1095 (2002).
[CrossRef]

Ma, X.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Martin, J. C.

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Michelson, A. D.

A. D. Michelson, "Flow cytometry: a clinical test of platelet function," Blood 87, 4925-4936 (1996).
[PubMed]

Miller, A. E.

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Müller, M.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

Naivar, M.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Nickel, D.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Nolan, J. P.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

Paulsen, H. N.

Pearson, K.

K. Pearson, "On lines and planes of closest fit to systems of points in space," Philosoph. Mag. 2, 559-572 (1901).

Petersen, P. B.

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Potma, E. O.

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Puorishaag, M.

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Quake, S. R.

T. M. Squires and S. R. Quake, "Microfluidics: fluid physics at the nanoliter scale," Rev. Mod. Phys. 77, 977-1026 (2005).
[CrossRef]

Rinia, H. A.

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

Roederer, M.

M. Roederer, "Spectral Compensation for Flow Cytometry: Visualization Artifacts, Limitations, and Caveats," Cytometry 45, 194-205 (2001).
[CrossRef] [PubMed]

N. Baumgarth and M. Roederer, "A practical approach to multicolor flow cytometry for immunophenotyping," J. Immunological Methods 243, 77-97 (2000).
[CrossRef]

Russell, P. St. J.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Saykally, R. J.

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Schafer, D.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

Schaffer, C. B.

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

Schins, J. M.

G.W. H. Wurpel, J. M. Schins, and M. M¨uller, "Chemical specificity in three-dimensional imaging with multiplex coherent anti-Stokes Raman scattering microscopy," Opt. Lett. 27, 1093-1095 (2002).
[CrossRef]

M. M¨uller and J. M. Schins, "Imaging the Thermodynamic State of Lipid Membranes with Multiplex CARS Microscopy," J. Phys. Chem. B,  106, 3715-3723 (2002).
[CrossRef]

Shuler, M. L.

M. L. Shuler, R. Aris, and H. M. Tsuchiya, "Hydrodynamic focusing and electronic cell-sizing techniques," Appl. Microbiol.,  24, 384-388 (1972).
[PubMed]

Squier, J. A.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

Squires, T. M.

T. M. Squires and S. R. Quake, "Microfluidics: fluid physics at the nanoliter scale," Rev. Mod. Phys. 77, 977-1026 (2005).
[CrossRef]

Taylor, D. S.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Thøgersen, J.

Tsuchiya, H. M.

M. L. Shuler, R. Aris, and H. M. Tsuchiya, "Hydrodynamic focusing and electronic cell-sizing techniques," Appl. Microbiol.,  24, 384-388 (1972).
[PubMed]

van Maarseveen, J.

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

Vartiainen, E. M.

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

Volkmer, A.

J. X. Cheng, A. Volkmer, and X. S. Xie, "Theoretical and experimental characterization of coherent anti-Stokes Raman scattering microscopy," J. Opt. Soc. Am. B 19, 1363-1375 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

Wadsworth, W. J.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Wang, H. W.

Watson, D. A.

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

Waxler, R. M.

Whitesides, G. M.

G. M. Whitesides, "The origins and the future of microfluidics," Nature 442, 368-373 (2006).
[CrossRef] [PubMed]

Wurpel, G.W. H.

Xie, X. S.

C. L. Evans and X. S. Xie, "Coherent anti-Stokes Raman scattering microscopy: chemical imaging for biology and medicine," Annu. Rev. Anal. Chem. 1, 883-909 (2008).
[CrossRef]

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

J. X. Cheng and X. S. Xie, "Coherent Anti-Stokes Raman Scattering Microscopy:Instrumentation, Theory, and Applications," J. Phys. Chem. B 108, 827-840 (2004).
[CrossRef]

J. X. Cheng, A. Volkmer, and X. S. Xie, "Theoretical and experimental characterization of coherent anti-Stokes Raman scattering microscopy," J. Opt. Soc. Am. B 19, 1363-1375 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

Yang, P.

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Zhavoronkov, N.

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

Zwerdling, T.

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Annu. Rev. Anal. Chem. (1)

C. L. Evans and X. S. Xie, "Coherent anti-Stokes Raman scattering microscopy: chemical imaging for biology and medicine," Annu. Rev. Anal. Chem. 1, 883-909 (2008).
[CrossRef]

Appl. Microbiol. (1)

M. L. Shuler, R. Aris, and H. M. Tsuchiya, "Hydrodynamic focusing and electronic cell-sizing techniques," Appl. Microbiol.,  24, 384-388 (1972).
[PubMed]

Appl. Opt. (1)

Biophys. J. (1)

J. W. Chan, D. S. Taylor, T. Zwerdling, S. M. Lane, K. Ihara, and T. Huser, "Micro-Raman spectroscopy detects individual neoplastic and normal hematopoietic cells," Biophys. J. 90, 648-656 (2006).
[CrossRef]

Blood (1)

A. D. Michelson, "Flow cytometry: a clinical test of platelet function," Blood 87, 4925-4936 (1996).
[PubMed]

Chem. Phys. Lett. (1)

