Abstract

Abstract

The ability to characterize the mitochondria in single living cells may provide a powerful tool in clinical applications. We have recently developed a 2D (both polar angle and azimuth angle dependences) light scattering cytometric technique which we apply here to assess experimental 2D light scattering patterns from single biological cells (yeast and human). We compare these patterns to those obtained from simulations using a 3D Finite-Difference Time-Domain (FDTD) method and demonstrate that microstructure (e.g., the cytoplasm and/or nucleus) of cells generates fringes of scattered light, while in the larger human cells the light scattered by the mitochondria dominates the scatter pattern, forming compact regions of high intensity that we term ‘blobs’. These blobs provide information on the mitochondria within the cell and their analysis may ultimately be useful as a diagnostic technique.

© 2007 Optical Society of America

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2007 (1)

X. T. Su, W. Rozmus, C. Capjack, and C. J. Backhouse, "Side scatter light for micro-size differentiation and cellular analysis," Proc. SPIE 6446, 64460W (2007).
[CrossRef]

2005 (5)

C. G. Liu, C. Capjack, and W. Rozmus, "3-D simulation of light scattering from biological cells and cell differentiation," J. Biomed. Opt. 10, 014007 (2005).
[CrossRef] [PubMed]

J. D. Wilson, C. E. Bigelow, D. J. Calkins, and T. H. Foster, "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling," Biophys. J. 88, 2929-2938 (2005).
[CrossRef] [PubMed]

J. Q. Lu, P. Yang, and X. H. Hu, "Simulations of light scattering from a biconcave red blood cell using the finite-difference time-domain method," J. Biomed. Opt. 10, 024022 (2005).
[CrossRef] [PubMed]

A. Karlsson, J. P. He, J. Swartling, and S. Andersson-Engels, "Numerical simulations of light scattering by red blood cells," IEEE Trans. Biomed. Eng. 52, 13-18 (2005).
[CrossRef] [PubMed]

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

2004 (2)

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
[CrossRef] [PubMed]

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
[CrossRef] [PubMed]

2003 (1)

N. Haga, N. Fujita, and T. Tsuruo, "Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis," Oncogene 22, 5579-5585 (2003).
[CrossRef] [PubMed]

2001 (1)

C. Bauer, V. Herzog, and M. F. Bauer, "Improved technique for electron microscope visualization of yeast membrane structure," Microsc. Microanal. 7, 530-534 (2001).

2000 (5)

T. G. Frey and C. A. Mannella, "The internal structure of mitochondria," Trends Biochem. Sci. 25, 319-324 (2000).
[CrossRef] [PubMed]

R. Drezek, A. Dunn, and R. Richards-Kortum, "A pulsed finite-difference time-domain (FDTD) method for calculating light scattering from biological cells over broad wavelength ranges," Opt. Express 6, 147-157 (2000).
[CrossRef] [PubMed]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

1999 (1)

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

1998 (1)

1996 (3)

A. Dunn and R. Richards-Kortum, "Three-dimensional computation of light scattering from cells," IEEE J. Sel. Top. Quantum Electron. 2, 898-905 (1996).
[CrossRef]

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
[CrossRef] [PubMed]

H. L. Liu, B. Beauvoit, M. Kimura, and B. Chance, "Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity," J. Biomed. Opt. 1, 200-211 (1996).
[CrossRef]

1994 (2)

1988 (1)

E. D. Robin and R. Wong, "Mitochondrial-DNA molecules and virtual number of Mitochondria per cell in Mammalian-Cells," J. Cell. Physiol. 136, 507-513 (1988).
[CrossRef] [PubMed]

1986 (1)

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

1985 (1)

H. B. Steen and T. Lindmo, "Differential of Light-Scattering Detection in an Arc-Lamp-Based Epi-Illumination Flow Cytometer," Cytometry 6, 281-285 (1985).
[CrossRef] [PubMed]

1974 (1)

A. Brunstin, and P. F. Mullaney, "Differential light-scattering from Spherical Mammalian-Cells," Biophys. J. 14, 439-453 (1974).
[CrossRef]

1973 (1)

R. E. Marquis, "Immersion refractometry of isolated bacterial cell-walls," J. Bacteriol. 116, 1273-1279 (1973).
[PubMed]

1908 (1)

G. Mie, "Articles on the optical characteristics of turbid tubes, especially colloidal metal solutions," Ann. Phys.-Berlin 25, 377-445 (1908).
[CrossRef]

Andersson-Engels, S.

