ACS Publications. Most Trusted. Most Cited. Most Read
Lateral Flow-Based Skin Patch for Rapid Detection of Protein Biomarkers in Human Dermal Interstitial Fluid
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Sens. 2024, 9, 11, 5792-5801
  • Open Access
Article

Lateral Flow-Based Skin Patch for Rapid Detection of Protein Biomarkers in Human Dermal Interstitial Fluid
Click to copy article linkArticle link copied!

  • Elizabeth C. Wilkirson
    Elizabeth C. Wilkirson
    Department of Mechanical Engineering, Rice University, Houston, Texas 77005, United States
    More by Elizabeth C. Wilkirson
  • Danika Li
    Danika Li
    Department of Bioengineering, Rice University, Houston, Texas 77030, United States
    More by Danika Li
  • Peter B. Lillehoj*
    Peter B. Lillehoj
    Department of Mechanical Engineering, Rice University, Houston, Texas 77005, United States
    Department of Bioengineering, Rice University, Houston, Texas 77030, United States
    *Email: [email protected]
    More by Peter B. Lillehoj
    Orcidhttps://orcid.org/0000-0002-0289-2634
Open PDFSupporting Information (1)

ACS Sensors

Cite this: ACS Sens. 2024, 9, 11, 5792–5801
Click to copy citationCitation copied!
https://doi.org/10.1021/acssensors.4c00956
Published October 25, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Rapid diagnostic tests (RDTs) offer valuable diagnostic information in a quick, easy-to-use and low-cost format. While RDTs are one of the most commonly used tools for in vitro diagnostic testing, they require the collection of a blood sample, which is painful, poses risks of infection and can lead to complications. We introduce a blood-free point-of-care diagnostic test for the rapid detection of protein biomarkers in dermal interstitial fluid (ISF). This device consists of a lateral flow immunochromatographic assay (LFIA) integrated within a microfluidic skin patch. ISF is collected from the skin using a microneedle array and vacuum-assisted extraction system integrated in the patch, and transported through the lateral flow strip via surface tension. Using this skin patch platform, we demonstrate in situ detection of anti-tetanus toxoid IgG and SARS-CoV-2 neutralizing antibodies, which could be accurately detected in human ISF in <20 min. We envision that this device can be readily modified to detect other protein biomarkers in dermal ISF, making it a promising tool for rapid diagnostic testing.

This publication is licensed under

CC-BY 4.0 .
  • cc licence
  • by licence
Copyright © 2024 The Authors. Published by American Chemical Society

Subjects

what are subjects

Keywords

what are keywords
Rapid diagnostic testing plays an important role in medicine and is used for various applications, including the detection of current or past infections, monitoring disease progression or therapeutic response, and determining immune status to guide vaccination decisions. One of the most common types of rapid diagnostic tests (RDTs) are lateral flow immunochromatographic assays (LFIAs), which use antibody-conjugated gold nanoparticles (AuNPs) and a lateral flow technique to detect the presence of specific protein biomarkers in the blood of an individual with a visible line on a test strip. Due to their low-cost, ease of use, and quick turnaround times, RDTs are the most widely used tool in the world for the detection and diagnosis of infectious diseases, such as malaria, HIV infection and hepatitis. While RDTs have revolutionized medical diagnostic testing, they traditionally require the collection of a blood sample, which poses risks of infection (1) and can lead to complications, particularly in newborns and individuals with blood clotting disorders. (2) Additionally, the pain associated with blood sampling can deter individuals with blood or needle phobias from getting tested. (3,4) While RDTs based on urine and saliva have been developed, these fluids offer limited diagnostic utility since they contain only subsets of the biomarkers found in blood (5) and typically at significantly lower concentrations. (6)
Recently, there has been growing interest in the use of interstitial fluid (ISF), the fluid in the extracellular space in tissues, for diagnostic testing. (7) ISF is abundant in the skin, which is comprised of up to 70% of ISF by volume, (8) making it readily accessible for sampling. Microneedle- (MN)-based techniques have been demonstrated for minimally invasive sampling of ISF from skin (i.e., dermal ISF), which are safe and nearly pain-free. (9) Dermal ISF has shown to have nearly the same analytes, including metabolites, proteins and RNA, as blood. (10−15) For example, >90% of circulating proteins in blood are also present in dermal ISF (8,14) suggesting that a significant number of blood-based biomarkers are also detectable in ISF. In addition to circulating proteins which are associated with systemic physiology, dermal ISF contains localized biomarkers associated with skin and tissue physiology that are not found in blood, (8,14,16) making it potentially useful for the diagnosis of skin diseases, conditions and disorders.
Owing to the rich biomolecular content of ISF, MN-based platforms have been developed to collect human ISF for ex situ analysis. Hydrogel-forming MNs made from cross-linked poly(methyl vinyl ether-co-maleic acid) were used by Caffarel-Salvador et al. to extract dermal ISF from human skin. (17) In this approach, MNs were applied to the skin for up to 3 h to allow the hydrogel to swell with ISF. After being removed from the skin, the ISF was extracted from the MNs and analyzed for glucose and caffeine using isocratic high-performance liquid chromatography. Ribet et al. developed an ISF sampling device consisting of a hollow MN and microfluidic chip. (11) In this approach, the ISF sample was stored in an analytical-grade paper matrix in a dry format, enabling it to be mailed to a centralized laboratory for biomolecular analysis. The dried ISF sample was extracted from the paper and analyzed for caffeine, SARS-CoV-2 antibodies and other proteins using liquid chromatography-tandem mass spectrometry, a proximity extension assay, and a single-molecule array assay. Samant et al. demonstrated the extraction of ISF from human skin using solid metal MNs and an electric vacuum pump. (8,15) Using this method, ∼170 clinically relevant metabolites were identified in dermal ISF obtained from volunteers via liquid chromatography mass spectrometry (LCMS). In another approach, a sampling device consisting of hollow MNs connected to capillary tubes was applied to the forearm of volunteers for 1–2 h for ISF extraction. Proteomic analysis using LCMS revealed the presence of >3000 proteins in the extracted ISF samples. (10,14) While these studies demonstrate the detection of clinically relevant analytes in human ISF, they involve time-consuming (>1 h) sampling procedures or tedious protocols to extract/elute ISF from MNs, and require sophisticated instrumentation for biomolecular analysis, all of which hinders their utility for point-of-care testing.
MN-based biosensing platforms have also been developed for transdermal detection and monitoring of analytes in human ISF. Zhu et al. reported a polymeric swellable MN patch coupled with an electrode array for potentiometric measurements of ions (Na+, K+, Ca2+) in human ISF. (18) A wearable MN- and field-effect transistor-based biosensor was developed by Zheng et al. and used for measurements of Na+ in human ISF. (19) Friedel et al. developed an aptamer-based electrochemical sensor for continuous measurements of phenylalanine in human ISF. (20) Continuous monitoring of metabolites (e.g., glucose, lactate) in dermal ISF has also been demonstrated using MN-based electrochemical sensors. (21−24) An integrated wearable device consisting of a MN array, electrochemical sensors, a miniature potentiostat and battery was reported by Tehrani et al. for continuous measurements of lactate, glucose, and alcohol in human ISF. (25) While these platforms demonstrate the ability to perform in situ measurements of analytes in dermal ISF, they required the use of bulky and/or specialized electronic components, such as electrochemical analyzers or custom circuits, and were limited to the detection of small molecules (e.g., metabolites, drugs).
Here, we report a point-of-care diagnostic test for rapid in situ detection of protein biomarkers in dermal ISF, which offers an instrument-free colorimetric readout that can be interpreted by the naked eye. In this approach, an MN array (Figure S1A,B) is used to generate micropores in skin from which ISF is extracted and transported into the skin patch using an integrated vacuum-assisted extraction system. For the first proof of principle demonstration, this device was designed to detect anti-tetanus toxoid IgG, which has clinical relevance in determining an individual’s immunity to tetanus infection. Measurements of anti-tetanus toxoid IgG in dermal ISF and blood obtained from four volunteers were performed using a commercial enzyme-linked immunosorbent assay (ELISA) kit to determine the anti-tetanus toxoid IgG levels in both fluids. The functionality of this device was evaluated by testing it on a volunteer, which revealed its ability to accurately detect anti-tetanus toxoid IgG in dermal ISF in <20 min. We also modified the skin patch for the detection of SARS-CoV-2 neutralizing antibodies and tested its functionality on another volunteer, showcasing its broad applicability for protein biomarker detection in dermal ISF. In addition to its quick turnaround time and ease of use, the only equipment required is a vacuum cup and hand pump (which are inexpensive [<$10] and widely available), making this device well suited for point-of-care diagnostic testing, particularly in resource-limited settings.

Experimental Section

Click to copy section linkSection link copied!

Design and Fabrication of the MN Array

The MN array is comprised of solid, conical MNs made from polymerized SU-8 photoresist coated with 1.5 μm of parylene for enhanced mechanical strength and biocompatibility. (26,27) The MNs were designed to have a compact profile to minimize the discomfort when inserted into skin. Each MN has a base diameter of 200 μm and height of 450 μm, which was determined in a prior study to be the optimal MN dimensions for collecting the greatest amount of ISF from human skin via vacuum-assisted extraction. (28) The MNs are configured in a two-dimensional 10 × 10 array to multiply the number of micropores generated per insertion, with a needle-to-needle spacing of 400 μm. The overall size of the MN array is 7.5 × 7.5 mm.
The MN array master was printed on a Photonic Professional GT lithography system (NanoScribe, MA, USA). MN array replicas were fabricated via centrifugation-assisted replica molding where master molds were constructed from polydimethylsiloxane (PDMS) (Sylgard 184, Dow, MI, USA) mixed at a 1:10 (curing agent-to-elastomer) ratio. The PDMS was degassed for 30 min, poured over the master, and heated in a convection oven at 80 °C for 2 h. Cured PDMS was cut into individual molds using a razor blade and cleaned in 70% isopropanol. SU-8 2025 photoresist (Kayaku Advanced Materials, MA, USA) was poured into the PDMS molds and centrifuged at 4000g for 15 min to create MN array replicas. Replicas were cured under a 50W UV (365 nm) lamp for 3 min, then coated with 1.5 μm of parylene using a Labcoater 2 parylene deposition system (Specialty Coating Systems, IN, USA). Three mm-thick poly(methyl methacrylate) (PMMA) (McMaster Carr, IL, USA) was attached to the backside of the MN arrays to enhance their rigidity. MNs were inspected and imaged using a VHX-7000 optical microscope (Keyence Corporation, Osaka, Japan).

Preparation of AuNP–Anti-human IgG Conjugates

200 μL of 30 nm-diameter AuNPs in solution (OD-50; Millipore Sigma, MA, USA) was aliquoted into a low-bind microcentrifuge tube (Eppendorf, Hamburg, Germany). 1-Ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) (Thermo Fisher Scientific, MA, USA) and N-hydroxysuccinimide (NHS) (Thermo Fisher Scientific) were prepared at 10 mg/mL in deionized water. 40 μL of EDC and 80 μL of NHS were added to the AuNP solution, incubated on a shaker at room temperature for 30 min, and then centrifuged at 10,000g for 10 min. The supernatant was removed, and the pellet was resuspended in 200 μL of reaction buffer to wash away excess EDC and NHS. The solution was vortexed and centrifuged at 10,000g for 10 min. The supernatant was removed and 200 μL of fresh reaction buffer was added. 1.55 μL of goat anti-human IgG (1.3 mg/mL; Jackson ImmunoResearch, PA, USA) was added to the solution, followed by 3 h of incubation on a shaker at room temperature. After incubation, 2 μL of quencher was added and incubated for 10 min, followed by 10 min of centrifugation at 10,000g. The supernatant was removed, and the pellet was resuspended in 200 μL of reaction buffer. The AuNP–anti-human IgG conjugate concentration was adjusted to OD-20 by adding 500 μL of conjugate diluent to the AuNP solution. Prepared AuNP–anti-human IgG conjugate solution was stored at 4 °C.

Preparation of the Conjugate Release Pad

Glass fiber strips (Millipore Sigma, MA, USA) were soaked in a phosphate-buffered saline (PBS) solution containing 10% sucrose (Millipore Sigma) in PBS, 2% bovine serum albumin (BSA) (Millipore Sigma) in PBS, and 0.25% Tween-20 (Millipore Sigma) in deionized water for 1 h at 4 °C. The strips were dried at 37 °C for 2 h and hand-cut into 3 mm-wide pads. Three μL of AuNP–anti-human IgG conjugate solution was dispensed onto the conjugate release pads, dried at 37 °C for 2 h and stored at 4 °C with desiccant.

