Abstract

Over the last decade microfluidics has created a versatile platform that has significantly advanced the ways in which micro-scale organisms and objects are controlled, processed and investigated, by improving the cost, compactness and throughput aspects of analysis. Microfluidics has also expanded into optics to create reconfigurable and flexible optical devices such as reconfigurable lenses, lasers, waveguides, switches, and on-chip microscopes. Here we present a new opto-fluidic microscopy modality, i.e., Holographic Opto-fluidic Microscopy (HOM), based on lensless holographic imaging. This imaging modality complements the miniaturization provided by microfluidics and would allow the integration of microscopy into existing on-chip microfluidic devices with various functionalities. Our imaging modality utilizes partially coherent in-line holography and pixel super-resolution to create high-resolution amplitude and phase images of the objects flowing within micro-fluidic channels, which we demonstrate by imaging C. elegans, Giardia lamblia, and Mulberry pollen. HOM does not involve complicated fabrication processes or precise alignment, nor does it require a highly uniform flow of objects within microfluidic channels.

© 2010 OSA

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2010

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

C. Oh, S. O. Isikman, B. Khademhosseinieh, and A. Ozcan, “On-chip differential interference contrast microscopy using lensless digital holography,” Opt. Express 18(5), 4717–4726 (2010).
[CrossRef] [PubMed]

W. Bishara, T. W. Su, A. F. Coskun, and A. Ozcan, “Lensfree on-chip microscopy over a wide field-of-view using pixel super-resolution,” Opt. Express 18(11), 11181–11191 (2010).
[CrossRef] [PubMed]

2007

C. Monat, P. Domachuk, and B. J. Eggleton, “Integrated optofluidics: A new river of light,” Nat. Photonics 1(2), 106–114 (2007).
[CrossRef]

S. Haeberle and R. Zengerle, “Microfluidic platforms for lab-on-a-chip applications,” Lab Chip 7(9), 1094–1110 (2007).
[CrossRef] [PubMed]

2006

H. Craighead, “Future lab-on-a-chip technologies for interrogating individual molecules,” Nature 442(7101), 387–393 (2006).
[CrossRef] [PubMed]

G. M. Whitesides, “The origins and the future of microfluidics,” Nature 442(7101), 368–373 (2006).
[CrossRef] [PubMed]

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

C. D. Chin, V. Linder, and S. K. Sia, “Lab-on-a-chip devices for global health: past studies and future opportunities,” Lab Chip 7(1), 41–57 (2006).
[CrossRef] [PubMed]

P. S. Dittrich and A. Manz, “Lab-on-a-chip: microfluidics in drug discovery,” Nat. Rev. Drug Discov. 5(3), 210–218 (2006).
[CrossRef] [PubMed]

D. Psaltis, S. R. Quake, and C. Yang, “Developing optofluidic technology through the fusion of microfluidics and optics,” Nature 442(7101), 381–386 (2006).
[CrossRef] [PubMed]

J. El-Ali, P. K. Sorger, and K. F. Jensen, “Cells on chips,” Nature 442(7101), 403–411 (2006).
[CrossRef] [PubMed]

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3(10), 793–796 (2006).
[CrossRef] [PubMed]

L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
[CrossRef] [PubMed]

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Z. Li, Z. Zhang, T. Emery, A. Scherer, and D. Psaltis, “Single mode optofluidic distributed feedback dye laser,” Opt. Express 14(2), 696–701 (2006).
[CrossRef] [PubMed]

J. Garcia-Sucerquia, W. Xu, M. H. Jericho, and H. J. Kreuzer, “Immersion digital in-line holographic microscopy,” Opt. Lett. 31(9), 1211–1213 (2006).
[CrossRef] [PubMed]

N. A. Woods, N. P. Galatsanos, and A. K. Katsaggelos, “Stochastic methods for joint registration, restoration, and interpolation of multiple undersampled images,” IEEE Trans. Image Process. 15(1), 201–213 (2006).
[CrossRef] [PubMed]

