Abstract

The sensitive detection and quantitative measurement of biological nanoparticles such as viruses or exosomes is of growing importance in biology and medicine since these structures are implicated in many biological processes and diseases. Interferometric reflectance imaging is a label-free optical biosensing method which can directly detect individual biological nanoparticles when they are immobilized onto a protein microarray. Previous efforts to infer bio-nanoparticle size and shape have relied on empirical calibration using a ‘ruler’ of particle samples of known size, which was inconsistent and qualitative. Here, we present a mechanistic physical explanation and experimental approach by which interferometric reflectance imaging may be used to not only detect but also quantitatively measure bio-nanoparticle size and shape. We introduce a comprehensive optical model that can quantitatively simulate the scattering of arbitrarily-shaped nanoparticles such as rod-shaped or filamentous virions. Finally, we optimize the optical design for the detection and quantitative measurement of small and low-index bio-nanoparticles immersed in water.

© 2017 Optical Society of America

Full Article  |  PDF Article
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References

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2017 (1)

2016 (5)

O. Avci, R. Adato, A. Y. Ozkumur, and M. S. Ünlü, “Physical modeling of interference enhanced imaging and characterization of single nanoparticles,” Opt. Express 24, 6094 (2016).
[Crossref] [PubMed]

J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

M. Boccara, Y. Fedala, C. V. Bryan, M. Bailly-Bechet, C. Bowler, and A. C. Boccara, “Full-field interferometry for counting and differentiating aquatic biotic nanoparticles: from laboratory to tara oceans,” Biomed. Opt. Express 7, 3736–3746 (2016).
[Crossref] [PubMed]

S. M. Scherr, G. G. Daaboul, J. Trueb, D. Sevenler, H. Fawcett, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Real-time capture and visualization of individual viruses in complex media,” ACS Nano 10, 2827–2833 (2016).
[Crossref] [PubMed]

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

2015 (4)

E. McLeod, T. U. Dincer, M. Veli, Y. N. Ertas, C. Nguyen, W. Luo, A. Greenbaum, A. Feizi, and A. Ozcan, “High-throughput and label-free single nanoparticle sizing based on time-resolved on-chip microscopy,” ACS Nano 9, 3265–3273 (2015).
[Crossref] [PubMed]

S. Patskovsky and M. Meunier, “Reflected light microspectroscopy for single-nanoparticle biosensing,” J. Biomed. Opt. 20, 097001 (2015).
[Crossref] [PubMed]

J. Waxenegger, A. Trügler, and U. Hohenester, “Plasmonics simulations with the mnpbem toolbox: Consideration of substrates and layer structures,” Computer Physics Communications 193, 138–150 (2015).
[Crossref]

S. Kourembanas, “Exosomes: Vehicles of intercellular signaling, biomarkers, and vectors of cell therapy,” Ann. Rev. Physiol. 77, 13–27 (2015).
[Crossref]

2014 (3)

H. Im, H. Shao, Y. I. Park, V. M. Peterson, C. M. Castro, R. Weissleder, and H. Lee, “Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor,” Nature Biotech. 32, 490–495 (2014).
[Crossref]

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Digital sensing and sizing of vesicular stomatitis virus pseudotypes in complex media; a model for ebola and marburg detection,” ACS Nano 8, 6047–6055(2014).
[Crossref]

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
[Crossref]

2013 (2)

O. Mudanyali, E. McLeod, W. Luo, A. Greenbaum, A. F. Coskun, Y. Hennequin, C. P. Allier, and A. Ozcan, “Wide-field optical detection of nanoparticles using on-chip microscopy and self-assembled nanolenses,” Nature Photon. 5, 247–254 (2013).

