Osmosis‐Powered Hydrogel Microneedles for Microliters of Skin Interstitial Fluid Extraction within Minutes

Abstract

open-flow microperfusion, are time-consuming, cumbersome, patient-unfriendly, requiring medical expertise and specialized equipment. [2] Microneedles (MNs) have then been proposed for the extraction of skin ISF due to their minimally invasive and easy-to-administrated properties. [3,4,5] Hydrogel-based swellable MNs are especially attractive because of their simplicity, efficiency, and biocompatibility. Samant et al. recently showed that polyvinyl alcohol (PVA)-based hydrogel patch could collect ISF from ex vivo pig skin [4] {[(Samant, 2018 #7)]} while our group developed the methacrylated hyaluronic acid (MeHA)-based hydrogel patch for ISF extraction from mouse skin in vivo without external devices. [5] Although the results from both systems were exciting, they were limited to the sampling time for the collection of the sufficient volume of ISF (1-10 µL) and the additional steps for quantifying the biomarkers in ISF. Assuming that both aforementioned systems maintain their performance in human skin as those in pig/mouse skin, PVA patch with 100 MNs can only extract 0.3 µL ISF after 12 h, while MeHA patch with 100 MNs required 20 min to collect 2.5 µL ISF. 20 min collection time is acceptable for the examination of biomarkers like cancer biomarkers or cholesterol that are relatively stable during this collection period but is definitely too long for biomarkers like O 2 and glucose whose concentration Hydrogel microneedle patch enables the extraction of skin interstitial fluid (ISF) through in situ swelling in a minimally invasive manner without assistance of mechano-chemical peripherals. However, existing hydrogel microneedles require tens of minutes with multistep process to collect sufficient volume (1 mL) for effective analysis. This study introduces an osmolyte-powered hydrogel microneedle patch that can extract ISF three times faster than the existing platforms and provide in situ analysis of extracted biomarkers. The microneedle patch is composed of osmolytes (i.e., maltose) and hydrogel (i.e., methacrylated hyaluronic acid). During the extraction process, the osmolytes dissolve in the matrix and provide the osmotic pressure that increases the diffusion of ISF from skin to the hydrogel matrix. A patch with 100 microneedles can extract 7.90 µL of ISF from pig skin ex vivo and 3.82 µL of ISF from mouse skin in vivo within 3 min, whereas the control (i.e., hydrogel microneedle without osmolytes) requires >10 min to achieve similar results. The extracted ISF allows the quantification of biomarkers such as glucose and/or drugs such as insulin in vivo. Through the integration with the electronic glucose sensors, the whole system permits the direct and rapid analysis of the extracted glucose.

Microneedle Arrays for Sampling and Sensing Dermal Interstitial Fluid

“…Zheng et al demonstrated faster extraction of ISF (3 folds) comparing with the existing platform. The team devised an osmolyte powered patch of 100 MNs array [66]. The MNs array was fabricated by a composition of osmolytes (maltose) and hydrogel (methacrylated hyaluronic acid) materials.…”

“…Hydrogel are liquid-swollen materials that are good candidate for ISF extraction [66,90,134]. Hydrogel MNs swell by ISF absorption without dissolution in the skin [135,136].…”

“…For example, hydrogel MNs were prepared from an aqueous mixture of hydrolysed poly (methyl-vinylether-co-maleic anhydride) and poly(ethyleneglycol) which was crosslinked by heating [135][136][137][138] and applied for lithium detection [138]. The other hydrogel MNs made of methacrylated hyaluronic acid [66,90], polyacrylamide [139], polyvinyl alcohol and chitosan [65], and gelatin methacryloyl [123,140] were reported for optical fluorescence sensing [139], cell-free DNA monitoring [141], glucose measurement [65] and urea sensing [140]. With respect to hydrogel properties, the casing method is the most appropriate fabrication method for hydrogel MNs.…”

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

“…However, conventional methods for ISF extraction, such as a suction blister, depth-limited hypodermic cannula, and open-ow microperfusion, are time-consuming, risky to patients, demanding medical expertise and specialized instrument 9-11 . To address the issues, microneedles (MNs) have been proposed to extract skin ISF with a painless and minimally invasive strategy. MNs are fabricated from metal or polymer with hundreds of microns in length and penetrate the main barrier of the skin, stratum corneum, thereby creating a pathway accessible to skin ISF 2,13,14 . The style of MN can be designed depending on the applications.…”

“…For example, a lateral ow strip can detect a target such as food poisoning bacteria with the naked eye by coloring reaction without expensive detection equipment [20][21][22] . Most of all, metal MNs including the paper reservoir, were reported to extract ISF at a rate of 2 to 4 µL per minute under in vivo conditions, which is faster than that of hydrogel MN 3,[13][14][15][16] It is essential to improve the diagnosis sensitivity by securing the stability of biomarkers and a su cient quantity of samples to minimize diagnostic errors such as false positives and false negatives 23,24 .…”