A. Karlsson, J. P. He, J. Swartling, and S. Andersson-Engels, "Numerical simulations of light scattering by red blood cells," IEEE Trans. Biomed. Eng. 52, 13-18 (2005).
[CrossRef] [PubMed]

Arendt, J. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Attardi, G.

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

Backhouse, C. J.

X. T. Su, W. Rozmus, C. Capjack, and C. J. Backhouse, "Side scatter light for micro-size differentiation and cellular analysis," Proc. SPIE 6446, 64460W (2007).
[CrossRef]

Backman, V.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Badizadegan, K.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Barrett, K. E.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

Bauer, C.

C. Bauer, V. Herzog, and M. F. Bauer, "Improved technique for electron microscope visualization of yeast membrane structure," Microsc. Microanal. 7, 530-534 (2001).

Bauer, M. F.

C. Bauer, V. Herzog, and M. F. Bauer, "Improved technique for electron microscope visualization of yeast membrane structure," Microsc. Microanal. 7, 530-534 (2001).

Beauvoit, B.

H. L. Liu, B. Beauvoit, M. Kimura, and B. Chance, "Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity," J. Biomed. Opt. 1, 200-211 (1996).
[CrossRef]

Bennett, J. P.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Beuthan, J.

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
[CrossRef] [PubMed]

Bigelow, C. E.

J. D. Wilson, C. E. Bigelow, D. J. Calkins, and T. H. Foster, "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling," Biophys. J. 88, 2929-2938 (2005).
[CrossRef] [PubMed]

Bocker, D.

Bonaly, R.

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

Bresolin, N.

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

Brunstin, A.

A. Brunstin, and P. F. Mullaney, "Differential light-scattering from Spherical Mammalian-Cells," Biophys. J. 14, 439-453 (1974).
[CrossRef]

Calkins, D. J.

J. D. Wilson, C. E. Bigelow, D. J. Calkins, and T. H. Foster, "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling," Biophys. J. 88, 2929-2938 (2005).
[CrossRef] [PubMed]

Capjack, C.

X. T. Su, W. Rozmus, C. Capjack, and C. J. Backhouse, "Side scatter light for micro-size differentiation and cellular analysis," Proc. SPIE 6446, 64460W (2007).
[CrossRef]

C. G. Liu, C. Capjack, and W. Rozmus, "3-D simulation of light scattering from biological cells and cell differentiation," J. Biomed. Opt. 10, 014007 (2005).
[CrossRef] [PubMed]

Chachisvilis, M.

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
[CrossRef] [PubMed]

Chance, B.

H. L. Liu, B. Beauvoit, M. Kimura, and B. Chance, "Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity," J. Biomed. Opt. 1, 200-211 (1996).
[CrossRef]

Charpentier, C.

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

Cope, M.

Copeland, R. G.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

Crawford, J. M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Dasari, R. R.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Davis, R. E.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Diver, J.

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
[CrossRef] [PubMed]

Drezek, R.

Dunn, A.

Eick, A. A.

Essenpreis, M.

Fantini, S.

Feld, M. S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Feng, L.

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

Feuillat, M.

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

Fitzmaurice, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Foster, T. H.

J. D. Wilson, C. E. Bigelow, D. J. Calkins, and T. H. Foster, "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling," Biophys. J. 88, 2929-2938 (2005).
[CrossRef] [PubMed]

Franceschini, M. A.

Frey, T. G.

T. G. Frey and C. A. Mannella, "The internal structure of mitochondria," Trends Biochem. Sci. 25, 319-324 (2000).
[CrossRef] [PubMed]

Freyer, J. P.

Friedrich, M. G.

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
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Fujita, N.

N. Haga, N. Fujita, and T. Tsuruo, "Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis," Oncogene 22, 5579-5585 (2003).
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Giess, F.

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
[CrossRef] [PubMed]

Gourley, C. R.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

Gourley, P. L.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
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Gratton, E.

Gurjar, R.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Haga, N.

N. Haga, N. Fujita, and T. Tsuruo, "Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis," Oncogene 22, 5579-5585 (2003).
[CrossRef] [PubMed]

Hagen, N.

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
[CrossRef] [PubMed]

He, J. P.

