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 Optical Society of America

1. Introduction

Optical fiber probes offer exciting opportunities to broaden the application range of fluorescence spectroscopy to conditions where conventional optical microscopy cannot be used [14]. Up to date, the large luminescence background generated in the silica cores of conventional fibers has been a severe limit to the detection sensitivity [5]. To circumvent this issue, one approach restricts the fluorescent probes to bright sources such as fluorescent nanospheres of at least 24 nm in diameter [68]. Another approach works only at fluorophore concentrations larger than 500 nM to guarantee that several hundreds of fluorescent molecules contribute to the detected signal [9, 10]. Detecting a single fluorescent molecule at concentrations down to a few nanomolars with an optical fiber probe remains a challenge [11].

Here, we demonstrate that it is possible to detect and analyze single fluorescent molecules in solution with concentrations down to the nanomolar range using a hollow-core photonic crystal fiber (HC-PCF) probe. HC-PCF guide the light in an air core, with only a small fraction of the light penetrating into the glass [12, 13]. Hence, the luminescence background generated in the HC-PCF can be reduced by about two orders of magnitude compared to conventional silica fibers [1416]. The large mode size and low numerical aperture of the HC-PCF command the use of an objective coupler lens to efficiently excite and collect the fluorescence from the sample. Here, we use a 20 μm polystyrene microsphere set at the HC-PCF end-face. Recently, it was demonstrated that a micron-scale dielectric sphere with a refractive index of approximately 1.6 can focus light in a beam of subwavelength transverse dimensions and low divergence termed “photonic nanojet” [1719]. Dielectric microspheres offer attractive solutions for designing focusing devices with excellent optical properties and compactness at minimal costs [9, 2023].

To analyze the fluorescence signal, we implement fluorescence correlation spectroscopy (FCS), which is a versatile and widely used method for the characterization of fluorescent probes [24, 25]. FCS analyzes the temporal correlation of the fluorescence intensity fluctuations, and provides information about any molecular process inducing a change in the fluorescence intensity. Applications go much beyond fluorescence detection based on photon counts levels, and include determining translational and rotational diffusion, molecular concentrations, chemical kinetics, and binding reactions.

2. Materials and methods

2.1. Hollow-core photonic crystal fiber

The large-pitch Kagome-lattice fiber is fabricated using the conventional stack-and-draw technique [13]. Figure 1(a) shows a scanning electron micrograph of its end-face. Its transmission spectrum, measured by the cutback technique, is shown on Fig. 1(b) together with the 633 nm laser line and the 650–690 nm spectral region used for fluorescence collection. The background luminescence spectrum, acquired by a spectrometer with a Peltier-cooled CCD camera (Horiba Jobin Yvon iHR320), is shown on Fig. 1(c). The background luminescence intensity measured by the avalanche photodiode in the normal conditions for FCS experiments (Fig. 1(d)) typically amounts to 1.2 kHz for 750 μW excitation power at the fiber input.

 

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.

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2.2. Polystyrene microsphere as focusing lens

Numerical modelling is based on the finite-difference time-domain FDTD method using the commercial software Rsoft Fullwave version 6.0. The model considers mesh sizes of 20 nm and 50 nm along the horizontal and vertical directions, respectively, and perfect matched layers boundary conditions on all faces. The 20 μm sphere has a refractive index of 1.59, while the surrounding medium is water (refractive index 1.33). The sphere is illuminated by a Gaussian-shaped beam at λ = 633 nm with 14 μm transverse waist, corresponding to the HC-PCF fundamental mode. Figure 1(e) shows the computed electric field intensity. The focusing ability of the sphere is quantified from Fig. 1(f) and (g) to transverse and axial FWHMs of 560 nm and 6.5 μm respectively. This corresponds to what can be achieved with a water-immersion objective of 0.6 NA.