Preparation of the Nitrocellulose Membrane

Nitrocellulose membrane (GE Healthcare, IL, USA) was adhered to a 60 mm × 300 mm backing card (DCN Dx, CA, USA). For anti-tetanus toxoid IgG detection, solutions of tetanus toxoid antigen reconstituted in deionized water (3 mg/mL; Enzo Life Sciences, NY, USA) and rabbit anti-goat IgG (H/L) in PBS (1 mg/mL; Bio-Rad Antibodies, CA, USA) were dispensed onto the membrane to generate test and control lines, respectively, using an automated liquid dispensing platform (BioDot XYZ3060, CA, USA). For SARS-CoV-2 neutralizing antibody detection, solutions of SARS-CoV-2 spike glycoprotein S1 reconstituted in deionized water (0.5 mg/mL, Abcam, Cambridge, U.K.) and rabbit anti-goat IgG (H/L) in PBS (1 mg/mL; Bio-Rad Antibodies) were drawn onto the membrane using a fine-tip paint brush (Zem Brush, Ohio, USA) for the test and control lines, respectively. The membranes were dried at 37 °C for 2 h.

Assembly of the Lateral Flow Test Strip

A 3 mm × 20 mm cellulose absorbent pad (Millipore Sigma) was adhered to the backing card slightly overlapping (∼1 mm) the end of the prepared nitrocellulose membrane. The card was cut into 3 mm-wide strips using a guillotine cutter (BioDot, CA, USA). Prepared strips were stored at 4 °C with desiccant.

Fabrication and Assembly of the Skin Patch

The skin patch was designed using AutoCAD (Autodesk, CA, USA) and Solidworks (SolidWorks Corp., MA, USA) software. The microfluidic substrate was fabricated from 3 mm-thick PMMA (McMaster Carr) and microchannels were etched into the substrate using a CNC micromilling machine (Minitech Machinery Corporation, GA, USA). A CO2 laser cutter (Universal Laser System, Inc., AZ, USA) was used to create the vacuum and sampling ports in the microfluidic substrate, double-sided pressure-sensitive tape (3M, MN, USA), poly(ethylene terephthalate) (PET) film (Optiazure) and bandage tape (3M). The LFIA test strip was inserted into the microfluidic substrate and a prepared conjugate release pad was placed at the front of the strip. The assembled test strip was enclosed within the patch using PET film and double-sided pressure-sensitive tape. The PMMA-LFIA-PET assembly was sandwiched between two layers of medical-grade tape, securing it within the patch.

MN Penetration Testing

Cadaver porcine skin with hair, fat and subcutaneous tissue removed was purchased from Animal Technologies, Inc. (TX, USA). The skin was cut into 10 cm × 10 cm sections, vacuum sealed, and stored at −20 °C. Prior to testing, a frozen skin section was thawed at room temperature and mounted onto foil-wrapped cardboard using safety pins. MNs were coated in blue ink and the MN array was inserted into the skin section using a MN applicator (Micropoint Technologies, Singapore). MN insertion wounds were visualized using a Keyence VHX-7000 microscope.
Histological analysis was performed on porcine skin sections following MN insertion. MNs were coated with Trypan blue (Sigma-Aldrich, MA, USA) in glycerol (Sigma-Aldrich) solution, and the MN array was inserted into the skin section using a MN applicator. The skin sample was fixed in a 10% formalin solution (Sigma-Aldrich) for at least 48 h, transferred and stored in a 70% ethanol solution. The sample was then embedded in paraffin (Sigma-Aldrich), dehydrated, sectioned, and stained with hematoxylin and eosin (H&E). Optical images of H&E-stained skin sections were captured using a Keyence VHX-7000 microscope.

ISF and Blood Collection from Human Volunteers

Dermal ISF and fingerstick blood was collected from volunteers, which was performed under the guidance and approval from the Rice University Institutional Review Board (IRB-FY2021-147). Potential participants were provided with informed consent to participate in the study. Participants were explained the entirety of the sample collection process prior to beginning the study and informed consent was obtained from each individual. Criteria for participation was as follows: healthy adults or Rice University students ages 18 or older with no blood clotting disorders (including hemophilia, or factor II, V, VII, X, or XII deficiencies) or known skin allergies to medical adhesives. For ISF collection, the participant’s forearm was cleaned using an alcohol prep pad (Fisher Healthcare, MA, USA). An adhesive stencil with cutouts for the MN insertion sites was adhered to the forearm and the MN array was applied two times at the insertion sites using a MN applicator (Figure S2A). A rigid PMMA plate with cutouts at the MN insertion sites was attached to the stencil, followed by the attachment of a vacuum cup (Figure S2B). Vacuum pressure was generated inside the cup using a hand pump (Hansol Medical, South Korea) (Figure S2C). After 20 min, the vacuum cup was removed and the extracted ISF was collected using capillary tubes (Thermo Fisher Scientific, MA, USA and Drummond Scientific Company, PA, USA) (Figure S2D). The collected ISF was transferred to a low-bind microcentrifuge tube, incubated at room temperature for 1 h and centrifuged at 10,000g for 10 min. The supernatant was collected for analysis. Blood samples were obtained via fingerstick using a lancing device (Bayer Microlet) and 30G lancets (CareTouch). Blood was collected in capillary tubes, transferred to a low-bind microcentrifuge tube, incubated for 1 h at room temperature, and centrifuged at 10,000g for 10 min. The purified serum sample was transferred to a new low-bind microcentrifuge tube for analysis.

Anti-tetanus Toxoid IgG Quantification in Blood and ISF Samples

Anti-tetanus toxoid IgG levels were measured in dermal ISF and blood samples using a human anti-tetanus toxoid IgG ELISA kit (Alpha Diagnostics, TX, USA). Measurements were performed according to the manufacturer’s instructions. The absorbance values were measured at 450 nm using a Biotek Epoch absorbance reader. A standard curve was calculated and used to determine the anti-tetanus toxoid IgG concentration in the samples.

Fluid Flow Characterization through the Skin Patch

We assessed the fluid flow characteristics through the skin patch using an artificial skin model. (29) Briefly, 2% agar gel (Sigma-Aldrich) solution was boiled, poured into a 100 mm Petri dish, cured at room temperature, and stored at 4 °C. Blue dye solution was dispensed on top of the agar gel and covered by Parafilm (Bemis Company, Inc., WI), which was carefully stretched over the Petri dish to prevent the entrapment of air bubbles. To initiate the experiment, a MN array was applied to the artificial skin using a MN applicator, followed by the attachment of the patch. A vacuum cup was attached to the vacuum port and vacuum pressure was generated using a hand pump. Video recordings and frame extractions were performed using an iPhone 14 Pro.

Evaluating the Sensitivity and Selectivity of the Tetanus Lateral Flow Immunoassay

For sensitivity testing, 15 μL of tetanus toxoid standard IgG (Alpha Diagnostics) spiked in ISF simulant (10.3 mg/mL human serum albumin diluted in Tyrode’s salts (30)) at varying concentrations was dispensed onto the conjugate pad of the lateral flow test strip. For selectivity testing, measurements were performed by dispensing 15 μL of tetanus toxoid standard IgG (Alpha Diagnostics), diphtheria toxoid IgG (Virion, Wurzburg, Germany) or Bordetella pertussis toxin IgG (Virion) at 0.1 IU/mL onto the conjugate pad. Images of the test results were obtained using a Canon CanoScan 9000F scanner.

In Situ Protein Detection in Dermal ISF Using the Skin Patch

Positive control measurements were carried out by testing the patch on volunteers with up-to-date vaccinations. The volunteers’ anterior forearm was first cleaned using an alcohol prep pad and the MN array was applied to the skin using a MN applicator. Next, the patch was adhered to the skin and a vacuum cup was attached to the vacuum port of the patch. Vacuum pressure was generated using a hand pump. After 18 min, a photograph of the test result was captured using an iPhone 14 Pro. Afterward, the vacuum cup was detached from the patch, the patch was peeled off and the forearm was cleaned using a new alcohol prep pad. Photographs of the volunteer’s forearm were captured at various time intervals after testing.
Negative control measurements were performed by testing the patch on cadaver porcine skin (Animal Technologies, Inc.) with hair, fat and subcutaneous tissue removed. The skin was dermally injected with 20 μL of ISF simulant using a syringe. The MN array was applied to the skin, followed by the attachment of the skin patch and vacuum cup, and application of vacuum pressure. After 18 min, a photograph of the test result was captured using an iPhone 14 Pro.

Characterization of ISF Extraction Volume

We assessed the volume of dermal ISF extracted by the skin patch by testing it on volunteers. The volunteers’ anterior forearm was first cleaned using an alcohol prep pad and the MN array was applied to the skin using a MN applicator. Next, the patch was adhered to the skin and a vacuum cup was attached to the vacuum port of the patch. Vacuum pressure was generated using a hand pump. After 18 min, the vacuum cup was detached from the patch and the patch was removed from the skin. The mass of the LFIA test strip saturated with ISF was measured and compared to its dry mass (measured prior to the experiment), and the difference in mass was used to determine the volume based on the fluid density. The density of each ISF sample was calculated independently using a known mass and volume of fluid, which was collected using the method described above in “ISF and Blood Collection from Human Volunteers.”

Results

Click to copy section linkSection link copied!

Design of the Skin Patch

This device consists of a colloid gold-based LFIA integrated within a skin patch, which is comprised of a PMMA microfluidic network and PET film sandwiched between three layers of adhesive tape (Figure 1A). The lateral flow test strip is based on a conventional LFIA architecture, (31) and consists of a glass fiber conjugate release pad, cellulose absorbent pad, and nitrocellulose membrane on a poly(vinyl chloride) backing card. The conjugate release pad contains AuNPs conjugated with anti-human IgG and the nitrocellulose membrane contains immobilized tetanus toxoid antigen and rabbit anti-goat IgG representing the test line and control line, respectively. During testing, anti-tetanus toxoid IgG in the sample binds to the AuNP–anti-human IgG conjugates on the conjugate pad forming AuNP–anti-human IgG–anti-tetanus toxoid IgG conjugates, which migrate toward the test line where they are captured to generate a red line. Uncaptured AuNP–anti-human IgG conjugates subsequently bind to the control line to generate a second red line, providing validation of a functioning test. The intensity of the test line is correlated with the concentration of anti-tetanus toxoid IgG in the sample where higher anti-tetanus toxoid IgG levels result in the generation of darker lines. Based on this detection scheme, this assay was designed to generate a test line (denoting a “positive” result) only when the anti-tetanus toxoid IgG concentration in the sample is equal or higher than the protective threshold concentration, indicating that the individual possesses sufficient protection against tetanus infection. When the anti-tetanus toxoid IgG concentration is below the protective threshold concentration, then no test line is generated (denoting a “negative” result), which indicates that the individual possesses inadequate immunity against tetanus infection and requires a booster vaccine.

Figure 1

Figure 1. Overview of the skin patch design. (A) Exploded view depicting the individual layers of the patch. Topside (B) and internal (C) views of the assembled patch. Scale bars, 6 mm.

High Resolution Image
Download MS PowerPoint Slide
The microfluidic network is fabricated from 3 mm-thick PMMA and contains cutouts for the fluidic channels, which are connected to three 6 mm × 6 mm sampling ports and an 18 mm-diameter vacuum port. The LFIA test strip is secured within a 3 mm-wide channel in the microfluidic network using the PET film and double-sided pressure-sensitive tape, and the PMMA-LFIA-PET assembly is sandwiched between two layers of medical-grade tape (the top layer is bandage tape, and the bottom layer is double-sided adhesive tape). The topside of the patch contains cutouts for the sampling ports (to facilitate alignment with the MN insertion sites), test (“T”) and control (“C”) line indicators, a test result window, and the vacuum port (Figure 1B). The internal view of the patch reveals the configuration of the sampling ports, microchannels, LFIA strip, and the vacuum port (Figure 1C). The adhesive backing enables the patch to remain securely attached to the skin during testing.

Characterization of MN Penetration

The mechanical strength of the MN array was evaluated in a prior study, which revealed its ability to withstand up to 50 N of compression without exhibiting signs of failure (i.e., fracture) and be repeatedly inserted into porcine skin for at least 36 times with no discernible deformation or damage. (28) We briefly assessed the capability of the MN array to generate micropores in skin via insertion into cadaver porcine skin, which was used as an anatomically and biochemically similar model to human skin. (32) Prior to skin insertion, MNs were coated with blue ink for improved visualization. Distinct pores were generated by each MN, which were confined to the needle penetration sites with no impact to the surrounding tissue (Figure S1C). Histological analysis was performed to evaluate the effects of microneedle penetration in skin tissue. Each MN insertion site was characterized by a conical micropore that pierced through the epidermis (Figure S1D). The formation of these cavities provides access to ISF in the upper dermis, while avoiding the dense collection of nerves and vascular structures located in the lower dermis. (33)

Analysis of Dermal ISF and Blood for Anti-tetanus Toxoid IgG

Paired dermal ISF and blood samples from four healthy volunteers (demographics are listed in Table S1) were analyzed for anti-tetanus toxoid IgG levels using a commercial ELISA kit. Antibodies to tetanus toxoid were detected in ISF of all the volunteers at concentrations from ∼0.6 to 1.1 IU/mL (Figure 2). Anti-tetanus toxoid IgG levels in ISF were well-correlated with those in blood where the average ISF-to-blood ratio for all the samples was ∼0.8 (i.e., ∼20% lower in ISF than blood). These results are consistent with prior experimental studies which show that levels of moderately large (∼100–150 kDa) antibodies in ISF are 15–39% lower than in blood. (34−39) These collective results provide compelling evidence that immune antibodies generated in response to infections and vaccinations are present in dermal ISF.