2005

M. G. L. Gustafsson, “Nonlinear structured-illumination microscopy: wide-field fluorescence imaging with theoretically unlimited resolution,” Proc. Natl. Acad. Sci. U.S.A. 102(37), 13081–13086 (2005).
[CrossRef] [PubMed]

T. Squires and S. Quake, “Microfluidics: Fluid physics at the nanoliter scale,” Rev. Mod. Phys. 77(3), 977–1026 (2005).
[CrossRef]

2003

B. H. Weigl, R. L. Bardell, and C. R. Cabrera, “Lab-on-a-chip for drug development,” Adv. Drug Deliv. Rev. 55(3), 349–377 (2003).
[CrossRef] [PubMed]

S. C. Park, M. K. Park, and M. G. Kang, “Super-resolution image reconstruction: a technical overview,” IEEE Signal Process. Mag. 20(3), 21–36 (2003).
[CrossRef]

2001

W. Xu, M. H. Jericho, I. A. Meinertzhagen, and H. J. Kreuzer, “Digital in-line holography for biological applications,” Proc. Natl. Acad. Sci. U.S.A. 98(20), 11301–11305 (2001).
[CrossRef] [PubMed]

1998

R. C. Hardie, J. G Bognar, E. E Armstrong, and E. A Watson, “High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system,” Opt. Eng. 37, 247 (1998).
[CrossRef]

1997

R. C. Hardie, K. J. Barnard, and E. E. Armstrong, “Joint MAP registration and high-resolution image estimation using a sequence of undersampled images,” IEEE Trans. Image Process. 6(12), 1621–1633 (1997).
[CrossRef] [PubMed]

1992

Agarwal, A. K.

L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
[CrossRef] [PubMed]

Armstrong, E. E

R. C. Hardie, J. G Bognar, E. E Armstrong, and E. A Watson, “High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system,” Opt. Eng. 37, 247 (1998).
[CrossRef]

Armstrong, E. E.

R. C. Hardie, K. J. Barnard, and E. E. Armstrong, “Joint MAP registration and high-resolution image estimation using a sequence of undersampled images,” IEEE Trans. Image Process. 6(12), 1621–1633 (1997).
[CrossRef] [PubMed]

Bardell, R. L.

B. H. Weigl, R. L. Bardell, and C. R. Cabrera, “Lab-on-a-chip for drug development,” Adv. Drug Deliv. Rev. 55(3), 349–377 (2003).
[CrossRef] [PubMed]

Barnard, K. J.

R. C. Hardie, K. J. Barnard, and E. E. Armstrong, “Joint MAP registration and high-resolution image estimation using a sequence of undersampled images,” IEEE Trans. Image Process. 6(12), 1621–1633 (1997).
[CrossRef] [PubMed]

Bates, M.

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3(10), 793–796 (2006).
[CrossRef] [PubMed]

Baugh, L. R.

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Beebe, D. J.

L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
[CrossRef] [PubMed]

Betzig, E.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Bishara, W.

W. Bishara, T. W. Su, A. F. Coskun, and A. Ozcan, “Lensfree on-chip microscopy over a wide field-of-view using pixel super-resolution,” Opt. Express 18(11), 11181–11191 (2010).
[CrossRef] [PubMed]

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Bognar, J. G

R. C. Hardie, J. G Bognar, E. E Armstrong, and E. A Watson, “High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system,” Opt. Eng. 37, 247 (1998).
[CrossRef]

Bonifacino, J. S.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Boyer, K.

Cabrera, C. R.

B. H. Weigl, R. L. Bardell, and C. R. Cabrera, “Lab-on-a-chip for drug development,” Adv. Drug Deliv. Rev. 55(3), 349–377 (2003).
[CrossRef] [PubMed]

Chin, C. D.

C. D. Chin, V. Linder, and S. K. Sia, “Lab-on-a-chip devices for global health: past studies and future opportunities,” Lab Chip 7(1), 41–57 (2006).
[CrossRef] [PubMed]

Coskun, A. F.

