Abstract

Wide-field interferometric microscopy techniques have demonstrated their utility in sensing minute changes in the optical path length as well as visualization of sub-diffraction-limited nanoparticles. In this work, we demonstrate enhanced signal levels for nanoparticle detection by pupil function engineering in wide-field common-path interferometric microscopy. We quantify the improvements in nanoparticle signal achieved by novel optical filtering schemes, benchmark them against theory, and provide physical explanations for the signal enhancements. Our refined common-path interferometric microscopy technique provides an overall ten-fold enhancement in the visibility of low-index, non-resonant polystyrene nanospheres (r∼25  nm), resulting in nearly 8% signal-to-background ratio. Our method can be a highly sensitive, low-cost, label-free, high-throughput platform for accurate detection and characterization of weakly scattering low-index nanoparticles with sizes ranging from several hundred down to a few tens of nanometers, covering nearly the entire size spectrum of biological particles.

© 2017 Optical Society of America

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2016 (4)

Y. Cao, J. Li, F. Liu, X. Li, Q. Jiang, S. Cheng, and Y. Gu, “Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: a review,” Environ. Toxicol. Pharmacol. 46, 206–210 (2016).
[Crossref]

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]

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]

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, 6094–6114 (2016).
[Crossref]

2015 (2)

O. Avci, N. L. Ünlü, A. Y. Ozkumur, and M. S. Ünlü, “Interferometric Reflectance Imaging Sensor (IRIS)–A platform technology for multiplexed diagnostics and digital detection,” Sensors 15, 17649–17665 (2015).
[Crossref]

J. Zhang, S. Li, L. Li, M. Li, C. Guo, J. Yao, and S. Mi, “Exosome and exosomal MicroRNA: trafficking, sorting, and function,” Genomics Proteomics Bioinf. 13, 17–24 (2015).
[Crossref]

2014 (2)

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. 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]

E. Gefroh, H. Dehghani, M. McClure, L. Connell-Crowley, and G. Vedantham, “Use of MMV as a single worst-case model virus in viral filter validation studies,” PDA J. Pharm. Sci. Technol. 68, 297–311 (2014).
[Crossref]

2010 (2)

E. van der Pol, A. G. Hoekstra, A. Sturk, C. Otto, T. G. van Leeuwen, and R. Nieuwland, “Optical and non-optical methods for detection and characterization of microparticles and exosomes,” J. Thromb. Haemost. 8, 2596–2607 (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]

2009 (3)

S. R. P. Pavani, M. A. Thompson, J. S. Biteen, S. J. Lord, N. Liu, R. J. Twieg, R. Piestun, and W. Moerner, “Three-dimensional, single molecule fluorescence imaging beyond the diffraction limit by using a double-helix point spread function,” Proc. Natl. Acad. Sci. USA 106, 2995–2999 (2009).
[Crossref]

C. Thery, M. Ostrowski, and E. Segura, “Membrane vesicles as conveyors of immune responses,” Nat. Rev. Immunol. 9, 581–593 (2009).
[Crossref]

P. Fara, “A microscopic reality tale,” Nature 459, 642–644 (2009).
[Crossref]

2008 (1)

E. Ozkumur, J. W. Needham, D. A. Bergstein, R. Gonzalez, M. Cabodi, J. M. Gershoni, B. B. Goldberg, and M. S. Ünlü, “Label-free and dynamic detection of biomolecular interactions for high-throughput microarray applications,” Proc. Natl. Acad. Sci. USA 105, 7988–7992 (2008).
[Crossref]

2006 (2)

M. V. Yezhelyev, X. Gao, Y. Xing, A. Al-Hajj, S. Nie, and R. M. O’Regan, “Emerging use of nanoparticles in diagnosis and treatment of breast cancer,” Lancet Oncol. 7, 657–667 (2006).
[Crossref]