Figure 2

Figure 2. Anti-tetanus toxoid IgG levels in human blood and ISF. Concentration of anti-tetanus toxoid IgG in blood and dermal ISF sampled from four volunteers measured using a commercial ELISA kit. Each bar represents the mean ± standard deviation (SD) of two measurements (n = 2).

High Resolution Image
Download MS PowerPoint Slide

Fluid Flow through the Skin Patch

The flow characteristics of liquid within the patch were first evaluated using an artificial skin model. For this experiment, the bandage tape was removed from the patch to facilitate visualization of fluid flow through the microchannels and LFIA test strip. Within 2 min of applying suction to the patch, liquid was extracted from the micropores (Figure 3A, ii). The extracted liquid flowed into to patch (via the sampling ports) and through the microchannels (Figure 3A, iii). Upon encountering the LFIA test strip, the liquid was wicked through the strip via surface tension (Figure 3A, iv). As the liquid moved across the conjugate pad, AuNP–anti-human IgG conjugates were reconstituted and transported to the test and control lines. By maintaining a constant vacuum pressure, fluid was continuously extracted from the skin, which served to wash away unbound AuNP–anti-human IgG conjugates from the test strip. After ∼11 min, the strip was fully wetted by the liquid and unbound AuNP–anti-human IgG conjugates were completely removed from the strip, resulting in a negligible background signal (Figure 3A, v). Further experimentation was performed to evaluate the extraction of dermal ISF from human skin and its transport through the skin patch (Figure S3). Similar flow characteristics were observed where dermal ISF could be quickly extracted and transported through the LFIA test strip within 18 min. We attribute the slightly longer time required for full wetting of the test strip and removal of unbound AuNP–anti-human IgG conjugates in human skin compared with the artificial skin model to the higher viscosity of ISF.

Figure 3

Figure 3. Characterization of the skin patch. (A) Sequential still frame images showing the extraction and transport of liquid through the patch (without the bandage tape) in an artificial skin model. Arrows indicate the location(s) of the liquid front. Time stamps (min:s) are in the upper right corner. (B) Test results of ISF samples with increasing concentration of anti-tetanus toxoid IgG antibody. The dashed box indicates the desired protective threshold concentration. (C) Test results of ISF samples spiked with anti-tetanus toxoid IgG, anti-diphtheria toxoid IgG, or anti-B. pertussis toxin IgG, and PBS which was used as a blank control.

High Resolution Image
Download MS PowerPoint Slide

Sensitivity and Selectivity of the Tetanus Lateral Flow Assay

We first assessed the analytical sensitivity of the tetanus assay using ISF simulant spiked with varying concentrations of anti-tetanus toxoid IgG. A test line was generated for samples containing anti-tetanus toxoid IgG at concentrations ≥0.08 IU/mL, where the intensity of line was correlated with the antibody concentration (Figure 3B). Several assay parameters, including the AuNP concentration and antibody concentrations, were optimized so that a test line was generated only when the anti-tetanus toxoid IgG concentration in the sample was ≥0.08 IU/mL, which was used as the protective threshold concentration for ISF, indicating immunity against tetanus infection. This threshold concentration was determined by applying the ratio of anti-tetanus toxoid IgG levels in ISF to blood (0.8) (Figure 2) to the established protective threshold concentration of anti-tetanus toxoid IgG in blood (0.1 IU/mL). (40−42) No test line was generated for samples containing anti-tetanus toxoid IgG at concentrations <0.08 IU/mL. All the samples generated a dark control line, confirming the validity of the tests.
The analytical specificity of the assay was evaluated by testing ISF samples containing anti-tetanus toxoid IgG, anti-B. pertussis toxoid IgG or anti-diphtheria toxoid IgG. Vaccination for diphtheria, pertussis and tetanus is commonly administered as a single dose (Tdap); (43) therefore, antibodies to diphtheria and pertussis toxoids were selected for specificity testing due to their potential to interfere with the tetanus toxoid antigen. (44) Measurement of a PBS sample was performed and used as a blank control. As shown in Figure 3C, only the sample containing anti-tetanus toxoid IgG generated both test and control lines, indicating a positive test result. In contrast, only the control line was generated for the samples containing irrelevant antibodies, which was identical to the PBS sample, indicating a negative test result. These results demonstrate that this assay is highly specific to anti-tetanus toxoid IgG and exhibits negligible cross-reactivity with potentially interfering antibodies.

In Situ Detection of Anti-tetanus Toxoid IgG Using the Skin Patch

To evaluate the functionality of the patch for in situ protein detection, we tested it on a volunteer with an up-to-date tetanus vaccination. To initiate the test, the MN array was first applied to the anterior forearm using a MN applicator (Figure 4A, i). The patch was adhered to the skin in a manner such that the sampling ports were aligned with the MN insertion sites (Figure 4A, ii). Next, a vacuum cup was attached to the vacuum port of the patch and vacuum pressure was generated using a hand pump (Figure 4A, iii). The pump was detached from the cup and vacuum was maintained until ISF was wicked through the entirety of the test strip (Figure 4A, iv). The test results were observable within 18 min of vacuum application (Figure 4B). Both the test line and control line were generated, indicating an anti-tetanus toxoid IgG concentration of ≥0.08 IU/mL, which is consistent with the IgG concentration that was measured in the dermal ISF of this individual (Participant No. 1, Figure 2) using ELISA.

Figure 4

Figure 4. In situ detection of anti-tetanus toxoid IgG in ISF using the skin patch and associated adverse effects. (A) MN insertion in the skin using a MN applicator (i); attachment of the patch to the skin (ii); application of vacuum pressure using a hand pump (iii), followed by removal of the pump and vacuum incubation (iv). (B) Observation of the test results. Inset shows a close-up view of the test result window. (C) Photographs of the forearm of a volunteer before MN insertion (i); immediately following MN insertion (ii); immediately after testing and removal of the skin patch (iii); 5 min after testing (iv); 6 h after testing (v); 24 h after testing (vi). Dashed boxes indicate the MN insertion sites.

High Resolution Image
Download MS PowerPoint Slide

In Situ Detection of SARS-CoV-2 Neutralizing Antibodies Using the Skin Patch

A second proof of principle demonstration was performed by fabricating another patch designed to detect SARS-CoV-2 neutralizing antibodies and testing it on a volunteer who was recently (within 6 months) vaccinated for SARS-CoV-2. The same testing procedure was used as described above. Both test and control lines were generated within 18 min (Figure S4A), indicating the presence of SARS-CoV-2 neutralizing antibodies in dermal ISF of this individual. For a negative control measurement, this patch was tested on porcine skin dermally injected with ISF simulant. Only the control line was generated on this patch, indicating the absence of SARS-CoV-2 neutralizing antibodies (Figure S4B).
We also investigated whether the use of the patch or testing procedure caused any adverse effects to the skin. MN insertion resulted in slight redness at the MN application sites (Figure 4C, ii). Skin redness and mild swelling localized at the MN insertion sites was observed as a result of suction being applied to the skin (Figure 4C, iii,iv), however, these reactions are common and benign effects associated with vacuum/cupping therapy. (45) Within 6 h, swelling had completely subsided, and only very faint redness remained (Figure 4C, v). No other reactions were observed, and the redness completed resolved within 24 h after testing (Figure 4C, vi). Overall, testing resulted in very minor adverse effects that were quickly resolved.

Discussion

Click to copy section linkSection link copied!
Rapid diagnostic testing is used for various applications, including the detection of current or past infections, monitoring disease progression or therapeutic response, and determining immune status to guide vaccination decisions. RDTs enable such testing to be performed outside of laboratory settings by individuals with minimal or no training. Due to their low-cost, quick turnaround time and ease of use, RDTs are widely used throughout the world, particularly in resource-limited settings that lack basic infrastructure and medical resources. However, these tests commonly rely on blood sampling, which poses risks of infection, can lead to complications in infants and individuals with blood disorders, and can deter individuals with blood or needle phobias from getting tested. To address these challenges, this skin patch offers blood-free detection of protein biomarkers in ISF, which can be sampled from the skin in a minimally invasive and nearly painless manner. MN-based biosensing platforms for in situ ISF extraction and analyte detection have previously been reported, (18−24) however, they required the use of bulky and/or specialized electronic components, such as electrochemical analyzers or custom circuits, and were limited to the detection of small molecules (e.g., metabolites, drugs). In our approach, a MN-based ISF sampling technique is combined with a colloid gold-based LFIA and vacuum-assisted extraction system integrated on a microfluidic skin patch, enabling rapid in situ detection of protein biomarkers in dermal ISF. This device does not require any sample processing (e.g., centrifugation, purification, dilution), resulting in a simplified testing protocol and a reduced risk of disease transmission due to no sample handling. Furthermore, the colorimetric readout enables the test result to be observed by the naked eye without requiring specialized instrumentation. Unlike previously reported ISF sampling techniques that rely on specialized equipment or electric vacuum pumps, this device uses an inexpensive (<$10) vacuum cup and hand pump commonly used in cupping therapy, making it portable and amenable for use in both clinical and point-of-care settings.
A major limitation of existing MN-based ISF sampling techniques is that the collected fluid volumes are too low (1–6 μL) (8,11,46) for biomolecular analysis using LFIAs, which require at least ∼10 μL of sample for testing. One of the key advantages of this device is its ability to extract larger (14.8 ± 2.9 μL [mean ± SD], Figure S5) amounts of dermal ISF within a short period of time. A comparison of this skin patch with other MN- and vacuum-assisted techniques for sampling ISF from human skin is presented in Table S2. Several strategies were implemented to enhance the ISF sampling efficiency of this device. First, a high-density MN array is used to generate hundreds of micropores in the skin, providing multiple paths for ISF extraction. A major challenge associated with vacuum-assisted ISF sampling is that human skin is highly elastic and easily deforms when vacuum pressure is applied, causing the micropores to close. To overcome this challenge, the microfluidic network is fabricated using a semirigid PMMA substrate, which keeps the skin taut when suction is applied and induces the opening of the micropores, facilitating ISF extraction. We observed that fabricating the microfluidic network from thinner/less-rigid PMMA caused the skin to deform significantly when suction was applied to the patch, resulting in no ISF extraction. Additionally, the adhesive backing of the patch creates an airtight seal with the skin, enabling vacuum pressure to be maintained throughout the test. Combining the use of the vacuum cup with the skin patch to generate suction resulted in the creation of a large pressure gradient across the skin, driving the flow of ISF through the micropores. While applying suction to the skin resulted in minor adverse effects (e.g., slight redness), these effects completely resolved within 24 h. Compared to the adverse reactions and complications that can occur with blood sampling (e.g., pain, bruising, hematoma and thromboembolism), (47,48) this test is significantly less invasive and safer, which will make it more readily accepted by individuals with blood or needle phobias.
Measurements of IgG antibodies have clinical relevance in determining an individual’s immunity to specific pathogens and guiding vaccination decisions. The ability to determine an individual’s immunity to diseases in a rapid and minimally invasive manner is particularly valuable for individuals who are under-vaccinated or unaware of their vaccination status, putting them at an elevated risk of infection. (49) In this work, anti-tetanus toxoid IgG and SARS-CoV-2 neutralizing antibodies were used as target biomarkers to demonstrate proof of principle of this technology. Using a MN- and vacuum-assisted sampling technique, ISF was successfully collected from human volunteers. ELISA measurements of ISF and blood samples revealed the presence of anti-tetanus toxoid antibodies in both fluids, where concentrations in ISF were correlated with those in blood. This result is significant since it validates the diagnostic utility of dermal ISF for the detection of disease-specific immune antibodies and protein biomarkers. The functionality of the skin patch was further demonstrated through rapid ISF extraction from human skin and generation of test results in <20 min, showcasing its potential for rapid diagnostic testing.
The parylene-coated SU-8 MNs used in this work offer several advantages, including ease of fabrication, high mechanical strength and excellent biocompatibility. However, MN arrays fabricated from other types of biocompatible materials (e.g., polymers, metals, and ceramics) could also be used for generating micropores in skin. We envision that this device can be readily modified to determine immunity to other diseases, such as diphtheria and pertussis, by replacing the tetanus toxoid protein with a different capture antigen and modifying the assay parameters to adjust the protective threshold concentration. Alternatively, modifications can be made to the assay enabling the detection of other protein biomarkers associated with viral, parasitic, and bacterial infections, such as HIV infection, malaria, Dengue fever or Lyme disease, further expanding the utility of this device for diagnostic testing.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssensors.4c00956.

