Article | Published:

Focal molography is a new method for the in situ analysis of molecular interactions in biological samples

Nature Nanotechnology volume 12, pages 10891095 (2017) | Download Citation

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Abstract

Focal molography is a next-generation biosensor that visualizes specific biomolecular interactions in real time. It transduces affinity modulation on the sensor surface into refractive index modulation caused by target molecules that are bound to a precisely assembled nanopattern of molecular recognition sites, termed the ‘mologram’. The mologram is designed so that laser light is scattered at specifically bound molecules, generating a strong signal in the focus of the mologram via constructive interference, while scattering at nonspecifically bound molecules does not contribute to the effect. We present the realization of molograms on a chip by submicrometre near-field reactive immersion lithography on a light-sensitive monolithic graft copolymer layer. We demonstrate the selective and sensitive detection of biomolecules, which bind to the recognition sites of the mologram in various complex biological samples. This allows the label-free analysis of non-covalent interactions in complex biological samples, without a need for extensive sample preparation, and enables novel time- and cost-saving ways of performing and developing immunoassays for diagnostic tests.

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Change history

  • 25 October 2017

    In the version of this Article originally published, the illumination pattern below the phase mask was incorrectly positioned in Fig. 1b (ii) and Zeptosens was misspelled in two instances in Methods. These errors have been corrected in all versions of the Article.

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Acknowledgements

The authors thank V. Guzenko (ETH) and W. Arens (IMT) for technical support in fabrication of the phase mask, S. Tosatti (SuSoS) and S. Zürcher (SuSoS) for consulting regarding surface science questions and production of the copolymer, A. Nichtl (Roche Diagnostics) for support with various reagents, H.P. Herzig (EPFL) and A. Naqavi (EPFL) for support with numerical simulations and J. Hehl and T. Schwarz (ScopeM/ETH) for STED support. For designing and fabricating numerous hardware components, the authors thank T. Kissling, R. Rietmann (Roche) and S. Wheeler (ETH). The authors also thank A. Lieb for support with ZeptoReader-related issues. The authors thank the following for discussions on various aspects of the project: M. Hennig, K. Mueller, M. Lauer, A. Rufer, G. Dernick, M. Marcinowski, M. Essenpreis, M. Hein, O. Gutmann, A. Drechsler, M. Glauser, N. Milicevic, J. Spinke, A. Maurer, C. Patsch, C. Cusulin, J. Fingerle, R. Staack and A. Poehler. The authors acknowledge the Roche Postdoc Fellowship (RPF) Program, ETH Zurich and the NCCR Molecular Systems Engineering for funding.

Author information

Author notes

    • Volker Gatterdam
    •  & Andreas Frutiger

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, ETH Zurich, 8092 Zurich, Switzerland

    • Volker Gatterdam
    • , Andreas Frutiger
    •  & Janos Vörös
  2. Roche Diagnostics GmbH, 82377 Penzberg, Germany

    • Klaus-Peter Stengele
    •  & Dieter Heindl
  3. Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland

    • Thomas Lübbers
    •  & Christof Fattinger

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Contributions

Experiments were designed by V.G., K.-P.S., D.H., T.L., J.V. and C.F. C.F. performed the calculations for the phase mask and all other optical components. Molographic experiments were performed by V.G. A.F. performed the numerical simulations and wrote the evaluation software with support from J.V. and C.F. All authors read and approved the manuscript for submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Janos Vörös or Christof Fattinger.

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DOI

https://doi.org/10.1038/nnano.2017.168

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