F. V. Ignatovich and L. Novotny, “Real-time and background-free detection of nanoscale particles,” Phys. Rev. Lett. 96, 1–4 (2006).
[Crossref]

2005 (1)

C. A. Suttle, “Viruses in the sea,” Nature 437, 356–361 (2005).
[Crossref]

2004 (2)

C. M. Somers, B. E. McCarry, F. Malek, and J. S. Quinn, “Reduction of particulate air pollution lowers the risk of heritable mutations in mice,” Science 304, 1008–1010 (2004).
[Crossref]

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, 37401 (2004).
[Crossref]

2001 (1)

2000 (1)

P. A. Rosen, S. Hensley, I. R. Joughin, F. K. Li, S. N. Madsen, E. Rodriguez, and R. M. Goldstein, “Synthetic aperture radar interferometry,” Proc. IEEE 88, 333–382 (2000).
[Crossref]

1999 (1)

R. W. Hendrix, M. C. M. Smith, R. N. Burns, M. E. Ford, and G. F. Hatfull, “Evolutionary relationships among diverse bacteriophages and prophages: All the world’s a phage,” Proc. Natl. Acad. Sci. USA 96, 2192–2197 (1999).
[Crossref]

1998 (1)

D. W. Piston, “Choosing objective lenses: the importance of numerical aperture and magnification in digital optical microscopy,” Biol. Bull. 195, 1–4 (1998).
[Crossref]

1996 (1)

R. H. Webb, “Confocal optical microscopy,” Rep. Prog. Phys. 59, 427–471 (1996).
[Crossref]

1991 (2)

H. Fukuda, T. Terasawa, and S. Okazaki, “Spatial filtering for depth of focus and resolution enhancement in optical lithography,” J. Vac. Sci. Technol. B 9, 3113–3116 (1991).
[Crossref]

K. Kamon, T. Miyamoto, Y. Myoi, H. Nagata, M. Tanaka, and K. Horie, “Photolithography system using annular illumination,” Jpn. J. Appl. Phys. 30, 3021–3029 (1991).
[Crossref]

Adato, R.

Al-Hajj, A.

M. V. Yezhelyev, X. Gao, Y. Xing, A. Al-Hajj, S. Nie, and R. M. O’Regan, “Emerging use of nanoparticles in diagnosis and treatment of breast cancer,” Lancet Oncol. 7, 657–667 (2006).
[Crossref]

Avci, O.

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, 6094–6114 (2016).
[Crossref]

O. Avci, N. L. Ünlü, A. Y. Ozkumur, and M. S. Ünlü, “Interferometric Reflectance Imaging Sensor (IRIS)–A platform technology for multiplexed diagnostics and digital detection,” Sensors 15, 17649–17665 (2015).
[Crossref]

Balanis, C. A.

C. A. Balanis, Antenna Theory: Analysis and Design (Wiley-Interscience, 2005).

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]

Bergstein, D. A.

E. Ozkumur, J. W. Needham, D. A. Bergstein, R. Gonzalez, M. Cabodi, J. M. Gershoni, B. B. Goldberg, and M. S. Ünlü, “Label-free and dynamic detection of biomolecular interactions for high-throughput microarray applications,” Proc. Natl. Acad. Sci. USA 105, 7988–7992 (2008).
[Crossref]

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]

Biteen, J. S.

S. R. P. Pavani, M. A. Thompson, J. S. Biteen, S. J. Lord, N. Liu, R. J. Twieg, R. Piestun, and W. Moerner, “Three-dimensional, single molecule fluorescence imaging beyond the diffraction limit by using a double-helix point spread function,” Proc. Natl. Acad. Sci. USA 106, 2995–2999 (2009).
[Crossref]

Boustany, N. N.

Brooks, G. F.

G. F. Brooks, K. C. Carroll, J. S. Butel, S. A. Morse, and T. A. Mietzner, “Chapter 29. General Properties of Viruses,” in Jawetz, Melnick, & Adelberg’s Medical Microbiology, 26e (McGraw-Hill, 2013).