E. van der Pol, F. Coumans, Z. Varga, M. Krumrey, and R. Nieuwland, “Innovation in detection of microparticles and exosomes,” J. Thromb. Haemostatis 11, 36–45 (2013).
[Crossref]

2012 (4)

E. van der Pol, A. N. Böing, P. Harrison, A. Sturk, and R. Nieuwland, “Classification, functions, and clinical relevance of extracellular vesicles,” Pharmacol. Rev. 64, 676–705 (2012).
[Crossref] [PubMed]

A. Mitra, F. Ignatovich, and L. Novotny, “Real-time optical detection of single human and bacterial viruses based on dark-field interferometry,” Biosens. Bioelectron. 31, 499–504 (2012).
[Crossref]

E. Van Der Pol, M. J. C. Van Gemert, A. Sturk, R. Nieuwland, and T. G. Van Leeuwen, “Single vs. swarm detection of microparticles and exosomes by flow cytometry,” J. Thromb. Haemostasis 10, 919–930 (2012).
[Crossref]

U. Hohenester and A. Trügler, “Mnpbem - a matlab toolbox for the simulation of plasmonic nanoparticles,” Comput. Phys. Commun. 183, 370–381 (2012).
[Crossref]

2011 (1)

S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
[Crossref]

2010 (2)

S. Wang, X. Shan, U. Patel, X. Huang, J. Lu, J. Li, and N. Tao, “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance,” Proc. Natl. Acad. Sci. 107, 16028–16032 (2010).
[Crossref]

G. G. Daaboul, A. Yurt, X. Zhang, G. M. Hwang, B. B. Goldberg, and M. S. Ünlü, “High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification,” Nano Lett. 10, 4727–4731 (2010).
[Crossref] [PubMed]

2009 (2)

P. Kukura, H. Ewers, C. Müller, A. Renn, A. Helenius, and V. Sandoghdar, “High-speed nanoscopic tracking of the position and orientation of a single virus,” Nature Methods 6, 923–927 (2009).
[Crossref] [PubMed]

C. M. Lawrence, S. Menon, B. J. Eilers, B. Bothner, R. Khayat, T. Douglas, and M. J. Young, “Structural and functional studies of archaeal viruses,” J. Biol. Chem. 284, 12599–12603 (2009).
[Crossref] [PubMed]

2008 (1)

F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods 5, 591–596 (2008).
[Crossref] [PubMed]

2007 (1)

2005 (1)

M. A. van Dijk, M. Lippitz, and M. Orrit, “Far-field optical microscopy of single metal nanoparticles,” Acc. Chem. Res. 38, 594–601 (2005).
[Crossref] [PubMed]

2004 (2)

K. Lindfors, T. Kalkbrenner, P. Stoller, and V. Sandoghdar, “Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy,” Phys. Rev. Lett. 93, 037401 (2004).
[Crossref] [PubMed]

B. D. Lichty, A. T. Power, D. F. Stojdl, and J. C. Bell, “Vesicular stomatitis virus: re-inventing the bullet,” Trends Mol. Med. 10, 210–216 (2004).
[Crossref] [PubMed]

2003 (1)

Y. G. Kuznetsov, J. G. Victoria, W. E. Robinson, and A. McPherson, “Atomic force microscopy investigation of human immunodeficiency virus (hiv) and hiv-infected lymphocytes,” J. Virol. 77, 11896–11909 (2003).
[Crossref] [PubMed]

2002 (2)

F. J. García de Abajo, “Retarded field calculation of electron energy loss in inhomogeneous dielectrics,” Phys. Rev. B 65, 115418 (2002).
[Crossref]

A. Büttner and U. D. Zeitner, “Wave optical analysis of light-emitting diode beam shaping using microlens arrays,” Opt. Eng. 41, 2393–2401 (2002).
[Crossref]

2001 (1)

F. d. Lange, A. Cambi, R. Huijbens, B. d. Bakker, W. Rensen, M. Garcia-Parajo, N. v. Hulst, and C. G. Figdor, “Cell biology beyond the diffraction limit: near-field scanning optical microscopy,” J. Cell Sci. 114, 4153–4160 (2001).
[PubMed]

1999 (1)

L. Berthoux, C. Pèchoux, and J.-L. Darlix, “Multiple effects of an anti-human immunodeficiency virus nucleocapsid inhibitor on virus morphology and replication,” J. Virol. 73, 10000–10009 (1999).
[PubMed]

