Abstract

Fluorescence and phosphorescence lifetime imaging are powerful techniques for studying intracellular protein interactions and for diagnosing tissue pathophysiology. While lifetime-resolved microscopy has long been in the repertoire of the biophotonics community, current implementations fall short in terms of simultaneously providing 3D resolution, high throughput, and good tissue penetration. This report describes a new highly efficient lifetime-resolved imaging method that combines temporal focusing wide-field multiphoton excitation and simultaneous acquisition of lifetime information in frequency domain using a nanosecond gated imager from a 3D-resolved plane. This approach is scalable allowing fast volumetric imaging limited only by the available laser peak power. The accuracy and performance of the proposed method is demonstrated in several imaging studies important for understanding peripheral nerve regeneration processes. Most importantly, the parallelism of this approach may enhance the imaging speed of long lifetime processes such as phosphorescence by several orders of magnitude.

© 2012 OSA

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2012

L. C. Cheng, C. Y. Chang, C. Y. Lin, K. C. Cho, W. C. Yen, N. S. Chang, C. Xu, C. Y. Dong, and S. J. Chen, “Spatiotemporal focusing-based widefield multiphoton microscopy for fast optical sectioning,” Opt. Express20(8), 8939–8948 (2012).
[CrossRef] [PubMed]

E. C. Soller, D. S. Tzeranis, K. Miu, P. T. So, and I. V. Yannas, “Common features of optimal collagen scaffolds that disrupt wound contraction and enhance regeneration both in peripheral nerves and in skin,” Biomaterials33(19), 4783–4791 (2012).
[CrossRef] [PubMed]

2011

2010

S. Sakadzić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

2009

E. Dimitrow, I. Riemann, A. Ehlers, M. J. Koehler, J. Norgauer, P. Elsner, K. König, and M. Kaatz, “Spectral fluorescence lifetime detection and selective melanin imaging by multiphoton laser tomography for melanoma diagnosis,” Exp. Dermatol.18(6), 509–515 (2009).
[CrossRef] [PubMed]

N. A. A. Rahim, W. McDaniel, K. Bardon, S. Srinivas, V. Vickerman, P. T. C. So, and J. H. Moon, “Conjugated polymer nanoparticles for two-photon imaging of endothelial cells in a tissue model,” Adv. Mater. (Deerfield Beach Fla.)21(34), 3492–3496 (2009).
[CrossRef]

D. Sud and M. A. Mycek, “Calibration and validation of an optical sensor for intracellular oxygen measurements,” J. Biomed. Opt.14(2), 020506 (2009).
[CrossRef] [PubMed]

2008

P. Walczysko, U. Kuhlicke, S. Knappe, C. Cordes, and T. R. Neu, “In situ activity of suspended and immobilized microbial communities as measured by fluorescence lifetime imaging,” Appl. Environ. Microbiol.74(1), 294–299 (2008).
[CrossRef] [PubMed]

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J.94(2), L14–L16 (2008).
[CrossRef] [PubMed]

J. McGinty, K. B. Tahir, R. Laine, C. B. Talbot, C. Dunsby, M. A. Neil, L. Quintana, J. Swoger, J. Sharpe, and P. M. French, “Fluorescence lifetime optical projection tomography,” J Biophotonics1(5), 390–394 (2008).
[CrossRef] [PubMed]

2007

D. M. Owen, E. Auksorius, H. B. Manning, C. B. Talbot, P. A. de Beule, C. Dunsby, M. A. Neil, and P. M. French, “Excitation-resolved hyperspectral fluorescence lifetime imaging using a UV-extended supercontinuum source,” Opt. Lett.32(23), 3408–3410 (2007).
[CrossRef] [PubMed]

S. Kumar, C. Dunsby, P. A. De Beule, D. M. Owen, U. Anand, P. M. Lanigan, R. K. Benninger, D. M. Davis, M. A. Neil, P. Anand, C. Benham, A. Naylor, and P. M. French, “Multifocal multiphoton excitation and time correlated single photon counting detection for 3-D fluorescence lifetime imaging,” Opt. Express15(20), 12548–12561 (2007).
[CrossRef] [PubMed]

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech.70(5), 398–402 (2007).
[CrossRef] [PubMed]

G. Mehta, K. Mehta, D. Sud, J. W. Song, T. Bersano-Begey, N. Futai, Y. S. Heo, M. A. Mycek, J. J. Linderman, and S. Takayama, “Quantitative measurement and control of oxygen levels in microfluidic poly(dimethylsiloxane) bioreactors during cell culture,” Biomed. Microdevices9(2), 123–134 (2007).
[CrossRef] [PubMed]

