• Featured in Physics
  • Open Access

Focal Molography: Coherent Microscopic Detection of Biomolecular Interaction

Christof Fattinger
Phys. Rev. X 4, 031024 – Published 11 August 2014; Erratum Phys. Rev. X 4, 049901 (2014)
Physics logo See Viewpoint: Coherent Signal Picks Out Biomolecular Interactions
PDFHTMLExport Citation

Abstract

We introduce and theoretically investigate here a novel analytical method that we have called focal molography, in which molecular interactions are made visible through scattering of coherent light by a coherent pattern of molecules. The scattered light quantifies the presence of molecules at molecular interaction sites. It is separated from noncoherent background scatter by a combination of local dark-field illumination, interference enhancement, and spatial filtering. The latter is achieved by holographic focusing of the wave field generated by the coherently assembled molecules onto an Airy disk and by subtraction of the noncoherent irradiance in the focal plane outside the disk from the irradiance in the disk. This new microscopic method allows distinct detection of low-refractive-index contrast in the nanoenvironment of biomolecules from which information on the interaction of the coherently assembled molecules with molecules in a liquid or gaseous sample may be deduced. The noncoherent surroundings of the coherently assembled molecules consist of freely diffusing solvent and solute molecules. The surroundings, as well as changes in temperature, do not contribute to the coherent signal in the diffraction focus. Interference lithography or high-resolution-imaging lithography can be used to synthesize the coherent pattern of molecules on a monolithic substrate. The coherent pattern of molecules constitutes a synthetic phase hologram that creates a diffraction-limited light wave. We suggest the term “mologram” for the coherent assembly of functional nanostructures and the term “focal molography” for label-free or labeled analysis of molecular interactions through the measurement of the properties of light in the focus of the mologram. We derive analytical formulas that express the detection signal and the sensitivity of focal molography on the surface of a high-refractive-index thin-film optical waveguide in terms of known parameters. We discuss the implementation of a readout system for molograms on a thin-film optical waveguide by adapting a confocal laser-scanning microscope to a bifocal laser-scanning microscope.

  • Figure
  • Figure
  • Figure
  • Figure
  • Figure
  • Received 29 July 2013
  • Corrected 17 October 2014

DOI:https://doi.org/10.1103/PhysRevX.4.031024

This article is available under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.

Published by the American Physical Society

Corrections

17 October 2014

Erratum

Viewpoint

Key Image

Coherent Signal Picks Out Biomolecular Interactions

Published 11 August 2014

A new analytical technique, with unique advantages over existing molecular sensing methods, would allow the ultrasensitive and selective characterization of biomolecular interactions on a chip.

See more in Physics

Authors & Affiliations

Christof Fattinger*

  • Roche Pharmaceutical Research and Early Development, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland

  • *christof.fattinger@roche.com

Popular Summary

Current state-of-the-art molecular sensing devices have a number of shortcomings and limited sensitivity. In particular, nonbiospecific interactions of solute and solvent molecules to the sensor surface can interfere with the measurement of a biospecific molecular interaction. Our novel analytical method “focal molography” can overcome these limitations; focal molography relies on using diffraction-limited focusing of light.

Focal molography combines state-of-the-art lithography, molecular self-assembly, and optical technology into one powerful technique. The technique allows biospecific molecular binding to be observed by cleverly exploiting the weak diffraction of light by a coherent pattern of molecules (or nanoparticles). Molecules that bind nonspecifically to the sensor surface contribute only incoherently to the sensor signal, and the coherent signal from analyte molecules on the sensor surface is much stronger than the signal from molecules that contribute incoherently. The focal molography method has two unique advantages in comparison with existing molecular sensing methods: (i) it eliminates the effect of nonbiospecific binding, which is the limiting factor in all current state-of-the-art molecular sensing devices, and (ii) it has a very high sensitivity that can be amplified by increasing the size of the sensor.

Focal molography is expected to open new investigative possibilities in the analysis of biospecific affinity binding with broad application potentials in molecular biology and diagnostics. Our method may furthermore enable the detection of diagnostic biomarkers by a small optoelectronic device.

Key Image

Article Text

Click to Expand

Supplemental Material

Click to Expand

References

Click to Expand
Issue

Vol. 4, Iss. 3 — July - September 2014

Subject Areas
Reuse & Permissions
Author publication services for translation and copyediting assistance advertisement

Authorization Required


×
×

Images

×

Sign up to receive regular email alerts from Physical Review X

Reuse & Permissions

It is not necessary to obtain permission to reuse this article or its components as it is available under the terms of the Creative Commons Attribution 3.0 License. This license permits unrestricted use, distribution, and reproduction in any medium, provided attribution to the author(s) and the published article's title, journal citation, and DOI are maintained. Please note that some figures may have been included with permission from other third parties. It is your responsibility to obtain the proper permission from the rights holder directly for these figures.

×

Log In

Cancel
×

Search


Article Lookup

Paste a citation or DOI

Enter a citation
×