2.3. Experimental setup

Alexa Fluor 647 (Invitrogen, Carlsbad, CA), a common dye for FCS with absorption / emission maxima at 650 and 670 nm, is used as fluorescent probe. The excitation beam is provided by a linearly polarized CW He-Ne laser operating at 633 nm, and is coupled into the 1.5 m long HC-PCF by a 150 mm lens, matching the 0.02 NA of the HC-PCF. The total transmission of the HC-PCF, including coupling and transmission losses, is about 60%. To avoid filling the HC-PCF with the fluorescent liquid, a standard microscope coverslip (thickness 140 μm) is set in contact with the fiber end-face (Fig. 1(d)). The same glass coverslip holds the polystyrene microsphere, which is centered respective to the HC-PCF core with the help of a micrometer driven three-axis translation stage under visual control with an optical microscope equipped with 10x objective. The microsphere used for laser focusing also collects the fluorescence light and couples it into the HC-PCF, where both laser and fluorescence beams are counter-propagating. We use a dichroic mirror (Omega Filters 650DRLP), a long-pass filter (Omega Filters 640AELP) and a bandpass filter (Omega Filters 670DF40) to separate the fluorescence light from the reflected and elastically scattered laser light. A 20 μm pinhole is conjugated to the fiber output with a 1:1 magnification to spatially filter the HC-PCF mode carrying the fluorescence light. The fluorescence signal is finally detected by an avalanche photodiode (Perkin-Elmer SPCM-AQR-13). To perform FCS, the fluorescence intensity temporal fluctuations are analyzed by computing the temporal correlation of the APD signal with a Flex-02C hardware correlator (Correlator.com). Each FCS measurement is the average of 10 runs of 10 s duration.

2.4. FCS analysis

As for earlier work [9, 22], analysis of the FCS data is based on the analytical model established for Brownian three-dimensional diffusion in the case of a Gaussian molecular detection efficiency [24, 25]:

g(2)(τ)=1+1N(1BF)2[1+nTexp(ττT)]1(1+τ/τd)1+s2τ/τd
where N is the average number of molecules, F the total signal, B the background noise, nT the amplitude of the dark state population, τT the dark state blinking time, τd the mean (transverse) diffusion time and s the ratio of transversal to axial dimensions of the analysis volume, fixed to s = 0.2. Lastly, we compute the fluorescence count rates back to per molecule CRM = (FB)/N.

3. Experimental results with a 20 μm sphere

Figure 2(a) and (b) show the fluorescence time trace and correlation function obtained while dipping the HC-PCF-microsphere probe into the Alexa Fluor 647 solution at 3 nM concentration. We stress that no temporal correlation was found in the absence of the microsphere; this highlights the crucial role of the microsphere as focusing element to confine the excitation beam and collect the fluorescence light. Thanks to the fiber hollow core, the background noise in Fig. 2(a) amounts to only 1.2 kHz, which is more than 40x lower than the fluorescence intensity at 3 nM concentration and appears almost negligible. Earlier work with a microsphere attached to a silica fiber probe [9] reported for background noise of 270 kHz, which was at the same level as the detected fluorescence signal at a much higher 500 nM concentration.

 

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.

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To compare the performance of the HC-PCF-microsphere probe to conventional microscope objectives, Fig. 2(c) and (d) show the fluorescence time trace and correlation function obtained with a 1.2 NA planapochromat objective. The results of the FCS fits according to Eq. (1) are indicated in Fig. 2(b) and (d) respectively. About 10 molecules are detected on average with the HC-PCF-microsphere probe at 3 nM dye concentration, this is 11x larger than the number of molecules detected with the 1.2 NA objective and relate to the larger focal volume with the HC-PCF-microsphere probe. Accordingly, the diffusion time is larger with the HC-PCF-microsphere (225 μs) than with the 1.2 NA objective (64 μs). Given the calibrated translational diffusion coefficient D = 3.0×10−6 cm2/s for Alexa Fluor 647 at 21°C [26, 27] and the relation τd = w2/4D, a transverse waist of w = 520 nm is inferred for the HC-PCF-microsphere probe; this stands in good agreement with the numerical simulations shown in Fig. 1(e) and (f) and further confirms the focusing properties of the 20 μm polystyrene sphere.