A. Karlsson, J. P. He, J. Swartling, and S. Andersson-Engels, "Numerical simulations of light scattering by red blood cells," IEEE Trans. Biomed. Eng. 52, 13-18 (2005).
[CrossRef] [PubMed]

Heberle, J.

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
[CrossRef] [PubMed]

Helfmann, J.

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
[CrossRef] [PubMed]

Hendricks, J. K.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
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Herrig, M.

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
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Herzog, V.

C. Bauer, V. Herzog, and M. F. Bauer, "Improved technique for electron microscope visualization of yeast membrane structure," Microsc. Microanal. 7, 530-534 (2001).

Hielscher, A. H.

Hu, X. H.

J. Q. Lu, P. Yang, and X. H. Hu, "Simulations of light scattering from a biconcave red blood cell using the finite-difference time-domain method," J. Biomed. Opt. 10, 024022 (2005).
[CrossRef] [PubMed]

Huang, P.

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

Itzkan, I.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Johnson, T. M.

Kabani, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Karlsson, A.

A. Karlsson, J. P. He, J. Swartling, and S. Andersson-Engels, "Numerical simulations of light scattering by red blood cells," IEEE Trans. Biomed. Eng. 52, 13-18 (2005).
[CrossRef] [PubMed]

Keating, M. J.

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

Keeney, P.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Kimura, M.

H. L. Liu, B. Beauvoit, M. Kimura, and B. Chance, "Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity," J. Biomed. Opt. 1, 200-211 (1996).
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Kline, E.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Knoll, W.

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
[CrossRef] [PubMed]

Kohl, M.

Levin, H. S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Lindmo, T.

H. B. Steen and T. Lindmo, "Differential of Light-Scattering Detection in an Arc-Lamp-Based Epi-Illumination Flow Cytometer," Cytometry 6, 281-285 (1985).
[CrossRef] [PubMed]

Liu, C. G.

C. G. Liu, C. Capjack, and W. Rozmus, "3-D simulation of light scattering from biological cells and cell differentiation," J. Biomed. Opt. 10, 014007 (2005).
[CrossRef] [PubMed]

Liu, H. L.

H. L. Liu, B. Beauvoit, M. Kimura, and B. Chance, "Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity," J. Biomed. Opt. 1, 200-211 (1996).
[CrossRef]

Lu, J. Q.

J. Q. Lu, P. Yang, and X. H. Hu, "Simulations of light scattering from a biconcave red blood cell using the finite-difference time-domain method," J. Biomed. Opt. 10, 024022 (2005).
[CrossRef] [PubMed]

Maier, J. S.

Mannella, C. A.

T. G. Frey and C. A. Mannella, "The internal structure of mitochondria," Trends Biochem. Sci. 25, 319-324 (2000).
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Marchand, P.

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
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Marquis, R. E.

R. E. Marquis, "Immersion refractometry of isolated bacterial cell-walls," J. Bacteriol. 116, 1273-1279 (1973).
[PubMed]

Mazzucchelli, F.

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

McDonald, A. E.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

McGillican, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Michikawa, Y.

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

Mie, G.

G. Mie, "Articles on the optical characteristics of turbid tubes, especially colloidal metal solutions," Ann. Phys.-Berlin 25, 377-445 (1908).
[CrossRef]

Miller, S. W.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Minet, O.

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
[CrossRef] [PubMed]

Mourant, J. R.

Mullaney, P. F.

A. Brunstin, and P. F. Mullaney, "Differential light-scattering from Spherical Mammalian-Cells," Biophys. J. 14, 439-453 (1974).
[CrossRef]

Muller, G.

J. Beuthan, O. Minet, J. Helfmann, M. Herrig, and G. Muller, "The spatial variation of the refractive index in biological cells," Phys. Med. Biol. 41, 369-382 (1996).
[CrossRef] [PubMed]

Muller, M. G.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Naumann, R. L.

F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The protein-tethered lipid bilayer: A novel mimic of the biological membrane," Biophys. J. 87, 3213-3220 (2004).
[CrossRef] [PubMed]

Naviaux, R. K.

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
[CrossRef]

Oldham, E. A.

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

Parker, W. D.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Parks, J. K.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Perelman, L. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Plunkett, W.

P. Huang, L. Feng, E. A. Oldham, M. J. Keating, and W. Plunkett, "Superoxide dismutase as a target for the selective killing of cancer cells," Nature 407, 390-395 (2000).
[CrossRef] [PubMed]

Richards-Kortum, R.