2006

D. Sud, G. Mehta, K. Mehta, J. Linderman, S. Takayama, and M. A. Mycek, “Optical imaging in microfluidic bioreactors enables oxygen monitoring for continuous cell culture,” J. Biomed. Opt.11(5), 050504 (2006).
[CrossRef] [PubMed]

D. Sud, W. Zhong, D. G. Beer, and M. A. Mycek, “Time-resolved optical imaging provides a molecular snapshot of altered metabolic function in living human cancer cell models,” Opt. Express14(10), 4412–4426 (2006).
[CrossRef] [PubMed]

2005

A. Nagy, J. Wu, and K. M. Berland, “Observation volumes and gamma-factors in two-photon fluorescence fluctuation spectroscopy,” Biophys. J.89(3), 2077–2090 (2005).
[CrossRef] [PubMed]

L. S. Ziemer, W. M. Lee, S. A. Vinogradov, C. Sehgal, and D. F. Wilson, “Oxygen distribution in murine tumors: characterization using oxygen-dependent quenching of phosphorescence,” J. Appl. Physiol.98(4), 1503–1510 (2005).
[CrossRef] [PubMed]

G. I. Redford and R. M. Clegg, “Polar plot representation for frequency-domain analysis of fluorescence lifetimes,” J. Fluoresc.15(5), 805–815 (2005).
[CrossRef] [PubMed]

D. M. Grant, D. S. Elson, D. Schimpf, C. Dunsby, J. Requejo-Isidro, E. Auksorius, I. Munro, M. A. Neil, P. M. French, E. Nye, G. Stamp, and P. Courtney, “Optically sectioned fluorescence lifetime imaging using a Nipkow disk microscope and a tunable ultrafast continuum excitation source,” Opt. Lett.30(24), 3353–3355 (2005).
[CrossRef] [PubMed]

2004

K. Suhling, J. Siegel, P. M. Lanigan, S. Lévêque-Fort, S. E. Webb, D. Phillips, D. M. Davis, and P. M. French, “Time-resolved fluorescence anisotropy imaging applied to live cells,” Opt. Lett.29(6), 584–586 (2004).
[CrossRef] [PubMed]

J. Requejo-Isidro, J. McGinty, I. Munro, D. S. Elson, N. P. Galletly, M. J. Lever, M. A. Neil, G. W. Stamp, P. M. French, P. A. Kellett, J. D. Hares, and A. K. Dymoke-Bradshaw, “High-speed wide-field time-gated endoscopic fluorescence-lifetime imaging,” Opt. Lett.29(19), 2249–2251 (2004).
[CrossRef] [PubMed]

M. Weinmann, C. Belka, and L. Plasswilm, “Tumour hypoxia: impact on biology, prognosis and treatment of solid malignant tumours,” Onkologie27(1), 83–90 (2004).
[CrossRef] [PubMed]

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

S. Pelet, M. J. Previte, L. H. Laiho, and P. T. So, “A fast global fitting algorithm for fluorescence lifetime imaging microscopy based on image segmentation,” Biophys. J.87(4), 2807–2817 (2004).
[CrossRef] [PubMed]

2003

E. Gratton, S. Breusegem, J. Sutin, Q. Ruan, and N. Barry, “Fluorescence lifetime imaging for the two-photon microscope: time-domain and frequency-domain methods,” J. Biomed. Opt.8(3), 381–390 (2003).
[CrossRef] [PubMed]

S. M. Evans and C. J. Koch, “Prognostic significance of tumor oxygenation in humans,” Cancer Lett.195(1), 1–16 (2003).
[CrossRef] [PubMed]

M. I. Koukourakis, A. Giatromanolaki, R. A. Brekken, E. Sivridis, K. C. Gatter, A. L. Harris, and E. H. Sage, “Enhanced expression of SPARC/osteonectin in the tumor-associated stroma of non-small cell lung cancer is correlated with markers of hypoxia/acidity and with poor prognosis of patients,” Cancer Res.63(17), 5376–5380 (2003).
[PubMed]

X. Zhuang and M. Rief, “Single-molecule folding,” Curr. Opin. Struct. Biol.13(1), 88–97 (2003).
[CrossRef] [PubMed]

2002

A. L. Harris, “Hypoxia--a key regulatory factor in tumour growth,” Nat. Rev. Cancer2(1), 38–47 (2002).
[CrossRef] [PubMed]

J. M. Brown, “Tumor microenvironment and the response to anticancer therapy,” Cancer Biol. Ther.1(5), 448–458 (2002).
[CrossRef] [PubMed]

2000

E. K. Rofstad, “Microenvironment-induced cancer metastasis,” Int. J. Radiat. Biol.76(5), 589–605 (2000).
[CrossRef] [PubMed]