1998 (1)

A. J. Darling, J. A. Boose, and J. Spaltro, “Virus assay methods: Accuracy and validation,” Biologicals 26, 105–110 (1998).
[Crossref] [PubMed]

1997 (1)

S. Nie and S. R. Emory, “Probing single molecules and single nanoparticles by surface-enhanced raman scattering,” Science 275, 1102–1106 (1997).
[Crossref] [PubMed]

1990 (1)

F. Clavel and J. M. Orenstein, “A mutant of human immunodeficiency virus with reduced rna packaging and abnormal particle morphology,” J. Virol. 64, 5230–5234 (1990).
[PubMed]

1980 (1)

F. W. Doane, “Virus morphology as an aid for rapid diagnosis,” Yale J. Biol. Med. 53, 19–25 (1980).
[PubMed]

Adato, R.

Allier, C. P.

O. Mudanyali, E. McLeod, W. Luo, A. Greenbaum, A. F. Coskun, Y. Hennequin, C. P. Allier, and A. Ozcan, “Wide-field optical detection of nanoparticles using on-chip microscopy and self-assembled nanolenses,” Nature Photon. 5, 247–254 (2013).

Arnold, S.

F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods 5, 591–596 (2008).
[Crossref] [PubMed]

Avci, O.

Bailly-Bechet, M.

Bakker, B. d.

F. d. Lange, A. Cambi, R. Huijbens, B. d. Bakker, W. Rensen, M. Garcia-Parajo, N. v. Hulst, and C. G. Figdor, “Cell biology beyond the diffraction limit: near-field scanning optical microscopy,” J. Cell Sci. 114, 4153–4160 (2001).
[PubMed]

Bell, J. C.

B. D. Lichty, A. T. Power, D. F. Stojdl, and J. C. Bell, “Vesicular stomatitis virus: re-inventing the bullet,” Trends Mol. Med. 10, 210–216 (2004).
[Crossref] [PubMed]

Benussi, L.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Berthoux, L.

L. Berthoux, C. Pèchoux, and J.-L. Darlix, “Multiple effects of an anti-human immunodeficiency virus nucleocapsid inhibitor on virus morphology and replication,” J. Virol. 73, 10000–10009 (1999).
[PubMed]

Bettotti, P.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Boccara, A. C.

Boccara, M.

Bohren, C. F.

C. F. Bohren and D. R. Huffman, Absorption and Scattering of Light by Small Particles (John Wiley & Sons, 2008).

Böing, A. N.

E. van der Pol, A. N. Böing, P. Harrison, A. Sturk, and R. Nieuwland, “Classification, functions, and clinical relevance of extracellular vesicles,” Pharmacol. Rev. 64, 676–705 (2012).
[Crossref] [PubMed]

Boose, J. A.

A. J. Darling, J. A. Boose, and J. Spaltro, “Virus assay methods: Accuracy and validation,” Biologicals 26, 105–110 (1998).
[Crossref] [PubMed]

Bothner, B.

C. M. Lawrence, S. Menon, B. J. Eilers, B. Bothner, R. Khayat, T. Douglas, and M. J. Young, “Structural and functional studies of archaeal viruses,” J. Biol. Chem. 284, 12599–12603 (2009).
[Crossref] [PubMed]

Bowler, C.

Bryan, C. V.

Büttner, A.

A. Büttner and U. D. Zeitner, “Wave optical analysis of light-emitting diode beam shaping using microlens arrays,” Opt. Eng. 41, 2393–2401 (2002).
[Crossref]

Cambi, A.

F. d. Lange, A. Cambi, R. Huijbens, B. d. Bakker, W. Rensen, M. Garcia-Parajo, N. v. Hulst, and C. G. Figdor, “Cell biology beyond the diffraction limit: near-field scanning optical microscopy,” J. Cell Sci. 114, 4153–4160 (2001).
[PubMed]

Campana, M. I.

Castro, C. M.

H. Im, H. Shao, Y. I. Park, V. M. Peterson, C. M. Castro, R. Weissleder, and H. Lee, “Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor,” Nature Biotech. 32, 490–495 (2014).
[Crossref]

Chiari, M.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Chinnala, J.