  • Design of the MN array and characterization of MN penetration in porcine skin; overview of the ISF sampling procedure; characterization of ISF extraction from human skin and fluid transport through the patch; skin patch test results for the detection of SARS-CoV-2 neutralizing antibodies; characterization of ISF volume extracted by the patch (Figures S1–S5). Demographics of volunteers whose samples were collected and analyzed; comparison of MN- and vacuum-assisted ISF sampling techniques (Tables S1, S2) (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
  • Authors
    • Elizabeth C. Wilkirson - Department of Mechanical Engineering, Rice University, Houston, Texas 77005, United States
    • Danika Li - Department of Bioengineering, Rice University, Houston, Texas 77030, United States
  • Author Contributions

    E.C.W. and P.B.L. designed the experiments. E.C.W. and P.B.L. prepared and submitted the human subjects experiment document for IRB approval. E.C.W. and D.L. performed the experiments. E.C.W., D.L., and P.B.L. analyzed the data and wrote the manuscript. All authors have given approval to the final version of the manuscript.

  • Funding

    This research was funded by the Wellcome Trust [215826/Z/19/Z]. E.C.W. provided material based upon work supported by the National Science Foundation Graduate Research Fellowship [1842494].

  • Notes
    The authors declare the following competing financial interest(s): E.C.W. and P.B.L. are co-inventors of a provisional patent application filed by Rice University on the subject of this work.

Acknowledgments

Click to copy section linkSection link copied!

We acknowledge the Shared Equipment Authority at Rice University for the use of the cleanroom facilities to fabricate the MN arrays.

Abbreviations

Click to copy section linkSection link copied!
RDT

rapid diagnostic test

ISF

interstitial fluid

LFIA

lateral flow immunochromatographic assay

AuNP

gold nanoparticle

MN

microneedle

LCMS

liquid chromatography mass spectrometry

ELISA

enzyme-linked immunosorbent assay

PDMS

polydimethylsiloxane

PET

poly(ethylene terephthalate)

PMMA

poly(methyl methacrylate)

PBS

phosphate-buffered saline

EDC

1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide

NHS

N-hydroxysuccinimide (NHS)

References

Click to copy section linkSection link copied!

This article references 49 other publications.

