Abstract

Current optical fiber probes for fluorescence spectroscopy struggle with large luminescence background and low detection sensitivities that challenge the detection of fluorescent molecules at sub-micromolar concentration. Here we report the demonstration of a hollow-core photonic crystal fiber (HC-PCF) probe for remote fluorescence sensing with single molecule sensitivity down to nanomolar concentrations, where both the excitation and fluorescence beams are counter-propagating through the same fiber. A 20 μm polystyrene microsphere is used to efficiently excite and collect the fluorescence from the sample solution thanks to a photonic nanojet effect. Compared to earlier work with silica fibers, the new HC-PCF-microsphere probe achieves a 200x improvement of the signal-to-noise ratio for a single molecule detection event, and a 1000x reduction of the minimum detectable concentration. The device is implemented with fluorescence correlation spectroscopy to distinguish between molecules of similar fluorescence spectra based on the analysis of their translational diffusion properties, and provides similar performance as conventional confocal microscopes.

© 2012 OSA

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2012

2011

N. K. Singh, J. V. Chacko, V. K. A. Sreenivasan, S. Nag, and S. Maiti, “Ultracompact alignment-free single molecule fluorescence device with a foldable light path,” J. Biomed. Opt.16, 025004 (2011).
[CrossRef] [PubMed]

A. Darafsheh, A. Fardad, N. M. Fried, A. N. Antoszyk, H. S. Ying, and V. N. Astratov, “Contact focusing multimodal microprobes for ultraprecise laser tissue surgery,” Opt. Express19, 3440–3448 (2011).
[CrossRef] [PubMed]

2010

N. Ma, P. C. Ashok, D. J. Stevenson, F. J. Gunn-Moore, and K. Dholakia, “Integrated optical transfection system using a microlens fiber combined with microfluidic gene delivery,” Biomed. Opt. Express1, 694–705 (2010).
[CrossRef]

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

2009

2008

2007

K. Garai, R. Sureka, and S. Maiti, “Detecting amyloid-beta aggregation with fiber-based fluorescence correlation spectroscopy,” Biophys. J.92, L55–L57 (2007).
[CrossRef] [PubMed]

F. H. C. Wong, D. S. Banks, A. Abu-Arish, and C. Fradin, “A Molecular Thermometer Based on Fluorescent Protein Blinking,” J. Am. Chem. Soc.129, 10302–10303 (2007).
[CrossRef] [PubMed]

2006

2005

2004

2003

J. R. Epstein and D. R. Walt, “Fluorescence-based fibre optic arrays: a universal platform for sensing,” Chem. Soc. Rev.32, 203–214 (2003).
[CrossRef] [PubMed]

U. Utzinger and R. R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt.8, 121–147 (2003).
[CrossRef] [PubMed]

N. Opitz, P. J. Rothwell, B. Oeke, and P. Schwille, “Single molecule FCS-based oxygen sensor (O2-FCSensor): a new intrinsically calibrated oxygen sensor utilizing fluorescence correlation spectroscopy (FCS) with single fluorescent molecule detection sensitivity,” Sensors and Actuators B96, 460–467 (2003).
[CrossRef]

2002

V. Gerke and S. E. Moss, “Annexins: from structure to function,” Physiol. Rev.82, 331–371 (2002).
[PubMed]

F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol.87, 737–745 (2002).
[CrossRef] [PubMed]

1999

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

1998

M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy,” Nature Medicine4, 832–834 (1998).
[CrossRef] [PubMed]

1997

S. Maiti, U. Haupts, and W. W. Webb, “Fluorescence correlation spectroscopy: diagnostics for sparse molecules,” Proc. Natl. Acad. Sci. U.S.A.94, 11753–11757 (1997).
[CrossRef] [PubMed]

1996

Abu-Arish, A.

F. H. C. Wong, D. S. Banks, A. Abu-Arish, and C. Fradin, “A Molecular Thermometer Based on Fluorescent Protein Blinking,” J. Am. Chem. Soc.129, 10302–10303 (2007).
[CrossRef] [PubMed]

Addison, C. J.