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Digital sensing and sizing of vesicular stomatitis virus pseudotypes in complex media; a model for ebola and marburg detection,” ACS Nano 8, 6047–6055(2014).
[Crossref]

Chiu, C.-y.

S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
[Crossref]

Ciani, M.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Clavel, F.

F. Clavel and J. M. Orenstein, “A mutant of human immunodeficiency virus with reduced rna packaging and abnormal particle morphology,” J. Virol. 64, 5230–5234 (1990).
[PubMed]

Connor, J.

J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

Connor, J. H.

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G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Power, A. T.

B. D. Lichty, A. T. Power, D. F. Stojdl, and J. C. Bell, “Vesicular stomatitis virus: re-inventing the bullet,” Trends Mol. Med. 10, 210–216 (2004).
[Crossref] [PubMed]

Prosperi, D.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Redman, C. W.

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
[Crossref]

Renn, A.

P. Kukura, H. Ewers, C. Müller, A. Renn, A. Helenius, and V. Sandoghdar, “High-speed nanoscopic tracking of the position and orientation of a single virus,” Nature Methods 6, 923–927 (2009).
[Crossref] [PubMed]

Rensen, W.

F. d. Lange, A. Cambi, R. Huijbens, B. d. Bakker, W. Rensen, M. Garcia-Parajo, N. v. Hulst, and C. G. Figdor, “Cell biology beyond the diffraction limit: near-field scanning optical microscopy,” J. Cell Sci. 114, 4153–4160 (2001).
[PubMed]

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Y. G. Kuznetsov, J. G. Victoria, W. E. Robinson, and A. McPherson, “Atomic force microscopy investigation of human immunodeficiency virus (hiv) and hiv-infected lymphocytes,” J. Virol. 77, 11896–11909 (2003).
[Crossref] [PubMed]

Saleh, B. E. A.

B. E. A. Saleh and M. C. Teich, Fundamentals of Photonics, Wiley series in pure and applied opticsWiley Inter-science, 2007), 2nd ed

Sandoghdar, V.

P. Kukura, H. Ewers, C. Müller, A. Renn, A. Helenius, and V. Sandoghdar, “High-speed nanoscopic tracking of the position and orientation of a single virus,” Nature Methods 6, 923–927 (2009).
[Crossref] [PubMed]

K. Lindfors, T. Kalkbrenner, P. Stoller, and V. Sandoghdar, “Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy,” Phys. Rev. Lett. 93, 037401 (2004).
[Crossref] [PubMed]

Santini, B.

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

Sargent, I. L.

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
[Crossref]

Scherr, S. M.

S. M. Scherr, G. G. Daaboul, J. Trueb, D. Sevenler, H. Fawcett, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Real-time capture and visualization of individual viruses in complex media,” ACS Nano 10, 2827–2833 (2016).
[Crossref] [PubMed]

Sevenler, D.

S. M. Scherr, G. G. Daaboul, J. Trueb, D. Sevenler, H. Fawcett, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Real-time capture and visualization of individual viruses in complex media,” ACS Nano 10, 2827–2833 (2016).
[Crossref] [PubMed]

J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

Shan, X.

S. Wang, X. Shan, U. Patel, X. Huang, J. Lu, J. Li, and N. Tao, “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance,” Proc. Natl. Acad. Sci. 107, 16028–16032 (2010).
[Crossref]

Shao, H.

H. Im, H. Shao, Y. I. Park, V. M. Peterson, C. M. Castro, R. Weissleder, and H. Lee, “Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor,” Nature Biotech. 32, 490–495 (2014).
[Crossref]

Shaw, M.

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
[Crossref]

Shepard, K. L.

S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
[Crossref]

Smith, J.

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
[Crossref]

Sorgenfrei, S.

