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Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy

Nature Methods volume 9, pages 889–895 (2012)Cite this article

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Abstract

We discuss unique features of lens-free computational imaging tools and report some of their emerging results for wide-field on-chip microscopy, such as the achievement of a numerical aperture (NA) of ∼0.8–0.9 across a field of view (FOV) of more than 20 mm2 or an NA of ∼0.1 across a FOV of ∼18 cm2, which corresponds to an image with more than 1.5 gigapixels. We also discuss the current challenges that these computational on-chip microscopes face, shedding light on their future directions and applications.

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Figure 1: Partially coherent lens-free on-chip microscope.
Figure 2: Lens-free gigapixel imaging using a CCD sensor chip.
Figure 3: High–numerical aperture lens-free imaging using a color CMOS sensor chip.

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References

  1. Garcia-Sucerquia, J., Xu, W., Jericho, M.H. & Kreuzer, H.J. Immersion digital in-line holographic microscopy. Opt. Lett. 31, 1211–1213 (2006).This work introduces oil-immersion microscopy in lens-free holographic imaging.

    Article  CAS  Google Scholar 

  2. Garcia-Sucerquia, J. et al. Digital in-line holographic microscopy. Appl. Opt. 45, 836–850 (2006).

    Article  Google Scholar 

  3. Kanka, M., Riesenberg, R. & Kreuzer, H.J. Reconstruction of high-resolution holographic microscopic images. Opt. Lett. 34, 1162–1164 (2009).

    Article  CAS  Google Scholar 

  4. Kanka, M., Riesenberg, R., Petruck, P. & Graulig, C. High resolution (NA=0.8) in lensless in-line holographic microscopy with glass sample carriers. Opt. Lett. 36, 3651–3653 (2011).

    Article  CAS  Google Scholar 

  5. Mudanyali, O. et al. Compact, light-weight and cost-effective microscope based on lensless incoherent holography for telemedicine applications. Lab Chip 10, 1417–1428 (2010).

    Article  CAS  Google Scholar 

  6. Bishara, W., Su, T.-W., Coskun, A.F. & Ozcan, A. Lensfree on-chip microscopy over a wide field-of-view using pixel super-resolution. Opt. Express 18, 11181–11191 (2010).

    Article  Google Scholar 

  7. Bishara, W. et al. Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array. Lab Chip 11, 1276–1279 (2011).This work, together with ref. 6, introduces the use of pixel super-resolution algorithms in lens-free on-chip microscopy for mitigating the pixel size limitation under unit magnification.

    Article  CAS  Google Scholar 

  8. Bishara, W., Zhu, H. & Ozcan, A. Holographic opto-fluidic microscopy. Opt. Express 18, 27499–27510 (2010).

    Article  CAS  Google Scholar 

  9. Mudanyali, O., Bishara, W. & Ozcan, A. Lensfree super-resolution holographic microscopy using wetting films on a chip. Opt. Express 19, 17378–17389 (2011).

    Article  CAS  Google Scholar 

  10. Greenbaum, A., Sikora, U. & Ozcan, A. Field-portable wide-field microscopy of dense samples using multi-height pixel super-resolution based lensfree imaging. Lab Chip 12, 1242–1245 (2012).

    Article  CAS  Google Scholar 

  11. Stybayeva, G. et al. Lensfree holographic imaging of antibody microarrays for high-throughput detection of Leukocyte numbers and function. Anal. Chem. 82, 3736–3744 (2010).

    Article  CAS  Google Scholar 

  12. Su, T.-W., Erlinger, A., Tseng, D. & Ozcan, A. Compact and light-weight automated semen analysis platform using lensfree on-chip microscopy. Anal. Chem. 82, 8307–8312 (2010).

    Article  CAS  Google Scholar 

  13. Isikman, S.O., Bishara, W., Zhu, H. & Ozcan, A. Optofluidic tomography on a chip. Appl. Phys. Lett. 98, 161109 (2011).

    Article  Google Scholar 

  14. Isikman, S.O. et al. Lens-free optical tomographic microscope with a large imaging volume on a chip. Proc. Natl. Acad. Sci. USA 108, 7296–7301 (2011).This work introduces lens-free tomographic imaging on a chip.

