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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 20, Iss. 13 — Jun. 18, 2012
  • pp: 14100–14108
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Laser oblique scanning optical microscopy (LOSOM) for phase relief imaging

Yichen Ding, Hao Xie, Tong Peng, Yiqing Lu, Dayong Jin, Junlin Teng, Qiushi Ren, and Peng Xi  »View Author Affiliations


Optics Express, Vol. 20, Issue 13, pp. 14100-14108 (2012)
http://dx.doi.org/10.1364/OE.20.014100


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Abstract

The visualization of optical phase can provide abundant information when imaging transparent specimen. We present a novel phase sensitive imaging design capable of obtaining phase contours of transparent biological cells through laser oblique scanning optical microscope (LOSOM). LOSOM is based on the introduction of a fluorescent medium behind the specimen to generate a differential phase-sensitive image, thus, the complicated phase retardation alignment procedure associated with differential interference contrast (DIC) microscopy can be eliminated. Moreover, multi-modality fluorescence and phase relief imaging can be attained in a single system with fluorescently labeled specimens.

© 2012 OSA

1. Introduction

Although optical microscopy has been applied to the study of biological material since the 17th century, the transparent nature of biological cells makes optical observation difficult. Frits Zernike won the Nobel Prize in Physics in 1953 for rendering the invisible phase alteration to a detectable amplitude modulation. Among the numerous phase sensing microscopy techniques, phase contrast (PhC) microscopy [1

1. F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects,” Physica 9(7), 686–698 (1942). [CrossRef]

,2

2. F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects part II,” Physica 9(10), 974–986 (1942). [CrossRef]

] and differential interference contrast (DIC) microscopy [3

3. G. Nomarski, “Differential microinterferometer with polarized waves,” J. Phys. Radium 16, 9S–11S (1955).

,4

4. C. Preza, D. L. Snyder, and J. A. Conchello, “Theoretical development and experimental evaluation of imaging models for differential-interference-contrast microscopy,” J. Opt. Soc. Am. A 16(9), 2185–2199 (1999). [CrossRef] [PubMed]

] are considered the most applicable to biological material. In particular, phase relief imaging together with fluorescent microscopy has been widely applied to the study of cell cycle monitoring [5

5. H. Hama, C. Hara, K. Yamaguchi, and A. Miyawaki, “PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes,” Neuron 41(3), 405–415 (2004). [CrossRef] [PubMed]

,6

6. A. Sakaue-Sawano, H. Kurokawa, T. Morimura, A. Hanyu, H. Hama, H. Osawa, S. Kashiwagi, K. Fukami, T. Miyata, H. Miyoshi, T. Imamura, M. Ogawa, H. Masai, and A. Miyawaki, “Visualizing spatiotemporal dynamics of multicellular cell-cycle progression,” Cell 132(3), 487–498 (2008). [CrossRef] [PubMed]

] and high throughput RNAi screening [7

7. I. Maeda, Y. Kohara, M. Yamamoto, and A. Sugimoto, “Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi,” Curr. Biol. 11(3), 171–176 (2001). [CrossRef] [PubMed]

]. Nevertheless, difficulties, such as the non-straightforward illustration of the phase in the PhC microscopy, and the expense of polarized prisms utilized in DIC microscopy, are associated with these techniques [8

8. M. W. Davidson and M. Abramowitz, “Optical microscopy,” in Encyclopedia of Imaging Science and Technology, (John Wiley & Sons, New York, 2002).

,9

9. H. Gundlach, “Phase contrast and differential interference contrast instrumentation and applications in cell, developmental, and marine biology,” Opt. Eng. 32(12), 3223–3228 (1993). [CrossRef]

]. Additionally, other phase sensitive methods using distinct perspectives, such as oblique microscopy [10

10. R. Yi, K. K. Chu, and J. Mertz, “Graded-field microscopy with white light,” Opt. Express 14(12), 5191–5200 (2006). [CrossRef] [PubMed]

], Hoffman modulation contrast microscopy [11

11. R. Hoffman, “The modulation contrast microscope: principles and performance,” J. Microsc. 110(3), 205–222 (1977). [CrossRef]