Craighead, H.

H. Craighead, “Future lab-on-a-chip technologies for interrogating individual molecules,” Nature 442(7101), 387–393 (2006).
[CrossRef] [PubMed]

Cullen, D.

Davidson, M. W.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Dittrich, P. S.

P. S. Dittrich and A. Manz, “Lab-on-a-chip: microfluidics in drug discovery,” Nat. Rev. Drug Discov. 5(3), 210–218 (2006).
[CrossRef] [PubMed]

Domachuk, P.

C. Monat, P. Domachuk, and B. J. Eggleton, “Integrated optofluidics: A new river of light,” Nat. Photonics 1(2), 106–114 (2007).
[CrossRef]

Dong, L.

L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
[CrossRef] [PubMed]

Edwards, T.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

Eggleton, B. J.

C. Monat, P. Domachuk, and B. J. Eggleton, “Integrated optofluidics: A new river of light,” Nat. Photonics 1(2), 106–114 (2007).
[CrossRef]

El-Ali, J.

J. El-Ali, P. K. Sorger, and K. F. Jensen, “Cells on chips,” Nature 442(7101), 403–411 (2006).
[CrossRef] [PubMed]

Emery, T.

Erickson, D.

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Fu, E.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

Galatsanos, N. P.

N. A. Woods, N. P. Galatsanos, and A. K. Katsaggelos, “Stochastic methods for joint registration, restoration, and interpolation of multiple undersampled images,” IEEE Trans. Image Process. 15(1), 201–213 (2006).
[CrossRef] [PubMed]

Garcia-Sucerquia, J.

Gustafsson, M. G. L.

M. G. L. Gustafsson, “Nonlinear structured-illumination microscopy: wide-field fluorescence imaging with theoretically unlimited resolution,” Proc. Natl. Acad. Sci. U.S.A. 102(37), 13081–13086 (2005).
[CrossRef] [PubMed]

Haddad, W. S.

Haeberle, S.

S. Haeberle and R. Zengerle, “Microfluidic platforms for lab-on-a-chip applications,” Lab Chip 7(9), 1094–1110 (2007).
[CrossRef] [PubMed]

Hardie, R. C.

R. C. Hardie, J. G Bognar, E. E Armstrong, and E. A Watson, “High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system,” Opt. Eng. 37, 247 (1998).
[CrossRef]

R. C. Hardie, K. J. Barnard, and E. E. Armstrong, “Joint MAP registration and high-resolution image estimation using a sequence of undersampled images,” IEEE Trans. Image Process. 6(12), 1621–1633 (1997).
[CrossRef] [PubMed]

Hell, S. W.

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

Helton, K.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

Heng, X.

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Hess, H. F.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Isikman, S. O.

C. Oh, S. O. Isikman, B. Khademhosseinieh, and A. Ozcan, “On-chip differential interference contrast microscopy using lensless digital holography,” Opt. Express 18(5), 4717–4726 (2010).
[CrossRef] [PubMed]

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Jahn, R.

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

Jensen, K. F.

J. El-Ali, P. K. Sorger, and K. F. Jensen, “Cells on chips,” Nature 442(7101), 403–411 (2006).
[CrossRef] [PubMed]

Jericho, M. H.

J. Garcia-Sucerquia, W. Xu, M. H. Jericho, and H. J. Kreuzer, “Immersion digital in-line holographic microscopy,” Opt. Lett. 31(9), 1211–1213 (2006).
[CrossRef] [PubMed]

W. Xu, M. H. Jericho, I. A. Meinertzhagen, and H. J. Kreuzer, “Digital in-line holography for biological applications,” Proc. Natl. Acad. Sci. U.S.A. 98(20), 11301–11305 (2001).
[CrossRef] [PubMed]

Jiang, H.

L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
[CrossRef] [PubMed]

Kang, M. G.

