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Shape-changing magnetic assemblies as high-sensitivity NMR-readable nanoprobes

Nature volume 520, pages 73–77 (2015)Cite this article

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Abstract

Fluorescent and plasmonic labels and sensors have revolutionized molecular biology, helping visualize cellular and biomolecular processes1,2,3. Increasingly, such probes are now being designed to respond to wavelengths in the near-infrared region, where reduced tissue autofluorescence and photon attenuation enable subsurface in vivo sensing4. But even in the near-infrared region, optical resolution and sensitivity decrease rapidly with increasing depth. Here we present a sensor design that obviates the need for optical addressability by operating in the nuclear magnetic resonance (NMR) radio-frequency spectrum, where signal attenuation and distortion by tissue and biological media are negligible, where background interferences vanish, and where sensors can be spatially located using standard magnetic resonance imaging (MRI) equipment. The radio-frequency-addressable sensor assemblies presented here comprise pairs of magnetic disks spaced by swellable hydrogel material; they reversibly reconfigure in rapid response to chosen stimuli, to give geometry-dependent, dynamic NMR spectral signatures. The sensors can be made from biocompatible materials, are themselves detectable down to low concentrations, and offer potential responsive NMR spectral shifts that are close to a million times greater than those of traditional magnetic resonance spectroscopies. Inherent adaptability should allow such shape-changing systems to measure numerous different environmental and physiological indicators, thus providing broadly generalizable, MRI-compatible, radio-frequency analogues to optically based probes for use in basic chemical, biological, medical and engineering research.

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Figure 1: Principles of shape-changing RF colorimetric sensors.
Figure 2: Spatiotemporal mapping of ion concentrations.
Figure 3: Tracking cell metabolism.
Figure 4: Sensor multiplexing.

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Acknowledgements

This work was supported in part by the NIH NINDS Intramural Research Program. We thank the NIH Mouse Imaging Facility for use of their 14 T MRI, Y. Chen for providing the MDCK cells, and J. Moreland for discussion and NIST Boulder cleanroom access.

Author information

Authors and Affiliations

  1. Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    G. Zabow, S. J. Dodd & A. P. Koretsky

  2. Electromagnetics Division, Physical Measurements Laboratory, National Institute of Standards and Technology, Boulder, 80305, Colorado, USA

    G. Zabow

Authors
  1. G. Zabow
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  2. S. J. Dodd
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  3. A. P. Koretsky
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Contributions

G.Z. conceived of the project, designed the experiments, fabricated the sensors, analysed the data, and wrote the manuscript. S.J.D. designed all NMR/MRI pulse sequences used, helped acquire all NMR/MRI data, and helped write the manuscript. A.P.K. oversaw the work, provided critical feedback, and helped write the manuscript.

Corresponding author

Correspondence to G. Zabow.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Schematic of microfabrication protocol.

See Methods for explanation of panels a–o.

Extended Data Figure 2 Hydrogel expansion.

Hydrogel sample in compressed (top) and expanded (bottom) state, showing ∼20% linear expansion.

Extended Data Figure 3 Diffusion simulations.

Logarithmically shaded (greyscale bar) plots of numerically simulated ion-concentrations (normalized to initial concentration of unity) due to diffusion between pH buffer solution and water-based agarose gel.

Extended Data Figure 4 Pulse protocol.

Schematic showing off-resonant preparatory pulse train, followed by on-resonant excitation pulse and free-induction-decay (FID) acquisition. The sequence is repeated, each time with different offset frequency, to acquire each point in the z-spectrum.

Extended Data Figure 5 Sensor sensitivity.

z-spectrum, showing magnetization saturated out MS, normalized to the initial water magnetization M0, from sensors with Fe disks of radii 900 nm and thickness 10 nm with resonance around –325 kHz.

Extended Data Figure 6 Sensor miniaturization.

z-spectrum, showing magnetization saturated out MS, normalized to the initial water magnetization M0, for double-disk structures of radii 250 nm with resonance around –525 kHz.

Extended Data Figure 7 Optically probed sensor response rates.

Top panel, a series of consecutive still frames from Supplementary Video 1, showing the propagation of an acid front over an array of sensors. The resulting changes in reflected colours are due to changes in spacing between the top and bottom disks of the sensor, indicating rapid sensor response to introduced acid. Bottom panels, reflected light intensity in green and red channels (normalized to average light intensity across all colour channels) recorded frame-by-frame at the substrate points a and b indicated in leftmost top panel. Slightly different starting and end points within colour oscillation are due to unintentional sensor microfabrication variation across the substrate.

Supplementary information

Video 1: Sensor response to acid pulse (observed through optical intereference)

The video (in real-time at 30 frames per second) shows rapid colour change, which implies rapid sensor response, following the acid front (see online methods). (MP4 1029 kb)

Video S2: Sensor enabled MRI mapping of diffusion-driven spatial ion concentration variations

This animated file, derived from the sensor-recorded ion concentration data was generated by automatically curve-fitting all z-spectra collected, in space and time. The animation comprises a sequential time series of spatial maps of the measured sensor resonant frequencies (see online methods). (MP4 656 kb)

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Zabow, G., Dodd, S. & Koretsky, A. Shape-changing magnetic assemblies as high-sensitivity NMR-readable nanoprobes. Nature 520, 73–77 (2015). https://doi.org/10.1038/nature14294

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