  1. 1
    Bogers, J. P. A. M.; Bui, H.; Herruer, M.; Cohen, D. Capillary Compared to Venous Blood Sampling in Clozapine Treatment: Patients’ and Healthcare Practitioners’ Experiences with a Point-of-Care Device. Eur. Neuropsychopharmacol. 2015, 25 (3), 319– 324,  DOI: 10.1016/j.euroneuro.2014.11.022
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Lassandro, G.; Amoruso, A.; Palladino, V.; Valeria, V.; Giordano, P. The Risk of Venipuncture in Newborn with Severe Hemophilia: Case Report of a Large Elbow Hemorrhage and Literature Review of Compartment Syndrome. Hematol. Rep. 2021, 13 (2), 8967  DOI: 10.4081/h.2021.8967
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    McMurtry, C. M.; Riddell, R. P.; Taddio, A.; Racine, N.; Asmundson, G. J. G.; Noel, M.; Chambers, C. T.; Shah, V. Far from “Just a Poke”: Common Painful Needle Procedures and the Development of Needle Fear. Clin. J. Pain 2015, 31 (10), S3– S11,  DOI: 10.1097/AJP.0000000000000272
    Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Öst, L.-G. Blood and Injection Phobia: Background and Cognitive, Physiological, and Behavioral Variables. J. Abnormal Psychol. 1992, 101 (1), 68– 74,  DOI: 10.1037/0021-843X.101.1.68
    Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Piorino, F.; Patterson, A. T.; Styczynski, M. P. Low-Cost, Point-of-Care Biomarker Quantification. Curr. Opin. Biotechnol. 2022, 76, 102738  DOI: 10.1016/j.copbio.2022.102738
    Google Scholar
    5
    Low-cost, point-of-care biomarker quantification
    Piorino, Fernanda; Patterson, Alexandra T.; Styczynski, Mark P.
    Current Opinion in Biotechnology (2022), 76 (), 102738CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
    Low-cost, point-of-care (POC) devices that allow fast, on-site disease diagnosis could have a major global health impact, particularly if they can provide quant. measurement of mols. indicative of a diseased state (biomarkers). Accurate quantification of biomarkers in patient samples is already challenging when research-grade, sophisticated equipment is available; it is even more difficult when constrained to simple, cost-effective POC platforms. Here, we summarize the main challenges to accurate, low-cost POC biomarker quantification. We also review recent efforts to develop and implement POC tools beyond qual. readouts, and we conclude by identifying important future research directions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhtl2iu77P&md5=048cad436b2e72b1aaefe2572d2a9d3c
  6. 6
    Sim, D.; Brothers, M. C.; Slocik, J. M.; Islam, A. E.; Maruyama, B.; Grigsby, C. C.; Naik, R. R.; Kim, S. S. Biomarkers and Detection Platforms for Human Health and Performance Monitoring: A Review. Adv. Sci. 2022, 9 (7), 1– 29,  DOI: 10.1002/advs.202104426
    Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Friedel, M.; Thompson, I. A. P.; Kasting, G.; Polsky, R.; Cunningham, D.; Soh, H. T.; Heikenfeld, J. Opportunities and Challenges in the Diagnostic Utility of Dermal Interstitial Fluid. Nat. Biomed. Eng. 2023, 7, 1541,  DOI: 10.1038/s41551-022-00998-9
    Google Scholar
    7
    Opportunities and challenges in the diagnostic utility of dermal interstitial fluid
    Friedel Mark; Heikenfeld Jason; Thompson Ian A P; Soh Hyongsok Tom; Kasting Gerald; Polsky Ronen; Cunningham David; Soh Hyongsok Tom
    Nature biomedical engineering (2023), 7 (12), 1541-1555 ISSN:.
    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.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB28jgslOnsQ%253D%253D&md5=a456744660b14ecaeaa19b6c16827da9
  8. 8
    Samant, P. P.; Niedzwiecki, M. M.; Raviele, N.; Tran, V.; Mena-Lapaix, J.; Walker, D. I.; Felner, E. I.; Jones, D. P.; Miller, G. W.; Prausnitz, M. R. Sampling interstitial fluid from human skin using a microneedle patch. Sci. Transl. Med. 2020, 12 (571), eaaw0285  DOI: 10.1126/scitranslmed.aaw0285
    Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Saifullah, K. M.; Faraji Rad, Z. Sampling Dermal Interstitial Fluid Using Microneedles: A Review of Recent Developments in Sampling Methods and Microneedle-Based Biosensors. Adv. Mater. Interfaces 2023, 10 (10), 2201763  DOI: 10.1002/admi.202201763
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Miller, P. R.; Taylor, R. M.; Tran, B. Q.; Boyd, G.; Glaros, T.; Chavez, V. H.; Krishnakumar, R.; Sinha, A.; Poorey, K.; Williams, K. P.; Branda, S. S.; Baca, J. T.; Polsky, R. Extraction and Biomolecular Analysis of Dermal Interstitial Fluid Collected with Hollow Microneedles. Commun. Biol. 2018, 1 (1), 173  DOI: 10.1038/s42003-018-0170-z
    Google Scholar
    10
    Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedles
    Miller Philip R; Chavez Victor H; Polsky Ronen; Taylor Robert M; Baca Justin T; Tran Bao Quoc; Boyd Gabrielle; Glaros Trevor; Krishnakumar Raga; Sinha Anupama; Poorey Kunal; Williams Kelly P; Branda Steven S
    Communications biology (2018), 1 (), 173 ISSN:.
    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.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvks1CgtQ%253D%253D&md5=22fe34aba32973b987646d6e045345c2
  11. 11
    Ribet, F.; Bendes, A.; Fredolini, C.; Dobielewski, M.; Böttcher, M.; Beck, O.; Schwenk, J. M.; Stemme, G.; Roxhed, N. Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS-CoV-2 Antibodies, and Protein Profiling. Adv. Healthcare Mater. 2023, 12, 2202564  DOI: 10.1002/adhm.202202564
    Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Kool, J.; Reubsaet, L.; Wesseldijk, F.; Maravilha, R. T.; Pinkse, M. W.; D’Santos, C. S.; van Hilten, J. J.; Zijlstra, F. J.; Heck, A. J. R. Suction Blister Fluid as Potential Body Fluid for Biomarker Proteins. Proteomics 2007, 7 (20), 3638– 3650,  DOI: 10.1002/pmic.200600938
    Google Scholar
    There is no corresponding record for this reference.
  13. 13
    Müller, A. C.; Breitwieser, F. P.; Fischer, H.; Schuster, C.; Brandt, O.; Colinge, J.; Superti-Furga, G.; Stingl, G.; Elbe-Bürger, A.; Bennett, K. L. A Comparative Proteomic Study of Human Skin Suction Blister Fluid from Healthy Individuals Using Immunodepletion and ITRAQ Labeling. J. Proteome Res. 2012, 11 (7), 3715– 3727,  DOI: 10.1021/pr3002035
    Google Scholar
    13
    A comparative proteomic study of human skin suction blister fluid from healthy individuals using immunodepletion and iTRAQ labeling
    Muller Andre C; Breitwieser Florian P; Fischer Heinz; Schuster Christopher; Brandt Oliver; Colinge Jacques; Superti-Furga Giulio; Stingl Georg; Elbe-Burger Adelheid; Bennett Keiryn L
    Journal of proteome research (2012), 11 (7), 3715-27 ISSN:.
    Aberrations in skin morphology and functionality can cause acute and chronic skin-related diseases that are the focus of dermatological research. Mechanically induced skin suction blister fluid may serve as a potential, alternative human body fluid for quantitative mass spectrometry (MS)-based proteomics in order to assist in the understanding of the mechanisms and causes underlying skin-related diseases. The combination of abundant-protein removal with iTRAQ technology and multidimensional fractionation techniques improved the number of identified protein groups. A relative comparison of a cohort of 8 healthy volunteers was thus recruited in order to assess the net variability encountered in a healthy scenario. The technology enabled the identification, to date, of the highest number of reported protein groups (739) with concomitant relative quantitative data for over 90% of all proteins with high reproducibility and accuracy. The use of iTRAQ 8-plex resulted in a 66% decrease in protein identifications but, despite this, provided valuable insight into interindividual differences of the healthy control samples. The geometric mean ratio was close to 1 with 95% of all ratios ranging between 0.45 and 2.05 and a calculated mean coefficient of variation of 15.8%, indicating a lower biological variance than that reported for plasma or urine. By applying a multistep sample processing, the obtained sensitivity and accuracy of quantitative MS analysis demonstrates the prospective value of the approach in future research into skin diseases.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38nisVWruw%253D%253D&md5=b4caf7859f8064c93e2258a897397757
  14. 14
    Tran, B. Q.; Miller, P. R.; Taylor, R. M.; Boyd, G.; Mach, P. M.; Rosenzweig, C. N.; Baca, J. T.; Polsky, R.; Glaros, T. Proteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted Technique. J. Proteome Res. 2018, 17 (1), 479– 485,  DOI: 10.1021/acs.jproteome.7b00642
    Google Scholar
    14
    Proteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted Technique
    Tran, Bao Quoc; Miller, Philip R.; Taylor, Robert M.; Boyd, Gabrielle; Mach, Phillip M.; Rosenzweig, C. Nicole; Baca, Justin T.; Polsky, Ronen; Glaros, Trevor
    Journal of Proteome Research (2018), 17 (1), 479-485CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    As wearable fitness devices have gained com. acceptance, interest in real-time monitoring of an individual's physiol. status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clin. monitoring and diagnosis, but little is known about its compn. 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 quant. 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 anal. 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.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGgtrzO&md5=d471d7ccc19eee31fad145b85b30096c
  15. 15
    Samant, P. P.; Prausnitz, M. R. Mechanisms of Sampling Interstitial Fluid from Skin Using a Microneedle Patch. Proc. Natl. Acad. Sci. U.S.A. 2018, 115 (18), 4583– 4588,  DOI: 10.1073/pnas.1716772115
    Google Scholar
    15
    Mechanisms of sampling interstitial fluid from skin using a microneedle patch
    Samant Pradnya P; Prausnitz Mark R
    Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (18), 4583-4588 ISSN:.
    Although interstitial fluid (ISF) contains biomarkers of physiological significance and medical interest, sampling of ISF for clinical applications has made limited impact due to a lack of simple, clinically useful techniques that collect more than nanoliter volumes of ISF. This study describes experimental and theoretical analysis of ISF transport from skin using microneedle (MN) patches and demonstrates collection of >1 μL of ISF within 20 min in pig cadaver skin and living human subjects using an optimized system. MN patches containing arrays of submillimeter solid, porous, or hollow needles were used to penetrate superficial skin layers and access ISF through micropores (μpores) formed upon insertion. Experimental studies in pig skin found that ISF collection depended on transport mechanism according to the rank order diffusion < capillary action < osmosis < pressure-driven convection, under the conditions studied. These findings were in agreement with independent theoretical modeling that considered transport within skin, across the interface between skin and μpores, and within μpores to the skin surface. This analysis indicated that the rate-limiting step for ISF sampling is transport through the dermis. Based on these studies and other considerations like safety and convenience for future clinical use, we designed an MN patch prototype to sample ISF using suction as the driving force. Using this approach, we collected ISF from human volunteers and identified the presence of biomarkers in the collected ISF. In this way, sampling ISF from skin using an MN patch could enable collection of ISF for use in research and medicine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mjjslyruw%253D%253D&md5=4f5cd1e369878d1ca93859cf0cd4cfd5
  16. 16
    Kim, S. H.; Kim, J. H.; Lee, S. J.; Jung, M. S.; Jeong, D. H.; Lee, K. H. Minimally Invasive Skin Sampling and Transcriptome Analysis Using Microneedles for Skin Type Biomarker Research. Skin Res. Technol. 2022, 28 (2), 322– 335,  DOI: 10.1111/srt.13135
    Google Scholar
    There is no corresponding record for this reference.
  17. 17
    Caffarel-Salvador, E.; Brady, A. J.; Eltayib, E.; Meng, T.; Alonso-Vicente, A.; Gonzalez-Vazquez, P.; Torrisi, B. M.; Vicente-Perez, E. M.; Mooney, K.; Jones, D. S.; Bell, S. E. J.; McCoy, C. P.; McCarthy, H. O.; McElnay, J. C.; Donnelly, R. F. Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose in Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring. PLoS One 2015, 10 (12), e0145644  DOI: 10.1371/journal.pone.0145644
    Google Scholar
    17
    Hydrogel-forming microneedle arrays allow detection of drugs and glucose in vivo: potential for use in diagnosis and therapeutic drug monitoring
    Caffarel-Salvador, Ester; Brady, Aaron J.; Eltayib, Eyman; Meng, Teng; Alonso-Vicente, Ana; Gonzalez-Vazquez, Patricia; Torrisi, Barbara M.; Vicente-Perez, Eva Maria; Mooney, Karen; Jones, David S.; Bell, Steven E. J.; McCoy, Colin P.; McCarthy, Helen O.; McElnay, James C.; Donnelly, Ryan F.
    PLoS One (2015), 10 (12), e0145644/1-e0145644/21CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extn. and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepd. from aq. blends of hydrolyzed poly(methyl-vinylether-co-maleic anhydride) (11.1% wt./wt.) and poly(ethyleneglycol) 10,000 daltons (5.6% wt./wt.) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extd. from MN and detd. using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiol.-relevant analyte concns. showed rapid (5 min) analyte uptake. For example, mean concns. of 0.16 μg/mL and 0.85 μg/mL, resp., were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concns. of theophylline after 5 min insertion. A mean concn. of 0.10 μg/mL was obtained by extn. of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concn. obtained by extn. of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concn. after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concn. detected following extn. from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, while a max. concn. of 0.063 μg/mL was detected following extn. from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concn. of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concn. extd. from MN was 4.29 nmol/L, detected after 3 h skin insertion in human volunteers. While not directly correlated, concns. extd. from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clin. insertion times and develop math. algorithms enabling detn. of blood levels directly from MN measurements.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFSjt7w%253D&md5=dea38d619ed29623dcfb76ae1ce9c3a3
  18. 18
    Zhu, D. D.; Tan, Y. R.; Zheng, L. W.; Lao, J. Z.; Liu, J. Y.; Yu, J.; Chen, P. Microneedle-Coupled Epidermal Sensors for In-Situ-Multiplexed Ion Detection in Interstitial Fluids. ACS Appl. Mater. Interfaces 2023, 15, 14146– 14154,  DOI: 10.1021/acsami.3c00573
    Google Scholar
    18
    Microneedle-Coupled Epidermal Sensors for In-Situ-Multiplexed Ion Detection in Interstitial Fluids
    Zhu, Dan Dan; Tan, Yu Rong; Zheng, Le Wen; Lao, Jia Zheng; Liu, Ji Yang; Yu, Jing; Chen, Peng
    ACS Applied Materials & Interfaces (2023), 15 (11), 14146-14154CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Maintaining the concns. of various ions in body fluids is crit. to all living organisms. In this contribution, we designed a flexible microneedle patch coupled electrode array (MNP-EA) for the in situ multiplexed detection of ion species (Na+, K+, Ca2+, and H+) in tissue interstitial fluid (ISF). The microneedles (MNs) are mech. robust for skin or cuticle penetration (0.21 N/needle) and highly swellable to quickly ext. sufficient ISF onto the ion-selective electrochem. electrodes (~ 6.87 μL/needle in 5 min). The potentiometric sensor can simultaneously detect these ion species with nearly Nernstian response in the ranges wider enough for diagnosis purposes (Na+: 0.75-200 mM, K+: 1-128 mM, Ca2+: 0.25-4.25 mM, pH: 5.5-8.5). The in vivo expts. on mice, humans, and plants demonstrate the feasibility of MNP-EA for timely and convenient diagnosis of ion imbalances with minimal invasiveness. This transdermal sensing platform shall be instrumental to home-based diagnosis and health monitoring of chronic diseases and is also promising for smart agriculture and the study of plant biol.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkvFWrt7s%253D&md5=bd63251d3e7c89f1820265cb97ac0e81
  19. 19
    Zheng, Y.; Omar, R.; Zhang, R.; Tang, N.; Khatib, M.; Xu, Q.; Milyutin, Y.; Saliba, W.; Broza, Y. Y.; Wu, W.; Yuan, M.; Haick, H. A Wearable Microneedle-Based Extended Gate Transistor for Real-Time Detection of Sodium in Interstitial Fluids. Adv. Mater. 2022, 34, 2108607  DOI: 10.1002/adma.202108607
    Google Scholar
    19
    A wearable microneedle-based extended gate transistor for real-time detection of sodium in interstitial fluids
    Zheng, Youbin; Omar, Rawan; Zhang, Rongjun; Tang, Ning; Khatib, Muhammad; Xu, Qi; Milyutin, Yana; Saliba, Walaa; Broza, Yoav Y.; Wu, Weiwei; Yuan, Miaomiao; Haick, Hossam
    Advanced Materials (Weinheim, Germany) (2022), 34 (10), 2108607CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Sodium is a prominent prognostic biomarker for assessing health status, such as dysnatremia. As of now, detection and monitoring of sodium levels in the human body is carried out by means of laborious and bulky lab. equipmentand/or by offline anal. of various body fluids. Herein, an innovative stretchable, skin-conformal and fast-response microneedle extended-gate FET biosensor is reported for real-time detection of sodium in interstitial fluids for minimally invasive health monitoring along with high sensitivity, low limit of detection, excellent biocompatibility, and on-body mech. stability. The integration of the reported device with a wireless-data transmitter and the Internet-of-Things cloud for real-time monitoring and long-term anal. is reported and discussed. This platform would eventually help bringing unlimited possibilities for effecient medical care and accurate clin. decision-making.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvVaks7g%253D&md5=a2c0c64d779be15a03f714d391bfa07b
  20. 20
    Friedel, M.; Werbovetz, B.; Drexelius, A.; Watkins, Z.; Bali, A.; Plaxco, K. W.; Heikenfeld, J. Continuous Molecular Monitoring of Human Dermal Interstitial Fluid with Microneedle-Enabled Electrochemical Aptamer Sensors. Lab Chip 2023, 23 (14), 3289– 3299,  DOI: 10.1039/D3LC00210A
    Google Scholar
    20
    Continuous molecular monitoring of human dermal interstitial fluid with microneedle-enabled electrochemical aptamer sensors
    Friedel, Mark; Werbovetz, Benjamin; Drexelius, Amy; Watkins, Zach; Bali, Ahilya; Plaxco, Kevin W.; Heikenfeld, Jason
    Lab on a Chip (2023), 23 (14), 3289-3299CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
    The ability to continually collect diagnostic information from the body during daily activity has revolutionized the monitoring of health and disease. Much of this monitoring, however, has been of phys. "vital signs", with the monitoring of mol. markers having been limited to glucose, primarily due to the lack of other medically relevant mols. for which continuous measurements are possible in bodily fluids. Electrochem. aptamer sensors, however, have a recent history of successful in vivo demonstrations in rat animal models. Herein, we present the first report of real-time human mol. data collected using such sensors, successfully demonstrating their ability to measure the concn. of phenylalanine in dermal interstitial fluid after an oral bolus. To achieve this, we used a device that employs three hollow microneedles to couple the interstitial fluid to an ex vivo, phenylalanine-detecting sensor. The resulting architecture achieves good precision over the physiol. concn. range and clin. relevant, 20 min lag times. By also demonstrating 90 days dry room-temp. shelf storage, the reported work also reaches another important milestone in moving such sensors to the clinic. While the devices demonstrated are not without remaining challenges, the results at min. provide a simple method by which aptamer sensors can be quickly moved into human subjects for testing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhtlKqtLfM&md5=ad2f06f0af80db180aec154b71269850
  21. 21
    Ribet, F.; Stemme, G.; Roxhed, N. Microneedle-Based System for Minimally Invasive Continuous Monitoring of Glucose in the Dermal Interstitial Fluid. In 2018 IEEE Micro Electro Mechanical Systems (MEMS) 2018; pp 408– 411.  DOI: 10.1109/MEMSYS.2018.8346574 .
    Google Scholar
    There is no corresponding record for this reference.
  22. 22
    Freeman, D. M. E.; Ming, D. K.; Wilson, R.; Herzog, P. L.; Schulz, C.; Felice, A. K. G.; Chen, Y. C.; O’Hare, D.; Holmes, A. H.; Cass, A. E. G. Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes. ACS Sens. 2023, 8 (4), 1639– 1647,  DOI: 10.1021/acssensors.2c02780