S. C. Park, M. K. Park, and M. G. Kang, “Super-resolution image reconstruction: a technical overview,” IEEE Signal Process. Mag. 20(3), 21–36 (2003).
[CrossRef]

Katsaggelos, A. K.

N. A. Woods, N. P. Galatsanos, and A. K. Katsaggelos, “Stochastic methods for joint registration, restoration, and interpolation of multiple undersampled images,” IEEE Trans. Image Process. 15(1), 201–213 (2006).
[CrossRef] [PubMed]

Khademhosseini, B.

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Khademhosseinieh, B.

Kreuzer, H. J.

J. Garcia-Sucerquia, W. Xu, M. H. Jericho, and H. J. Kreuzer, “Immersion digital in-line holographic microscopy,” Opt. Lett. 31(9), 1211–1213 (2006).
[CrossRef] [PubMed]

W. Xu, M. H. Jericho, I. A. Meinertzhagen, and H. J. Kreuzer, “Digital in-line holography for biological applications,” Proc. Natl. Acad. Sci. U.S.A. 98(20), 11301–11305 (2001).
[CrossRef] [PubMed]

Lee, S. A.

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

Li, Z.

Linder, V.

C. D. Chin, V. Linder, and S. K. Sia, “Lab-on-a-chip devices for global health: past studies and future opportunities,” Lab Chip 7(1), 41–57 (2006).
[CrossRef] [PubMed]

Lindwasser, O. W.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Lippincott-Schwartz, J.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
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W. Xu, M. H. Jericho, I. A. Meinertzhagen, and H. J. Kreuzer, “Digital in-line holography for biological applications,” Proc. Natl. Acad. Sci. U.S.A. 98(20), 11301–11305 (2001).
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O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
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C. Oh, S. O. Isikman, B. Khademhosseinieh, and A. Ozcan, “On-chip differential interference contrast microscopy using lensless digital holography,” Opt. Express 18(5), 4717–4726 (2010).
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E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
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W. Bishara, T. W. Su, A. F. Coskun, and A. Ozcan, “Lensfree on-chip microscopy over a wide field-of-view using pixel super-resolution,” Opt. Express 18(11), 11181–11191 (2010).
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C. Oh, S. O. Isikman, B. Khademhosseinieh, and A. Ozcan, “On-chip differential interference contrast microscopy using lensless digital holography,” Opt. Express 18(5), 4717–4726 (2010).
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O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
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O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
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Park, S. C.

S. C. Park, M. K. Park, and M. G. Kang, “Super-resolution image reconstruction: a technical overview,” IEEE Signal Process. Mag. 20(3), 21–36 (2003).
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E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
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Z. Li, Z. Zhang, T. Emery, A. Scherer, and D. Psaltis, “Single mode optofluidic distributed feedback dye laser,” Opt. Express 14(2), 696–701 (2006).
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X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
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T. Squires and S. Quake, “Microfluidics: Fluid physics at the nanoliter scale,” Rev. Mod. Phys. 77(3), 977–1026 (2005).
[CrossRef]

Quake, S. R.

D. Psaltis, S. R. Quake, and C. Yang, “Developing optofluidic technology through the fusion of microfluidics and optics,” Nature 442(7101), 381–386 (2006).
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Rhodes, C. K.

Rizzoli, S. O.

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
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M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3(10), 793–796 (2006).
[CrossRef] [PubMed]

Scherer, A.

Sencan, I.

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Seo, S.

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Sia, S. K.

C. D. Chin, V. Linder, and S. K. Sia, “Lab-on-a-chip devices for global health: past studies and future opportunities,” Lab Chip 7(1), 41–57 (2006).
[CrossRef] [PubMed]

Solem, J. C.

Sorger, P. K.

J. El-Ali, P. K. Sorger, and K. F. Jensen, “Cells on chips,” Nature 442(7101), 403–411 (2006).
[CrossRef] [PubMed]

Sougrat, R.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
[CrossRef] [PubMed]

Squires, T.