S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
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A. J. Darling, J. A. Boose, and J. Spaltro, “Virus assay methods: Accuracy and validation,” Biologicals 26, 105–110 (1998).
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B. D. Lichty, A. T. Power, D. F. Stojdl, and J. C. Bell, “Vesicular stomatitis virus: re-inventing the bullet,” Trends Mol. Med. 10, 210–216 (2004).
[Crossref] [PubMed]

Stoller, P.

K. Lindfors, T. Kalkbrenner, P. Stoller, and V. Sandoghdar, “Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy,” Phys. Rev. Lett. 93, 037401 (2004).
[Crossref] [PubMed]

Stolwijk, D.

Sturk, A.

E. van der Pol, A. N. Böing, P. Harrison, A. Sturk, and R. Nieuwland, “Classification, functions, and clinical relevance of extracellular vesicles,” Pharmacol. Rev. 64, 676–705 (2012).
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E. Van Der Pol, M. J. C. Van Gemert, A. Sturk, R. Nieuwland, and T. G. Van Leeuwen, “Single vs. swarm detection of microparticles and exosomes by flow cytometry,” J. Thromb. Haemostasis 10, 919–930 (2012).
[Crossref]

Tannetta, D.

C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
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Tao, N.

S. Wang, X. Shan, U. Patel, X. Huang, J. Lu, J. Li, and N. Tao, “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance,” Proc. Natl. Acad. Sci. 107, 16028–16032 (2010).
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Teich, M. C.

B. E. A. Saleh and M. C. Teich, Fundamentals of Photonics, Wiley series in pure and applied opticsWiley Inter-science, 2007), 2nd ed

Trueb, J.

J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

S. M. Scherr, G. G. Daaboul, J. Trueb, D. Sevenler, H. Fawcett, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Real-time capture and visualization of individual viruses in complex media,” ACS Nano 10, 2827–2833 (2016).
[Crossref] [PubMed]

Trügler, A.

J. Waxenegger, A. Trügler, and U. Hohenester, “Plasmonics simulations with the mnpbem toolbox: Consideration of substrates and layer structures,” Computer Physics Communications 193, 138–150 (2015).
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U. Hohenester and A. Trügler, “Mnpbem - a matlab toolbox for the simulation of plasmonic nanoparticles,” Comput. Phys. Commun. 183, 370–381 (2012).
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O. Avci, M. I. Campana, C. Yurdakul, and M. S. Ünlü, “Pupil function engineering for enhanced nanoparticle visibility in wide-field interferometric microscopy,” Optica 4, 247–254 (2017).
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S. M. Scherr, G. G. Daaboul, J. Trueb, D. Sevenler, H. Fawcett, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Real-time capture and visualization of individual viruses in complex media,” ACS Nano 10, 2827–2833 (2016).
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O. Avci, R. Adato, A. Y. Ozkumur, and M. S. Ünlü, “Physical modeling of interference enhanced imaging and characterization of single nanoparticles,” Opt. Express 24, 6094 (2016).
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J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
[Crossref] [PubMed]

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Digital sensing and sizing of vesicular stomatitis virus pseudotypes in complex media; a model for ebola and marburg detection,” ACS Nano 8, 6047–6055(2014).
[Crossref]

G. G. Daaboul, A. Yurt, X. Zhang, G. M. Hwang, B. B. Goldberg, and M. S. Ünlü, “High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification,” Nano Lett. 10, 4727–4731 (2010).
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van der Pol, E.