Figure 3(a) shows the linear evolution of the total number of molecules detected with the HC-PCF-microsphere versus the concentration of fluorescent dye. Remarkably, experiments could be conducted down to 0.4 nM, which is 1000x lower than with the previous system [9]. From the slope in Fig. 3(a), we quantify the analysis volume to 6.0 fL. Figure 3(b) presents the fluorescence count rates computed back to per molecule for different excitation powers. A transition to fluorescence saturation occurs for excitation powers higher than 1 mW at the fiber input (focal spot intensity 70 kW/cm2). The background noise from the fiber remains remarkably below 2 kHz, even at high excitation powers. At 750 μW excitation power, the average count rate CRM for a single molecule is about 4x higher than the total background noise. This allows for routine detection of single molecule in solution with the HC-PCF-microsphere probe. Please note the background noise in Fig. 3(b) also includes the APD dark counts of 480 counts/s. Further reduction of this noise could be obtained by selecting a photodiode with lower dark counts and/or time gating the photodetection events.

 

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.

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One of the main interest of FCS is to distinguish between different fluorescent molecules based on their diffusion properties, which are directly related to their molecular weight and hydrodynamic radius. As a proof-of-principle, we investigate the detection of the cellular protein Annexin A5b labelled with the Cyanine Cy5 fluorescent dye. Annexin A5b is a 36 kDa phospholipid-binding protein and has a high affinity to phospholipid phosphatidylserine in the presence of physiological concentrations of calcium [28]. Figure 4(a) and (b) show the fluorescence correlation functions obtained with the HC-PCF-microsphere and the 1.2NA objective, respectively. As compared to the Alexa Fluor 647 free dye (dashed lines), the diffusion time τd is shifted from 225 μs to 910 μs for the A5B-Cy5 labelled protein measured by the HC-PCF-microsphere. A similar ∼ 4× increase in the diffusion time is observed with the 1.2NA objective, confirming the results with the HC-PCF probe. Translating these results into hydrodynamic radii, we find an hydrodynamic radius of 2.8 nm for A5B-Cy5, while the hydrodynamic radius of Alexa Fluor 647 is 0.7 nm. These results demonstrate that the HC-PCF-microsphere probe can be readily used to distinguish between molecules of similar fluorescence spectra based on the FCS analysis of their translational diffusion properties.

 

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.

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4. Matching the HC-PCF numerical aperture

To further improve the system sensitivity, the fluorescence signal per molecule should be increased by tighter focusing the excitation light and better collecting the fluorescence radiation. This could be conveniently done by reducing the microsphere diameter [20]. However, experiments using 2 μm microspheres instead of 20 μm were a failure, as no correlation functions could be obtained. This can be explained as the fluorescence beam exiting the 2 μm microsphere has necessarily a diameter of d = 2 μm, which sets an angular divergence limited by diffraction of θ ≈ 2λ/πd ≈ 0.2. For efficient collection of the fluorescence beam by the HC-PCF, the angular divergence θ has to match the fiber numerical aperture. However, because of the large core and single-defect design, the Kagome-lattice HC-PCF used here has a numerical aperture of only 0.02, which is about 10x lower than the angular divergence θ emerging from a 2 μm microsphere and results in improper collection of the fluorescence signal by the HC-PCF.

Some relay optics need to be inserted in order to match the HC-PCF numerical aperture (0.02) to the angular divergence (0.2) of the fluorescence beam exiting the 2 μm microsphere. This can be elegantly done by a microscope objective of 10x magnification (the angular magnification being the inverse of the lateral magnification). The experimental setup is pictured in Fig. 5(a). With this configuration, the results found with the HC-PCF and the 2 μm microsphere (Fig. 5(b) and (c)) indicate a 0.8 fL detection volume, short diffusion times and high count rates. The performance of this configuration is comparable to that of a conventional confocal microscope (Fig. 5(d) and (e)), while preserving the property of foldable light path. However, since the relay optics introduce some complexity in the optical alignment of the probe, we believe the simple configuration with the 20 μm sphere is more relevant for practical applications. The experiment in Fig. 5 is rather an exploration of the influence of the HC-PCF numerical aperture and of the best performance that could be reached without considering optical complexity.

 

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.