    Google Scholar
    There is no corresponding record for this reference.
  23. 23
    De la Paz, E.; Saha, T.; Del Caño, R.; Seker, S.; Kshirsagar, N.; Wang, J. Non-Invasive Monitoring of Interstitial Fluid Lactate through an Epidermal Iontophoretic Device. Talanta 2023, 254 (November 2022), 124122  DOI: 10.1016/j.talanta.2022.124122
    Google Scholar
    There is no corresponding record for this reference.
  24. 24
    De la Paz, E.; Barfidokht, A.; Rios, S.; Brown, C.; Chao, E.; Wang, J. Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch. Anal. Chem. 2021, 93 (37), 12767– 12775,  DOI: 10.1021/acs.analchem.1c02887
    Google Scholar
    24
    Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch
    De la Paz, Ernesto; Barfidokht, Abbas; Rios, Samantha; Brown, Christopher; Chao, Edward; Wang, Joseph
    Analytical Chemistry (Washington, DC, United States) (2021), 93 (37), 12767-12775CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    An effective, noninvasive glucose monitoring technol. could be a pivotal factor for addressing the major unmet needs for managing diabetes mellitus (DM). Here, we describe a skin-worn, disposable, wireless electrochem. biosensor for extended noninvasive monitoring of glucose in the interstitial fluid (ISF). The wearable platform integrates three components: a screen-printed iontophoretic electrode system for ISF extn. by reverse iontophoresis (RI), a printed three-electrode amperometric glucose biosensor, and an electronic interface for control and wireless communication. Prolonged on-body glucose monitoring of up to 8 h, including clin. trials conducted in individuals with and without DM, demonstrated good correlation between glucose blood and ISF concns. and the ability to monitor dynamically changing glucose levels upon food consumption, with no evidence of skin irritation or discomfort. Such successful extended operation addresses the challenges reported for the GlucoWatch platform by using a lower RI c.d. at shorter extn. times, along with a lower measurement frequency. Such a noninvasive skin-worn platform could address long-standing challenges with existing glucose monitoring platforms.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFeltbbJ&md5=ade1e3f59638c656f670a7bb674eb80c
  25. 25
    Tehrani, F.; Teymourian, H.; Wuerstle, B.; Kavner, J.; Patel, R.; Furmidge, A.; Aghavali, R.; Hosseini-Toudeshki, H.; Brown, C.; Zhang, F.; Mahato, K.; Li, Z.; Barfidokht, A.; Yin, L.; Warren, P.; Huang, N.; Patel, Z.; Mercier, P. P.; Wang, J. An Integrated Wearable Microneedle Array for the Continuous Monitoring of Multiple Biomarkers in Interstitial Fluid. Nat. Biomed. Eng. 2022, 6 (11), 1214– 1224,  DOI: 10.1038/s41551-022-00887-1
    Google Scholar
    25
    An integrated wearable microneedle array for the continuous monitoring of multiple biomarkers in interstitial fluid
    Tehrani, Farshad; Teymourian, Hazhir; Wuerstle, Brian; Kavner, Jonathan; Patel, Ravi; Furmidge, Allison; Aghavali, Reza; Hosseini-Toudeshki, Hamed; Brown, Christopher; Zhang, Fangyu; Mahato, Kuldeep; Li, Zhengxing; Barfidokht, Abbas; Yin, Lu; Warren, Paul; Huang, Nickey; Patel, Zina; Mercier, Patrick P.; Wang, Joseph
    Nature Biomedical Engineering (2022), 6 (11), 1214-1224CODEN: NBEAB3; ISSN:2157-846X. (Nature Portfolio)
    Abstr.: Implementations of wearable microneedle-based arrays of sensors for the monitoring of multiple biomarkers in interstitial fluid have lacked system integration and evidence of robust anal. performance. Here we report the development and testing of a fully integrated wearable array of microneedles for the wireless and continuous real-time sensing of two metabolites (lactate and glucose, or alc. and glucose) in the interstitial fluid of volunteers performing common daily activities. The device works with a custom smartphone app for data capture and visualization, comprises reusable electronics and a disposable microneedle array, and is optimized for system integration, cost-effective fabrication via advanced micromachining, easier assembly, biocompatibility, pain-free skin penetration and enhanced sensitivity. Single-analyte and dual-analyte measurements correlated well with the corresponding gold-std. measurements in blood or breath. Further validation of the technol. in large populations with concurrent validation of sensor readouts through centralized lab. tests should det. the robustness and utility of real-time simultaneous monitoring of several biomarkers in interstitial fluid.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFSgs7rI&md5=63cad1c14626a654e8a3d3d5ae0f8ffa
  26. 26
    Chen, Z.; Lee, J. B. Biocompatibility of SU-8 and Its Biomedical Device Applications. Micromachines 2021, 12 (7). 794 DOI: 10.3390/mi12070794 .
    Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Kuppusami, S.; Oskouei, R. H. Parylene Coatings in Medical Devices and Implants: A Review. Univ. J. Biomed. Eng. 2015, 3 (2), 9– 14,  DOI: 10.13189/ujbe.2015.030201
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Jiang, X.; Wilkirson, E. C.; Bailey, A. O.; Russell, W. K.; Lillehoj, P. B. Microneedle-Based Sampling of Dermal Interstitial Fluid Using a Vacuum-Assisted Skin Patch. Cell Rep. Phys. Sci. 2024, 5, 101975  DOI: 10.1016/j.xcrp.2024.101975
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Makvandi, P.; Kirkby, M.; Hutton, A. R. J.; Shabani, M.; Yiu, C. K. Y.; Baghbantaraghdari, Z.; Jamaledin, R.; Carlotti, M.; Mazzolai, B.; Mattoli, V.; Donnelly, R. F. Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion; Springer: Singapore, 2021; Vol. 13  DOI: 10.1007/s40820-021-00611-9 .
    Google Scholar
    There is no corresponding record for this reference.
  30. 30
    Jiang, X.; Lillehoj, P. B. Microneedle-Based Skin Patch for Blood-Free Rapid Diagnostic Testing. Microsyst. Nanoeng. 2020, 6 (1), 96  DOI: 10.1038/s41378-020-00206-1
    Google Scholar
    30
    Microneedle-based skin patch for blood-free rapid diagnostic testing
    Jiang, Xue; Lillehoj, Peter B.
    Microsystems & Nanoengineering (2020), 6 (1), 96CODEN: MNIACT; ISSN:2055-7434. (Nature Research)
    Rapid diagnostic tests are one of the most commonly used tests to detect and screen for infectious diseases in the developing world. While these tests are simple, inexpensive, and readily available, they rely on finger-prick blood sampling, which requires trained medical personnel, poses risks of infection, and can complicate cooperation in young children, asymptomatic individuals, and communities with blood taboos. Here, we report a novel microneedle-based skin patch for the rapid detection of protein biomarkers in dermal interstitial fluid. Sample collection is facilitated by a hydrophilic hollow microneedle array that autonomously exts. and transports interstitial fluid to an antibody-based lateral flow test strip via surface tension for colorimetric antigen detection. We employ a simple gold enhancement treatment to enhance the detection sensitivity of this colloidal gold-based lateral flow assay and elucidate the underlying mechanism of this enhancement mechanism through exptl. investigation. For proof-of-concept, this device was used to detect Plasmodium falciparum histidine-rich protein 2, a biomarker for malaria infection, which could be detected at concns. as low as 8 ng/mL. Each test can be completed in <20 min and requires no equipment. To the best of our knowledge, this work is the first demonstration of a microneedle-based lateral flow assay for rapid protein detection in dermal interstitial fluid. In addn. to its simplicity, minimally invasive nature, and low cost, this diagnostic device can be readily adapted to detect other protein biomarkers in interstitial fluid, making it a promising tool for point-of-care testing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1OrurbM&md5=18ac3696e43fcfd617d8aeb97b034e07
  31. 31
    Parolo, C.; Sena-Torralba, A.; Bergua, J. F.; Calucho, E.; Fuentes-Chust, C.; Hu, L.; Rivas, L.; Álvarez-Diduk, R.; Nguyen, E. P.; Cinti, S.; Quesada-González, D.; Merkoçi, A. Tutorial: Design and Fabrication of Nanoparticle-Based Lateral-Flow Immunoassays. Nat. Protoc. 2020, 15 (12), 3788– 3816,  DOI: 10.1038/s41596-020-0357-x
    Google Scholar
    31
    Tutorial: design and fabrication of nanoparticle-based lateral-flow immunoassays
    Parolo, Claudio; Sena-Torralba, Amadeo; Bergua, Jose Francisco; Calucho, Enric; Fuentes-Chust, Celia; Hu, Liming; Rivas, Lourdes; Alvarez-Diduk, Ruslan; Nguyen, Emily P.; Cinti, Stefano; Quesada-Gonzalez, Daniel; Merkoci, Arben
    Nature Protocols (2020), 15 (12), 3788-3816CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
    A review. Lateral-flow assays (LFAs) are quick, simple and cheap assays to analyze various samples at the point of care or in the field, making them one of the most widespread biosensors currently available. They have been successfully employed for the detection of a myriad of different targets (ranging from atoms up to whole cells) in all type of samples (including water, blood, foodstuff and environmental samples). Their operation relies on the capillary flow of the sample throughout a series of sequential pads, each with different functionalities aiming to generate a signal to indicate the absence/presence (and, in some cases, the concn.) of the analyte of interest. To have a user-friendly operation, their development requires the optimization of multiple, interconnected parameters that may overwhelm new developers. In this tutorial, we provide the readers with: (i) the basic knowledge to understand the principles governing an LFA and to take informed decisions during lateral flow strip design and fabrication, (ii) a roadmap for optimal LFA development independent of the specific application, (iii) a step-by-step example procedure for the assembly and operation of an LF strip for the detection of human IgG and (iv) an extensive troubleshooting section addressing the most frequent issues in designing, assembling and using LFAs. By changing only the receptors, the provided example procedure can easily be adapted for cost-efficient detection of a broad variety of targets.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFGqtb7I&md5=60908ae715c25c21320ff448726e38df
  32. 32
    Schmook, F. P.; Meingassner, J. G.; Billich, A. Comparison of Human Skin or Epidermis Models with Human and Animal Skin in In-Vitro Percutaneous Absorption. Int. J. Pharm. 2001, 215 (1–2), 51– 56,  DOI: 10.1016/S0378-5173(00)00665-7
    Google Scholar
    32
    Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption
    Schmook, F. P.; Meingassner, J. G.; Billich, A.
    International Journal of Pharmaceutics (2001), 215 (1-2), 51-56CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)
    For the study of in-vitro skin penetration of candidate drugs, excised animal skin is frequently used as a replacement for human skin. Reconstructed human skin or epidermis equiv. have been proposed as alternatives. We compared the penetration properties of human, pig and rat skin with the Graftskin LSE (living skin equiv.) and the Skinethic HRE (human reconstructed epidermis) models using four topical dermatol. drugs (salicylic acid, hydrocortisone, clotrimazole and terbinafine) with widely varying polarity. In agreement with published data, pig skin appeared as the most suitable model for human skin: the fluxes through the skin and concns. in the skin were of the same order of magnitude for both tissues, with differences of at most two- or fourfold, resp. Graftskin LSE provided an adequate barrier to salicylic acid, but was very permeable for the more hydrophobic compds. (e.g. about 900-fold higher flux and 50-fold higher skin concns. of clotrimazole as compared to human skin), even more than rat skin. In the case of the Skinethic HRE, we found similar concns. of salicylic acid as in human skin and an approx. sevenfold higher flux. In contrast, the permeation of hydrophobic compds. through the epidermal layer was vastly higher than through split-thickness human skin (up to a factor of about 800). To conclude, currently available reconstituted skin models cannot be regarded as generally useful for in-vitro penetration studies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsleltLc%253D&md5=0e9495996adaaed4ab6115c9493cf892
  33. 33
    Waghule, T.; Singhvi, G.; Dubey, S. K.; Pandey, M. M.; Gupta, G.; Singh, M.; Dua, K. Microneedles: A Smart Approach and Increasing Potential for Transdermal Drug Delivery System. Biomed. Pharmacother. 2019, 109 (September 2018), 1249– 1258,  DOI: 10.1016/j.biopha.2018.10.078
    Google Scholar
    There is no corresponding record for this reference.
  34. 34
    Dragatin, C.; Polus, F.; Bodenlenz, M.; Calonder, C.; Aigner, B. Secukinumab Distributes into Dermal Interstitial Fluid of Psoriasis Patients as Demonstrated by Open Flow Microperfusion. Exp. Dermatol. 2016, 25, 151– 164,  DOI: 10.1111/exd.12863
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Lönsmann Poulsen, H. Interstitial Fluid Concentrations of Albumin and Immunoglobulin g in Normal Men. Scand. J. Clin. Lab. Invest. 1974, 34 (2), 119– 122,  DOI: 10.1080/00365517409050824
    Google Scholar
    There is no corresponding record for this reference.
  36. 36
    Wang, Z.; Luan, J.; Seth, A.; Liu, L.; You, M.; Gupta, P.; Rathi, P.; Wang, Y.; Cao, S.; Jiang, Q.; Zhang, X.; Gupta, R.; Zhou, Q.; Morrissey, J. J.; Scheller, E. L.; Rudra, J. S.; Singamaneni, S. Microneedle Patch for the Ultrasensitive Quantification of Protein Biomarkers in Interstitial Fluid. Nat. Biomed. Eng. 2021, 5 (1), 64– 76,  DOI: 10.1038/s41551-020-00672-y
    Google Scholar
    36
    Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid
    Wang, Zheyu; Luan, Jingyi; Seth, Anushree; Liu, Lin; You, Minli; Gupta, Prashant; Rathi, Priya; Wang, Yixuan; Cao, Sisi; Jiang, Qisheng; Zhang, Xiao; Gupta, Rohit; Zhou, Qingjun; Morrissey, Jeremiah J.; Scheller, Erica L.; Rudra, Jai S.; Singamaneni, Srikanth
    Nature Biomedical Engineering (2021), 5 (1), 64-76CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)
    Abstr.: The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and anal. Here we report the use of a microneedle patch for fast in vivo sampling and on-needle quantification of target protein biomarkers in interstitial fluid. We used plasmonic fluor-an ultrabright fluorescent label-to improve the limit of detection of various interstitial fluid protein biomarkers by nearly 800-fold compared with conventional fluorophores, and a magnetic backing layer to implement conventional immunoassay procedures on the patch and thus improve measurement consistency. We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum-a challenging site for biomarker detection-and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids. Microneedle patches for the minimally invasive collection and anal. of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXmvVKnu7g%253D&md5=954d96d02accd13f64e33c0213c22f29
  37. 37
    Kolluru, C.; Williams, M.; Yeh, J. S.; Noel, R. K.; Knaack, J.; Prausnitz, M. R. Monitoring Drug Pharmacokinetics and Immunologic Biomarkers in Dermal Interstitial Fluid Using a Microneedle Patch. Biomed. Microdevices 2019, 21 (1), 14  DOI: 10.1007/s10544-019-0363-3
    Google Scholar
    37
    Monitoring drug pharmacokinetics and immunologic biomarkers in dermal interstitial fluid using a microneedle patch
    Kolluru Chandana; Williams Mikayla; Prausnitz Mark R; Yeh Jihee Stephanie; Knaack Jennifer; Noel Richard K
    Biomedical microdevices (2019), 21 (1), 14 ISSN:.
    Minimally invasive point-of-care diagnostic devices are of great interest for rapid detection of biomarkers in diverse settings. Although blood is the most common source of biomarkers, interstitial fluid (ISF) is an alternate body fluid that does not clot or contain red blood cells that often complicate analysis. However, ISF is difficult to collect. In this study, we assessed the utility of a microneedle patch to sample microliter volumes of ISF in a simple and minimally invasive manner. We demonstrated the use of ISF collected in this way for therapeutic drug monitoring by showing similar vancomycin pharmacokinetic profiles in ISF and serum from rats. We also measured polio-specific neutralizing antibodies and anti-polio IgG in ISF similar to serum in rats immunized with polio vaccine. These studies demonstrate the potential utility of ISF collected by microneedle patch in therapeutic drug monitoring and immunodiagnostic applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjps1akug%253D%253D&md5=7b1779972527b501fbb3be98cdd527f5
  38. 38
    Xu, M.; Liu, Y.; Chen, H.; Hu, W.; Li, Y.; Zhang, Y.; Wang, Q.; Ma, T. Rapid Detection of Antibodies in Skin Interstitial Fluid via Fluorescent Testing Using Antigen-Modified Porous Microneedles. Colloids Surf., A 2024, 693 (April), 133987  DOI: 10.1016/j.colsurfa.2024.133987
    Google Scholar
    There is no corresponding record for this reference.
  39. 39
    Rafidi, H.; Rajan, S.; Urban, K.; Shatz-Binder, W. Effect of Molecular Size on Interstitial Pharmacokinetics and Tissue Catabolism of Antibodies. MAbs 2022, 14 (1), 2085535  DOI: 10.1080/19420862.2022.2085535
    Google Scholar
    There is no corresponding record for this reference.
  40. 40
    Tiwari, T. S. P.; Moro, P. L.; Acosta, A. M. Pinkbook: Tetanus | CDC. Centers Dis. Control Prev. 2021, 315– 328
    Google Scholar
    There is no corresponding record for this reference.
  41. 41
    Hanvatananukul, P.; Prasarakee, C.; Sarachai, S.; Aurpibul, L.; Sintupat, K.; Khampan, R.; Saheng, J.; Sudjaritruk, T. Seroprevalence of Antibodies against Diphtheria, Tetanus, and Pertussis among Healthy Thai Adolescents. Int. J. Infect. Dis. 2020, 96, 422– 430,  DOI: 10.1016/j.ijid.2020.04.088
    Google Scholar
    There is no corresponding record for this reference.
  42. 42
    Broder, K. R.; Cortese, M. M.; Iskander, J. K.; Kretsinger, K.; Slade, B. A.; Brown, K. H.; Mijalski, C. M.; Tiwari, T.; Weston, E. J.; Cohn, A. C.; Srivastava, P. U.; Moran, J. S.; Schwartz, B.; Murphy, T. V. Preventing Tetanus, Diphtheria, and Pertussis among Adolescents: Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) PsycEXTRA Dataset, American Psychological Association (APA), 2006.
    Google Scholar
    There is no corresponding record for this reference.
  43. 43
    Havers, F. P.; Moro, P. L.; Hunter, P.; Hariri, S.; Bernstein, H. Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccines: Updated Recommendations of the Advisory Committee on Immunization Practices ─ United States, 2019. MMWR. Morb. Mortal. Wkly. Rep. 2020, 69 (3), 77– 83,  DOI: 10.15585/mmwr.mm6903a5
    Google Scholar
    There is no corresponding record for this reference.
  44. 44
    Kadam, L.; Patel, K.; Gautam, M.; Thorat, S.; Kale, P.; Ghule, A. K.; Gairola, A.; Rao, H.; Shinde, Y.; Shaligram, U.; Gairola, S. Development and Validation of Magnetic Bead Pentaplex Immunoassay for Simultaneous Quantification of Murine Serum IgG Antibodies to Acellular Pertussis, Diphtheria and Tetanus Antigens Used in Combination Vaccines. Methods 2019, 158 (September 2018), 33– 43,  DOI: 10.1016/j.ymeth.2019.01.015
    Google Scholar
    There is no corresponding record for this reference.
  45. 45
    Dalton, E. L.; Velasquez, B. J. Cupping Therapy: An Alternative Method of Treating Pain. Public Health – Open J. 2017, 2 (2), 59– 63,  DOI: 10.17140/phoj-2-122
    Google Scholar
    There is no corresponding record for this reference.
  46. 46
    Kim, S.; Lee, M. S.; Yang, H. S.; Jung, J. H. Enhanced Extraction of Skin Interstitial Fluid Using a 3D Printed Device Enabling Tilted Microneedle Penetration. Sci. Rep. 2021, 11 (1), 14018  DOI: 10.1038/s41598-021-93235-3
    Google Scholar
    There is no corresponding record for this reference.
  47. 47
    Heinemann, L. Finger Pricking and Pain: A Never Ending Story. J. Diabetes Sci. Technol. 2008, 2 (5), 919– 921,  DOI: 10.1177/193229680800200526
    Google Scholar
    There is no corresponding record for this reference.
  48. 48
    Robb, S. S. All the Adverse Effects of Drawing Blood. IRB Ethics Hum. Res. 1985, 7 (3), 7– 9,  DOI: 10.2307/3563629
    Google Scholar
    There is no corresponding record for this reference.
  49. 49
    Causey, K.; Fullman, N.; Sorensen, R. J. D.; Galles, N. C.; Zheng, P.; Aravkin, A.; Danovaro-Holliday, M. C.; Martinez-Piedra, R.; Sodha, S. V.; Velandia-González, M. P.; Gacic-Dobo, M.; Castro, E.; He, J.; Schipp, M.; Deen, A.; Hay, S. I.; Lim, S. S.; Mosser, J. F. Estimating Global and Regional Disruptions to Routine Childhood Vaccine Coverage during the COVID-19 Pandemic in 2020: A Modelling Study. Lancet 2021, 398 (10299), 522– 534,  DOI: 10.1016/S0140-6736(21)01337-4
    Google Scholar
    There is no corresponding record for this reference.