E. van der Pol, F. Coumans, Z. Varga, M. Krumrey, and R. Nieuwland, “Innovation in detection of microparticles and exosomes,” J. Thromb. Haemostatis 11, 36–45 (2013).
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E. van der Pol, A. N. Böing, P. Harrison, A. Sturk, and R. Nieuwland, “Classification, functions, and clinical relevance of extracellular vesicles,” Pharmacol. Rev. 64, 676–705 (2012).
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E. Van Der Pol, M. J. C. Van Gemert, A. Sturk, R. Nieuwland, and T. G. Van Leeuwen, “Single vs. swarm detection of microparticles and exosomes by flow cytometry,” J. Thromb. Haemostasis 10, 919–930 (2012).
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E. van der Pol, F. Coumans, Z. Varga, M. Krumrey, and R. Nieuwland, “Innovation in detection of microparticles and exosomes,” J. Thromb. Haemostatis 11, 36–45 (2013).
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F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods 5, 591–596 (2008).
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S. Wang, X. Shan, U. Patel, X. Huang, J. Lu, J. Li, and N. Tao, “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance,” Proc. Natl. Acad. Sci. 107, 16028–16032 (2010).
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J. Waxenegger, A. Trügler, and U. Hohenester, “Plasmonics simulations with the mnpbem toolbox: Consideration of substrates and layer structures,” Computer Physics Communications 193, 138–150 (2015).
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H. Im, H. Shao, Y. I. Park, V. M. Peterson, C. M. Castro, R. Weissleder, and H. Lee, “Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor,” Nature Biotech. 32, 490–495 (2014).
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S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
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Yurt, A.

G. G. Daaboul, A. Yurt, X. Zhang, G. M. Hwang, B. B. Goldberg, and M. S. Ünlü, “High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification,” Nano Lett. 10, 4727–4731 (2010).
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A. Büttner and U. D. Zeitner, “Wave optical analysis of light-emitting diode beam shaping using microlens arrays,” Opt. Eng. 41, 2393–2401 (2002).
[Crossref]

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G. G. Daaboul, A. Yurt, X. Zhang, G. M. Hwang, B. B. Goldberg, and M. S. Ünlü, “High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification,” Nano Lett. 10, 4727–4731 (2010).
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ACS Nano (3)

E. McLeod, T. U. Dincer, M. Veli, Y. N. Ertas, C. Nguyen, W. Luo, A. Greenbaum, A. Feizi, and A. Ozcan, “High-throughput and label-free single nanoparticle sizing based on time-resolved on-chip microscopy,” ACS Nano 9, 3265–3273 (2015).
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[Crossref] [PubMed]

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. Goldberg, J. H. Connor, and M. S. Ünlü, “Digital sensing and sizing of vesicular stomatitis virus pseudotypes in complex media; a model for ebola and marburg detection,” ACS Nano 8, 6047–6055(2014).
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J. Waxenegger, A. Trügler, and U. Hohenester, “Plasmonics simulations with the mnpbem toolbox: Consideration of substrates and layer structures,” Computer Physics Communications 193, 138–150 (2015).
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IEEE Journal of Selected Topics in Quantum Electronics (1)

J. Trueb, O. Avci, D. Sevenler, J. Connor, and M. S. Ünlü, “Robust visualization and discrimination of nanoparticles by interferometric imaging,” IEEE Journal of Selected Topics in Quantum Electronics 23, 6900610 (2016).

J. Biol. Chem. (1)

C. M. Lawrence, S. Menon, B. J. Eilers, B. Bothner, R. Khayat, T. Douglas, and M. J. Young, “Structural and functional studies of archaeal viruses,” J. Biol. Chem. 284, 12599–12603 (2009).
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F. d. Lange, A. Cambi, R. Huijbens, B. d. Bakker, W. Rensen, M. Garcia-Parajo, N. v. Hulst, and C. G. Figdor, “Cell biology beyond the diffraction limit: near-field scanning optical microscopy,” J. Cell Sci. 114, 4153–4160 (2001).
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C. Gardiner, M. Shaw, P. Hole, J. Smith, D. Tannetta, C. W. Redman, and I. L. Sargent, “Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles,” J. Extracell. Vesicles 3, 25361 (2014).
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J. Thromb. Haemostasis (1)

E. Van Der Pol, M. J. C. Van Gemert, A. Sturk, R. Nieuwland, and T. G. Van Leeuwen, “Single vs. swarm detection of microparticles and exosomes by flow cytometry,” J. Thromb. Haemostasis 10, 919–930 (2012).
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E. van der Pol, F. Coumans, Z. Varga, M. Krumrey, and R. Nieuwland, “Innovation in detection of microparticles and exosomes,” J. Thromb. Haemostatis 11, 36–45 (2013).
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Y. G. Kuznetsov, J. G. Victoria, W. E. Robinson, and A. McPherson, “Atomic force microscopy investigation of human immunodeficiency virus (hiv) and hiv-infected lymphocytes,” J. Virol. 77, 11896–11909 (2003).
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G. G. Daaboul, A. Yurt, X. Zhang, G. M. Hwang, B. B. Goldberg, and M. S. Ünlü, “High-throughput detection and sizing of individual low-index nanoparticles and viruses for pathogen identification,” Nano Lett. 10, 4727–4731 (2010).
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Nat. Methods (1)

