Abstract

Optical microscopy provides noninvasive imaging of biological tissues at subcellular level. The optical aberrations induced by the inhomogeneous refractive index of biological samples limits the resolution and can decrease the penetration depth. To compensate refractive aberrations, adaptive optics with Shack-Hartmann wavefront sensing has been used in microscopes. Wavefront measurement requires light from a guide-star inside of the sample. The scattering effect limits the intensity of the guide-star, hence reducing the signal to noise ratio of the wavefront measurement. In this paper, we demonstrate the use of interferometric focusing of excitation light onto a guide-star embedded deeply in tissue to increase its fluorescent intensity, thus overcoming the excitation signal loss caused by scattering. With interferometric focusing, we more than doubled the signal to noise ratio of the laser guide-star through scattering tissue as well as potentially extend the imaging depth through using AO microscopy.

© 2013 Optical Society of America

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References

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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]

2013

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

2012

2011

2010

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

I. Vellekoop and C. Aegerter, “Focusing light through living tissue,” Proc. SPIE7554, 755430 (2010).
[CrossRef]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

I. M. Vellekoop, A. Lagendijk, and A. P. Mosk, “Exploiting disorder for perfect focusing,” Nat. Photonics4(5), 320–322 (2010).
[CrossRef]

2009

2008

2006

M. Rueckel, J. A. Mack-Bucher, and W. Denk, “Adaptive wavefront correction in two-photon microscopy using coherence-gated wavefront sensing,” Proc. Natl. Acad. Sci. U.S.A.103(46), 17137–17142 (2006).
[CrossRef] [PubMed]

2003

2002

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

2000

1998

Aegerter, C.

I. Vellekoop and C. Aegerter, “Focusing light through living tissue,” Proc. SPIE7554, 755430 (2010).
[CrossRef]

Albert, O.

Azucena, O.

Betzig, E.

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

Bifano, T.

Booth, M. J.

D. Débarre, E. J. Botcherby, T. Watanabe, S. Srinivas, M. J. Booth, and T. Wilson, “Image-based adaptive optics for two-photon microscopy,” Opt. Lett.34(16), 2495–2497 (2009).
[CrossRef] [PubMed]

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

Botcherby, E. J.

Brown, A. N.

Burns, D.

Caravaca-Aguirre, A. M.

Chaigneau, E.

Chen, D. C.

Conkey, D. B.

Crest, J.

Cui, M.

K. Si, R. Fiolka, and M. Cui, “Fluorescence imaging beyond the ballistic regime by ultrasound pulse guided digital phase conjugation,” Nat. Photonics6(10), 657–661 (2012).
[CrossRef] [PubMed]

R. Fiolka, K. Si, and M. Cui, “Parallel wavefront measurements in ultrasound pulse guided digital phase conjugation,” Opt. Express20(22), 24827–24834 (2012).
[CrossRef] [PubMed]

J. Tang, R. N. Germain, and M. Cui, “Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique,” Proc. Natl. Acad. Sci. U.S.A.109(22), 8434–8439 (2012).
[CrossRef] [PubMed]

M. Cui, “A high speed wavefront determination method based on spatial frequency modulations for focusing light through random scattering media,” Opt. Express19(4), 2989–2995 (2011).
[CrossRef] [PubMed]

Débarre, D.

Denk, W.

M. Rueckel, J. A. Mack-Bucher, and W. Denk, “Adaptive wavefront correction in two-photon microscopy using coherence-gated wavefront sensing,” Proc. Natl. Acad. Sci. U.S.A.103(46), 17137–17142 (2006).
[CrossRef] [PubMed]

Eick, A. A.

Feld, M. S.

Z. Yaqoob, D. Psaltis, M. S. Feld, and C. Yang, “Optical phase conjugation for turbidity suppression in biological samples,” Nat. Photonics2(2), 110–115 (2008).
[CrossRef] [PubMed]

Fernandez, B.

Fiolka, R.

R. Fiolka, K. Si, and M. Cui, “Parallel wavefront measurements in ultrasound pulse guided digital phase conjugation,” Opt. Express20(22), 24827–24834 (2012).
[CrossRef] [PubMed]

K. Si, R. Fiolka, and M. Cui, “Fluorescence imaging beyond the ballistic regime by ultrasound pulse guided digital phase conjugation,” Nat. Photonics6(10), 657–661 (2012).
[CrossRef] [PubMed]

Freyer, J. P.