T. Squires and S. Quake, “Microfluidics: Fluid physics at the nanoliter scale,” Rev. Mod. Phys. 77(3), 977–1026 (2005).
[CrossRef]

Sternberg, P. W.

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Su, T. W.

Tam, M. R.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

Tseng, D.

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

Watson, E. A

R. C. Hardie, J. G Bognar, E. E Armstrong, and E. A Watson, “High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system,” Opt. Eng. 37, 247 (1998).
[CrossRef]

Weigl, B. H.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

B. H. Weigl, R. L. Bardell, and C. R. Cabrera, “Lab-on-a-chip for drug development,” Adv. Drug Deliv. Rev. 55(3), 349–377 (2003).
[CrossRef] [PubMed]

Westphal, V.

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

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G. M. Whitesides, “The origins and the future of microfluidics,” Nature 442(7101), 368–373 (2006).
[CrossRef] [PubMed]

Willig, K. I.

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

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N. A. Woods, N. P. Galatsanos, and A. K. Katsaggelos, “Stochastic methods for joint registration, restoration, and interpolation of multiple undersampled images,” IEEE Trans. Image Process. 15(1), 201–213 (2006).
[CrossRef] [PubMed]

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J. Garcia-Sucerquia, W. Xu, M. H. Jericho, and H. J. Kreuzer, “Immersion digital in-line holographic microscopy,” Opt. Lett. 31(9), 1211–1213 (2006).
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W. Xu, M. H. Jericho, I. A. Meinertzhagen, and H. J. Kreuzer, “Digital in-line holography for biological applications,” Proc. Natl. Acad. Sci. U.S.A. 98(20), 11301–11305 (2001).
[CrossRef] [PubMed]

Yager, P.

P. Yager, T. Edwards, E. Fu, K. Helton, K. Nelson, M. R. Tam, and B. H. Weigl, “Microfluidic diagnostic technologies for global public health,” Nature 442(7101), 412–418 (2006).
[CrossRef] [PubMed]

Yang, C.

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

D. Psaltis, S. R. Quake, and C. Yang, “Developing optofluidic technology through the fusion of microfluidics and optics,” Nature 442(7101), 381–386 (2006).
[CrossRef] [PubMed]

Yang, S.

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

Yaqoob, Z.

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
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S. Haeberle and R. Zengerle, “Microfluidic platforms for lab-on-a-chip applications,” Lab Chip 7(9), 1094–1110 (2007).
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Zheng, G.

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

Zhuang, X.

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3(10), 793–796 (2006).
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Adv. Drug Deliv. Rev.

B. H. Weigl, R. L. Bardell, and C. R. Cabrera, “Lab-on-a-chip for drug development,” Adv. Drug Deliv. Rev. 55(3), 349–377 (2003).
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Appl. Opt.

IEEE Signal Process. Mag.

S. C. Park, M. K. Park, and M. G. Kang, “Super-resolution image reconstruction: a technical overview,” IEEE Signal Process. Mag. 20(3), 21–36 (2003).
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IEEE Trans. Image Process.

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N. A. Woods, N. P. Galatsanos, and A. K. Katsaggelos, “Stochastic methods for joint registration, restoration, and interpolation of multiple undersampled images,” IEEE Trans. Image Process. 15(1), 201–213 (2006).
[CrossRef] [PubMed]

Lab Chip

S. Haeberle and R. Zengerle, “Microfluidic platforms for lab-on-a-chip applications,” Lab Chip 7(9), 1094–1110 (2007).
[CrossRef] [PubMed]

C. D. Chin, V. Linder, and S. K. Sia, “Lab-on-a-chip devices for global health: past studies and future opportunities,” Lab Chip 7(1), 41–57 (2006).
[CrossRef] [PubMed]

G. Zheng, S. A. Lee, S. Yang, and C. Yang, “Sub-pixel resolving optofluidic microscope for on-chip cell imaging,” Lab Chip 10(22), 3125–3129 (2010).
[CrossRef] [PubMed]