K. P. Knutsen, J. C. Johnson, A. E. Miller, P. B. Petersen, R. J. Saykally, "High spectral resolution multiplex CARS spectroscopy using chirped pulses," Chem. Phys. Lett. 387, 436-441 (2004).
[CrossRef]

Cytometry (1)

M. Roederer, "Spectral Compensation for Flow Cytometry: Visualization Artifacts, Limitations, and Caveats," Cytometry 45, 194-205 (2001).
[CrossRef] [PubMed]

Cytometry Part A (2)

G. Goddard, J. C. Martin, M. Naivar, P. M. Goodwin, S. W. Graves, R. Habbersett, J. P. Nolan, and J. H. Jett, "Single particle high resolution spectral analysis flow cytometry," Cytometry Part A 69A, 842-851 (2006).
[CrossRef]

D. A. Watson, L. O. Brown, D. F. Gaskill, M. Naivar, S. W. Graves, S. K. Doorn, and J. P. Nolan. "A flow cytometer for the measurement of Raman spectra," Cytometry Part A 73A, 119-128 (2008).
[CrossRef]

J. Am. Chem. Soc. (1)

D. Schafer, J. A. Squier, J. van Maarseveen, D. Bonn, M. Bonn, and M. Müller, "In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy," J. Am. Chem. Soc. 130, 11592-11593 (2008).
[CrossRef] [PubMed]

J. Biomed. Opt. (1)

H. A. Rinia, M. Bonn, E. M. Vartiainen, C. B. Schaffer, and M. M¨uller, "Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering," J. Biomed. Opt. 11, 050502(2006).
[CrossRef] [PubMed]

J. Immunological Methods (1)

N. Baumgarth and M. Roederer, "A practical approach to multicolor flow cytometry for immunophenotyping," J. Immunological Methods 243, 77-97 (2000).
[CrossRef]

J. Opt. Soc. Am. B (2)

J. Phys. Chem. B (4)

M. M¨uller and J. M. Schins, "Imaging the Thermodynamic State of Lipid Membranes with Multiplex CARS Microscopy," J. Phys. Chem. B,  106, 3715-3723 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "Multiplex Coherent Anti-Stokes Raman Scattering Microspectroscopy and Study of Lipid Vesicles," J. Phys. Chem. B 106, 8493-8498 (2002).
[CrossRef]

J. X. Cheng, A. Volkmer, L. D. Book, and X. S. Xie, "An Epi-Detected Coherent Anti-Stokes Raman Scattering (E-CARS) Microscope with High Spectral Resolution and High Sensitivity," J. Phys. Chem. B 105, 1277-1280 (2001).
[CrossRef]

J. X. Cheng and X. S. Xie, "Coherent Anti-Stokes Raman Scattering Microscopy:Instrumentation, Theory, and Applications," J. Phys. Chem. B 108, 827-840 (2004).
[CrossRef]

J. Raman Spectrosc. (1)

H. Kano, "Molecular vibrational imaging of a human cell by multiplex coherent anti-Stokes Raman scattering microspectroscopy using a supercontinuum light source," J. Raman Spectrosc. 39, 1649-1652 (2008).
[CrossRef]

Lab on a Chip (1)

A. Y. Lau, L. P. Leeb, and J.W. Chan, "An integrated optofluidic platform for Raman-activated cell sorting," Lab on a Chip 8, 1116-1120 (2008).
[CrossRef] [PubMed]

Nature (1)

G. M. Whitesides, "The origins and the future of microfluidics," Nature 442, 368-373 (2006).
[CrossRef] [PubMed]

Opt. Express (2)

Opt. Lett. (2)

Philosoph. Mag. (1)

K. Pearson, "On lines and planes of closest fit to systems of points in space," Philosoph. Mag. 2, 559-572 (1901).

Phys. Med. Biol. (1)

X. Ma, J. Q. Lu, R. S. Brock, K. M. Jacobs, P. Yang, and X. H. Hu, "Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm," Phys. Med. Biol. 48, 4165-4172 (2003).
[CrossRef]

Phys. Rev. Lett. (1)

J. Herrmann, U. Griebner, N. Zhavoronkov, A. Husakou, D. Nickel, J. C. Knight, W. J. Wadsworth, P. St. J. Russell, and G. Korn, "Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers," Phys. Rev. Lett. 88, 173901 (2002).
[CrossRef] [PubMed]

PNAS (1)

C. L. Evans, E. O. Potma, M. Puorishaag, D. Cote, C. P. Lin, and X. S. Xie, "Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy," PNAS 102, 16807-16812 (2005).
[CrossRef] [PubMed]

Proceedings of the National Electronics Conference (1)

W. H. Coulter, "High speed automatic blood cell counter and analyzer," inProceedings of the National Electronics Conference,  12, 1034-1040 (1956).

