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


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.


  1. Zhang, J., Campbell, R. E., Ting, A. Y. & Tsien, R. Y. Creating new fluorescent probes for cell biology. Nature Rev. Mol. Cell Biol. 3, 906–918 (2002); erratum. 4, 80 (2003)

    CAS  Article  Google Scholar 

  2. Michalet, X. et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–554 (2005)

    ADS  CAS  Article  Google Scholar 

  3. Anker, J. N. et al. Biosensing with plasmonic nanosensors. Nature Mater. 7, 442–453 (2008)

    ADS  CAS  Article  Google Scholar 

  4. Hilderbrand, S. A. & Weissleder, R. Near-infrared fluorescence: application to in vivo molecular imaging. Curr. Opin. Chem. Biol. 14, 71–79 (2010)

    CAS  Article  Google Scholar 

  5. Yoo, B. & Pagel, M. D. An overview of responsive MRI contrast agents for molecular imaging. Front. Biosci. 13, 1733–1752 (2008)

    CAS  Article  Google Scholar 

  6. Martinez, G. V. et al. Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents. NMR Biomed. 24, 1380–1391 (2011)

    CAS  Article  Google Scholar 

  7. Schröder, L., Lowery, T. J., Hilty, C., Wemmer, D. E. & Pines, A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science 314, 446–449 (2006)

    ADS  Article  Google Scholar 

  8. Woods, M., Woessner, D. E. & Sherry, A. D. Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. Chem. Soc. Rev. 35, 500–511 (2006)

    CAS  Article  Google Scholar 

  9. Ward, K. M. & Balaban, R. S. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn. Reson. Med. 44, 799–802 (2000)

    CAS  Article  Google Scholar 

  10. Zabow, G., Dodd, S., Moreland, J. & Koretsky, A. Micro-engineered local field control for high-sensitivity multispectral MRI. Nature 453, 1058–1063 (2008)

    ADS  CAS  Article  Google Scholar 

  11. Zabow, G., Dodd, S. J., Moreland, J. & Koretsky, A. P. The fabrication of uniform cylindrical shells and their use as spectrally tunable MRI contrast agents. Nanotechnology 20, 385301 (2009)

    CAS  Article  Google Scholar 

  12. Zabow, G., Dodd, S. J. & Koretsky, A. P. Ellipsoidal microcavities: electromagnetic properties, fabrication, and use as multispectral MRI agents. Small 10, 1902–1907 (2014)

    CAS  Article  Google Scholar 

  13. Wang, X., Wang, C., Anderson, S. & Zhang, X. Microfabricated iron oxide particles for tunable, multispectral magnetic resonance imaging. Mater. Lett. 110, 122–126 (2013)

    CAS  Article  Google Scholar 

  14. Wang, C., Wang, X., Anderson, S. W. & Zhang, X. Biocompatible, micro- and nano-fabricated magnetic cylinders for potential use as contrast agents for magnetic resonance imaging. Sens. Actuators B Chem. 196, 670–675 (2014)

    CAS  Article  Google Scholar 

  15. Peppas, N. A., Hilt, J. Z., Khademhosseini, A. & Langer, R. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv. Mater. 18, 1345–1360 (2006)

    CAS  Article  Google Scholar 

  16. Pan, J. W., Hamm, J. R., Rothman, D. L. & Shulman, R. G. Intracellular pH in human skeletal muscle by 1H NMR. Proc. Natl Acad. Sci. USA 85, 7836–7839 (1988)

    ADS  CAS  Article  Google Scholar 

  17. Taylor, J. S. & Deutsch, C. Fluorinated α-methylamino acids as 19F NMR indicators of intracellular pH. Biophys. J. 43, 261–267 (1983)

    CAS  Article  Google Scholar 

  18. Moon, R. B. & Richards, J. H. Determination of intracellular pH by 31P magnetic resonance. J. Biol. Chem. 248, 7276–7278 (1973)

    CAS  Article  Google Scholar 

  19. Wu, Y., Soesbe, T. C., Kiefer, G. E., Zhao, P. & Sherry, A. D. A responsive europium(III) chelate that provides a direct readout of pH by MRI. J. Am. Chem. Soc. 132, 14002–14003 (2010)