Aebi, U.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Allan, D. C.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Antoszyk, A. N.

Aouani, H.

H. Aouani, F. Deiss, J. Wenger, P. Ferrand, N. Sojic, and H. Rigneault, “Optical-fiber-microsphere for remote fluorescence correlation spectroscopy,” Opt. Express17, 19085–19092 (2009).
[CrossRef]

J. Wenger, D. Gérard, H. Aouani, and H. Rigneault, “Disposable microscope objective lenses for fluorescence correlation spectroscopy using latex microspheres,” Anal. Chem.80, 6800–6804 (2008).
[CrossRef] [PubMed]

Ashok, P. C.

Astratov, V. N.

Backman, V.

Baker, J. R.

Banks, D. S.

F. H. C. Wong, D. S. Banks, A. Abu-Arish, and C. Fradin, “A Molecular Thermometer Based on Fluorescent Protein Blinking,” J. Am. Chem. Soc.129, 10302–10303 (2007).
[CrossRef] [PubMed]

Birks, T. A.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Blades, M. W.

Boned, A.

Bonod, N.

Calame, M.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Chacko, J. V.

N. K. Singh, J. V. Chacko, V. K. A. Sreenivasan, S. Nag, and S. Maiti, “Ultracompact alignment-free single molecule fluorescence device with a foldable light path,” J. Biomed. Opt.16, 025004 (2011).
[CrossRef] [PubMed]

Chang, Y.-C.

Chen, Y.

Chen, Z.

Conchonaud, F.

Cregan, R. F.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Darafsheh, A.

Deiss, F.

Devilez, A.

Dholakia, K.

Dintinger, J.

Ebbesen, T. W.

Enderlein, J.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Epstein, J. R.

J. R. Epstein and D. R. Walt, “Fluorescence-based fibre optic arrays: a universal platform for sensing,” Chem. Soc. Rev.32, 203–214 (2003).
[CrossRef] [PubMed]

Fardad, A.

Ferrand, P.

Flammer, J.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Fradin, C.

F. H. C. Wong, D. S. Banks, A. Abu-Arish, and C. Fradin, “A Molecular Thermometer Based on Fluorescent Protein Blinking,” J. Am. Chem. Soc.129, 10302–10303 (2007).
[CrossRef] [PubMed]

Fried, N. M.

Frosz, M.

Gachet, D.

Garai, K.

K. Garai, R. Sureka, and S. Maiti, “Detecting amyloid-beta aggregation with fiber-based fluorescence correlation spectroscopy,” Biophys. J.92, L55–L57 (2007).
[CrossRef] [PubMed]

K. Garai, M. Muralidhar, and S. Maiti, “Fiber-optic fluorescence correlation spectrometer,” Appl. Opt.45, 7538–7542 (2006).
[CrossRef] [PubMed]

Gérard, D.

Gerke, V.

V. Gerke and S. E. Moss, “Annexins: from structure to function,” Physiol. Rev.82, 331–371 (2002).
[PubMed]

Ghenuche, P.

Grange, W.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Gunn-Moore, F. J.

Haas, P.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Haupt, M.

M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy,” Nature Medicine4, 832–834 (1998).
[CrossRef] [PubMed]

Haupts, U.

S. Maiti, U. Haupts, and W. W. Webb, “Fluorescence correlation spectroscopy: diagnostics for sparse molecules,” Proc. Natl. Acad. Sci. U.S.A.94, 11753–11757 (1997).
[CrossRef] [PubMed]

Haustein, E.

E. Haustein and P. Schwille, “Single-molecule spectroscopic methods,” Curr. Opinion Struct. Biol.14, 531–540 (2004).
[CrossRef]

Hecht, B.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Hegner, M.

P. Haas, P. Then, A. Wild, W. Grange, S. Zorman, M. Hegner, M. Calame, U. Aebi, J. Flammer, and B. Hecht, “Fast Quantitative Single-Molecule Detection at Ultralow Concentrations,” Anal. Chem.82, 6299–6302 (2010).
[CrossRef] [PubMed]

Heifetz, A.

