Dermal interstitial fluid (ISF) is an underutilized information-rich biofluid potentially useful in health status monitoring applications whose contents remain challenging to characterize. Here, we present a facile microneedle approach for dermal ISF extraction with minimal pain and no blistering for human subjects and rats. Extracted ISF volumes were sufficient for determining transcriptome, and proteome signatures. We noted similar profiles in ISF, serum, and plasma samples, suggesting that ISF can be a proxy for direct blood sampling. Dynamic changes in RNA-seq were recorded in ISF from induced hypoxia conditions. Finally, we report the first isolation and characterization, to our knowledge, of exosomes from dermal ISF. The ISF exosome concentration is 12–13 times more enriched when compared to plasma and serum and represents a previously unexplored biofluid for exosome isolation. This minimally invasive extraction approach can enable mechanistic studies of ISF and demonstrates the potential of ISF for real-time health monitoring applications.
As wearable fitness devices have gained commercial acceptance, interest in real-time monitoring of an individual's physiological status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clinical monitoring and diagnosis, but little is known about its composition. In this study, a novel microneedle array was used to collect dermal ISF from three healthy human donors and compared with matching serum and plasma samples. Using a shotgun quantitative proteomic approach, 407 proteins were quantified with at least one unique peptide, and of those, 135 proteins were differently expressed at least 2-fold. Collectively, these proteins tended to originate from the cytoplasm, membrane bound vesicles, and extracellular vesicular exosomes. Proteomic analysis confirmed previously published work that indicates that ISF is highly similar to both plasma and serum. In this study, less than one percent of proteins were uniquely identified in ISF. Taken together, ISF could serve as a minimally invasive alternative for blood-derived fluids with potential for real-time monitoring applications.
Background: There is considerable disagreement regarding the concentration of glucose in tears and its relationship to the concentration in blood. Improved sampling and analysis methods may resolve these discrepancies and possibly provide a basis for in situ tear glucose sensors. Methods: We used liquid chromatography (LC) with electrospray ionization mass spectrometry (ESI-MS) to determine glucose in 1-L tear fluid samples obtained from 25 fasting study participants. Tear fluid was collected with microcapillaries and a slitlamp microscope. Results: The median (range) of fasting tear glucose concentrations was 28 (7-161) mol/L or 0.50 (0.13-2.90) mg/dL. The SD of tear glucose measurements for individuals varied linearly with the mean tear glucose concentration and was approximately half of the mean. We found no significant difference in tear glucose concentrations between contact lens users and nonusers (P ؍ 0.715). We observed significant correlations between fasting blood and tear glucose concentrations (R ؍ 0.50, P ؍ 0.01). Conclusions: Our tear fluid collection and analysis method enables reliable measurement of equilibrium, fasting tear glucose concentrations. These concentrations are lower than those previously reported for nondiabetic persons. Larger population studies are required to determine correlations between blood and tear glucose concentrations and to determine the utility of contact lens-based sensors for the monitoring of diabetes. Our methods are applicable for study of other tear fluid analytes and may prove useful for monitoring other disease states. © 2007 American Association for Clinical ChemistryGlucose has been a recognized component of tear fluid since the early 1900s, but disagreement continues regarding its concentration in tear fluid and its correlation with blood glucose concentration (1)(2)(3)(4)(5)(6). Literature reports of normal tear glucose concentrations range between 0 and 9.1 mmol/L (164 mg/dL), with median values of 110 -280 mol/L (1.98 and 5.04 mg/dL) (1, 7 ). In a recent study of 121 persons, tear glucose concentrations ranged from below the limit of detection to 9.1 mmol/L (164 mg/dL) (7 ). Much of the difference in reported tear glucose concentrations is likely from the use of different tear collection techniques (8 ). Collection techniques causing severe eye irritation [such as filter paper collection (6 )] are associated with the highest tear glucose concentrations, whereas less irritating techniques (such as glass capillary collection) are associated with the lowest (2, 3 ). Chemically stimulated tears have increased tear glucose (8, 9 ). Reliable tear sampling may also be confounded by individual differences in tolerance to real or expected eye stimulation during sampling. (See the Data Supplement that accompanies the online version of this Technical Brief at http://www.clinchem.org/content/vol53/issue7 for an extensive review of the tear glucose literature.)Improved tear fluid collection, and the ability to analyze very low volumes of tear fluid, may dramatic...
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