O. Mudanyali, D. Tseng, C. Oh, S. O. Isikman, I. Sencan, W. Bishara, C. Oztoprak, S. Seo, B. Khademhosseini, and A. Ozcan, “Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications,” Lab Chip 10(11), 1417–1428 (2010).
[CrossRef] [PubMed]

X. Heng, D. Erickson, L. R. Baugh, Z. Yaqoob, P. W. Sternberg, D. Psaltis, and C. Yang, “Optofluidic microscopy--a method for implementing a high resolution optical microscope on a chip,” Lab Chip 6(10), 1274–1276 (2006).
[CrossRef] [PubMed]

Nat. Methods

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3(10), 793–796 (2006).
[CrossRef] [PubMed]

Nat. Photonics

C. Monat, P. Domachuk, and B. J. Eggleton, “Integrated optofluidics: A new river of light,” Nat. Photonics 1(2), 106–114 (2007).
[CrossRef]

Nat. Rev. Drug Discov.

P. S. Dittrich and A. Manz, “Lab-on-a-chip: microfluidics in drug discovery,” Nat. Rev. Drug Discov. 5(3), 210–218 (2006).
[CrossRef] [PubMed]

Nature

G. M. Whitesides, “The origins and the future of microfluidics,” Nature 442(7101), 368–373 (2006).
[CrossRef] [PubMed]

D. Psaltis, S. R. Quake, and C. Yang, “Developing optofluidic technology through the fusion of microfluidics and optics,” Nature 442(7101), 381–386 (2006).
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H. Craighead, “Future lab-on-a-chip technologies for interrogating individual molecules,” Nature 442(7101), 387–393 (2006).
[CrossRef] [PubMed]

J. El-Ali, P. K. Sorger, and K. F. Jensen, “Cells on chips,” Nature 442(7101), 403–411 (2006).
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L. Dong, A. K. Agarwal, D. J. Beebe, and H. Jiang, “Adaptive liquid microlenses activated by stimuli-responsive hydrogels,” Nature 442(7102), 551–554 (2006).
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[CrossRef] [PubMed]

K. I. Willig, S. O. Rizzoli, V. Westphal, R. Jahn, and S. W. Hell, “STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis,” Nature 440(7086), 935–939 (2006).
[CrossRef] [PubMed]

Opt. Eng.

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Opt. Express

Opt. Lett.

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

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T. Squires and S. Quake, “Microfluidics: Fluid physics at the nanoliter scale,” Rev. Mod. Phys. 77(3), 977–1026 (2005).
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E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313(5793), 1642–1645 (2006).
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Other

L. M. Lee, X. Cui, and C. Yang, “The application of on-chip optofluidic microscopy for imaging Giardia lamblia trophozoites and cysts,” Biomed Microdevices (2009).

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R. Oosterbroek, Lab-on-a-Chip: Miniaturized Systems for (bio)chemical Analysis and Synthesis, 1st ed. (Elsevier, 2003).

Z. Zalevsky, and D. Mendlovic, Optical Superresolution (Springer Verlag, 2004).

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Figures (9)

Fig. 1
Fig. 1

A schematic of the experimental set-up of Holographic Opto-fluidic Microscopy (HOM). The sample to be imaged flows within a micro-fluidic channel, due to either electro-kinetic or pressure driven motion, and is illuminated by partially coherent light emanating from a large aperture (~0.05-0.1mm) placed ~50-100 mm from the sample. The micro-channel is placed directly on a digital sensor array with no additional manipulation of the sensor-chip. (Not to scale.) The propagation distance between the aperture and the sample allows for spatial coherence to develop at the sample plane, and light scattered by the sample interferes with the background light to form a hologram on the sensor array plane.

