Abstract

We evaluate the performance of line-scan Raman microscopy (LSRM), a versatile label-free technique, for high-throughput chemical imaging of cell population. We provide detailed design and configuration of a home-built LSRM system developed in our laboratory. By exploiting parallel acquisition, the LSRM system achieves a significant throughput advantage over conventional point-scan Raman microscopy by projecting a laser line onto the sample and imaging the Raman scattered light from the entire line using a grating spectrograph and a charge-coupled device (CCD) camera. Two-dimensional chemical maps can be generated by scanning the projected line in the transverse direction. The resolution in the x and y direction has been characterized to be 600800nm for 785 nm laser excitation. Our system enables rapid classification of microparticles with similar shape, size, and refractive index based on their chemical composition. An equivalent imaging throughput of 100microparticles/s for 1 μm polystyrene beads has been achieved. We demonstrate the application of LSRM to imaging bacterial spores by identifying endogenous calcium dipicolinate. We also demonstrate that LSRM enables the study of intact microalgal cells at the colonial level and the identification of intra- and extracellular chemical constituents and metabolites, such as chlorophyll, carotenoids, lipids, and hydrocarbons. We conclude that LSRM can be an effective and practical tool for obtaining endogenous microscopic chemical and molecular information from cell population.

© 2014 Optical Society of America

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    [CrossRef]

2013 (2)

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

J. Qi, J. Li, and W.-C. Shih, “High-speed hyperspectral Raman imaging for label-free compositional microanalysis,” Biomed. Opt. Express 4, 2376–2382 (2013).
[CrossRef]

2012 (1)

2011 (1)

V. V. Pully, A. T. M. Lenferink, and C. Otto, “Time-lapse Raman imaging of single live lymphocytes,” J. Raman Spectrosc. 42, 167–173 (2011).
[CrossRef]

2010 (5)

B. D. Beier, R. G. Quivey, and A. J. Berger, “Identification of different bacterial species in biofilms using confocal Raman microscopy,” J. Biomed. Opt. 15, 066001 (2010).
[CrossRef]

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

M. Okuno and H. Hamaguchi, “Multifocus confocal Raman microspectroscopy for fast multimode vibrational imaging of living cells,” Opt. Lett. 35, 4096–4098 (2010).
[CrossRef]

2009 (2)

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

2008 (3)

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Intrinsic Raman spectroscopy for quantitative biological spectroscopy Part I: theory and simulations,” Opt. Express 16, 12726–12736 (2008).
[CrossRef]

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

2007 (1)

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Constrained regularization: hybrid method for multivariate calibration,” Anal. Chem. 79, 234–239 (2007).
[CrossRef]

2006 (1)

2005 (3)

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

2004 (2)

M. B. Sinclair, J. A. Timlin, D. M. Haaland, and M. Werner-Washburne, “Design, construction, characterization, and application of a hyperspectral microarray scanner,” Appl. Opt. 43, 2079–2088 (2004).
[CrossRef]

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

2003 (1)

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

1999 (1)

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

1998 (1)

1994 (1)

1990 (1)

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Amiji, M.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

Arndtjovin, D. J.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Beal, C. M.

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

Bechtel, K. L.

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Intrinsic Raman spectroscopy for quantitative biological spectroscopy Part I: theory and simulations,” Opt. Express 16, 12726–12736 (2008).
[CrossRef]

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Constrained regularization: hybrid method for multivariate calibration,” Anal. Chem. 79, 234–239 (2007).
[CrossRef]

Beier, B. D.

B. D. Beier, R. G. Quivey, and A. J. Berger, “Identification of different bacterial species in biofilms using confocal Raman microscopy,” J. Biomed. Opt. 15, 066001 (2010).
[CrossRef]

Ben-Amotz, D.

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

Berger, A. J.

B. D. Beier, R. G. Quivey, and A. J. Berger, “Identification of different bacterial species in biofilms using confocal Raman microscopy,” J. Biomed. Opt. 15, 066001 (2010).
[CrossRef]

Bohme, R.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Boydston-White, S.

Brennan, C.

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

Cai, W. W.

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

Chan, J. W.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Chernenko, T.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

Christensen, K. A.

Chun, H. J.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Cote, D.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Crowe, J.

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Dasari, R. R.

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Demul, F. F. M.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Devarenne, T. P.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Diem, M.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

C. Matthaus, S. Boydston-White, M. Miljkovic, M. Romeo, and M. Diem, “Raman and infrared microspectral imaging of mitotic cells,” Appl. Spectrosc. 60, 1–8 (2006).
[CrossRef]

Elschner, M.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Enejder, A. M. K.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Esposito, A. P.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Evans, C. L.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Feld, M. S.

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Intrinsic Raman spectroscopy for quantitative biological spectroscopy Part I: theory and simulations,” Opt. Express 16, 12726–12736 (2008).
[CrossRef]

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Constrained regularization: hybrid method for multivariate calibration,” Anal. Chem. 79, 234–239 (2007).
[CrossRef]

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Fitzmaurice, M.

