Hydrogel-Forming Microneedles and Applications in Interstitial Fluid Diagnostic Devices

Abstract

Hydrogel-forming microneedles are constructed from or coated with polymeric, hydrophilic materials that swell upon insertion into the skin. Designed to dissolve or disintegrate postinsertion, these microneedles can deliver drugs, vaccines, or other therapeutics. Recent advancements have broadened their application scope to include the collection, transport, and extraction of dermal interstitial fluid (ISF) for medical diagnostics. This review presents a brief introduction to the characteristics of dermal ISF, methods for extraction and sampling, and critical assessment of the state-of-the-art in hydrogel-forming microneedles for ISF diagnostics. Key factors are evaluated including material composition, swelling behavior, biocompatibility, and mechanical strength necessary for effective microneedle performance and ISF collection. The review also discusses successful examples of dermal ISF assays and microneedle sensor integrations, highlighting notable achievements, identifying research opportunities, and addressing challenges with potential solutions. Despite the predominance of synthetic hydrogels in reported hydrogel-forming microneedle technologies due to their favorable swelling and gelation properties, there is a significant variety of biopolymers and composites reported in the literature. The field lacks consensus on the optimal material, composition, or fabrication methods, though emerging evidence suggests that processing and fabrication techniques are critical to the performance and utility of hydrogel-forming microneedles for ISF diagnostics.

Keywords: biosensor; hydrogel; interstitial fluid; microneedles; point‐of‐care.

Figure 1

Microneedle architectures for sampling of dermal interstitial fluid. representation of hollow, hydrogel‐coated, hydrogel‐forming, and porous microneedles. Considerations for each microneedle architecture in administration and extraction of dermal interstitial fluid.

Figure 2

Scanning electron micrographs of porous, hydrogel, and hollow microneedles. a) Porous polylactic acid microneedles after heat treatment. Reproduced with permission.^{[ 54 ]} Copyright 2022, Springer Nature. b) Methacrylated hyaluronic acid hydrogel microneedle—morphology of single needle view (left) and side view (right). (Scale bar: 50 µm (left) and 500 µm (right)). Reproduced with permission.^{[ 55 ]} Copyright 2022, American Chemical Society. c) Photolithographic‐formed polymeric hollow microneedles (scale bar: 1 mm). Adapted with permission.^{[ 56 ]} Copyright 2022, MDPI.

Figure 3

Material chemistry of popular hydrogel‐forming microneedles. Synthesis and crosslinking methods of methacrylated hyaluronic acid (MeHA), gelatin methacryloyl (GelMA), and poly(methyl vinyl ether‐maleic acid) (PMVE/MA).

Figure 4

Microneedles for diagnostic tests. Examples of point‐of‐care diagnostics using microneedles to probe or extract dermal ISF. A) top‐left: Microneedle array coated with alginate polymers functionalized with peptide nucleic acid applied to human skin biopsies; bottom‐left: optical image of the microneedle pattern with trypan blue on human skin (scale bar: 300 µm); right: DNA assay showing signal‐to‐noise ratio after incubation of microneedles with skin containing only noncomplementary (left) or only complimentary (right) DNA. Reproduced with permission.^{[ 233 ]} Copyright 2022, American Chemical Society. B) Optical images of microneedles made with PEGDA, PEG, and HMPP loaded with photonic crystal barcodes (scale bar: 300 µm). Reproduced with permission.^{[ 232 ]} Copyright 2019, Wiley. C) Top‐left: optical image of GO‐GelMA microneedle (scale bar: 200 µm); Top‐right: Micrographs of GO‐GelMA microneedle after sampling in 1% agarose for 30 min. Bottom: Fluorescence confocal micrograph of micro‐RNAs captured by GelMA microneedles/GOGelMA (scale bar: 200 µm). Reproduced with permission.^{[ 49 ]} Copyright 2022, American Chemical Society. D) Left: MeHA microneedles with fluorescently tagged aptamer probes applied into the dorsal skin of rats. Right: Fluorescence micrographs of MeHA patches functionalized with an aptamer probe only (left) and aptamer‐quencher complex (right). (scale bar: 250 µm). Reproduced with permission.^{[ 55 ]} Copyright 2022, American Chemical Society. E) Top: Photographs of PVA‐GOx double‐layer microneedles applied to mice at different time points (scale bar: 3 mm), microneedles next to one cent coin, and colorimetric response of microneedle patches after ISF extraction from mice with normoglycemia and hyperglycemia (scale bar: 4 mm). Reproduced with permission.^{[ 235 ]} Copyright 2020, Elsevier, Ltd. F) Photographs of microneedle patch (top‐left) and pig skin (top‐right) after insertion of the microneedle patch (scale bar: 400 µm) and colorimetric response microneedle patch as a function of uric acid concentration (bottom). Reproduced with permission.^{[ 236 ]} Copyright 2022, Elsevier, Ltd. G) Photo‐ and micrographs of PVA/PVP microneedle patches for extraction of ISF and measurement of glucose level in rats detected with the commercial glucometer and the D‐glucose content assay kit by microneedle patches. Reproduced with permission.^{[ 140 ]} Copyright 2022, Analyst. H) Photo‐ and electron micrographs of PVA/CS hydrogel microneedle patches demonstrated for the measurement of glucose in ISF (red) and blood (black) of rabbits. Reproduced with permission.^{[ 228 ]} Copyright 2020, Wiley. I) Photographs of PMVE/MA microneedle swollen after removal from the back of a rat (top) and human volunteer (bottom). Reproduced with permission.^{[ 88 ]} Copyright 2015, PLoS. J) Collection of dermal ISF from rat and subsequent proteomic analysis. Reproduced with permission.^{[ 234 ]} Copyright 2021, Wiley.

Figure 5

Microneedles integrated to sensors. A) Images of Mal2‐MeHA microneedle patch before insertion (first) and after removal (second) from mouse back; image of microneedles tips after the extraction(third); metal electrodes and the glucose sensor after enzyme immobilization (fourth). Reproduced with permission.^{[ 48 ]} Copyright 2020, Wiley. B) Image of the AuNWs@hydrogel microneedle patch. Reproduced with permission.^{[ 237 ]} Copyright 2029, American Chemical Society. C) Top: hyaluronic acid with dopamine and PEDOT:PSS side view (left) front view (middle) and swollen after penetration through agarose hydrogel (right). Bottom: three microneedle electrode setup from a top view. Reproduced with permission.^{[ 238 ]} Copyright 2022, Wiley. D) Left: image of rats after insertion of PAA‐Na and PMVE/MA microneedle and detached microneedle after insertion (inset). Right: image of lateral flow assays from samples collected from microneedles inserted in healthy and chronic kidney disease (CKD) rats. Reproduced with permission.^{[ 239 ]} Copyright 2022, Elsevier, Ltd. E) Front (left) and back (right) of a PEGDA microneedle based enzymatic electrode. Reproduced with permission.^{[ 240 ]} Copyright 2016, Elsevier, Ltd. F) Three microneedle electrodes made of hyaluronic acid, dopamine and PEDOT:PSS applied into the dorsal skin of rats for glucose measurement. Reproduced with permission.^{[ 207 ]} Copyright 2022, Wiley. G) Left: 4‐in‐1 patterned test paper microneedles on mice back. Right: microneedle patch applied to human arms, before and after insertion. Reproduced with permission.^{[ 47 ]} Copyright 2022, Elsevier, Ltd.