Fu, M.

Garcia, D.

Germain, R. N.

J. Tang, R. N. Germain, and M. Cui, “Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique,” Proc. Natl. Acad. Sci. U.S.A.109(22), 8434–8439 (2012).
[CrossRef] [PubMed]

Girkin, J.

Girkin, J. M.

Hielscher, A. H.

Hoffman, S.

Horstmeyer, R.

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

Ji, N.

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

Johnson, T. M.

Judkewitz, B.

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

Juskaitis, R.

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

Kotadia, S.

Kubby, J.

Lagendijk, A.

I. M. Vellekoop, A. Lagendijk, and A. P. Mosk, “Exploiting disorder for perfect focusing,” Nat. Photonics4(5), 320–322 (2010).
[CrossRef]

I. M. Vellekoop, E. G. van Putten, A. Lagendijk, and A. P. Mosk, “Demixing light paths inside disordered metamaterials,” Opt. Express16(1), 67–80 (2008).
[CrossRef] [PubMed]

Liu, H.

X. Xu, H. Liu, and L. V. Wang, “Time-reversed ultrasonically encoded optical focusing into scattering media,” Nat. Photonics5(3), 154–157 (2011).
[CrossRef] [PubMed]

Lu, Y.

Mack-Bucher, J. A.

M. Rueckel, J. A. Mack-Bucher, and W. Denk, “Adaptive wavefront correction in two-photon microscopy using coherence-gated wavefront sensing,” Proc. Natl. Acad. Sci. U.S.A.103(46), 17137–17142 (2006).
[CrossRef] [PubMed]

Marsh, P.

Mathy, A.

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

Milkie, D. E.

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

Moore, J.

Mosk, A. P.

Mourant, J. R.

Mourou, G.

Neil, M. A.

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

Norris, T. B.

Paxman, R.

Piestun, R.

Poland, S. P.

Psaltis, D.

Z. Yaqoob, D. Psaltis, M. S. Feld, and C. Yang, “Optical phase conjugation for turbidity suppression in biological samples,” Nat. Photonics2(2), 110–115 (2008).
[CrossRef] [PubMed]

Rueckel, M.

M. Rueckel, J. A. Mack-Bucher, and W. Denk, “Adaptive wavefront correction in two-photon microscopy using coherence-gated wavefront sensing,” Proc. Natl. Acad. Sci. U.S.A.103(46), 17137–17142 (2006).
[CrossRef] [PubMed]

Schofield, M. A.

Shen, D.

Sherman, L.

Si, K.

K. Si, R. Fiolka, and M. Cui, “Fluorescence imaging beyond the ballistic regime by ultrasound pulse guided digital phase conjugation,” Nat. Photonics6(10), 657–661 (2012).
[CrossRef] [PubMed]

R. Fiolka, K. Si, and M. Cui, “Parallel wavefront measurements in ultrasound pulse guided digital phase conjugation,” Opt. Express20(22), 24827–24834 (2012).
[CrossRef] [PubMed]

Silver, R. A.

Srinivas, S.

Stockbridge, C.

Sullivan, W.

Tang, J.

J. Tang, R. N. Germain, and M. Cui, “Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique,” Proc. Natl. Acad. Sci. U.S.A.109(22), 8434–8439 (2012).
[CrossRef] [PubMed]

Tao, X.

Toussaint, K.

van Putten, E. G.

Vdovin, G.

Vellekoop, I.

I. Vellekoop and C. Aegerter, “Focusing light through living tissue,” Proc. SPIE7554, 755430 (2010).
[CrossRef]

Vellekoop, I. M.

Wang, L. V.

X. Xu, H. Liu, and L. V. Wang, “Time-reversed ultrasonically encoded optical focusing into scattering media,” Nat. Photonics5(3), 154–157 (2011).
[CrossRef] [PubMed]

Wang, Y. M.

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

Watanabe, T.

Wilson, T.

D. Débarre, E. J. Botcherby, T. Watanabe, S. Srinivas, M. J. Booth, and T. Wilson, “Image-based adaptive optics for two-photon microscopy,” Opt. Lett.34(16), 2495–2497 (2009).
[CrossRef] [PubMed]

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

Wright, A. J.

Xu, X.

X. Xu, H. Liu, and L. V. Wang, “Time-reversed ultrasonically encoded optical focusing into scattering media,” Nat. Photonics5(3), 154–157 (2011).
[CrossRef] [PubMed]

Yang, C.