], differential phase contrast microscopy [12

12. B. Kachar, “Asymmetric illumination contrast: a method of image formation for video light microscopy,” Science 227(4688), 766–768 (1985). [CrossRef] [PubMed]

14

14. S. B. Mehta and C. J. R. Sheppard, “Quantitative phase-gradient imaging at high resolution with asymmetric illumination-based differential phase contrast,” Opt. Lett. 34(13), 1924–1926 (2009). [CrossRef] [PubMed]

], Hilbert phase microscopy [15

15. T. Ikeda, G. Popescu, R. R. Dasari, and M. S. Feld, “Hilbert phase microscopy for investigating fast dynamics in transparent systems,” Opt. Lett. 30(10), 1165–1167 (2005). [CrossRef] [PubMed]

], and digital holographic microscopy [16

16. E. Cuche, P. Marquet, and C. Depeursinge, “Simultaneous amplitude-contrast and quantitative phase-contrast microscopy by numerical reconstruction of Fresnel off-axis holograms,” Appl. Opt. 38(34), 6994–7001 (1999). [CrossRef] [PubMed]

,17

17. P. Marquet, B. Rappaz, P. J. Magistretti, E. Cuche, Y. Emery, T. Colomb, and C. Depeursinge, “Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy,” Opt. Lett. 30(5), 468–470 (2005). [CrossRef] [PubMed]

], have demonstrated their potential applications in transparent specimen imaging.

2. Methods

In essence, the major hardware of LOSOM is identical to CLSM (Fig. 1
Fig. 1 (a) Simplified schematic diagram of the LOSOM system. The incident beam and the dichroic of the confocal system are not illustrated. The red beam represents the axial beam pathway of a confocal microscope, and the light blue beam indicates the beam pathway in the LOSOM. (b) Geometrical relationship between a light beam diameter (red circle) and an aperture of the collecting lens (yellow circle). O and O', are centers of the beam and the aperture, respectively; r1 and r2, are radii of the beam and the aperture, respectively; D denotes the distance of |OO'|; L denotes a common chordal length of the overlapping areas; S1, S2 are the areas of the beam and aperture, respectively; θ, θ1, θ2 are the angles in the presented triangle. (c) The entire LOSOM system is illustrated, highlighting the telescope composed of the scan lens and the tube lens. The galvo-scanner is tilted to provide the oblique illumination with the aid of a fluorescent medium. DC: dichroic mirror.
). However, in LOSOM, the tilted illumination induces an oblique illumination to the specimen with the assistance of a fluorescent medium behind the specimen. The collecting lens is tuned offset for oblique detection, modulating the retro-reflected signal as a window function. As shown in the theoretical analysis below, the collected SOM images can reflect the phase gradient of the specimen.

2.1 Theoretical analysis

Figure 1(a) shows a simplified schematic diagram of the LOSOM. First we consider a right angled illumination and the modulation by the sample, ρ(x1,y1), from which the electric field after travelling through a transparent sample can be expressed as u0(x1,y1)=Aρ(x1,y1). At distance z from the objective, the complex electric field can be expressed as [24

24. J. W. Goodman, Introduction to Fourier Optics, 3rd ed. (Roberts & Company Publishers, Greenwood, 2004).

]
U(ξ,η)=X,Yu0(x1,y1)exp[ikf1(x1ξ+y1η)]exp(ikz)dx1dy1,
(1)
where X and Y denote the boundaries of x1 and y1, respectively. Then, at the focal distance f2 of the collecting lens, the electric field becomes
u1(x2,y2)=Ξ,ΩU(ξ,η)exp[ikf2(x2ξ+y2η)]dξdη=exp(ikz)Ξ,ΩX,Yu0(x1,y1)exp{ik[(x1f1+x2f2)ξ+(y1f1+y2f2)η]}dx1dy1dξdη,
(2)
where Ξ and Ω denote the boundaries of ξ and η, respectively. Let M=f2/f1, and we can see that for x2=Mx1, y2=My1, and Eq. (2) becomes
u1(Mx1,My1)=u0(x1,y1)exp(ikz),
(3)
and consequently I1(Mx1,My1)=I0(x1,y1) which indicates a magnified imaging relationship. Note that for the above analysis, we assume the presence of infinitely large lenses to collect all the diffractive angular spectra.