F. Vollmer and S. Arnold, “Whispering-gallery-mode biosensing: label-free detection down to single molecules,” Nat. Methods 5, 591–596 (2008).
[Crossref] [PubMed]

Nature Biotech. (1)

H. Im, H. Shao, Y. I. Park, V. M. Peterson, C. M. Castro, R. Weissleder, and H. Lee, “Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor,” Nature Biotech. 32, 490–495 (2014).
[Crossref]

Nature Methods (1)

P. Kukura, H. Ewers, C. Müller, A. Renn, A. Helenius, and V. Sandoghdar, “High-speed nanoscopic tracking of the position and orientation of a single virus,” Nature Methods 6, 923–927 (2009).
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Nature Nanotechn. (1)

S. Sorgenfrei, C.-y. Chiu, R. L. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of dna-hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechn. 6, 126–132 (2011).
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O. Mudanyali, E. McLeod, W. Luo, A. Greenbaum, A. F. Coskun, Y. Hennequin, C. P. Allier, and A. Ozcan, “Wide-field optical detection of nanoparticles using on-chip microscopy and self-assembled nanolenses,” Nature Photon. 5, 247–254 (2013).

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A. Büttner and U. D. Zeitner, “Wave optical analysis of light-emitting diode beam shaping using microlens arrays,” Opt. Eng. 41, 2393–2401 (2002).
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Pharmacol. Rev. (1)

E. van der Pol, A. N. Böing, P. Harrison, A. Sturk, and R. Nieuwland, “Classification, functions, and clinical relevance of extracellular vesicles,” Pharmacol. Rev. 64, 676–705 (2012).
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Proc. Natl. Acad. Sci. (1)

S. Wang, X. Shan, U. Patel, X. Huang, J. Lu, J. Li, and N. Tao, “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance,” Proc. Natl. Acad. Sci. 107, 16028–16032 (2010).
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Sci. Rep. (1)

G. G. Daaboul, P. Gagni, L. Benussi, P. Bettotti, M. Ciani, M. Cretich, D. S. Freedman, R. Ghidoni, A. Y. Ozkumur, C. Piotto, D. Prosperi, B. Santini, M. S. Ünlü, and M. Chiari, “Digital detection of exosomes by interferometric imaging,” Sci. Rep. 6, 37246 (2016).
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A. Mitra and L. Novotny, “Real-time optical detection of single nanoparticles and viruses using heterodyne interferometry,” in “Nano-Optics for Enhancing Light-Matter Interactions on a Molecular Scale,” B. D. Bartolo and J. Collins, eds. (SpringerNetherlands, 2013), NATO Science for Peace and Security Series B: Physics and Biophysics, pp. 3–22.
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Figures (9)

