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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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.
The authors declare no competing financial interests.
Extended data figures and tables
See Methods for explanation of panels a–o.
Hydrogel sample in compressed (top) and expanded (bottom) state, showing ∼20% linear expansion.
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.
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.
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.
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.
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.
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)
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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