    Article  CAS  Google Scholar 

  15. Brady, D.J., Choi, K., Marks, D.L., Horisaki, R. & Lim, S. Compressive holography. Opt. Express 17, 13040–13049 (2009).This work introduces compressive holographic imaging.

    Article  CAS  Google Scholar 

  16. Hahn, J., Lim, S., Choi, K., Horisaki, R. & Brady, D.J. Video-rate compressive holographic microscopic tomography. Opt. Express 19, 7289–7298 (2011).

    Article  Google Scholar 

  17. Lee, M., Yaglidere, O. & Ozcan, A. Field-portable reflection and transmission microscopy based on lensless holography. Biomed. Opt. Express 2, 2721–2730 (2011).

    Article  Google Scholar 

  18. Cui, X. et al. Lensless high-resolution on-chip optofluidic microscopes for Caenorhabditis elegans and cell imaging. Proc. Natl. Acad. Sci. USA 105, 10670–10675 (2008).This work introduces an optofluidic lens-free microscope that is based on sampling of flowing object shadows.

    Article  CAS  Google Scholar 

  19. Pang, S. et al. Implementation of a color-capable optofluidic microscope on a RGB CMOS color sensor chip substrate. Lab Chip 10, 411–414 (2010).

    Article  CAS  Google Scholar 

  20. Zheng, G., Lee, S.A., Antebi, Y., Elowitz, M.B. & Yang, C. The ePetri dish, an on-chip cell imaging platform based on subpixel perspective sweeping microscopy (SPSM). Proc. Natl. Acad. Sci. USA 108, 16889–16894 (2011).This work introduces contact-mode lens-free shadow imaging of static objects.

    Article  CAS  Google Scholar 

  21. Lee, S.A. et al. Color capable sub-pixel resolving optofluidic microscope and its application to blood cell imaging for Malaria diagnosis. PLoS ONE 6, e26127 (2011).

    Article  CAS  Google Scholar 

  22. Maiden, A.M., Humphry, M.J., Zhang, F. & Rodenburg, J.M. Superresolution imaging via ptychography. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 28, 604–612 (2011).

    Article  Google Scholar 

  23. Maiden, A.M., Rodenburg, J.M. & Humphry, M.J. Optical ptychography: a practical implementation with useful resolution. Opt. Lett. 35, 2585–2587 (2010).

    Article  Google Scholar 

  24. Martínez-León, L. & Javidi, B. Synthetic aperture single-exposure on-axis digital holography. Opt. Express 16, 161–169 (2008).

    Article  Google Scholar 

  25. Kikuchi, Y., Barada, D., Kiire, T. & Yatagai, T. Doppler phase-shifting digital holography and its application to surface shape measurement. Opt. Lett. 35, 1548–1550 (2010).

    Article  Google Scholar 

  26. Coskun, A.F., Sencan, I., Su, T.-W. & Ozcan, A. Lensless wide-field fluorescent imaging on a chip using compressive decoding of sparse objects. Opt. Express 18, 10510–10523 (2010).

    Article  CAS  Google Scholar 

  27. Coskun, A.F., Sencan, I., Su, T.-W. & Ozcan, A. Lensfree fluorescent on-chip imaging of transgenic Caenorhabditis elegans over an ultra-wide field of view. PLoS One 6, e15955 (2011).This work, together with ref. 26, introduces the use of compressive decoding for lens-free fluorescence on-chip imaging.

    Article  CAS  Google Scholar 

  28. Coskun, A.F., Sencan, I., Su, T.-W. & Ozcan, A. Wide-field lensless fluorescent microscopy using a tapered fiber-optic faceplate on a chip. Analyst 136, 3512–3518 (2011).

    Article  CAS  Google Scholar 

  29. Pang, S., Han, C., Lee, L.M. & Yang, C. Fluorescence microscopy imaging with a Fresnel zone plate array based optofluidic microscope. Lab Chip 11, 3698–3702 (2011).