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5. Conclusion

Hollow-core photonic crystal fiber probes offer reduced luminescence background as compared to conventional glass fibers. The combination of the HC-PCF with a polystyrene microsphere realizes a new probe for remote fluorescence sensing with single molecule sensitivity down to nanomolar concentrations. As compared to earlier work [9], the HC-PCF probe enables a 200x improvement of the signal-to-noise ratio for a single molecule detection event, and a 1000x reduction of the minimum detectable concentration with FCS. Further improvement of the detection sensitivity can be obtained by selecting photodiodes with lower dark counts and time gating the photodetection events [11].

Realizing portable single molecule fluorescence sensing devices is of great interest due to the widespread popularity of molecular-fluorescence-based measurements in fields such as chemistry, molecular biology, materials science, and medicine. Portable systems for fluorescence analysis with similar sensitivity as conventional microscope can be foreseen, with applications for instance in early diagnosis of Alzheimer’s disease [29], oxygen sensing [30], temperature sensing [31] or molecular sorting [32]. This system could also be extended to laser contact surgery [23] or optical transfection [33].

Acknowledgments

The authors acknowledge Nicolas Y. Joly and Philip St. J. Russell for stimulating discussions and providing the HC-PCF, and Alain Brisson for providing the Annexin sample. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) / ERC Grant agreements 278242 (ExtendFRET) and the Provence-Alpes-Côte d’Azur Region. PG is on leave from Institute for Space Sciences, Bucharest-Măgurele RO-077125, Romania.

References and links

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

2. 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]  

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

4. O. S. Wolfbeis, “Fiber-optic chemical sensors and biosensors,” Anal. Chem. 78, 3859–3873 (2006). [CrossRef]   [PubMed]  

5. J. Ma and Y.-S. Li, “Fiber Raman background study and its application in setting up optical fiber Raman probes,” Appl. Opt. 35, 2527–2533 (1996). [CrossRef]   [PubMed]  

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

7. 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]  

8. Y.-C. Chang, J. Y. Ye, T. Thomas, Y. Chen, J. R. Baker, and T. B. Norris, “Two-photon fluorescence correlation spectroscopy through dual-clad optical fiber,” Opt. Express 16, 12640–12649 (2008). [CrossRef]   [PubMed]  

9. H. Aouani, F. Deiss, J. Wenger, P. Ferrand, N. Sojic, and H. Rigneault, “Optical-fiber-microsphere for remote fluorescence correlation spectroscopy,” Opt. Express 17, 19085–19092 (2009). [CrossRef]  

10. 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]  

11. 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]  

12. 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,” Science 285, 1537–1539 (1999). [CrossRef]   [PubMed]  

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

14. 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]  

15. S. O. Konorov, A. Zheltikov, and M. Scalora, “Photonic-crystal fiber as a multifunctional optical sensor and sample collector,” Opt. Express 13, 3454–3459 (2005). [CrossRef]   [PubMed]  

16. S. O. Konorov, C. J. Addison, H. G. Schulze, R. F. B. Turner, and M. W. Blades, “Hollow-core photonic crystal fiber-optic probes for Raman spectroscopy,” Opt. Lett. 31, 1911–1913 (2006). [CrossRef]   [PubMed]  

17. Z. Chen, A. Taflove, and V. Backman, “Photonic nanojet enhancement of backscattering of light by nanoparticles: a potential novel visible-light ultramicroscopy technique,” Opt. Express 12, 1214–1220 (2004). [CrossRef]   [PubMed]  

18. X. Li, Z. Chen, A. Taflove, and V. Backman, “Optical analysis of nanoparticles via enhanced backscattering facilitated by 3-D photonic nanojets,” Opt. Express 13, 526–533 (2005). [CrossRef]   [PubMed]  

19. P. Ferrand, J. Wenger, M. Pianta, H. Rigneault, A. Devilez, B. Stout, N. Bonod, and E. Popov, “Direct imaging of photonic nanojets,” Opt. Express 16, 6930–6940 (2008). [CrossRef]   [PubMed]  

20. 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]  

21. D. Gérard, J. Wenger, A. Devilez, D. Gachet, B. Stout, N. Bonod, E. Popov, and H. Rigneault, “Strong electromagnetic confinement near dielectric microspheres to enhance single-molecule fluorescence,” Opt. Express 16, 15297–15303 (2008). [CrossRef]   [PubMed]  

22. 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]  