Robin, E. D.

E. D. Robin and R. Wong, "Mitochondrial-DNA molecules and virtual number of Mitochondria per cell in Mammalian-Cells," J. Cell. Physiol. 136, 507-513 (1988).
[CrossRef] [PubMed]

Rozmus, W.

X. T. Su, W. Rozmus, C. Capjack, and C. J. Backhouse, "Side scatter light for micro-size differentiation and cellular analysis," Proc. SPIE 6446, 64460W (2007).
[CrossRef]

C. G. Liu, C. Capjack, and W. Rozmus, "3-D simulation of light scattering from biological cells and cell differentiation," J. Biomed. Opt. 10, 014007 (2005).
[CrossRef] [PubMed]

Scarlato, G.

Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication," Science 286, 774-779 (1999).
[CrossRef] [PubMed]

Seiler, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Shapshay, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Shen, D.

Steen, H. B.

H. B. Steen and T. Lindmo, "Differential of Light-Scattering Detection in an Arc-Lamp-Based Epi-Illumination Flow Cytometer," Cytometry 6, 281-285 (1985).
[CrossRef] [PubMed]

Su, X. T.

X. T. Su, W. Rozmus, C. Capjack, and C. J. Backhouse, "Side scatter light for micro-size differentiation and cellular analysis," Proc. SPIE 6446, 64460W (2007).
[CrossRef]

Swartling, J.

A. Karlsson, J. P. He, J. Swartling, and S. Andersson-Engels, "Numerical simulations of light scattering by red blood cells," IEEE Trans. Biomed. Eng. 52, 13-18 (2005).
[CrossRef] [PubMed]

Swerdlow, R. H.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Trimmer, P. A.

P. A. Trimmer, R. H. Swerdlow, J. K. Parks, P. Keeney, J. P. Bennett, S. W. Miller, R. E. Davis, and W. D. Parker, "Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines," Exp. Neurol. 162, 37-50 (2000).
[CrossRef] [PubMed]

Tsuruo, T.

N. Haga, N. Fujita, and T. Tsuruo, "Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis," Oncogene 22, 5579-5585 (2003).
[CrossRef] [PubMed]

Valdez, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Van Dam, J.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Vanlong, T. N.

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

Walker, S. A.

Wallace, M. B.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Watson, D.

D. Watson, N. Hagen, J. Diver, P. Marchand, and M. Chachisvilis, "Elastic light scattering from single cells: Orientational dynamics in optical trap," Biophys. J. 87, 1298-1306 (2004).
[CrossRef] [PubMed]

Wilson, J. D.

J. D. Wilson, C. E. Bigelow, D. J. Calkins, and T. H. Foster, "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling," Biophys. J. 88, 2929-2938 (2005).
[CrossRef] [PubMed]

Wong, R.

E. D. Robin and R. Wong, "Mitochondrial-DNA molecules and virtual number of Mitochondria per cell in Mammalian-Cells," J. Cell. Physiol. 136, 507-513 (1988).
[CrossRef] [PubMed]

Yang, P.

J. Q. Lu, P. Yang, and X. H. Hu, "Simulations of light scattering from a biconcave red blood cell using the finite-difference time-domain method," J. Biomed. Opt. 10, 024022 (2005).
[CrossRef] [PubMed]

Zhang, Q.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Zonios, G.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Appl. Microbiol. Biotechnol. (1)

C. Charpentier, T. N. Vanlong, R. Bonaly, and M. Feuillat, "Alteration of cell-wall structure in Saccharomyces-Cerevisiae and Saccharomyces-Bayanus during autolysis," Appl. Microbiol. Biotechnol. 24, 405-413 (1986).
[CrossRef]

Appl. Opt. (1)

Berlin (1)

G. Mie, "Articles on the optical characteristics of turbid tubes, especially colloidal metal solutions," Ann. Phys.-Berlin 25, 377-445 (1908).
[CrossRef]

Biomed. Microdevices (1)

P. L. Gourley, J. K. Hendricks, A. E. McDonald, R. G. Copeland, K. E. Barrett, C. R. Gourley, and R. K. Naviaux, "Ultrafast nanolaser flow device for detecting cancer in single cells," Biomed. Microdevices 7, 331-339 (2005).
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Figures (11)

Fig. 1.
Fig. 1.