With an angular illumination of ϕ, the electric field after the sample can be written as u2(x1,y1)=u0(x1,y1)exp(iϕx1). Here for simplicity, we take the azimuth angle on the x1 axis. Thus,
U(ξ',η')=X,Yu0(x1,y1)exp{ik[x1(ξ'f1+ϕ)+η'f1y1]}exp(ikz)dx1dy1,
(4)
and therefore U(ξ',η')=U(ξϕf1,η) which denotes that the angular spectrum is shifted by ϕf1 due to the oblique illumination.

Now we consider the intensity of I0(0,0), which is the imaging region of the confocal system. If the aperture diameter of the objective is set to be a, then at distance z, the intensity distribution can be expressed as I(ξ,η,z)=4I0πa2circ(0,0,a2), where the circ function can be defined as:

circ(x0,y0,r)={1,(xx0)2+(yy0)2r20,otherwise.
(5)

For angular illumination, I(ξ,η,z)=4I0πa2circ(ϕf1,0,a2). If we define the aperture diameter of the collecting lens to be W, then the collected intensity is modulated by the window function
I'(ξ,η,z)=4I0πa2circ(ϕf1,0,a2)circ(0,0,W2).
(6)
This is the intensity detected by the confocal point scanning setup. Now, consider that within the resolution of the confocal system, a phase gradient of ρ is present; this will contribute to the illumination angle ϕ so the total phase gradient becomes ϕ+ρ. In Fig. 1(b), we make D=(ϕ+ρ)f1, r1=a/2, r2=W/2 and S=S1+S2, hence dDdx=f1dρdx. Based on the geometrical relationship, it is obvious that S1=SsectorStri=r22θ2(r22sin2θ2)/2, therefore, dS1dD=2r22sin2θ2dθ2dD=L22dθ2dD, and similarly dS2dD=L22dθ1dD, and then
dSdD=dS1dD+dS2dD=L22dθdD..
(7)
According to the Cosine Theorem, cosθ=(r12+r22D2)/(2r1r2), and the Sine Theorem, D/sinθ=r2/sinθ1, this finally yields
dθdD=Dr1r2sinθ=2L,
(8)
dSdx=dSdDdDdx=Lf1dρdx.
(9)
The overlapped area S represents the collected fluorescent intensity I. When omitting all the components that are not changed with x2, Eq. (9) becomes
dIdx=Cdρdx,
(10)
where C denotes a constant. Equation (10) shows that, the intensity of the collected signal is linearly modulated with the phase gradient of the specimen. It is superimposed on top of a uniform background denoted by Eq. (9), when dρ(x1)dx1=0, i.e. the phase gradient inside the detectable confocal region is zero.

The advantage of LOSOM is that it easily transforms a confocal microscope into a phase relief imaging microscope. Although oblique microscopy can produce similar phase-relief results [10

10. R. Yi, K. K. Chu, and J. Mertz, “Graded-field microscopy with white light,” Opt. Express 14(12), 5191–5200 (2006). [CrossRef] [PubMed]

], the LOSOM detection is made more sensitive by taking advantage of the sensitivity of the point detector, such as a photomultiplier (PMT). As a result, the excitation power can be minimized compared to that used with 2-Dimensional oblique microscopy. Note that, with the introduction of the scanning telescope consisting of scan and tube lenses, the back aperture of the objective will always be filled during imaging [26

26. P. Xi, Y. Liu, and Q. Ren, “Scanning and image reconstruction techniques in confocal laser scanning microscopy,” in Laser Scanning, Theory and Applications, C.-C. Wang, ed. (Intech Open, 2009), pp. 523–542.

]. Yet, due to the shift of the collecting lens in relation to the center of the retro-reflection, the overall resolution is sacrificed compared to confocal counterparts.

Here, a uniform intensity distribution was assumed when obtaining the analytic solution to Eq. (10), instead of a Gaussian distribution. Thus, a higher order phase contribution has to be taken into account in conjunction with the linear modulation, when quantitative phase analysis is performed with this method.