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

Z. Yaqoob, D. Psaltis, M. S. Feld, and C. Yang, “Optical phase conjugation for turbidity suppression in biological samples,” Nat. Photonics2(2), 110–115 (2008).
[CrossRef] [PubMed]

Yaqoob, Z.

Z. Yaqoob, D. Psaltis, M. S. Feld, and C. Yang, “Optical phase conjugation for turbidity suppression in biological samples,” Nat. Photonics2(2), 110–115 (2008).
[CrossRef] [PubMed]

Zhu, Y.

Zuo, Y.

Appl. Opt.

Nat. Methods

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods7(2), 141–147 (2010).
[CrossRef] [PubMed]

Nat. Photonics

Z. Yaqoob, D. Psaltis, M. S. Feld, and C. Yang, “Optical phase conjugation for turbidity suppression in biological samples,” Nat. Photonics2(2), 110–115 (2008).
[CrossRef] [PubMed]

X. Xu, H. Liu, and L. V. Wang, “Time-reversed ultrasonically encoded optical focusing into scattering media,” Nat. Photonics5(3), 154–157 (2011).
[CrossRef] [PubMed]

K. Si, R. Fiolka, and M. Cui, “Fluorescence imaging beyond the ballistic regime by ultrasound pulse guided digital phase conjugation,” Nat. Photonics6(10), 657–661 (2012).
[CrossRef] [PubMed]

B. Judkewitz, Y. M. Wang, R. Horstmeyer, A. Mathy, and C. Yang, “Speckle-scale focusing in the diffusive regime with time-reversal of variance-encoded light (TROVE),” Nat. Photonics7(4), 300–305 (2013).
[CrossRef] [PubMed]

I. M. Vellekoop, A. Lagendijk, and A. P. Mosk, “Exploiting disorder for perfect focusing,” Nat. Photonics4(5), 320–322 (2010).
[CrossRef]

Opt. Express

D. B. Conkey, A. N. Brown, A. M. Caravaca-Aguirre, and R. Piestun, “Genetic algorithm optimization for focusing through turbid media in noisy environments,” Opt. Express20(5), 4840–4849 (2012).
[CrossRef] [PubMed]

M. Cui, “A high speed wavefront determination method based on spatial frequency modulations for focusing light through random scattering media,” Opt. Express19(4), 2989–2995 (2011).
[CrossRef] [PubMed]

R. Fiolka, K. Si, and M. Cui, “Parallel wavefront measurements in ultrasound pulse guided digital phase conjugation,” Opt. Express20(22), 24827–24834 (2012).
[CrossRef] [PubMed]

D. B. Conkey, A. M. Caravaca-Aguirre, and R. Piestun, “High-speed scattering medium characterization with application to focusing light through turbid media,” Opt. Express20(2), 1733–1740 (2012).
[CrossRef] [PubMed]

C. Stockbridge, Y. Lu, J. Moore, S. Hoffman, R. Paxman, K. Toussaint, and T. Bifano, “Focusing through dynamic scattering media,” Opt. Express20(14), 15086–15092 (2012).
[CrossRef] [PubMed]

I. M. Vellekoop, E. G. van Putten, A. Lagendijk, and A. P. Mosk, “Demixing light paths inside disordered metamaterials,” Opt. Express16(1), 67–80 (2008).
[CrossRef] [PubMed]

X. Tao, J. Crest, S. Kotadia, O. Azucena, D. C. Chen, W. Sullivan, and J. Kubby, “Live imaging using adaptive optics with fluorescent protein guide-stars,” Opt. Express20(14), 15969–15982 (2012).
[CrossRef] [PubMed]

P. Marsh, D. Burns, and J. Girkin, “Practical implementation of adaptive optics in multiphoton microscopy,” Opt. Express11(10), 1123–1130 (2003).
[CrossRef] [PubMed]

E. Chaigneau, A. J. Wright, S. P. Poland, J. M. Girkin, and R. A. Silver, “Impact of wavefront distortion and scattering on 2-photon microscopy in mammalian brain tissue,” Opt. Express19(23), 22755–22774 (2011).
[CrossRef] [PubMed]

Opt. Lett.

Proc. Natl. Acad. Sci. U.S.A.

