Sampling interstitial fluid from human skin using a microneedle patch

Abstract

Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.

Sensitive sensing of biomarkers in interstitial fluid

“…In fact, the metabolomic and proteomic profiles of ISF and blood are similar and can be used for the monitoring of systemic biomarkers. ISF also contains biomarkers not found in blood plasma that are associated with cellular metabolic processes and that provide local information about cellular and tissue physiology [2][3][4] . Moreover, because ISF does not clot, it can be advantageous for continuous monitoring.…”

“…ISF can also be collected for offline analysis via the brief application of microneedles or laser light to create micropores in the skin (Fig. 2c); the ISF can then be pulled out through the micropores by creating vacuum 3,9 , but this requires bulky instruments. ISF can also be collected without the need for vacuum by using microneedle arrays that can be repeatedly pressed in and out of the skin to induce ISF to flow out of the skin and into a paper reservoir at the base of the microneedles 10 (Fig.…”

Fluorescence Signal Enhancement in Antibody Microarrays Using Lightguiding Nanowires

“…It is clear from the results presented in this study that the high surface-to-footprint ratio of the nanowires, combined with their lightguiding properties, could be used to greatly increase the detection limit of immunoassays or, alternatively, to decrease the amount of biological material required. Moreover, the increased signal quality on nanowires at very low serum concentrations opens up possibilities for developing a platform able to reliably detect very low abundance biomarkers in complex proteomes, important in, for example, the context of early-stage cancer detection [27,45] or miniaturization of diagnostic tools [46]. Although the aim of this work was not to quantify the limit of detection in terms of target concentration, which requires biomarker-free serum spiked with pure biomarker, it is worthwhile noting that while the serum dilution for the standard protocol developed for antibody microarray on the MaxiSorp Plastic is 2%, a fluorescent signal appreciably larger than the background could be detected on nanowires exposed to serum 20 times less concentrated (0.1%).…”

Enhanced Extraction of Skin Interstitial Fluid Using a Tilted Microneedle Device Fabricated by 3D Printing

“…On the other hand, when a rapid on-site diagnosis is needed, ISF extraction using metal MNs is advantageous. Typically, the metal MNs are incorporated with a piece of paper where biomarkers can be detected 3,7,17,18,20 . As the surface of metals such as steel and stainless steel is hydrophilic, once it penetrates the stratum corneum, it attracts skin ISF and allows it to wet across the surface of the metal MNs, transferring ISF to the papers.…”

“…ISF components are similar to plasma and serum and can be directly used for biomarker analysis without pretreatment as an alternative to other body uids such as blood, urine, and saliva 6 . Moreover, ISF contains various biomarkers that are not present in the blood 7,12 . For instance, exosomes are present in ISF 12 to 13 times more than blood, so they can be used to diagnose diseases, including cancer 8 .…”