2.2 Simulation

Figure 2
Fig. 2 Simulation of LOSOM in response to variations in the optical path. (a) Object optical path difference (OPD), the grayscale represents the optical phase. (b)-(c) Intensity distributions of the phase relief generated using opposite directions of illumination rays. (d) OPD along the azimuth axis, corresponding to (a). (e)-(f) Amplitude profiles along the azimuth axis, corresponding to (b)-(c), respectively.
illustrates a simulated uniform amplitude distribution of an artificial specimen that varies in optical thicknesses. The variation in amplitude intensity reflects the optical path difference (OPD). According to Eq. (10), the more rapid the change in optical thickness, the more acute the intensity change in the image will be. An artificial donut is represented as a transparent object in Fig. 2(a), and along the azimuth axis (dashed red line), its OPD is plotted in Fig. 2(d). The gradients of the specimen can be clearly visualized in Fig. 2(b) and 2(c) due to the oblique illumination, in which the phase features appear as pseudo 3-Dimensional structures owing to a sudden change of OPD. The opposing effect seen between Fig. 2(b) and 2(c) is a result of the contrasting oblique angles of incidence. The respective intensity distributions are shown in Figs. 2(e) and 2(f).

3. Experimental results

In addition, LOSOM can be applied to fluorescently labeled samples and used in conjunction with fluorescence microscopy to obtain multi-modality phase-relief/fluorescence images, provided that the contributed signal from the fluorescence medium is strong enough. Compared with conventional confocal fluorescent images (Fig. 4(a)
Fig. 4 Pseudo-color images of a mouse kidney section (F-24630, Invitrogen) using LOSOM to reveal DAPI fluorescent staining for nuclear material (a, d). Note that images of oblique fluorescent illumination show a relief-like structure in the tissue sections (b, e) and the combined images (c, f). Images (a-c) are taken with 10x, NA 0.3 objective, and (d-f) are taken with 20x, NA 0.45 objective. Scale bar: 30 μm.
, 4(d)), and LOSOM surface structure images (Fig. 4(b), 4(e)), the merged fluorescence and structure images shown in (c) and (f) represent information from both modalities. The images not only demonstrate the structures of the mouse kidney with their optical thicknesses, but also reveal the locations of the DAPI labeled cell nuclei, which can only be visualized with fluorescence imaging. In Fig. 4, the introduced fluorescence intensity from the fluorescent medium is so strong that a uniform background level four fold that of the maximum sample intensity is presented. Due to its multi-modality imaging capability, LOSOM can extend the applications of a conventional laser scanning optical system when using phase imaging of transparent specimens.

We have demonstrated that LOSOM can be used with objectives of different NAs. However, because a high-NA objective has a broader incident angle on the fluorescent medium, the phase-relief effect of LOSOM suffers from less illumination.

When using the phase relief imaging capability of LOSOM, the relative optical thicknesses of different domains in the sample can be evaluated even with a low magnification objective. Taking advantage of the phase relief appearance, this modality can optically section biological specimens by focusing on distinct optical planes, which is similar to the results reported in Ref [27

27. T. N. Ford, D. Lim, and J. Mertz, “Fast optically sectioned fluorescence HiLo endomicroscopy,” J. Biomed. Opt. 17(2), 021105 (2012). [CrossRef] [PubMed]

]. It should be noted that the axial resolution of an objective with NA = 0.3 is nearly 8 μm for λ=0.375 μm imaging. Figure 5
Fig. 5 A series of optical sections of the mouse kidney taken at 2 μm intervals using LOSOM with the 10x objective. Scale bar: 30 μm.
demonstrates the optical sectioning capability. The arrows in Fig. 5 highlight the variation within different z-axis imaging planes, within a 4 μm depth in the tissue.

