Abstract

We demonstrate a silo-filter (SF) complementary metal-oxide semiconductor (CMOS) image sensor for a chip-scale fluorescence microscope. The extruded pixel design with metal walls between neighboring pixels guides fluorescence emission through the thick absorptive filter to the photodiode of a pixel. Our prototype device achieves 13 μm resolution over a wide field of view (4.8mm×4.4mm). We demonstrate bright-field and fluorescence longitudinal imaging of living cells in a compact, low-cost configuration.

© 2013 Optical Society of America

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  1. V. Starkuviene and R. Pepperkok, Br. J. Pharmacol. 152, 62 (2007).
    [CrossRef]
  2. T. Schroeder, Nat. Methods 8, S30 (2011).
    [CrossRef]
  3. C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
    [CrossRef]
  4. X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
    [CrossRef]
  5. G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
    [CrossRef]
  6. S. Pang, C. Han, M. Kato, P. W. Sternberg, and C. Yang, Opt. Lett. 37, 5018 (2012).
    [CrossRef]
  7. A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
    [CrossRef]
  8. A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Opt. Express 18, 10510 (2010).
    [CrossRef]
  9. S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
    [CrossRef]
  10. W. Robert, Proc. Roy. Soc. 59, 781 (1947).
    [CrossRef]
  11. P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

2012 (1)

2011 (3)

T. Schroeder, Nat. Methods 8, S30 (2011).
[CrossRef]

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

2010 (1)

2008 (1)

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

2007 (2)

V. Starkuviene and R. Pepperkok, Br. J. Pharmacol. 152, 62 (2007).
[CrossRef]

C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
[CrossRef]

2003 (1)

S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
[CrossRef]

1947 (1)

W. Robert, Proc. Roy. Soc. 59, 781 (1947).
[CrossRef]

Antebi, Y.

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

Coskun, A. F.

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Opt. Express 18, 10510 (2010).
[CrossRef]

Cui, X.

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Duessmann, H.

P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

Elowitz, M. B.

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

Guan, J.-L.

C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
[CrossRef]

Han, C.

Heng, X.

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Huber, H.

P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

Kalamatianos, D.

P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

Kang, M. G.

S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
[CrossRef]

Kato, M.

Lee, L. M.

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Lee, S. A.

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

Liang, C.-C.

C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
[CrossRef]

Ozcan, A.

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Opt. Express 18, 10510 (2010).
[CrossRef]

Pang, S.

Park, A. Y.

C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
[CrossRef]

Park, M. K.

S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
[CrossRef]

Park, S. C.

S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
[CrossRef]

Paul, P.

P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

Pepperkok, R.

V. Starkuviene and R. Pepperkok, Br. J. Pharmacol. 152, 62 (2007).
[CrossRef]

Psaltis, D.

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Robert, W.

W. Robert, Proc. Roy. Soc. 59, 781 (1947).
[CrossRef]

Schroeder, T.

T. Schroeder, Nat. Methods 8, S30 (2011).
[CrossRef]

Sencan, I.

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Opt. Express 18, 10510 (2010).
[CrossRef]

Starkuviene, V.

V. Starkuviene and R. Pepperkok, Br. J. Pharmacol. 152, 62 (2007).
[CrossRef]

Sternberg, P. W.

S. Pang, C. Han, M. Kato, P. W. Sternberg, and C. Yang, Opt. Lett. 37, 5018 (2012).
[CrossRef]

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Su, T.-W.

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Opt. Express 18, 10510 (2010).
[CrossRef]

Yang, C.

S. Pang, C. Han, M. Kato, P. W. Sternberg, and C. Yang, Opt. Lett. 37, 5018 (2012).
[CrossRef]

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Zheng, G.

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

Zhong, W.

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

Analyst (1)

A. F. Coskun, I. Sencan, T.-W. Su, and A. Ozcan, Analyst 136, 3512 (2011).
[CrossRef]

Br. J. Pharmacol. (1)

V. Starkuviene and R. Pepperkok, Br. J. Pharmacol. 152, 62 (2007).
[CrossRef]

IEEE Signal Process. Mag (1)

S. C. Park, M. K. Park, and M. G. Kang, IEEE Signal Process. Mag. 20(3), 21 (2003).
[CrossRef]

Nat. Methods (1)

T. Schroeder, Nat. Methods 8, S30 (2011).
[CrossRef]

Nat. Protocols (1)

C.-C. Liang, A. Y. Park, and J.-L. Guan, Nat. Protocols 2, 329 (2007).
[CrossRef]

Opt. Express (1)

Opt. Lett. (1)

Proc. Natl. Acad. Sci. USA (2)

X. Cui, L. M. Lee, X. Heng, W. Zhong, P. W. Sternberg, D. Psaltis, and C. Yang, Proc. Natl. Acad. Sci. USA 105, 10670 (2008).
[CrossRef]

G. Zheng, S. A. Lee, Y. Antebi, M. B. Elowitz, and C. Yang, Proc. Natl. Acad. Sci. USA 108, 16889 (2011).
[CrossRef]

Proc. Roy. Soc. (1)

W. Robert, Proc. Roy. Soc. 59, 781 (1947).
[CrossRef]

Other (1)

P. Paul, D. Kalamatianos, H. Duessmann, and H. Huber, in Proceedings of IEEE International Conference on BioInformatics and BioEngineering (IEEE, 2008), pp. 1–6.

Supplementary Material (5)

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Figures (4)

Fig. 1.
Fig. 1.

(a) Schematic diagram of bright-field and fluorescence imaging system using a SF imager. (b) SEM micrograph of metal grid structure. (c) Schematic diagram of the SF structure.

Fig. 2.
Fig. 2.

(a) Transmission of light at varying incidence angles for uniform filter (UF) and silo-filter (SF) with 560 nm (green) and 625 nm (red) plane wave illumination. The transmission curve of the Orasol Red filter (3 μm) is shown (inset). (b) Bright-field and fluorescent images of fluorescent and non-fluorescent microbeads in UF and SF sensors (Full-field image available at Media 1). Results are confirmed with 10 × objective microscope images. (c) PSFs of fluorescent microbeads from (b).

Fig. 3.
Fig. 3.

Bright-field and fluorescence images of living cells taken with a SF sensor chip. (a) Large FOV images of HEK 293-mCherry cells (Media 2). (b) Bright-field, fluorescence, and overlay images of the area highlighted in (a). (c) MCF-7 cells stained with SYTO-64 nucleic acid stain. SF sensor images and a 20 × objective microscope image of the same type of cells on a conventional petri dish.

Fig. 4.
Fig. 4.

Long-term monitoring of living cells. (a) A SF-ePetri system is kept in a CO 2 incubator and controlled with a PC. (b) Time-lapse sequence indicating migration and mitosis (boxed) of HEK 293-mCherry cells (Media 3, Media 4, and Media 5).

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