Cited By

Click to copy section linkSection link copied!

This article has not yet been cited by other publications.

Download PDF
Go to ACS Sensors
Get e-Alerts
Get e-Alerts

ACS Sensors

Cite this: ACS Sens. 2024, 9, 11, 5792–5801
Click to copy citationCitation copied!
https://doi.org/10.1021/acssensors.4c00956
Published October 25, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Article Views

2048

Altmetric

-

Citations

-
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Overview of the skin patch design. (A) Exploded view depicting the individual layers of the patch. Topside (B) and internal (C) views of the assembled patch. Scale bars, 6 mm.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Anti-tetanus toxoid IgG levels in human blood and ISF. Concentration of anti-tetanus toxoid IgG in blood and dermal ISF sampled from four volunteers measured using a commercial ELISA kit. Each bar represents the mean ± standard deviation (SD) of two measurements (n = 2).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Characterization of the skin patch. (A) Sequential still frame images showing the extraction and transport of liquid through the patch (without the bandage tape) in an artificial skin model. Arrows indicate the location(s) of the liquid front. Time stamps (min:s) are in the upper right corner. (B) Test results of ISF samples with increasing concentration of anti-tetanus toxoid IgG antibody. The dashed box indicates the desired protective threshold concentration. (C) Test results of ISF samples spiked with anti-tetanus toxoid IgG, anti-diphtheria toxoid IgG, or anti-B. pertussis toxin IgG, and PBS which was used as a blank control.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. In situ detection of anti-tetanus toxoid IgG in ISF using the skin patch and associated adverse effects. (A) MN insertion in the skin using a MN applicator (i); attachment of the patch to the skin (ii); application of vacuum pressure using a hand pump (iii), followed by removal of the pump and vacuum incubation (iv). (B) Observation of the test results. Inset shows a close-up view of the test result window. (C) Photographs of the forearm of a volunteer before MN insertion (i); immediately following MN insertion (ii); immediately after testing and removal of the skin patch (iii); 5 min after testing (iv); 6 h after testing (v); 24 h after testing (vi). Dashed boxes indicate the MN insertion sites.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 49 other publications.

