Abstract
The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and analysis. Here we report the use of a microneedle patch for fast in vivo sampling and on-needle quantification of target protein biomarkers in interstitial fluid. We used plasmonic fluor—an ultrabright fluorescent label—to improve the limit of detection of various interstitial fluid protein biomarkers by nearly 800-fold compared with conventional fluorophores, and a magnetic backing layer to implement conventional immunoassay procedures on the patch and thus improve measurement consistency. We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum—a challenging site for biomarker detection—and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids. Microneedle patches for the minimally invasive collection and analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw data are available from figshare at https://doi.org/10.6084/m9.figshare.13331366.
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Acknowledgements
We acknowledge support from the National Science Foundation (CBET-1900277) and the National Institutes of Health (R01DE027098, R56DE027924, R01CA141521, R21DA036663, R21CA236652). We thank the Nano Research Facility and Institute of Materials Science and Engineering at Washington University for providing access to electron microscopy facilities, N. Huebsch for providing access to the fluorescence microscope, K. Magee for the help with mouse experiments, Y. Diao for help with digital photographs and M. Shen for inspiring discussions.
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S.S., Z.W. and J.L. conceived the project. S.S., J.S.R., E.L.S., Z.W. and J.L. designed the experiments. Z.W., J.L. and M.Y. fabricated the microneedle patches. Z.W., A.S., L.L., X.Z., J.S.R. and E.L.S. performed the animal experiments. Z.W., J.L., A.S., L.L., Q.Z. and J.J.M. performed the bioassays. J.L. and Q.J. synthesized the plasmonic fluors. P.G. synthesized the magnetic nanoparticles. R.G. performed TEM imaging. P.R. and Y.W. performed SEM imaging. S.C. collected fluorescence images of the microneedles. S.S., J.S.R., E.L.S., J.J.M., Z.W. and J.L. wrote the paper. All authors reviewed and commented on the manuscript.
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The authors declare the following competing financial interests: J.L., J.J.M. and S.S. are inventors on a provisional patent related to plasmonic fluor technology and the technology has been licensed by the Office of Technology Management at Washington University in St Louis to Auragent Bioscience LLC, which is developing plasmonic fluor products. J.L., J.J.M. and S.S. are co-founders and shareholders of Auragent Bioscience LLC. These potential conflicts of interest have been disclosed and are being managed by Washington University in St Louis.
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Wang, Z., Luan, J., Seth, A. et al. Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid. Nat Biomed Eng 5, 64–76 (2021). https://doi.org/10.1038/s41551-020-00672-y
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DOI: https://doi.org/10.1038/s41551-020-00672-y
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