Burns, R. N.

R. W. Hendrix, M. C. M. Smith, R. N. Burns, M. E. Ford, and G. F. Hatfull, “Evolutionary relationships among diverse bacteriophages and prophages: All the world’s a phage,” Proc. Natl. Acad. Sci. USA 96, 2192–2197 (1999).
[Crossref]

Butel, J. S.

G. F. Brooks, K. C. Carroll, J. S. Butel, S. A. Morse, and T. A. Mietzner, “Chapter 29. General Properties of Viruses,” in Jawetz, Melnick, & Adelberg’s Medical Microbiology, 26e (McGraw-Hill, 2013).

Cabodi, M.

E. Ozkumur, J. W. Needham, D. A. Bergstein, R. Gonzalez, M. Cabodi, J. M. Gershoni, B. B. Goldberg, and M. S. Ünlü, “Label-free and dynamic detection of biomolecular interactions for high-throughput microarray applications,” Proc. Natl. Acad. Sci. USA 105, 7988–7992 (2008).
[Crossref]

Cao, Y.

Y. Cao, J. Li, F. Liu, X. Li, Q. Jiang, S. Cheng, and Y. Gu, “Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: a review,” Environ. Toxicol. Pharmacol. 46, 206–210 (2016).
[Crossref]

Carroll, K. C.

G. F. Brooks, K. C. Carroll, J. S. Butel, S. A. Morse, and T. A. Mietzner, “Chapter 29. General Properties of Viruses,” in Jawetz, Melnick, & Adelberg’s Medical Microbiology, 26e (McGraw-Hill, 2013).

Cheng, S.

Y. Cao, J. Li, F. Liu, X. Li, Q. Jiang, S. Cheng, and Y. Gu, “Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: a review,” Environ. Toxicol. Pharmacol. 46, 206–210 (2016).
[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]

Chinnala, J.

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. 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]

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]

Connell-Crowley, L.

E. Gefroh, H. Dehghani, M. McClure, L. Connell-Crowley, and G. Vedantham, “Use of MMV as a single worst-case model virus in viral filter validation studies,” PDA J. Pharm. Sci. Technol. 68, 297–311 (2014).
[Crossref]

Connor, J. H.

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]

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. 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]

Cretich, 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]

Daaboul, G. G.

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]

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]

G. G. Daaboul, C. A. Lopez, J. Chinnala, B. 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).
[Crossref]

Dehghani, H.

E. Gefroh, H. Dehghani, M. McClure, L. Connell-Crowley, and G. Vedantham, “Use of MMV as a single worst-case model virus in viral filter validation studies,” PDA J. Pharm. Sci. Technol. 68, 297–311 (2014).
[Crossref]

Fara, P.

P. Fara, “A microscopic reality tale,” Nature 459, 642–644 (2009).
[Crossref]

Fawcett, H.

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]

Ford, M. E.

R. W. Hendrix, M. C. M. Smith, R. N. Burns, M. E. Ford, and G. F. Hatfull, “Evolutionary relationships among diverse bacteriophages and prophages: All the world’s a phage,” Proc. Natl. Acad. Sci. USA 96, 2192–2197 (1999).
[Crossref]

Freedman, D. S.

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]

Fukuda, H.

H. Fukuda, T. Terasawa, and S. Okazaki, “Spatial filtering for depth of focus and resolution enhancement in optical lithography,” J. Vac. Sci. Technol. B 9, 3113–3116 (1991).
[Crossref]

Gagni, 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]

Gao, X.

M. V. Yezhelyev, X. Gao, Y. Xing, A. Al-Hajj, S. Nie, and R. M. O’Regan, “Emerging use of nanoparticles in diagnosis and treatment of breast cancer,” Lancet Oncol. 7, 657–667 (2006).
[Crossref]

Gefroh, E.

