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  • Perspective
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Opportunities and challenges in the diagnostic utility of dermal interstitial fluid

Nature Biomedical Engineering volume 7, pages 1541–1555 (2023)Cite this article

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Abstract

The volume of interstitial fluid (ISF) in the human body is three times that of blood. Yet, collecting diagnostically useful ISF is more challenging than collecting blood because the extraction of dermal ISF disrupts the delicate balance of pressure between ISF, blood and lymph, and because the triggered local inflammation further skews the concentrations of many analytes in the extracted fluid. In this Perspective, we overview the most meaningful differences in the make-up of ISF and blood, and discuss why ISF cannot be viewed generally as a diagnostically useful proxy for blood. We also argue that continuous sensing of small-molecule analytes in dermal ISF via rapid assays compatible with nanolitre sample volumes or via miniaturized sensors inserted into the dermis can offer clinically advantageous utility, particularly for the monitoring of therapeutic drugs and of the status of the immune system.

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Fig. 1: Structure of the skin, and analyte partitioning into dermal ISF.
Fig. 2: Methods for the extraction of ISF.
Fig. 3: Sampling of dermal ISF for the continuous monitoring of glucose.
Fig. 4: Two successful biosensor formats for continuous sensing.

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Acknowledgements

The authors at the University of Cincinnati acknowledge support from the US Air Force Office of Scientific Research (USAF Contract No. FA9550-20-1-0117), a National Science Foundation CBET Award (No. 2125056), a National Science Foundation ECCS Award (No. 2025720) and a US Office of Naval Research Award (No. N00014-20-1-2764). The authors at Stanford University thank M. Eisenstein for his editorial contributions, and appreciate financial support from W. L Gore and Associates, the Helmsley Trust and the National Institutes of Health (NIH, OT2OD025342). I.A.P.T. acknowledges support from the Medtronic Foundation Stanford Graduate Fellowship and from the Natural Sciences and Engineering Research Council of Canada (NSERC, 416353855). Sandia National Laboratories is a multimission laboratory managed and operated by National Technology and Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International Inc., for the US Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525. This Perspective describes objective technical results and analysis. Any subjective views or opinions that might be expressed here do not necessarily represent the views of the US Department of Energy or the United States Government.

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Author notes

  1. These authors contributed equally: Mark Friedel, Ian A. P. Thompson.

Authors and Affiliations

  1. Novel Device Laboratory, Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA

    Mark Friedel & Jason Heikenfeld

  2. Department of Electrical Engineering, Stanford University, Stanford, CA, USA

    Ian A. P. Thompson & Hyongsok Tom Soh

  3. The James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, OH, USA

    Gerald Kasting

  4. Nano and Micro Sensors, Sandia National Laboratories, Albuquerque, NM, USA

    Ronen Polsky

  5. Department of Chemistry and Physics, Southeast Missouri State University, Cape Girardeau, MO, USA

    David Cunningham

  6. Department of Radiology, Stanford University, Stanford, CA, USA

    Hyongsok Tom Soh

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Contributions

M.F. and I.A.P.T. contributed equally to writing and revising all sections. G.K. contributed to the writing of the sections ‘Structure and composition of the dermis’ and ‘Partitioning of analytes in dermal ISF’. R.P. contributed to the sections ‘Partitioning of analytes in dermal ISF’ and ‘Applications of ISF in diagnostics’. D.C. contributed to the section ‘Challenges in obtaining true ISF via extraction’. J.H. and H.T.S led the project and contributed to the writing and revision of all sections.

Corresponding authors

Correspondence to Hyongsok Tom Soh or Jason Heikenfeld.

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Competing interests

J.H. is a co-founder of Kilele Health Inc., which is pursuing the commercialization of wearables for the continuous monitoring of analytes in ISF. H.T.S. is a co-founder of Eigen Biosciences, which seeks to commercialize technologies for measuring biomarkers in ISF. The other authors declare no competing interests.

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Friedel, M., Thompson, I.A.P., Kasting, G. et al. Opportunities and challenges in the diagnostic utility of dermal interstitial fluid. Nat. Biomed. Eng 7, 1541–1555 (2023). https://doi.org/10.1038/s41551-022-00998-9

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