23. 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. Express 19, 3440–3448 (2011). [CrossRef]   [PubMed]  

24. 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]  

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

26. 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,” EPL 83, 46001 (2008). [CrossRef]  

27. P. Kapusta, “Absolute diffusion coefficients: compilation of reference data for FCS calibration,” http://www.picoquant.com/technotes/appnotediffusioncoefficients.pdf

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

29. 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 Medicine 4, 832–834 (1998). [CrossRef]   [PubMed]  

30. 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 B 96, 460–467 (2003). [CrossRef]  

31. 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]  

32. J. Wenger, D. Gérard, P.-F. Lenne, H. Rigneault, J. Dintinger, T. W. Ebbesen, A. Boned, F. Conchonaud, and D. Marguet, “Dual-color fluorescence cross-correlation spectroscopy in a single nanoaperture : towards rapid multicomponent screening at high concentrations,” Opt. Express 14, 12206–12216 (2006). [CrossRef]   [PubMed]  

33. 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. Express 1, 694–705 (2010). [CrossRef]  

References

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  1. F. Helmchen, “Miniaturization of fluorescence microscopes using fibre optics,” Exp. Physiol. 87, 737–745 (2002).
    [Crossref] [PubMed]
  2. 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]
  3. U. Utzinger and R. R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
    [Crossref] [PubMed]
  4. O. S. Wolfbeis, “Fiber-optic chemical sensors and biosensors,” Anal. Chem. 78, 3859–3873 (2006).
    [Crossref] [PubMed]
  5. J. Ma and Y.-S. Li, “Fiber Raman background study and its application in setting up optical fiber Raman probes,” Appl. Opt. 35, 2527–2533 (1996).
    [Crossref] [PubMed]
  6. K. Garai, M. Muralidhar, and S. Maiti, “Fiber-optic fluorescence correlation spectrometer,” Appl. Opt. 45, 7538–7542 (2006).
    [Crossref] [PubMed]
  7. 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]
  8. Y.-C. Chang, J. Y. Ye, T. Thomas, Y. Chen, J. R. Baker, and T. B. Norris, “Two-photon fluorescence correlation spectroscopy through dual-clad optical fiber,” Opt. Express 16, 12640–12649 (2008).
    [Crossref] [PubMed]
  9. H. Aouani, F. Deiss, J. Wenger, P. Ferrand, N. Sojic, and H. Rigneault, “Optical-fiber-microsphere for remote fluorescence correlation spectroscopy,” Opt. Express 17, 19085–19092 (2009).
    [Crossref]
  10. 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]
  11. 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]
  12. 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,” Science 285, 1537–1539 (1999).
    [Crossref] [PubMed]
  13. P. St. J. Russell, “Photonic crystal fibers,” J. Ligthwave Technol. 24, 4729–4749 (2006).
    [Crossref]
  14. 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]
  15. S. O. Konorov, A. Zheltikov, and M. Scalora, “Photonic-crystal fiber as a multifunctional optical sensor and sample collector,” Opt. Express 13, 3454–3459 (2005).
    [Crossref] [PubMed]
  16. S. O. Konorov, C. J. Addison, H. G. Schulze, R. F. B. Turner, and M. W. Blades, “Hollow-core photonic crystal fiber-optic probes for Raman spectroscopy,” Opt. Lett. 31, 1911–1913 (2006).
    [Crossref] [PubMed]
  17. Z. Chen, A. Taflove, and V. Backman, “Photonic nanojet enhancement of backscattering of light by nanoparticles: a potential novel visible-light ultramicroscopy technique,” Opt. Express 12, 1214–1220 (2004).
    [Crossref] [PubMed]
  18. X. Li, Z. Chen, A. Taflove, and V. Backman, “Optical analysis of nanoparticles via enhanced backscattering facilitated by 3-D photonic nanojets,” Opt. Express 13, 526–533 (2005).
    [Crossref] [PubMed]
  19. P. Ferrand, J. Wenger, M. Pianta, H. Rigneault, A. Devilez, B. Stout, N. Bonod, and E. Popov, “Direct imaging of photonic nanojets,” Opt. Express 16, 6930–6940 (2008).
    [Crossref] [PubMed]
  20. 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]
  21. D. Gérard, J. Wenger, A. Devilez, D. Gachet, B. Stout, N. Bonod, E. Popov, and H. Rigneault, “Strong electromagnetic confinement near dielectric microspheres to enhance single-molecule fluorescence,” Opt. Express 16, 15297–15303 (2008).
    [Crossref] [PubMed]
  22. 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]
  23. 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. Express 19, 3440–3448 (2011).
    [Crossref] [PubMed]
  24. 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]
  25. E. Haustein and P. Schwille, “Single-molecule spectroscopic methods,” Curr. Opinion Struct. Biol. 14, 531–540 (2004).
    [Crossref]
  26. 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,” EPL 83, 46001 (2008).
    [Crossref]
  27. P. Kapusta, “Absolute diffusion coefficients: compilation of reference data for FCS calibration,” http://www.picoquant.com/technotes/appnotediffusioncoefficients.pdf
  28. V. Gerke and S. E. Moss, “Annexins: from structure to function,” Physiol. Rev. 82, 331–371 (2002).
    [PubMed]
  29. 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 Medicine 4, 832–834 (1998).
    [Crossref] [PubMed]
  30. 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 B 96, 460–467 (2003).
    [Crossref]
  31. 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]
  32. J. Wenger, D. Gérard, P.-F. Lenne, H. Rigneault, J. Dintinger, T. W. Ebbesen, A. Boned, F. Conchonaud, and D. Marguet, “Dual-color fluorescence cross-correlation spectroscopy in a single nanoaperture : towards rapid multicomponent screening at high concentrations,” Opt. Express 14, 12206–12216 (2006).
    [Crossref] [PubMed]
  33. 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. Express 1, 694–705 (2010).
    [Crossref]