    CAS  Article  Google Scholar 

  20. Gallagher, F. A. et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453, 940–943 (2008)

    ADS  CAS  Article  Google Scholar 

  21. Jindal, A. K. et al. Hyperpolarized 89Y complexes as pH sensitive NMR probes. J. Am. Chem. Soc. 132, 1784–1785 (2010)

    CAS  Article  Google Scholar 

  22. Wu, Y. et al. Polymeric PARACEST agents for enhancing MRI contrast sensitivity. J. Am. Chem. Soc. 130, 13854–13855 (2008)

    CAS  Article  Google Scholar 

  23. Aime, S., Delli Castelli, D. & Terreno, E. Supramolecular adducts between poly-L-arginine and [TmIIIdotp]: a route to sensitivity-enhanced magnetic resonance imaging-chemical exchange saturation transfer agents. Angew. Chem. Int. Ed. 42, 4527–4529 (2003)

    CAS  Article  Google Scholar 

  24. Zabow, G., Koretsky, A. P. & Moreland, J. Design and fabrication of a micromachined multispectral magnetic resonance imaging agent. J. Micromech. Microeng. 19, 025020 (2009)

    ADS  Article  Google Scholar 

  25. Sun, J.-Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012)

    ADS  CAS  Article  Google Scholar 

  26. Byrne, M. E., Park, K. & Peppas, N. A. Molecular imprinting within hydrogels. Adv. Drug Deliv. Rev. 54, 149–161 (2002)

    CAS  Article  Google Scholar 

  27. Fischel-Ghodsian, F., Brown, L., Mathiowitz, E., Brandendurg, D. & Langer, R. Enzymatically controlled drug delivery. Proc. Natl Acad. Sci. USA 85, 2403–2406 (1988)

    ADS  CAS  Article  Google Scholar 

  28. Plunkett, K. N., Berkowski, K. L. & Moore, J. S. Chymotrypsin responsive hydrogel: application of a disulfide exchange protocol for the preparation of methacrylamide containing peptides. Biomacromolecules 6, 632–637 (2005)

    CAS  Article  Google Scholar 

  29. Miyata, T., Asami, N. & Uragami, T. A reversibly antigen-responsive hydrogel. Nature 399, 766–769 (1999)

    ADS  CAS  Article  Google Scholar 

  30. Shapiro, E. M., Skrtic, S. & Koretsky, A. P. Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn. Reson. Med. 53, 329–338 (2005)

    Article  Google Scholar 

  31. Madou, M. J. Fundamentals of Microfabrication: the Science of Miniaturization (CRC Press, 2002)

    Book  Google Scholar 

  32. Kabiri, K., Mirzadeh, H. & Zohuriaan-Mehr, M. J. Undesirable effects of heating on hydrogels. J. Appl. Polym. Sci. 110, 3420–3430 (2008)

    CAS  Article  Google Scholar 

  33. Ulijn, R. V. et al. Bioresponsive hydrogels. Mater. Today 10, 40–48 (2007)

    CAS  Article  Google Scholar 

  34. Decker, C. & Jenkins, A. D. Kinetic approach of O2 inhibition in ultraviolet- and laser-induced polymerizations. Macromolecules 18, 1241–1244 (1985)

    ADS  CAS  Article  Google Scholar 

  35. Yoon, J., Cai, S., Suo, Z. & Hayward, R. C. Poroelastic swelling kinetics of thin hydrogel layers: comparison of theory and experiment. Soft Matter 6, 6004–6012 (2010)

    ADS  CAS  Article  Google Scholar 

  36. Henkelman, R. M., Stanisz, G. J. & Graham, S. J. Magnetization transfer in MRI: a review. NMR Biomed. 14, 57–64 (2001)

    CAS  Article  Google Scholar 

  37. Grad, J. & Bryant, R. G. Nuclear magnetic cross-relaxation spectroscopy. J. Magn. Reson. 90, 1–8 (1990)

    ADS  CAS  Google Scholar 

  38. Jorjani, P. & Ozturk, S. S. Effects of cell density and temperature on oxygen consumption rate for different mammalian cell lines. Biotechnol. Bioeng. 64, 349–356 (1999)

    CAS  Article  Google Scholar 

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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.

Author information

Authors and Affiliations



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 ao.

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).

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