A. A. Deniz, T. A. Laurence, G. S. Beligere, M. Dahan, A. B. Martin, D. S. Chemla, P. E. Dawson, P. G. Schultz, and S. Weiss, “Single-molecule protein folding: diffusion fluorescence resonance energy transfer studies of the denaturation of chymotrypsin inhibitor 2,” Proc. Natl. Acad. Sci. U.S.A.97(10), 5179–5184 (2000).
[CrossRef] [PubMed]

1999

H. C. Gerritsen, J. M. Vroom, and C. J. de Grauw, “Combining two-photon excitation with fluorescence lifetime imaging,” IEEE Eng. Med. Biol. Mag.18(5), 31–36 (1999).
[CrossRef] [PubMed]

D. Magde, G. E. Rojas, and P. G. Seybold, “Solvent dependence of the fluorescence lifetimes of xanthene dyes,” Photochem. Photobiol.70(5), 737–744 (1999).
[CrossRef]

1998

J. M. Brown and A. J. Giaccia, “The unique physiology of solid tumors: opportunities (and problems) for cancer therapy,” Cancer Res.58(7), 1408–1416 (1998).
[PubMed]

L. J. Chamberlain, I. V. Yannas, H. P. Hsu, G. Strichartz, and M. Spector, “Collagen-GAG substrate enhances the quality of nerve regeneration through collagen tubes up to level of autograft,” Exp. Neurol.154(2), 315–329 (1998).
[CrossRef] [PubMed]

1997

G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, “Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation,” Nat. Med.3(2), 177–182 (1997).
[CrossRef] [PubMed]

1996

I. Gryczynski, A. Razynska, and J. R. Lakowicz, “Two-photon induced fluorescence of linear alkanes; a possible intrinsic lipid probe,” Biophys. Chem.57(2-3), 291–295 (1996).
[CrossRef] [PubMed]

K. König, P. T. So, W. W. Mantulin, B. J. Tromberg, and E. Gratton, “Two-photon excited lifetime imaging of autofluorescence in cells during UVA and NIR photostress,” J. Microsc.183(Pt 3), 197–204 (1996).
[PubMed]

J. R. Lakowicz, “Emerging applications of fluorescence spectroscopy to cellular imaging: lifetime imaging, metal-ligand probes, multi-photon excitation and light quenching,” Scanning Microsc. Suppl.10, 213–224 (1996).
[PubMed]

1994

I. P. Torres Filho, M. Leunig, F. Yuan, M. Intaglietta, and R. K. Jain, “Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice,” Proc. Natl. Acad. Sci. U.S.A.91(6), 2081–2085 (1994).
[CrossRef] [PubMed]

1993

R. M. Clegg, A. I. Murchie, and D. M. Lilley, “The four-way DNA junction: a fluorescence resonance energy transfer study,” Braz. J. Med. Biol. Res.26(4), 405–416 (1993).
[PubMed]

1990

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

1989

P. I. Bastiaens, P. J. Bonants, F. Müller, and A. J. Visser, “Time-resolved fluorescence spectroscopy of NADPH-cytochrome P-450 reductase: demonstration of energy transfer between the two prosthetic groups,” Biochemistry28(21), 8416–8425 (1989).
[CrossRef] [PubMed]

I. F. Tannock and D. Rotin, “Acid pH in tumors and its potential for therapeutic exploitation,” Cancer Res.49(16), 4373–4384 (1989).
[PubMed]

1982

I. V. Yannas, J. F. Burke, D. P. Orgill, and E. M. Skrabut, “Wound tissue can utilize a polymeric template to synthesize a functional extension of skin,” Science215(4529), 174–176 (1982).
[CrossRef] [PubMed]

Anand, P.

Anand, U.

Arai, K.

S. Sakadzić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

Auksorius, E.

Bardon, K.

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Supplementary Material (4)

» Media 1: AVI (2009 KB)     
» Media 2: AVI (1671 KB)     
» Media 3: AVI (1414 KB)     
» Media 4: AVI (1390 KB)     

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Figures (11)

Fig. 1
Fig. 1

Temporal focusing wide-field (TFWF) FLIM/PLIM design. (a) Optical sub-system: temporal focusing widefield multiphoton microscopy, (b) Electronic sub-system: frequency domain lifetime measurement via heterodyne detection.

Fig. 2
Fig. 2

Demonstration of accurate measurement of fluorescence lifetime of Rhodamine B solutions in different solvents by TFWF FLIM. Fluorescence in water was used as a reference. (a) Tabulated results of estimated lifetime values of τ extracted from either phase (Ph) or modulation (Mod) measurements. Literature values are also included as a reference [33]. (b) Lifetime resolved data for each pixel from the fluorescein (FL) and rhodamine solution images shown in polar plot format.