M. Rueckel, J. A. Mack-Bucher, and W. Denk, “Adaptive wavefront correction in two-photon microscopy using coherence-gated wavefront sensing,” Proc. Natl. Acad. Sci. U.S.A.103(46), 17137–17142 (2006).
[CrossRef] [PubMed]

M. J. Booth, M. A. Neil, R. Juskaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U.S.A.99(9), 5788–5792 (2002).
[CrossRef] [PubMed]

J. Tang, R. N. Germain, and M. Cui, “Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique,” Proc. Natl. Acad. Sci. U.S.A.109(22), 8434–8439 (2012).
[CrossRef] [PubMed]

Proc. SPIE

I. Vellekoop and C. Aegerter, “Focusing light through living tissue,” Proc. SPIE7554, 755430 (2010).
[CrossRef]

Other

D. Malacara, Optical Shop Testing, (Wiley, New York, 2007).

I. M. Vellekoop, “Controlling the Propagation of Light in Disordered Scattering Media,” PhD thesis, Univ. Twente (2008).

J. Porter, H. Queener, J. Lin, K. Thorn, and A. A. S. Awwal, Adaptive Optics for Vision Science: Principles, Practices, Design and Applications, (Wiley, 2006).

J. W. Hardy, Adaptive Optics for Astronomical Telescopes (Oxford University Press, 1998).

J. A. Kubby, Adaptive Optics for Biological Imaging, (CRC Press, 2013).

M. Gu, Advanced Optical Imaging Theory (Springer-Verlag, New York, 1999).

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Figures (6)

Fig. 1
Fig. 1

System layout for testing IF of light on to a guide-star: A He-Ne laser emits light at 633 nm for excitation of a fluorescent reference beacon. The laser is modulated by a spatial light modulator (SLM) and generates interferometric focusing at the guide-star by an optimization process using the intensity information from an EMCCD camera. The emission light from the enhanced guide-star feeds into a SH wavefront sensor for direct wavefront measurement. L, lens; F, flipper mirror; P, polarizer; DB, dichroic beamplitters; E, emission filter; SF, spatial filter.

Fig. 2
Fig. 2

Modeling the intensity of guide-stars with aberration (blue solid line), aberration and double path scattering (blue dashed line), aberration and single path scattering (red line) and the Strehl ratio (green solid line).

Fig. 3
Fig. 3

A 1 µm diameter fluorescent bead under a 100 µm thick fixed mouse brain tissue sample used as a guide-star for wavefront measurement. (a) The image of the guide-star after compensation of system aberration (top) and the phase map displayed on the SLM (bottom). (b) The image of the guide-star after IF (top) and the phase map to compensate scattering (bottom). The intensity increases more than two times. (c) The image of the guide-star after refractive aberration correction (top) and the phase map measured from a SHWS (bottom). The scale bar is 2 µm.

Fig. 4
Fig. 4

Wavefront measurement results using IF guide-stars: Complete images from the SH wavefront sensor (grayscale inverted for clarity) and images of a single spot indicated by white square before (a) and after (b) IF. (c) The SNR improvement of wavefront measurement and intensity improvement for various depths. The error bars represent the standard deviation of the mean.

Fig. 5
Fig. 5

Effects of multiple guide-stars: Images of multiple guide-stars before IF (a) and after IF (b). Spot images from the wavefront sensor before IF (c) and after IF (d). Encircled energy of the guide-star before (solid blue line) and after IF (dashed red line) (e). The scale bar is 2 µm.

Fig. 6
Fig. 6

Spatial dependence of wavefront correction and scattering compensation. (a) Intensity improvement at different places using the phase map for the refractive aberration correction (red dashed line) and scattering compensation (blue dashed line) at the initial position. The data for scattering compensation is fitted by a Gaussian function shown as the green curve. Phase maps show the optimal phase of IF at the initial position for five tests. (b) The phase map for compensation of the refractive aberration in all the tests. RMS error is 0.32λ.

Equations (6)

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I GS (x,y)= | h psf (x,y) | 2 f flou (x,y)
f flou (x,y)={ α for x 2 + y 2 r b 0 otherwise
h( x 2 , y 2 )= i λ Σ P( x 1 , y 1 )exp[ikϕ( x 1 , y 1 ) ] exp[ik(rR)] Rr cos(n,r)d S p
P(x,y)= e ( z p 2 L se cos(n,r) )
σ m = 2 π 2 K g 4(SNR) [ ( 3 2 ) 2 + ( θd λ ) 2 ]
SNR= n p n p + N D [ n B 2 + (e/G) 2 ]

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