Fig. 2
Fig. 2

Electro-kinetic motion: As the object flows through the micro-channel due to electro-kinetic motion, lensfree in-line holograms are continuously captured by the CMOS sensor at a rate of ~5-6 frames/sec. Acquisition of ~15 consecutive frames is sufficient to generate a high-resolution HOM image, but for image comparison purposes, 230 frames were captured during ~45 seconds. (a) The two-dimensional lateral shifts of consecutive frames with respect to the first one. (b) In-plane rotation angles of consecutive frames with respect to the first one. (c) Sub-pixel shifts of 3 sequences (A, B and C), each composed of 15 consecutive frames are shown. These 3 sequences of lensfree raw holograms are used independently to generate 3 different HOM images. Integer pixel shifts are not useful for the super-resolution algorithm and are therefore digitally subtracted out.

Fig. 3
Fig. 3

(a) A super-resolved hologram of a C. elegans sample is shown. This high-resolution hologram is digitally computed using sequence A of Fig. 2 (15 consecutive lensfree raw holograms). (b) An enlarged section of (a), where sub-pixel holographic oscillation are observed. (c) An enlarged section of one of the raw holograms is shown. Contrast is digitally enhanced in (b) and (c) for better visualization of the differences between the raw and super-resolved holograms.

Fig. 4
Fig. 4

HOM images of a C. elegans sample. A single raw lensfree hologram gives a lower resolution image of the object after twin image elimination as shown in the far left image. When using 15 consecutive holographic frames of sequence A (Fig. 2) a super-resolved hologram is synthesized to create higher-resolution amplitude and phase images of the same worm. To demonstrate the robustness of this method, two additional sequences (B and C - see Fig. 2) were independently used to generate similar reconstructed images. The rightmost image of the worm is acquired using a conventional bright field microscope with a 40X objective lens (NA = 0.65), and is provided for comparison.

Fig. 5
Fig. 5

Electro-kinetic HOM images with different number of consecutive frames used as input to the pixel super-resolution algorithm. The images show progressive enhancement with increasing number of frames, however additional frames beyond 15 do not appear to offer further enhancement. ~3 seconds were required to capture 15 frames at 5fps, and a faster frame rate would allow significant reduction in image acquisition time.

Fig. 6
Fig. 6

Pressure flow: By creating a pressure imbalance between the two ends of the micro-fluidic channel, the sample was forced to flow along the channel and frames were continuously captured. Again, only 15 consecutive frames were used to generate the HOM images, but image acquisition continued for ~45 seconds to provide image comparisons. (a) The two-dimensional lateral shifts of consecutive frames with respect to the first one. (b) In-plane rotation angles of consecutive frames with respect to the first one. (c) Sub-pixel shifts of 3 sequences (A, B and C), each composed of 15 consecutive frames are shown.

Fig. 7
Fig. 7

Pressure driven HOM images of a C. elegans sample. As with the electro-kinetic flow case (Fig. 4), we have used 3 different sequences (A, B and C) of 15 consecutive frames to generate 3 independent HOM images. The HOM images from all sequences are comparable. A 10X microscope objective lens image (NA = 0.25) is shown for comparison.

Fig. 8
Fig. 8

HOM imaging results are summarized for a Giardia lamblia cyst and a Mulberry pollen. The low-resolution (LR) hologram exhibit aliasing which is resolved in the super-resolved (SR) hologram. Note that because of the smaller dimensions of these flowing objects, it is not practically feasible to provide the exact microscope comparison images of the same samples, and therefore representative microscope images of the same species are provided. The flow velocity in both cases was 2-3 μm/s, and the flow was electro-kinetic.

Fig. 9
Fig. 9

The radial spectral power of HOM images and images reconstructed from single raw holograms. (a) The radial spectral power of images with electro-kinetic flow (Fig. 4). (b) The radial spectral power of images with pressure flow (Fig. 7). In both cases the image radial frequency bandwidth is approximately doubled, leading to a doubling of the effective numerical aperture of the image. We therefore conclude that HOM has an effective NA of ~0.3-0.4.

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