E. Gefroh, H. Dehghani, M. McClure, L. Connell-Crowley, and G. Vedantham, “Use of MMV as a single worst-case model virus in viral filter validation studies,” PDA J. Pharm. Sci. Technol. 68, 297–311 (2014).
[Crossref]

Gershoni, J. M.

E. Ozkumur, J. W. Needham, D. A. Bergstein, R. Gonzalez, M. Cabodi, J. M. Gershoni, B. B. Goldberg, and M. S. Ünlü, “Label-free and dynamic detection of biomolecular interactions for high-throughput microarray applications,” Proc. Natl. Acad. Sci. USA 105, 7988–7992 (2008).
[Crossref]

Ghidoni, R.

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]

Goldberg, B.

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Supplementary Material (1)

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Figures (7)

Fig. 1.
Fig. 1. Köhler illumination geometry with integrated mask (Ail) for angular control over excitation light. (Adapted from [20].)

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Fig. 2.
Fig. 2. Layered sensor design can be utilized to enhance the horizontally aligned dipole scattering in direction of collection. (a) Layered sensor design for common-path interferometry; (b) normalized dipole radiation patterns in the plane of dipole axis and z axis for n1=1, n2=1.45, and n3=4 when d=0  nm and d=100  nm. Note that the excitation wavelength is chosen to be 525 nm.

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Fig. 3.
Fig. 3. Vertically oriented dipole atop a layered sensor and its scattering in the direction of collection. (a) Layered sensor design for common-path interferometry; (b) normalized dipole radiation patterns in the plane of dipole axis and z axis for n1=1, n2=1.45, and n3=4 when d=0  nm and d=100  nm. Note that the excitation wavelength is chosen to be 525 nm.

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Fig. 4.
Fig. 4. Wide-field interferometric microscopy setup. The mask in the illumination path controls the illumination NA, allowing for signal optimization.

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Fig. 5.
Fig. 5. (a) (Left) Maximum nanoparticle signal simulation with respect to illumination NA. For example, for a maximum illumination NA of 0.3, the sample gets illuminated by light rays spanning angles corresponding to 0° to 17°. The red dashed line around 1.01 indicates the limit of detection in terms of particle visibility, i.e., <1% normalized intensity is considered indistinguishable from the background fluctuations. (Right) Defocus scans of low-NA illumination (0.3 NA) and full-NA illumination (0.8 NA) cases. (b) Median normalized 25 nm radius polystyrene nanosphere images at their highest signal z plane for low- and full-NA configurations. (c) Experimentally obtained average defocus data benchmarked against the simulations. The experimental data points are laid on top of the red simulation curve from (a).

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Fig. 6.
Fig. 6. (a) Wide-field interferometric microscopy setup demonstrating masks in both the illumination and collection paths. The 4f system in the collection path relays the back focal plane of the objective to a conjugate plane where the filter is placed. (b) Custom-made filter transmission profile.

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Fig. 7.
Fig. 7. Further nanoparticle signal enhancement through spatial filtering. (a) Median normalized 25 nm radius polystyrene nanosphere images at their highest signal z plane for 1.3 OD spatial filter and no filter configurations. (b) Experimentally obtained average defocus data of polystyrene nanospheres with 25 nm nominal radius.

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Equations (11)

Equations on this page are rendered with MathJax. Learn more.

Et,m=H↔t,mEi,m,
Es,mu=ko2εoG↔s,mp,
G↔s,m=G↔o,m+G↔r,m,
p=εmαEt,m,
α=4πr3εp−εmεp+2εm.
Er,mu=H↔r,mEi,m,
It=∑mεNA|Er,mu+Es,mu|2.
It=|E1+E2|2=A12+A22+2A1A2 cos(φ1−φ2),
Inorm=1+A22A12+2A2A1 cos(φ1−φ2).
limA1→0 Inorm→∞
Spatial sampling rate=Effective pixel size=Pixel pitch/Magnification≤Resolution/2≈λ/(4  NA).

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