4. Conclusion and discussion

We report a novel method to achieve phase relief images based on a confocal system that places a fluorescent medium behind the sample to act as a passive back-illumination source, and an oblique laser scanning mechanism for image collection. LOSOM is compatible with fluorescently labeled specimens, and can obtain multi-modality fluorescence/structural images using a single system. Images from various depths can be readily resolved owing to its DIC-like phase relief imaging. Furthermore, quantitative phase extraction may be possible with algorithms developed for optical phase analysis [28

28. E. D. Barone-Nugent, A. Barty, and K. A. Nugent, “Quantitative phase-amplitude microscopy I: optical microscopy,” J. Microsc. 206(3), 194–203 (2002). [CrossRef] [PubMed]

]. Laser scanning microscopy is widely applied in biological studies, and our method can provide complimentary information to optical phase imaging, especially when studying cell cycle progression or high throughput screening.

Acknowledgment

The authors thank Dr. Thomas FitzGibbon for comments on earlier drafts of the manuscript, Olivia C. Hoy for proofreading, and funding support from the “973” Program of China (2011CB707502, 2010CB933901, 2011CB809101), and the Natural Science Foundation of China (61178076).

References and links

1.

F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects,” Physica 9(7), 686–698 (1942). [CrossRef]

2.

F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects part II,” Physica 9(10), 974–986 (1942). [CrossRef]

3.

G. Nomarski, “Differential microinterferometer with polarized waves,” J. Phys. Radium 16, 9S–11S (1955).

4.

C. Preza, D. L. Snyder, and J. A. Conchello, “Theoretical development and experimental evaluation of imaging models for differential-interference-contrast microscopy,” J. Opt. Soc. Am. A 16(9), 2185–2199 (1999). [CrossRef] [PubMed]

5.

H. Hama, C. Hara, K. Yamaguchi, and A. Miyawaki, “PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes,” Neuron 41(3), 405–415 (2004). [CrossRef] [PubMed]

6.

A. Sakaue-Sawano, H. Kurokawa, T. Morimura, A. Hanyu, H. Hama, H. Osawa, S. Kashiwagi, K. Fukami, T. Miyata, H. Miyoshi, T. Imamura, M. Ogawa, H. Masai, and A. Miyawaki, “Visualizing spatiotemporal dynamics of multicellular cell-cycle progression,” Cell 132(3), 487–498 (2008). [CrossRef] [PubMed]

7.

I. Maeda, Y. Kohara, M. Yamamoto, and A. Sugimoto, “Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi,” Curr. Biol. 11(3), 171–176 (2001). [CrossRef] [PubMed]

8.

M. W. Davidson and M. Abramowitz, “Optical microscopy,” in Encyclopedia of Imaging Science and Technology, (John Wiley & Sons, New York, 2002).

9.

H. Gundlach, “Phase contrast and differential interference contrast instrumentation and applications in cell, developmental, and marine biology,” Opt. Eng. 32(12), 3223–3228 (1993). [CrossRef]

10.

R. Yi, K. K. Chu, and J. Mertz, “Graded-field microscopy with white light,” Opt. Express 14(12), 5191–5200 (2006). [CrossRef] [PubMed]

11.

R. Hoffman, “The modulation contrast microscope: principles and performance,” J. Microsc. 110(3), 205–222 (1977). [CrossRef]

12.

B. Kachar, “Asymmetric illumination contrast: a method of image formation for video light microscopy,” Science 227(4688), 766–768 (1985). [CrossRef] [PubMed]

13.

W. B. Amos, S. Reichelt, D. M. Cattermole, and J. Laufer, “Re-evaluation of differential phase contrast (DPC) in a scanning laser microscope using a split detector as an alternative to differential interference contrast (DIC) optics,” J. Microsc. 210(2), 166–175 (2003). [CrossRef] [PubMed]

14.

S. B. Mehta and C. J. R. Sheppard, “Quantitative phase-gradient imaging at high resolution with asymmetric illumination-based differential phase contrast,” Opt. Lett. 34(13), 1924–1926 (2009). [CrossRef] [PubMed]

15.

T. Ikeda, G. Popescu, R. R. Dasari, and M. S. Feld, “Hilbert phase microscopy for investigating fast dynamics in transparent systems,” Opt. Lett. 30(10), 1165–1167 (2005). [CrossRef] [PubMed]

16.