A. Heifetz, S. C. Kong, A. V. Sahakian, A. Taflove, and V. Backman, “Photonic Nanojets,” J. Comput. Theor. Nanosci.6, 1979–1992 (2009).
[CrossRef] [PubMed]

Helmchen, F.

F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol.87, 737–745 (2002).
[CrossRef] [PubMed]

Joly, N. Y.

Knight, J. C.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Koberling, F.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Kong, S. C.

A. Heifetz, S. C. Kong, A. V. Sahakian, A. Taflove, and V. Backman, “Photonic Nanojets,” J. Comput. Theor. Nanosci.6, 1979–1992 (2009).
[CrossRef] [PubMed]

Konorov, S. O.

Lenne, P.-F.

Li, X.

Li, Y.-S.

Loman, A.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Ma, J.

Ma, N.

Maiti, S.

N. K. Singh, J. V. Chacko, V. K. A. Sreenivasan, S. Nag, and S. Maiti, “Ultracompact alignment-free single molecule fluorescence device with a foldable light path,” J. Biomed. Opt.16, 025004 (2011).
[CrossRef] [PubMed]

K. Garai, R. Sureka, and S. Maiti, “Detecting amyloid-beta aggregation with fiber-based fluorescence correlation spectroscopy,” Biophys. J.92, L55–L57 (2007).
[CrossRef] [PubMed]

K. Garai, M. Muralidhar, and S. Maiti, “Fiber-optic fluorescence correlation spectrometer,” Appl. Opt.45, 7538–7542 (2006).
[CrossRef] [PubMed]

S. Maiti, U. Haupts, and W. W. Webb, “Fluorescence correlation spectroscopy: diagnostics for sparse molecules,” Proc. Natl. Acad. Sci. U.S.A.94, 11753–11757 (1997).
[CrossRef] [PubMed]

Mangan, B. J.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Marguet, D.

Moss, S. E.

V. Gerke and S. E. Moss, “Annexins: from structure to function,” Physiol. Rev.82, 331–371 (2002).
[PubMed]

Müller, C.B.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Muralidhar, M.

Nag, S.

N. K. Singh, J. V. Chacko, V. K. A. Sreenivasan, S. Nag, and S. Maiti, “Ultracompact alignment-free single molecule fluorescence device with a foldable light path,” J. Biomed. Opt.16, 025004 (2011).
[CrossRef] [PubMed]

Norris, T. B.

Oeke, B.

N. Opitz, P. J. Rothwell, B. Oeke, and P. Schwille, “Single molecule FCS-based oxygen sensor (O2-FCSensor): a new intrinsically calibrated oxygen sensor utilizing fluorescence correlation spectroscopy (FCS) with single fluorescent molecule detection sensitivity,” Sensors and Actuators B96, 460–467 (2003).
[CrossRef]

Opitz, N.

N. Opitz, P. J. Rothwell, B. Oeke, and P. Schwille, “Single molecule FCS-based oxygen sensor (O2-FCSensor): a new intrinsically calibrated oxygen sensor utilizing fluorescence correlation spectroscopy (FCS) with single fluorescent molecule detection sensitivity,” Sensors and Actuators B96, 460–467 (2003).
[CrossRef]

Pacheco, V.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Pianta, M.

Pitschke, M.

M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy,” Nature Medicine4, 832–834 (1998).
[CrossRef] [PubMed]

Popov, E.

Prior, R.

M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy,” Nature Medicine4, 832–834 (1998).
[CrossRef] [PubMed]

Rammler, S.

Richards-Kortum, R. R.

U. Utzinger and R. R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt.8, 121–147 (2003).
[CrossRef] [PubMed]

Richtering, W.

C.B. Müller, A. Loman, V. Pacheco, F. Koberling, D. Willbold, W. Richtering, and J. Enderlein, “Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy,” EPL83, 46001 (2008).
[CrossRef]

Riesner, D.

M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy,” Nature Medicine4, 832–834 (1998).
[CrossRef] [PubMed]

Rigneault, H.

Roberts, P. J.

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Rothwell, P. J.