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Freudiger, C. W.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Fujita, K.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Gheewala, M.

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

Gift, A. D.

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

Greve, J.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Haaland, D. M.

Haber, K. S.

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

Haka, A. S.

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Hamada, K.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Hamaguchi, H.

Hartsuiker, L.

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

He, C. W.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Hollars, C. W.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Holtom, G. R.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Holzenburg, A.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Horowitz, G. L.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Huang, Y. Y.

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

Huffman, S. W.

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

Hunter, M.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Huser, T.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Inouye, Y.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Jovin, T. M.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Kang, J. X.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Kawata, S.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Kobayashi, M.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Laane, J.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Lane, S. M.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Lenferink, A. T. M.

V. V. Pully, A. T. M. Lenferink, and C. Otto, “Time-lapse Raman imaging of single live lymphocytes,” J. Raman Spectrosc. 42, 167–173 (2011).
[CrossRef]

Levin, I. W.

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

Li, J.

Lin, C. P.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Lu, S.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Ma, J. Y.

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

Masters, B. R.

Matthaus, C.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

C. Matthaus, S. Boydston-White, M. Miljkovic, M. Romeo, and M. Diem, “Raman and infrared microspectral imaging of mitotic cells,” Appl. Spectrosc. 60, 1–8 (2006).
[CrossRef]

McClain, B. L.

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

Meisel, S.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Milane, L.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

Miljkovic, M.

Min, W.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Morris, M. D.

Motwani, P.

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

Oh, J.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Okada, S.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Okuno, M.

Otto, C.

V. V. Pully, A. T. M. Lenferink, and C. Otto, “Time-lapse Raman imaging of single live lymphocytes,” J. Raman Spectrosc. 42, 167–173 (2011).
[CrossRef]

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Popp, J.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Potma, E. O.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Pully, V. V.

V. V. Pully, A. T. M. Lenferink, and C. Otto, “Time-lapse Raman imaging of single live lymphocytes,” J. Raman Spectrosc. 42, 167–173 (2011).
[CrossRef]

Puoris’haag, M.

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Puppels, G. J.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Qi, J.

Quintero, L.

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

Quivey, R. G.

B. D. Beier, R. G. Quivey, and A. J. Berger, “Identification of different bacterial species in biofilms using confocal Raman microscopy,” J. Biomed. Opt. 15, 066001 (2010).
[CrossRef]

Robertnicoud, M.

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Romeo, M.

Rosch, P.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Ruoff, R. S.

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

Saar, B. G.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Sasic, S.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Scecina, T. G.

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Schaeberle, M. D.

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

Schlucker, S.

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

Shafer-Peltier, K. E.

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

Shih, W. C.

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Intrinsic Raman spectroscopy for quantitative biological spectroscopy Part I: theory and simulations,” Opt. Express 16, 12726–12736 (2008).
[CrossRef]

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Constrained regularization: hybrid method for multivariate calibration,” Anal. Chem. 79, 234–239 (2007).
[CrossRef]

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

Shih, W.-C.

Sinclair, M. B.

Smith, N. I.

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

Stockel, S.

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

Talley, C. E.

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Terentjev, E. M.

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

Terstappen, L.

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

Thaer, A. A.

Timlin, J. A.

Tsai, J. S.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

Vitha, S.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Weiss, T. L.

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

Werner-Washburne, M.

Wolfe, J. C.

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

Xie, X. S.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Zeijen, N. J. L.

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

Acs Nano (1)

T. Chernenko, C. Matthaus, L. Milane, L. Quintero, M. Amiji, and M. Diem, “Label-free Raman spectral imaging of intracellular delivery and degradation of polymeric nanoparticle systems,” Acs Nano 3, 3552–3559 (2009).
[CrossRef]

Anal. Chem. (2)

W. C. Shih, K. L. Bechtel, and M. S. Feld, “Constrained regularization: hybrid method for multivariate calibration,” Anal. Chem. 79, 234–239 (2007).
[CrossRef]

J. W. Chan, A. P. Esposito, C. E. Talley, C. W. Hollars, S. M. Lane, and T. Huser, “Reagentless identification of single bacterial spores in aqueous solution by confocal laser tweezers Raman spectroscopy,” Anal. Chem. 76, 599–603 (2004).
[CrossRef]

Analyst (1)

L. Hartsuiker, N. J. L. Zeijen, L. Terstappen, and C. Otto, “A comparison of breast cancer tumor cells with varying expression of the Her2/neu receptor by Raman microspectroscopic imaging,” Analyst 135, 3220–3226 (2010).
[CrossRef]

Analyt. Chem. (1)

S. Schlucker, M. D. Schaeberle, S. W. Huffman, and I. W. Levin, “Raman microspectroscopy: a comparison of point, line, and wide-field imaging methodologies,” Analyt. Chem. 75, 4312–4318 (2003).
[CrossRef]

Appl. Opt. (2)

Appl. Spectrosc. (2)

Biomed. Opt. Express (1)

Biotechnol. Bioeng. (1)

Y. Y. Huang, C. M. Beal, W. W. Cai, R. S. Ruoff, and E. M. Terentjev, “Micro-Raman spectroscopy of algae: composition analysis and fluorescence background behavior,” Biotechnol. Bioeng. 105, 889–898 (2010).