E. Cuche, P. Marquet, and C. Depeursinge, “Simultaneous amplitude-contrast and quantitative phase-contrast microscopy by numerical reconstruction of Fresnel off-axis holograms,” Appl. Opt. 38(34), 6994–7001 (1999). [CrossRef] [PubMed]

17.

P. Marquet, B. Rappaz, P. J. Magistretti, E. Cuche, Y. Emery, T. Colomb, and C. Depeursinge, “Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy,” Opt. Lett. 30(5), 468–470 (2005). [CrossRef] [PubMed]

18.

T. Wilson and C. J. R. Sheppard, Theory and Practice of Scanning Optical Microscopy (Academic, London, 1984).

19.

T. Wilson and R. Juskaitis, “Confocal and differential microscopy using optical fiber detection, ” in Biomedical Image Processing and Three-Dimensional Microscopy, (Proc. SPIE, 1992), 497–502.

20.

P. Delaney and M. Harris, “Fiber-optics in scanning optical microscopy,” in Handbook of Biological Confocal Microscopy, 3rd ed., J. B. Pawley, ed. (Springer, Madison, 2006).

21.

C. J. Cogswell and C. J. R. Sheppard, “Confocal differential interference contrast (DIC) microscopy: including a theoretical analysis of conventional and confocal DIC imaging,” J. Microsc. 165(1), 81–101 (1992). [CrossRef]

22.

S. H. Cody, S. D. Xiang, M. J. Layton, E. Handman, M. H. C. Lam, J. E. Layton, E. C. Nice, and J. K. Heath, “A simple method allowing DIC imaging in conjunction with confocal microscopy,” J. Microsc. 217(3), 265–274 (2005). [CrossRef] [PubMed]

23.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, and C. A. Puliafito, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991). [CrossRef] [PubMed]

24.

J. W. Goodman, Introduction to Fourier Optics, 3rd ed. (Roberts & Company Publishers, Greenwood, 2004).

25.

T. Peng, H. Xie, Y. Ding, W. Wang, Z. Li, D. Jin, Y. Tang, Q. Ren, and P. Xi, “CRAFT: Multimodality confocal skin imaging for early cancer diagnosis,” J Biophotonics 5(5-6), 469–476 (2012). [CrossRef] [PubMed]

26.

P. Xi, Y. Liu, and Q. Ren, “Scanning and image reconstruction techniques in confocal laser scanning microscopy,” in Laser Scanning, Theory and Applications, C.-C. Wang, ed. (Intech Open, 2009), pp. 523–542.

27.

T. N. Ford, D. Lim, and J. Mertz, “Fast optically sectioned fluorescence HiLo endomicroscopy,” J. Biomed. Opt. 17(2), 021105 (2012). [CrossRef] [PubMed]

28.

E. D. Barone-Nugent, A. Barty, and K. A. Nugent, “Quantitative phase-amplitude microscopy I: optical microscopy,” J. Microsc. 206(3), 194–203 (2002). [CrossRef] [PubMed]

OCIS Codes
(120.5060) Instrumentation, measurement, and metrology : Phase modulation
(170.0180) Medical optics and biotechnology : Microscopy
(180.5810) Microscopy : Scanning microscopy

ToC Category:
Microscopy

History
Original Manuscript: May 7, 2012
Revised Manuscript: May 28, 2012
Manuscript Accepted: May 31, 2012
Published: June 11, 2012

Virtual Issues
Vol. 7, Iss. 8 Virtual Journal for Biomedical Optics

Citation
Yichen Ding, Hao Xie, Tong Peng, Yiqing Lu, Dayong Jin, Junlin Teng, Qiushi Ren, and Peng Xi, "Laser oblique scanning optical microscopy (LOSOM) for phase relief imaging," Opt. Express 20, 14100-14108 (2012)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-20-13-14100