    Article  CAS  Google Scholar 

  30. Chapman, H.N. & Nugent, K.A. Coherent lensless X-ray imaging. Nat. Photonics 4, 833–839 (2010).

    Article  CAS  Google Scholar 

  31. Nugent, K.A. Coherent methods in the X-ray sciences. Adv. Phys. 59, 1–99 (2010).

    Article  Google Scholar 

  32. Abbey, B. et al. Lensless imaging using broadband X-ray sources. Nat. Photonics 5, 420–424 (2011).

    Article  CAS  Google Scholar 

  33. Miao, J., Charalambous, P., Kirz, J. & Sayre, D. Extending the methodology of X-ray crystallography to allow imaging of micrometre-sized non-crystalline specimens. Nature 400, 342–344 (1999).

    Article  CAS  Google Scholar 

  34. Miao, J., Kirz, J. & Sayre, D. The oversampling phasing method. Acta Crystallogr. D. Biol. Crystallogr. 56, 1312–1315 (2000).

    Article  CAS  Google Scholar 

  35. Chen, C.-C., Miao, J., Wang, C.W. & Lee, T.K. Application of optimization technique to noncrystalline x-ray diffraction microscopy: guided hybrid input-output method. Phys. Rev. B 76, 064113 (2007).

    Article  Google Scholar 

  36. Humphry, M.J., Kraus, B., Hurst, A.C., Maiden, A.M. & Rodenburg, J.M. Ptychographic electron microscopy using high-angle dark-field scattering for sub-nanometre resolution imaging. Nat. Commun. 3, 730 (2012).

    Article  CAS  Google Scholar 

  37. Szameit, A. et al. Sparsity-based single-shot subwavelength coherent diffractive imaging. Nat. Mater. 11, 455–459 (2012).

    Article  CAS  Google Scholar 

  38. Thibault, P. Algorithmic Methods in Diffraction Microscopy (Cornell University, 2007).

  39. Miao, J., Sayre, D. & Chapman, H.N. Phase retrieval from the magnitude of the Fourier transforms of nonperiodic objects. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 15, 1662–1669 (1998).

    Article  Google Scholar 

  40. Millane, R.P. Phase retrieval in crystallography and optics. J. Opt. Soc. Am. A 7, 394–411 (1990).

    Article  Google Scholar 

  41. Allen, L.J. & Oxley, M.P. Phase retrieval from series of images obtained by defocus variation. Opt. Commun. 199, 65–75 (2001).

    Article  CAS  Google Scholar 

  42. Zhang, F., Pedrini, G. & Osten, W. Phase retrieval of arbitrary complex-valued fields through aperture-plane modulation. Phys. Rev. A 75, 043805 (2007).

    Article  Google Scholar 

  43. Repetto, L., Piano, E. & Pontiggia, C. Lensless digital holographic microscope with light-emitting diode illumination. Opt. Lett. 29, 1132–1134 (2004).

    Article  CAS  Google Scholar 

  44. Dubois, F., Joannes, L. & Legros, J.C. Improved three-dimensional imaging with a digital holography microscope with a source of partial spatial coherence. Appl. Opt. 38, 7085–7094 (1999).

    Article  CAS  Google Scholar 

  45. Park, S.C., Park, M.K. & Kang, M.G. Super-resolution image reconstruction: a technical overview. IEEE Signal Process. Mag. 20, 21–36 (2003).

    Article  Google Scholar 

  46. Hardie, R.C., Barnard, K.J., Bognar, J.G., Armstrong, E.E. & Watson, E.A. High-resolution image reconstruction from a sequence of rotated and translated frames and its application to an infrared imaging system. Opt. Eng. 37, 247–260 (1998).

    Article  Google Scholar 

  47. Elad, M. & Hel-Or, Y. A fast super-resolution reconstruction algorithm for pure translational motion and common space-invariant blur. IEEE Trans. Image Process. 10, 1187–1193 (2001).