Various cell models and their corresponding 2D FDTD scatter patterns. (a), a cell with a nucleus (cyan) and the cytoplasm (magenta) only. (b), randomly distributed mitochondria (random seed I) only. (c), a cell with a nucleus, the cytoplasm, and the randomly distributed mitochondria (random seed I). (d), a cell with a nucleus, the cytoplasm, and the randomly distributed mitochondria (random seed II). (a′), (b′), (c′) and (d′) are the calculated 2D FDTD scatter patterns for the cell models (a), (b), (c) and (d) in the microfluidic waveguide cytometer, respectively.

Fig. 2.
Fig. 2.

The 2D scatter pattern (showing several fringes) experimentally obtained from a yeast cell within an integrated waveguide cytometer.

Fig. 3.
Fig. 3.

The simulated 2D scatter patterns of a yeast cell with varying orientations. (a), a yeast cell with its long axis along the z direction. (b), the same yeast cell as in (a) but rotated by 450. The yeast cell has a long axis of 2.9µm, and both the two short axes are 2.4µm. The cyan sphere is the nucleus centered at the origin. The blue spheres are the randomly distributed mitochondria. The yeast cell wall and the cytoplasm are shown in different colors of grey and magenta, respectively. (c) and (d) are the FDTD scatter patterns corresponding to cell models (a) and (b), respectively.

Fig. 4.
Fig. 4.

The 2D scatter pattern (showing a sparse distribution of blobs) experimentally obtained from a human Raji cell within an integrated waveguide cytometer.

Fig. 5.
Fig. 5.

Raji cell models and their 2D FDTD scatter patterns. (a), a Raji cell with 300 randomly distributed mitochondria, a nucleus and cytoplasm. (b), a ‘cell’ with only the 300 randomly distributed mitochondria. (a) and (b) have the same mitochondrial distribution. (c) and (d) are the 2D FDTD scatter patterns for (a) and (b), respectively.

Fig. S1.
Fig. S1.

Geometry of the FDTD simulation. The incident wave vector is along the z axis, while polarized along the x axis. The scattered wave vector has a polar angle θ, and an azimuth angle φ. For all the studies in this report, the cell is centered at the origin.

Fig. S2.
Fig. S2.

The planar waveguide structure of the integrated microfluidic waveguide cytometer. The scattered light goes from a substrate (1.2mm, refractive index 1.47), through an air gap ‘1’ (0.35mm), a CCD cover glass (0.75mm, refractive index 1.5), and an air gap ‘2’ (1.25mm) onto a CCD surface.

Fig. S3.
Fig. S3.

Representative figures showing nucleus size and position effects on the scatter patterns. The cell models used here are with only the cell cytoplasm and a nucleus. The cell cytoplasm is with a constant diameter of 4µm, while the nucleus size and position varies with different cell models. Fig. S3(a) has a nucleus of 1.2µm in diameter, and Fig. S3(b) has a nucleus of 2.8µm in diameter. Fig. S3(c) and S3(d) have the same size of nucleus as in Fig. 1 but at different positions. The nucleus for Fig. S3(c) is centered at (0, 0, 0.4)µm, and the nucleus for Fig. S3(d) is centered at (0, 0, -0.4)µm. Fig. S3 (along with other such simulations) shows that variations in nucleus size and position will not generate the blobs in the 2D scatter patterns.

Fig. S4.
Fig. S4.

Representative figures showing that yeast cell orientation effects (cells without mitochondria) will not generate 2D blobs. Fig. S4(a) and S4(b) are the same yeast cells as in Fig. 3, but without the mitochondria. Fig. S4(a) is the yeast cell with the cell wall, the cell cytoplasm and the nucleus at an orientation of polar angle 00, while Fig. S4(b) at an orientation of polar angle 450. Figure S4 shows that the orientation effects of the microstructures in a yeast cell will not generate the blobs. The orientation effects change the fringe distributions.

Fig. S5.
Fig. S5.

Scatter patterns from different cell components. (a) is a scatter pattern from only the 40 randomly distributed yeast cell mitochondria shown in Fig. 3(a). Figure 3(b) is a scatter pattern from only the yeast cell wall shown in Fig. 3(a).

Fig. S6.
Fig. S6.

Scatter intensity level for different cell components. The scanning is performed for the same region in Fig. S5(a), Fig. S5(b) and Fig. 5(d), which are the scatter patterns for the 40 yeast mitochondria, the yeast cell wall and the 300 Raji mitochondria, respectively.

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