Rev. Mod. Phys. (1)

T. M. Squires and S. R. Quake, "Microfluidics: fluid physics at the nanoliter scale," Rev. Mod. Phys. 77, 977-1026 (2005).
[CrossRef]

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G. P. Agrawal, Nonlinear Fiber Optics, 3rd ed. (Academic, San Diego, Calif., 2001).

C. H. CampJr., A. A. Eftekhar, and A. Adibi, "Single-source interferometric multiplex coherent anti-Stokes Raman scattering with a photonic crystal fiber light source," Conference on Lasers and Electro-Optics (CLEO), San Jose, CA, May 4-9, 2008.

H. M. Shapiro, Practical Flow Cytometry, 4th ed. (Wiley Liss, New York, 2003).

M. G. Macey, "Principles of flow cytometry," in Flow Cytometry: Principles and Applications, M. G. Macey, ed. (Humana, Totowa, New Jersey, 2007), pp. 1-15.

D. A. McCarthy, "Fluorochromes and fluorescence," in Flow Cytometry: Principles and Applications, M. G. Macey, ed. (Humana, Totowa, New Jersey, 2007), pp. 59-112.

Z. Darzynkiewicz, M. Roederer, and H. J. Tanke, eds., Cytometry, 4th Edition: New Developments, 4th ed., 75, (Elsevier Academic, San Diego, Calif., 2004).

Newport Corporation, "Oriel InstaSpec X CCD," http://www.newport.com/store/genproductaspx?id=415018.

Andor Technology plc, "Andor Newton 970 EMCCD Camera," http://www.andor.com/scientific$_$cameras/newton/models/defaultaspxProductCodeID=48.

Princeton Instruments, "PIXIS - CCD (spectroscopy Version)," http://www.princetoninstruments.com/products/speccam/pixis/.

J. W. Bales, "Ultra-high-speed imaging: High-speed and ultra-high-speed imaging offers broad application coverage," Laser Focus World, http://www.laserfocusworld.com/articles/282677.

Cordin Scientific Imaging, "Rotating mirror cameras," http://www.cordin.com/productsrm.html.

Massachusetts Institute of Technology, "The Edgerton Center: High Speed Imaging Links," http://web. mit.edu/Edgerton/www/HSILinks.html.

Supplementary Material (2)

» Media 1: MOV (391 KB)     
» Media 2: MOV (441 KB)     

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Figures (6)

Fig. 1.
Fig. 1.

(Color online) Energy level diagrams of CARS (a) and MCARS (b).

Fig. 2.
Fig. 2.

(Color online) (a) Schematic of the MCARS microfluidic flow cytometer. The ultrafast source acts as both the CARS excitation pulse and a seed for a length of photonic crystal fiber, which is spectrally filtered and recombined with the pump (temporally and spatially overlapped). These sources are focused on the sample with an inverted microscope, and the emitted anti-Stokes signal is collected into a CCD-equipped spectrometer. (b) Image of the microfluidic chip, which has channel widths of 60 µm and depths of 20 µm. Each port of the chip is connected to a different size syringe that was selected to provide consistent hydrodynamic herding, in which sample particles are forced to flow against a side wall.

Fig. 3.
Fig. 3.

(Color online) CARS spectra of PS and PMMA measured with our MCARS spectrometer. Although PS and PMMA are optically similar polymers, they show distinct spectral CARS features.

Fig. 4.
Fig. 4.

(Color online) Using hydrodynamic herding, a sample polystyrene bead is forced against a side-wall. Video stills (a)-(c) show the progression of a single bead from the sample inlet (see Media 1). Frames (d)-(f) show the single bead still against the side and propagating 2 cm away from the cross junction (see Media 2).

Fig. 5.
Fig. 5.

(Color online) (a) Time-stack MCARS spectra of polystyrene and PMMA beads flowing at approximately 185 µm/s. The total data collection was carried out over 120 ms and the pump and Stokes source powers were approximately 38 and 8 mW, respectively. Example MCARS spectrum of (b) PMMA and (c) PS taken from this time-stack, respectively. (d) Classification of spectra using PCA: green=PMMA, red=PS, blue=water, black=signal below minimum. (e) Particle centers determined by local maxima of spectral intensities

Fig. 6.
Fig. 6.

(Color online) SNR of a variety of detectors: Newport InstaSpec X (low- and high-speed ADC settings), Andor DU970N-BV, PI/Acton PIXIS:100F, and a generic PMT. The solid-line portion of each plot represents currently available speeds. The dashed-portion of each plot is the calculated SNR if there were no hardware restrictions on the integration time. The black horizontal line denotes where SNR=0 dB.

Tables (1)

Tables Icon

Table 1. Specifications used to simulate SNR versus integration time of various CCD detectors (see Fig. 6): Newport InstaSpec X (low- and high-speed ADC settings) (Newport Stratford, Inc., Stratford, CT), Andor DU970N-BV (Andor Technology plc, Belfast, Ireland), Princeton Instruments PIXIS:100F (Princeton Instruments, Trenton, NJ). These performance specifications are typical numbers and do not necessarily represent optimized settings, but rather typical values [3840].

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