Fig. 3
Fig. 3

(a) An intensity scaled mean lifetime image of fixed fibroblasts with vacuoles loaded with endocytosed conjugated polymer nanoparticles of high two-photon absorption cross section. Color scale represents pixel lifetime values corresponding to the color bar with units of seconds. Image brightness represents pixel intensity values. Black regions are ignored in analysis corresponding to locations with intensity below 500 photons that are mostly outside the boundary of this cell. (b) Representative polar plot of pixel lifetime values for 10 ms data acquisition time. (c) Tabulated mean lifetime values and their standard deviations are estimated from the modulation or the phase data for four different image acquisition rates.

Fig. 4
Fig. 4

Fluorescence lifetime imaging of an ex vivo histological sample by TFWF FLIM. (a) Intensity-scaled fluorescence lifetime-resolved image of a regenerated ex vivo rat sciatic nerve after injury stained with FluroMyelin Green. The image field of view is approximately 20 × 20 μm2 (a) and 100 × 100 μm2(c). Scale bar has units of seconds. (b) Polar plot representation of the pixel lifetime estimated based on the phase data. (c) A larger view of the same sample acquired using a point scanning two-photon microscope equipped with TCSPC lifetime resolved imaging system. The scale bar has unit of nanoseconds. The lifetime measurements for both systems are in excellent agreement.

Fig. 5
Fig. 5

Demonstration of fast 3D-resolved lifetime imaging by TFWF FLIM system. (a) Intensity scaled lifetime images of 15 μm yellow-green beads and 4 μm red beads imaged at different axial plane locations z. Pixel lifetimes were estimated from modulation data. The scale bar represents 5 μm in length. (b) Representative polar plot of pixel lifetime information at z = 15 μm.

Fig. 6
Fig. 6

Fluorescence lifetime imaging of human fibroblasts seeded inside a collagen scaffold double-stained with Calcein AM and Syto 13 by TFWF FLIM. (a) Intensity scaled lifetime images. (b) Polar plot of fibroblasts labeled only with Calcein AM. (c) Polar plot of fibroblasts labeled with both Calcein AM and Syto 13. (d) Polar plot of fibroblasts labeled only with Syto 13.

Fig. 7
Fig. 7

Fast measurement of partial oxygen pressure by TFWF phosphorescence lifetime imaging. (a) Polar plot of phosphorescence lifetime of 1 mM Tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate solutions equilibrated with 0, 4, 8, and 21% pO2 gas mixtures. Inverse phosphorescence lifetimes ((b), from modulation data; (c), from phase data) are plotted against O2 concentration demonstrating Stern-Volmer dependence with R2 values of 0.99 and 0.95 respectively for linear regression.

Fig. 8
Fig. 8

Uncertainty in estimating the lifetime of 1mM TDRT solutions depends on the image integration time. (a) TDRT phosphorescence lifetime measurement uncertainties (FWHM) for images acquired with different integration times are plotted against the average number of photons contained in these images. (b) Representative polar plots of TDRT solution pixel phosphorescence lifetime measurements at integration times of 1.5, 3, and 6 sec.

Fig. 9
Fig. 9

Fast 3D-resolved TFWF PLIM in sample consisting of human fibroblasts stained with Rhodamine DHPE, seeded inside a collagen matrix and treated, in PBS buffer containing 1 mM TDRT ruthenium-based oxygen sensor. PLIM Images were acquired at 300 kHz modulation frequency. In sequence from left to right: intensity image, phosphorescence lifetime-resolved image from phase data, phosphorescence lifetime-resolved image from modulation data. On the far right is the polar plot of the pixel phosphorescence lifetime-resolved measurements. The pixel lifetime data in the polar plot distributes between the ruthenium phosphorescence lifetime that lies close to the universal circle and the rhodamine fluorescence lifetime at the lower right hand corner corresponding to an effective zero lifetime for 300 kHz modulation frequency. PLIM Movie sequences corresponding to phase and modulation lifetime measurements throughout a 3D matrix are included (Supplementary material Media 1, Media 2).

Fig. 10
Fig. 10

Representative single plane intensity scaled lifetime-resolved image measured at a modulation frequency of 300 kHz.

Fig. 11
Fig. 11

Fast sequential 3D-resolved TFWF FLIM and PLIM imaging of human dermal fibroblasts seeded in a collagen scaffold. Representative images of the fluorescence component emitted by Rhodamine DHPE (top), and the phosphorescence component, emitted by TDRT ruthenium-based oxygen sensor (bottom), of the signal emitted from a single 3D resolved plane. 3D resolved image stacks of these two components can be seen in accompanying movie sequences (Media 3, Media 4)

Equations (5)

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Δφ=tan(ωτ) and M= 1 1+ ω 2 τ 2
pr δ f 2 τ ( P N ) 2
1 τ p O 2
N δ Prτ p 0 f
r N Nf δ Prτ p 0

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