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References

  1. F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects,” Physica9(7), 686–698 (1942). [CrossRef]
  2. F. Zernike, “Phase contrast, a new method for the microscopic observation of transparent objects part II,” Physica9(10), 974–986 (1942). [CrossRef]
  3. G. Nomarski, “Differential microinterferometer with polarized waves,” J. Phys. Radium16, 9S–11S (1955).
  4. C. Preza, D. L. Snyder, and J. A. Conchello, “Theoretical development and experimental evaluation of imaging models for differential-interference-contrast microscopy,” J. Opt. Soc. Am. A16(9), 2185–2199 (1999). [CrossRef] [PubMed]
  5. H. Hama, C. Hara, K. Yamaguchi, and A. Miyawaki, “PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes,” Neuron41(3), 405–415 (2004). [CrossRef] [PubMed]
  6. A. Sakaue-Sawano, H. Kurokawa, T. Morimura, A. Hanyu, H. Hama, H. Osawa, S. Kashiwagi, K. Fukami, T. Miyata, H. Miyoshi, T. Imamura, M. Ogawa, H. Masai, and A. Miyawaki, “Visualizing spatiotemporal dynamics of multicellular cell-cycle progression,” Cell132(3), 487–498 (2008). [CrossRef] [PubMed]
  7. I. Maeda, Y. Kohara, M. Yamamoto, and A. Sugimoto, “Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi,” Curr. Biol.11(3), 171–176 (2001). [CrossRef] [PubMed]
  8. M. W. Davidson and M. Abramowitz, “Optical microscopy,” in Encyclopedia of Imaging Science and Technology, (John Wiley & Sons, New York, 2002).
  9. H. Gundlach, “Phase contrast and differential interference contrast instrumentation and applications in cell, developmental, and marine biology,” Opt. Eng.32(12), 3223–3228 (1993). [CrossRef]
  10. R. Yi, K. K. Chu, and J. Mertz, “Graded-field microscopy with white light,” Opt. Express14(12), 5191–5200 (2006). [CrossRef] [PubMed]
  11. R. Hoffman, “The modulation contrast microscope: principles and performance,” J. Microsc.110(3), 205–222 (1977). [CrossRef]
  12. B. Kachar, “Asymmetric illumination contrast: a method of image formation for video light microscopy,” Science227(4688), 766–768 (1985). [CrossRef] [PubMed]
  13. W. B. Amos, S. Reichelt, D. M. Cattermole, and J. Laufer, “Re-evaluation of differential phase contrast (DPC) in a scanning laser microscope using a split detector as an alternative to differential interference contrast (DIC) optics,” J. Microsc.210(2), 166–175 (2003). [CrossRef] [PubMed]
  14. S. B. Mehta and C. J. R. Sheppard, “Quantitative phase-gradient imaging at high resolution with asymmetric illumination-based differential phase contrast,” Opt. Lett.34(13), 1924–1926 (2009). [CrossRef] [PubMed]
  15. T. Ikeda, G. Popescu, R. R. Dasari, and M. S. Feld, “Hilbert phase microscopy for investigating fast dynamics in transparent systems,” Opt. Lett.30(10), 1165–1167 (2005). [CrossRef] [PubMed]
  16. E. Cuche, P. Marquet, and C. Depeursinge, “Simultaneous amplitude-contrast and quantitative phase-contrast microscopy by numerical reconstruction of Fresnel off-axis holograms,” Appl. Opt.38(34), 6994–7001 (1999). [CrossRef] [PubMed]
  17. P. Marquet, B. Rappaz, P. J. Magistretti, E. Cuche, Y. Emery, T. Colomb, and C. Depeursinge, “Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy,” Opt. Lett.30(5), 468–470 (2005). [CrossRef] [PubMed]
  18. T. Wilson and C. J. R. Sheppard, Theory and Practice of Scanning Optical Microscopy (Academic, London, 1984).
  19. T. Wilson and R. Juskaitis, “Confocal and differential microscopy using optical fiber detection, ” in Biomedical Image Processing and Three-Dimensional Microscopy, (Proc. SPIE, 1992), 497–502.
  20. P. Delaney and M. Harris, “Fiber-optics in scanning optical microscopy,” in Handbook of Biological Confocal Microscopy, 3rd ed., J. B. Pawley, ed. (Springer, Madison, 2006).
  21. C. J. Cogswell and C. J. R. Sheppard, “Confocal differential interference contrast (DIC) microscopy: including a theoretical analysis of conventional and confocal DIC imaging,” J. Microsc.165(1), 81–101 (1992). [CrossRef]
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