    Article  CAS  Google Scholar 

  48. Fienup, J.R. Phase retrieval algorithms: a comparison. Appl. Opt. 21, 2758–2769 (1982).

    Article  CAS  Google Scholar 

  49. Denis, L., Fournier, C., Fournel, T. & Ducottet, C. Numerical suppression of the twin image in in-line holography of a volume of micro-objects. Meas. Sci. Technol. 19, 074004 (2008).

    Article  Google Scholar 

  50. Charrière, F. et al. Living specimen tomography by digital holographic microscopy: morphometry of testate amoeba. Opt. Express 14, 7005–7013 (2006).

    Article  Google Scholar 

  51. Dierolf, M. et al. Ptychographic X-ray computed tomography at the nanoscale. Nature 467, 436–439 (2010).

    Article  CAS  Google Scholar 

  52. Rivenson, Y., Stern, A. & Javidi, B. Compressive Fresnel holography. J. Disp. Technol. 6, 506–509 (2010).

    Article  Google Scholar 

  53. Saini, A. New lens offers scientist a brighter outlook. Science 335, 1562–1563 (2012).

    Article  CAS  Google Scholar 

  54. Schumacher, S. et al. Highly-integrated lab-on-chip system for point-of-care multiparameter analysis. Lab Chip 12, 464–473 (2012).

    Article  CAS  Google Scholar 

  55. Srigunapalan, S., Eydelnant, I.A., Simmons, C.A. & Wheeler, A.R. A digital microfluidic platform for primary cell culture and analysis. Lab Chip 12, 369–375 (2012).

    Article  CAS  Google Scholar 

  56. Schnars, U. & Jüptner, W.P.O. Digital recording and numerical reconstruction of holograms. Meas. Sci. Technol. 13, R85–R101 (2002).

    Article  CAS  Google Scholar 

  57. Cuche, E., Marquet, P. & Depeursinge, C. Spatial filtering for zero-order and twin-image elimination in digital off-axis holography. Appl. Opt. 39, 4070–4075 (2000).

    Article  CAS  Google Scholar 

  58. Khademhosseinieh, B. et al. Lensfree on-chip imaging using nanostructured surfaces. Appl. Phys. Lett. 96, 171106 (2010).

    Article  Google Scholar 

  59. Shimobaba, T. et al. Computational wave optics library for C++: CWO++. library. Comput. Phys. Commun. 183, 1124–1138 (2012).

    Article  CAS  Google Scholar 

  60. Trelles, O., Prins, P., Snir, M. & Jansen, R.C. Big data, but are we ready? Nat. Rev. Genet. 12, 224 (2011).

    Article  CAS  Google Scholar 

  61. Mavandadi, S. et al. Distributed medical image analysis and diagnosis through crowd-sourced games: a malaria case study. PLoS One. 7, e37245 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

A.O. gratefully acknowledges the support of the Presidential Early Career Award for Scientists and Engineers, Army Research Office Young Investigator Award, National Science Foundation CAREER Award, Office of Naval Research Young Investigator Award and National Institutes of Health Director′s New Innovator Award DP2OD006427 from the Office of the Director, National Institutes of Health.

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Authors and Affiliations

  1. Electrical Engineering Department, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Alon Greenbaum, Wei Luo, Ting-Wei Su, Zoltán Göröcs, Liang Xue, Serhan O Isikman, Ahmet F Coskun, Onur Mudanyali & Aydogan Ozcan

  2. Department of Bioengineering, UCLA, Los Angeles, California, USA

    Alon Greenbaum, Wei Luo, Ting-Wei Su, Zoltán Göröcs, Liang Xue, Serhan O Isikman, Ahmet F Coskun, Onur Mudanyali & Aydogan Ozcan

  3. Department of Information Physics and Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China

    Liang Xue

  4. California NanoSystems Institute, UCLA, Los Angeles, California, USA

    Aydogan Ozcan

  5. Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA

    Aydogan Ozcan

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  1. Alon Greenbaum
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Correspondence to Aydogan Ozcan.

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A.O. is the founder of a start-up company that aims to commercialize optical imaging–based diagnostics tools.

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Greenbaum, A., Luo, W., Su, TW. et al. Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy. Nat Methods 9, 889–895 (2012). https://doi.org/10.1038/nmeth.2114

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