J. Biol. Chem. (1)

T. L. Weiss, H. J. Chun, S. Okada, S. Vitha, A. Holzenburg, J. Laane, and T. P. Devarenne, “Raman Spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii,” J. Biol. Chem. 285, 32458–32466 (2010).
[CrossRef]

J. Biomed. Opt. (3)

B. D. Beier, R. G. Quivey, and A. J. Berger, “Identification of different bacterial species in biofilms using confocal Raman microscopy,” J. Biomed. Opt. 15, 066001 (2010).
[CrossRef]

A. M. K. Enejder, T. G. Scecina, J. Oh, M. Hunter, W. C. Shih, S. Sasic, G. L. Horowitz, and M. S. Feld, “Raman spectroscopy for noninvasive glucose measurements,” J. Biomed. Opt. 10, 031114 (2005).
[CrossRef]

K. Hamada, K. Fujita, N. I. Smith, M. Kobayashi, Y. Inouye, and S. Kawata, “Raman microscopy for dynamic molecular imaging of living cells,” J. Biomed. Opt. 13, 044027 (2008).
[CrossRef]

J. Raman Spectrosc. (3)

S. Stockel, S. Meisel, R. Bohme, M. Elschner, P. Rosch, and J. Popp, “Effect of supplementary manganese on the sporulation of Bacillus endospores analysed by Raman spectroscopy,” J. Raman Spectrosc. 40, 1469–1477 (2009).
[CrossRef]

A. D. Gift, J. Y. Ma, K. S. Haber, B. L. McClain, and D. Ben-Amotz, “Near-infrared Raman imaging microscope based on fiber-bundle image compression,” J. Raman Spectrosc. 30, 757–765 (1999).
[CrossRef]

V. V. Pully, A. T. M. Lenferink, and C. Otto, “Time-lapse Raman imaging of single live lymphocytes,” J. Raman Spectrosc. 42, 167–173 (2011).
[CrossRef]

Nanoscale (1)

J. Qi, P. Motwani, M. Gheewala, C. Brennan, J. C. Wolfe, and W.-C. Shih, “Surface-enhanced Raman spectroscopy with monolithic nanoporous gold disk substrates,” Nanoscale 5, 4105–4109 (2013).
[CrossRef]

Nature (1)

G. J. Puppels, F. F. M. Demul, C. Otto, J. Greve, M. Robertnicoud, D. J. Arndtjovin, and T. M. Jovin, “Studying single living cells and chromosomes by confocal Raman microspectroscopy,” Nature 347, 301–303 (1990).
[CrossRef]

Opt. Express (1)

Opt. Lett. (2)

Proc. Natl. Acad. Sci. USA (2)

A. S. Haka, K. E. Shafer-Peltier, M. Fitzmaurice, J. Crowe, R. R. Dasari, and M. S. Feld, “Diagnosing breast cancer by using Raman spectroscopy,” Proc. Natl. Acad. Sci. USA 102, 12371–12376 (2005).
[CrossRef]

C. L. Evans, E. O. Potma, M. Puoris’haag, D. Cote, C. P. Lin, and X. S. Xie, “Chemical imaging of tissue in vivo with video-rate coherent anti-Stokes Raman scattering microscopy,” Proc. Natl. Acad. Sci. USA 102, 16807–16812 (2005).
[CrossRef]

Science (1)

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. W. He, J. S. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science 322, 1857–1861 (2008).
[CrossRef]

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Figures (5)

Fig. 1.
Fig. 1.

LSRM system configuration and intensity uniformity: (a) configuration; (b) map of polystyrene (PS) plate; (c) representative intensity profiles along the projected line and scanning directions.

Fig. 2.
Fig. 2.

LSRM system characterization. (a) 3 μm PS beads within a 60μm×100μm area (lower), zoom-in of the upper-left corner (upper). (b) Image of 1 μm PS beads within a 100μm×100μm area (three 3 μm PS beads are included). (c) 500 nm PS bead for estimating the lateral spatial resolution.

Fig. 3.
Fig. 3.

Rapid identification and counting of microparticles using LSRM. (a) Bright-field image of mixed PS and PMMA microspheres. (b) Map generated using PMMA Raman peak. (c) Map generated using PS Raman peak. (d) Raman spectra of PMMA and PS.

Fig. 4.
Fig. 4.

Rapid identification and counting of bacterial spores using LSRM. (a) Bright-field image of more than 100 spores. (b) Map generated using CaDPA Raman peak. (c) Mean and standard deviation of Raman spectra of Bacillus subtilis spores.

Fig. 5.
Fig. 5.

Chemical imaging of colonial microalgae using LSRM. (a) Bright-field image; Raman maps generated for (b) chlorophyll, (c) carotenoids, (d) lipids, and (e) botryococcenes with representative Raman spectrum under each map.

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