Fig. 1
Fig. 1 Coordinate system used to calculate the reflected field, showing the plane of incidence and coordinate unit vectors (Eqs. 26). An incident plane wave with kinc is decomposed into components perpendicular (ŝ) and parallel ( p ^ ) to the plane of incidence.
Fig. 2
Fig. 2 (a) The SP-IRIS substrate consists of a thin film of thermally grown oxide on polished silicon. Incident light (Einc) is both reflected by the substrate (Eref) and scattered by the immobilized nanoparticle (Escat). (b) Schematic of the reflection microscope. The LED source is imaged to the objective back pupil, providing Köhler illumination (dashed lines). Collected scattered light from a particular particle is indicated by red shadow.
Fig. 3
Fig. 3 (a–c) 3D simulated plots of the radiation pattern (Poynting vector magnitude) of total back-scattered light Escat of a 100 nm virus particle (n=1.5) on SP-IRIS substrates with a range of film thicknesses, compared with (d) a glass substrate (arbitrary units). Illumination is a normal-incident linearly polarized plane wave with λ = 530 nm. (e) Distribution function of back-scattered radiation vs polar angle (i.e, from surface normal) for the cases shown in (a–c). The dashed line indicates the maximum collection angle of a 0.9 NA water-immersion objective. Dotted lines indicate the mean polar angle of the collected light, for each case.
Fig. 4
Fig. 4 (a) Simulated images of a 100 nm virus with the microscope focal plane at three different positions with respect to the substrate top surface (NA = 0.9), scale bars are 1 1 µm). (b) The ‘defocus profile’: simulated normalized intensity at the center of the diffraction-limited image is plotted as a function of focus position, with the three focus positions labeled.
Fig. 5
Fig. 5 Validation of BEM simulations against the dipole approximation method and experimental measurements, in the case of (a) 60 nm gold spheres (34 particles), (b) 100 nm diameter polystyrene (n=1.60) spheres (63 particles), and (c) 145 nm polystyrene spheres (24 particles), showing good agreement amongst all three for the entire range of particle sizes. (NA = 0.8, λ = 525 nm in (a–b), λ = 630 nm in (c)).
Fig. 6
Fig. 6 Validation of BEM simulations of gold nanorods. (a–c) Cropped slices from the 25x71 nm gold nanorod dataset described in text, where θ is the illumination polarization angle. (d) Hue-Saturation-Value representation after fitting a sinusoid to each spatial position pixel as a function of illumination polarization angle. Value (i.e., brightness) indicates the presence of a particle and Hue (i.e., color) indicates particle orientation. (e) Comparison of simulated and measured normalized intensity of a 25x71 nm gold nanorod aligned parallel to the illumination polarization direction, as a function of defocus (59 particles, 50 × 0.8 NA, λ = 630 nm).
Fig. 7
Fig. 7 (a) Simulations of normalized intensity (at image center) of a 100 nm virus as a function of oxide film thickness and objective focus position. Two slices of this simulation where the film thickness is 50 or 100 nm are indicated by the dotted lines and plotted in (b) as defocus profiles. (c) NI Range for the range of oxide film thicknesses. (d) NI Range and (e) Peak plane separation are simulated for spherical virus between 50 and 150 nm in diameter on a 50 nm oxide film.
Fig. 8
Fig. 8 (a) Simulations of normalized intensity (at image center) of a 100 nm virus as a function of illumination NA and focus position. (b) The defocus profiles when illumination angles are restricted to a single plane wave (NA = 0), or NA = 0.45 or NA = 0.9.
Fig. 9
Fig. 9 (a) Simulated defocus profiles of a 100 nm virus on a range of nitride films (n=2.05). (b) Optimal NI Range is achieved with a film thickness of 190 nm. (c) The field magnitudes |Escat| (top) and |Eref| (bottom) are plotted individually, with the optimal nitride thickness indicated.

Equations (10)

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E s c a t ( r ) = i 2 π θ θ m a x E ( k x , k y ) e i ( k x x + k y y + k z z ) 1 k z d k x d k y
E r e f ( r ) = r s ( E i n c s ^ i n c ) s ^ r e f + r p ( E i n c p ^ i n c ) p ^ r e f
s ^ i n c = z ^ × k x y | k x y |
p ^ i n c = s ^ i n c × k k
s ^ r e f = s ^ i n c
p ^ r e f = [ 1 0 0 0 1 0 0 0 1 ] p ^ i n c
I ( r ) = | E r e f ( r ) + E s c a t ( r ) | 2 .
I t o t ( r ) = θ i n c θ m a x I ( k x , k y , r ) d k x d k y
I ( r ) = | E r e f ( r ) + E s c a t ( r ) | 2 = | E r e f | 2 + | E s c a t | 2 + 2 | E r e f | | E s c a t | cos ( ϕ ) .
Normalized Intensity = | E s c a t + E r e f | 2 | E r e f | 2

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