N. Opitz, P. J. Rothwell, B. Oeke, and P. Schwille, “Single molecule FCS-based oxygen sensor (O2-FCSensor): a new intrinsically calibrated oxygen sensor utilizing fluorescence correlation spectroscopy (FCS) with single fluorescent molecule detection sensitivity,” Sensors and Actuators B96, 460–467 (2003).
[CrossRef]

Russell, P. St. J.

P. Ghenuche, S. Rammler, N. Y. Joly, M. Scharrer, M. Frosz, J. Wenger, P. St. J. Russell, and H. Rigneault, “Kagome hollow-core photonic crystal fiber probe for Raman spectroscopy,” Opt. Lett.37, 4371–4373 (2012).
[CrossRef] [PubMed]

P. St. J. Russell, “Photonic crystal fibers,” J. Ligthwave Technol.24, 4729–4749 (2006).
[CrossRef]

R. F. Cregan, B. J. Mangan, J. C. Knight, T. A. Birks, P. St. J. Russell, P. J. Roberts, and D. C. Allan, “Single-Mode Photonic Band Gap Guidance of Light in Air,” Science285, 1537–1539 (1999).
[CrossRef] [PubMed]

Sahakian, A. V.

A. Heifetz, S. C. Kong, A. V. Sahakian, A. Taflove, and V. Backman, “Photonic Nanojets,” J. Comput. Theor. Nanosci.6, 1979–1992 (2009).
[CrossRef] [PubMed]

Scalora, M.

Scharrer, M.

Schulze, H. G.

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EPL

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Figures (5)

Fig. 1
Fig. 1

(a) Scanning electron micrograph of the Kagome-lattice HC-PCF. (b) Transmission losses. The red line indicates the 633 nm wavelength used for excitation and the orange shaded region is the spectral range used for fluorescence collection.(c) Luminescence background spectrum (red) with maximum 11 mW input power and 10 s integration time. The black line is the background noise of the spectrometer. (d) Experimental setup. (e) Computed electric field intensity with a 20 μm polystyrene sphere illuminated by the fundamental Gaussian-shaped fiber mode at λ = 633 nm. (f) Horizontal cut at the best focus plane. (g) Vertical cut along the microsphere center.

Fig. 2
Fig. 2

Fluorescence intensity time trace (a) and correlation function (b) obtained with the HC-PCF and the 20 μm sphere (excitation power 750 μW at the fiber input). The curves in (c) and (d) are for a conventional confocal microscope with a 63x 1.2NA water-immersion objective (excitation power 40 μW). Black lines in (b), (d) are numerical fits using Eq. (1). For both cases, the Alexa Fluor 647 concentration is 3 nM.

Fig. 3
Fig. 3

(a) Number of molecules in the FCS detection volume versus the molecular concentration. The inset shows the corresponding fluorescence correlation functions. (b) Fluorescence count rate computed back to per molecule (red) and background noise (gray) versus the excitation power.

Fig. 4
Fig. 4

Fluorescence correlation functions for the cellular protein Annexin A5b labelled with Cyanine-5 obtained with the HC-PCF-microsphere (a) and the 1.2NA objective (b). the dashed lines are the reference correlation functions for the Alexa Fluor 647 free dye. For all cases, the dye concentration is 13.6 nM.

Fig. 5
Fig. 5

(a) Experimental setup with the HC-PCF combined with a 10x 0.3NA objective and a 2 μm diameter polystyrene microsphere. The inset shows the electric field intensity computed for a 2 μm polystyrene sphere set at the focus of the 0.3NA objective. (b) Fluorescence intensity time trace and correlation function (c) obtained with the HC-PCF (excitation power 500 μW at the fiber input). The curves in (d) and (e) are for a conventional confocal microscope with a 63x 1.2NA water-immersion objective (excitation power 40 μW). For both cases, the Alexa Fluor 647 concentration is 30 nM.

Equations (1)

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g ( 2 ) ( τ ) = 1 + 1 N ( 1 B F ) 2 [ 1 + n T exp ( τ τ T ) ] 1 ( 1 + τ / τ d ) 1 + s 2 τ / τ d

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