2012 (1)

2011 (2)

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. Express 19, 3440–3448 (2011).
[Crossref] [PubMed]

2010 (2)

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. Express 1, 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 (2)

2008 (5)

2007 (2)

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 (5)

2005 (2)

2004 (2)

2003 (3)

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 B 96, 460–467 (2003).
[Crossref]

2002 (2)

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 (1)

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,” Science 285, 1537–1539 (1999).
[Crossref] [PubMed]

1998 (1)

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 Medicine 4, 832–834 (1998).
[Crossref] [PubMed]

1997 (1)

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 (1)

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,” Science 285, 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. Express 17, 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,” Science 285, 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,” Science 285, 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,” EPL 83, 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 Medicine 4, 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,” Science 285, 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,” EPL 83, 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,” EPL 83, 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,” Science 285, 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,” EPL 83, 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 B 96, 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 B 96, 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,” EPL 83, 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 Medicine 4, 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 Medicine 4, 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,” EPL 83, 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 Medicine 4, 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,” Science 285, 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 B 96, 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,” Science 285, 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.

Schwille, P.

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

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 B 96, 460–467 (2003).
[Crossref]

Singh, N. K.

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]

Sojic, N.

Sreenivasan, V. K. A.

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]

Stevenson, D. J.

Stout, B.

Sureka, R.

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]

Taflove, A.

Then, 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]

Thomas, T.

Turner, R. F. B.

Utzinger, U.

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

Walt, D. 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]

Webb, W. W.

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]

Wenger, J.

Wild, A.

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]

Willbold, D.

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,” EPL 83, 46001 (2008).
[Crossref]

Wolfbeis, O. S.

O. S. Wolfbeis, “Fiber-optic chemical sensors and biosensors,” Anal. Chem. 78, 3859–3873 (2006).
[Crossref] [PubMed]

Wong, F. H. 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]

Ye, J. Y.

Ying, H. S.

Zheltikov, A.

Zorman, S.

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]

Anal. Chem. (3)

O. S. Wolfbeis, “Fiber-optic chemical sensors and biosensors,” Anal. Chem. 78, 3859–3873 (2006).
[Crossref] [PubMed]

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]

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]

Appl. Opt. (2)

Biomed. Opt. Express (1)

Biophys. J. (1)

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]

Chem. Soc. Rev. (1)

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]

Curr. Opinion Struct. Biol. (1)

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

EPL (1)

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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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