    1. 1
      Bogers, J. P. A. M.; Bui, H.; Herruer, M.; Cohen, D. Capillary Compared to Venous Blood Sampling in Clozapine Treatment: Patients’ and Healthcare Practitioners’ Experiences with a Point-of-Care Device. Eur. Neuropsychopharmacol. 2015, 25 (3), 319– 324,  DOI: 10.1016/j.euroneuro.2014.11.022
      There is no corresponding record for this reference.
    2. 2
      Lassandro, G.; Amoruso, A.; Palladino, V.; Valeria, V.; Giordano, P. The Risk of Venipuncture in Newborn with Severe Hemophilia: Case Report of a Large Elbow Hemorrhage and Literature Review of Compartment Syndrome. Hematol. Rep. 2021, 13 (2), 8967  DOI: 10.4081/h.2021.8967
      There is no corresponding record for this reference.
    3. 3
      McMurtry, C. M.; Riddell, R. P.; Taddio, A.; Racine, N.; Asmundson, G. J. G.; Noel, M.; Chambers, C. T.; Shah, V. Far from “Just a Poke”: Common Painful Needle Procedures and the Development of Needle Fear. Clin. J. Pain 2015, 31 (10), S3– S11,  DOI: 10.1097/AJP.0000000000000272
      There is no corresponding record for this reference.
    4. 4
      Öst, L.-G. Blood and Injection Phobia: Background and Cognitive, Physiological, and Behavioral Variables. J. Abnormal Psychol. 1992, 101 (1), 68– 74,  DOI: 10.1037/0021-843X.101.1.68
      There is no corresponding record for this reference.
    5. 5
      Piorino, F.; Patterson, A. T.; Styczynski, M. P. Low-Cost, Point-of-Care Biomarker Quantification. Curr. Opin. Biotechnol. 2022, 76, 102738  DOI: 10.1016/j.copbio.2022.102738
      5
      Low-cost, point-of-care biomarker quantification
      Piorino, Fernanda; Patterson, Alexandra T.; Styczynski, Mark P.
      Current Opinion in Biotechnology (2022), 76 (), 102738CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
      Low-cost, point-of-care (POC) devices that allow fast, on-site disease diagnosis could have a major global health impact, particularly if they can provide quant. measurement of mols. indicative of a diseased state (biomarkers). Accurate quantification of biomarkers in patient samples is already challenging when research-grade, sophisticated equipment is available; it is even more difficult when constrained to simple, cost-effective POC platforms. Here, we summarize the main challenges to accurate, low-cost POC biomarker quantification. We also review recent efforts to develop and implement POC tools beyond qual. readouts, and we conclude by identifying important future research directions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhtl2iu77P&md5=048cad436b2e72b1aaefe2572d2a9d3c
    6. 6
      Sim, D.; Brothers, M. C.; Slocik, J. M.; Islam, A. E.; Maruyama, B.; Grigsby, C. C.; Naik, R. R.; Kim, S. S. Biomarkers and Detection Platforms for Human Health and Performance Monitoring: A Review. Adv. Sci. 2022, 9 (7), 1– 29,  DOI: 10.1002/advs.202104426
      There is no corresponding record for this reference.
    7. 7
      Friedel, M.; Thompson, I. A. P.; Kasting, G.; Polsky, R.; Cunningham, D.; Soh, H. T.; Heikenfeld, J. Opportunities and Challenges in the Diagnostic Utility of Dermal Interstitial Fluid. Nat. Biomed. Eng. 2023, 7, 1541,  DOI: 10.1038/s41551-022-00998-9
      7
      Opportunities and challenges in the diagnostic utility of dermal interstitial fluid
      Friedel Mark; Heikenfeld Jason; Thompson Ian A P; Soh Hyongsok Tom; Kasting Gerald; Polsky Ronen; Cunningham David; Soh Hyongsok Tom
      Nature biomedical engineering (2023), 7 (12), 1541-1555 ISSN:.
      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.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB28jgslOnsQ%253D%253D&md5=a456744660b14ecaeaa19b6c16827da9
    8. 8
      Samant, P. P.; Niedzwiecki, M. M.; Raviele, N.; Tran, V.; Mena-Lapaix, J.; Walker, D. I.; Felner, E. I.; Jones, D. P.; Miller, G. W.; Prausnitz, M. R. Sampling interstitial fluid from human skin using a microneedle patch. Sci. Transl. Med. 2020, 12 (571), eaaw0285  DOI: 10.1126/scitranslmed.aaw0285
      There is no corresponding record for this reference.
    9. 9
      Saifullah, K. M.; Faraji Rad, Z. Sampling Dermal Interstitial Fluid Using Microneedles: A Review of Recent Developments in Sampling Methods and Microneedle-Based Biosensors. Adv. Mater. Interfaces 2023, 10 (10), 2201763  DOI: 10.1002/admi.202201763
      There is no corresponding record for this reference.
    10. 10
      Miller, P. R.; Taylor, R. M.; Tran, B. Q.; Boyd, G.; Glaros, T.; Chavez, V. H.; Krishnakumar, R.; Sinha, A.; Poorey, K.; Williams, K. P.; Branda, S. S.; Baca, J. T.; Polsky, R. Extraction and Biomolecular Analysis of Dermal Interstitial Fluid Collected with Hollow Microneedles. Commun. Biol. 2018, 1 (1), 173  DOI: 10.1038/s42003-018-0170-z
      10
      Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedles
      Miller Philip R; Chavez Victor H; Polsky Ronen; Taylor Robert M; Baca Justin T; Tran Bao Quoc; Boyd Gabrielle; Glaros Trevor; Krishnakumar Raga; Sinha Anupama; Poorey Kunal; Williams Kelly P; Branda Steven S
      Communications biology (2018), 1 (), 173 ISSN:.
      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.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvks1CgtQ%253D%253D&md5=22fe34aba32973b987646d6e045345c2
    11. 11
      Ribet, F.; Bendes, A.; Fredolini, C.; Dobielewski, M.; Böttcher, M.; Beck, O.; Schwenk, J. M.; Stemme, G.; Roxhed, N. Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS-CoV-2 Antibodies, and Protein Profiling. Adv. Healthcare Mater. 2023, 12, 2202564  DOI: 10.1002/adhm.202202564
      There is no corresponding record for this reference.
    12. 12
      Kool, J.; Reubsaet, L.; Wesseldijk, F.; Maravilha, R. T.; Pinkse, M. W.; D’Santos, C. S.; van Hilten, J. J.; Zijlstra, F. J.; Heck, A. J. R. Suction Blister Fluid as Potential Body Fluid for Biomarker Proteins. Proteomics 2007, 7 (20), 3638– 3650,  DOI: 10.1002/pmic.200600938
      There is no corresponding record for this reference.
    13. 13
      Müller, A. C.; Breitwieser, F. P.; Fischer, H.; Schuster, C.; Brandt, O.; Colinge, J.; Superti-Furga, G.; Stingl, G.; Elbe-Bürger, A.; Bennett, K. L. A Comparative Proteomic Study of Human Skin Suction Blister Fluid from Healthy Individuals Using Immunodepletion and ITRAQ Labeling. J. Proteome Res. 2012, 11 (7), 3715– 3727,  DOI: 10.1021/pr3002035
      13
      A comparative proteomic study of human skin suction blister fluid from healthy individuals using immunodepletion and iTRAQ labeling
      Muller Andre C; Breitwieser Florian P; Fischer Heinz; Schuster Christopher; Brandt Oliver; Colinge Jacques; Superti-Furga Giulio; Stingl Georg; Elbe-Burger Adelheid; Bennett Keiryn L
      Journal of proteome research (2012), 11 (7), 3715-27 ISSN:.
      Aberrations in skin morphology and functionality can cause acute and chronic skin-related diseases that are the focus of dermatological research. Mechanically induced skin suction blister fluid may serve as a potential, alternative human body fluid for quantitative mass spectrometry (MS)-based proteomics in order to assist in the understanding of the mechanisms and causes underlying skin-related diseases. The combination of abundant-protein removal with iTRAQ technology and multidimensional fractionation techniques improved the number of identified protein groups. A relative comparison of a cohort of 8 healthy volunteers was thus recruited in order to assess the net variability encountered in a healthy scenario. The technology enabled the identification, to date, of the highest number of reported protein groups (739) with concomitant relative quantitative data for over 90% of all proteins with high reproducibility and accuracy. The use of iTRAQ 8-plex resulted in a 66% decrease in protein identifications but, despite this, provided valuable insight into interindividual differences of the healthy control samples. The geometric mean ratio was close to 1 with 95% of all ratios ranging between 0.45 and 2.05 and a calculated mean coefficient of variation of 15.8%, indicating a lower biological variance than that reported for plasma or urine. By applying a multistep sample processing, the obtained sensitivity and accuracy of quantitative MS analysis demonstrates the prospective value of the approach in future research into skin diseases.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38nisVWruw%253D%253D&md5=b4caf7859f8064c93e2258a897397757
    14. 14
      Tran, B. Q.; Miller, P. R.; Taylor, R. M.; Boyd, G.; Mach, P. M.; Rosenzweig, C. N.; Baca, J. T.; Polsky, R.; Glaros, T. Proteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted Technique. J. Proteome Res. 2018, 17 (1), 479– 485,  DOI: 10.1021/acs.jproteome.7b00642
      14
      Proteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted Technique
      Tran, Bao Quoc; Miller, Philip R.; Taylor, Robert M.; Boyd, Gabrielle; Mach, Phillip M.; Rosenzweig, C. Nicole; Baca, Justin T.; Polsky, Ronen; Glaros, Trevor
      Journal of Proteome Research (2018), 17 (1), 479-485CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      As wearable fitness devices have gained com. acceptance, interest in real-time monitoring of an individual's physiol. status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clin. monitoring and diagnosis, but little is known about its compn. 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 quant. 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 anal. 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.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGgtrzO&md5=d471d7ccc19eee31fad145b85b30096c
    15. 15
      Samant, P. P.; Prausnitz, M. R. Mechanisms of Sampling Interstitial Fluid from Skin Using a Microneedle Patch. Proc. Natl. Acad. Sci. U.S.A. 2018, 115 (18), 4583– 4588,  DOI: 10.1073/pnas.1716772115
      15
      Mechanisms of sampling interstitial fluid from skin using a microneedle patch
      Samant Pradnya P; Prausnitz Mark R
      Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (18), 4583-4588 ISSN:.
      Although interstitial fluid (ISF) contains biomarkers of physiological significance and medical interest, sampling of ISF for clinical applications has made limited impact due to a lack of simple, clinically useful techniques that collect more than nanoliter volumes of ISF. This study describes experimental and theoretical analysis of ISF transport from skin using microneedle (MN) patches and demonstrates collection of >1 μL of ISF within 20 min in pig cadaver skin and living human subjects using an optimized system. MN patches containing arrays of submillimeter solid, porous, or hollow needles were used to penetrate superficial skin layers and access ISF through micropores (μpores) formed upon insertion. Experimental studies in pig skin found that ISF collection depended on transport mechanism according to the rank order diffusion < capillary action < osmosis < pressure-driven convection, under the conditions studied. These findings were in agreement with independent theoretical modeling that considered transport within skin, across the interface between skin and μpores, and within μpores to the skin surface. This analysis indicated that the rate-limiting step for ISF sampling is transport through the dermis. Based on these studies and other considerations like safety and convenience for future clinical use, we designed an MN patch prototype to sample ISF using suction as the driving force. Using this approach, we collected ISF from human volunteers and identified the presence of biomarkers in the collected ISF. In this way, sampling ISF from skin using an MN patch could enable collection of ISF for use in research and medicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mjjslyruw%253D%253D&md5=4f5cd1e369878d1ca93859cf0cd4cfd5
    16. 16
      Kim, S. H.; Kim, J. H.; Lee, S. J.; Jung, M. S.; Jeong, D. H.; Lee, K. H. Minimally Invasive Skin Sampling and Transcriptome Analysis Using Microneedles for Skin Type Biomarker Research. Skin Res. Technol. 2022, 28 (2), 322– 335,  DOI: 10.1111/srt.13135
      There is no corresponding record for this reference.
    17. 17
      Caffarel-Salvador, E.; Brady, A. J.; Eltayib, E.; Meng, T.; Alonso-Vicente, A.; Gonzalez-Vazquez, P.; Torrisi, B. M.; Vicente-Perez, E. M.; Mooney, K.; Jones, D. S.; Bell, S. E. J.; McCoy, C. P.; McCarthy, H. O.; McElnay, J. C.; Donnelly, R. F. Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose in Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring. PLoS One 2015, 10 (12), e0145644  DOI: 10.1371/journal.pone.0145644
      17
      Hydrogel-forming microneedle arrays allow detection of drugs and glucose in vivo: potential for use in diagnosis and therapeutic drug monitoring
      Caffarel-Salvador, Ester; Brady, Aaron J.; Eltayib, Eyman; Meng, Teng; Alonso-Vicente, Ana; Gonzalez-Vazquez, Patricia; Torrisi, Barbara M.; Vicente-Perez, Eva Maria; Mooney, Karen; Jones, David S.; Bell, Steven E. J.; McCoy, Colin P.; McCarthy, Helen O.; McElnay, James C.; Donnelly, Ryan F.
      PLoS One (2015), 10 (12), e0145644/1-e0145644/21CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extn. and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepd. from aq. blends of hydrolyzed poly(methyl-vinylether-co-maleic anhydride) (11.1% wt./wt.) and poly(ethyleneglycol) 10,000 daltons (5.6% wt./wt.) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extd. from MN and detd. using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiol.-relevant analyte concns. showed rapid (5 min) analyte uptake. For example, mean concns. of 0.16 μg/mL and 0.85 μg/mL, resp., were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concns. of theophylline after 5 min insertion. A mean concn. of 0.10 μg/mL was obtained by extn. of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concn. obtained by extn. of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concn. after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concn. detected following extn. from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, while a max. concn. of 0.063 μg/mL was detected following extn. from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concn. of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concn. extd. from MN was 4.29 nmol/L, detected after 3 h skin insertion in human volunteers. While not directly correlated, concns. extd. from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clin. insertion times and develop math. algorithms enabling detn. of blood levels directly from MN measurements.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFSjt7w%253D&md5=dea38d619ed29623dcfb76ae1ce9c3a3
    18. 18
      Zhu, D. D.; Tan, Y. R.; Zheng, L. W.; Lao, J. Z.; Liu, J. Y.; Yu, J.; Chen, P. Microneedle-Coupled Epidermal Sensors for In-Situ-Multiplexed Ion Detection in Interstitial Fluids. ACS Appl. Mater. Interfaces 2023, 15, 14146– 14154,  DOI: 10.1021/acsami.3c00573
      18
      Microneedle-Coupled Epidermal Sensors for In-Situ-Multiplexed Ion Detection in Interstitial Fluids
      Zhu, Dan Dan; Tan, Yu Rong; Zheng, Le Wen; Lao, Jia Zheng; Liu, Ji Yang; Yu, Jing; Chen, Peng
      ACS Applied Materials & Interfaces (2023), 15 (11), 14146-14154CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Maintaining the concns. of various ions in body fluids is crit. to all living organisms. In this contribution, we designed a flexible microneedle patch coupled electrode array (MNP-EA) for the in situ multiplexed detection of ion species (Na+, K+, Ca2+, and H+) in tissue interstitial fluid (ISF). The microneedles (MNs) are mech. robust for skin or cuticle penetration (0.21 N/needle) and highly swellable to quickly ext. sufficient ISF onto the ion-selective electrochem. electrodes (~ 6.87 μL/needle in 5 min). The potentiometric sensor can simultaneously detect these ion species with nearly Nernstian response in the ranges wider enough for diagnosis purposes (Na+: 0.75-200 mM, K+: 1-128 mM, Ca2+: 0.25-4.25 mM, pH: 5.5-8.5). The in vivo expts. on mice, humans, and plants demonstrate the feasibility of MNP-EA for timely and convenient diagnosis of ion imbalances with minimal invasiveness. This transdermal sensing platform shall be instrumental to home-based diagnosis and health monitoring of chronic diseases and is also promising for smart agriculture and the study of plant biol.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkvFWrt7s%253D&md5=bd63251d3e7c89f1820265cb97ac0e81
    19. 19
      Zheng, Y.; Omar, R.; Zhang, R.; Tang, N.; Khatib, M.; Xu, Q.; Milyutin, Y.; Saliba, W.; Broza, Y. Y.; Wu, W.; Yuan, M.; Haick, H. A Wearable Microneedle-Based Extended Gate Transistor for Real-Time Detection of Sodium in Interstitial Fluids. Adv. Mater. 2022, 34, 2108607  DOI: 10.1002/adma.202108607
      19
      A wearable microneedle-based extended gate transistor for real-time detection of sodium in interstitial fluids
      Zheng, Youbin; Omar, Rawan; Zhang, Rongjun; Tang, Ning; Khatib, Muhammad; Xu, Qi; Milyutin, Yana; Saliba, Walaa; Broza, Yoav Y.; Wu, Weiwei; Yuan, Miaomiao; Haick, Hossam
      Advanced Materials (Weinheim, Germany) (2022), 34 (10), 2108607CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Sodium is a prominent prognostic biomarker for assessing health status, such as dysnatremia. As of now, detection and monitoring of sodium levels in the human body is carried out by means of laborious and bulky lab. equipmentand/or by offline anal. of various body fluids. Herein, an innovative stretchable, skin-conformal and fast-response microneedle extended-gate FET biosensor is reported for real-time detection of sodium in interstitial fluids for minimally invasive health monitoring along with high sensitivity, low limit of detection, excellent biocompatibility, and on-body mech. stability. The integration of the reported device with a wireless-data transmitter and the Internet-of-Things cloud for real-time monitoring and long-term anal. is reported and discussed. This platform would eventually help bringing unlimited possibilities for effecient medical care and accurate clin. decision-making.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvVaks7g%253D&md5=a2c0c64d779be15a03f714d391bfa07b
    20. 20
      Friedel, M.; Werbovetz, B.; Drexelius, A.; Watkins, Z.; Bali, A.; Plaxco, K. W.; Heikenfeld, J. Continuous Molecular Monitoring of Human Dermal Interstitial Fluid with Microneedle-Enabled Electrochemical Aptamer Sensors. Lab Chip 2023, 23 (14), 3289– 3299,  DOI: 10.1039/D3LC00210A
      20
      Continuous molecular monitoring of human dermal interstitial fluid with microneedle-enabled electrochemical aptamer sensors
      Friedel, Mark; Werbovetz, Benjamin; Drexelius, Amy; Watkins, Zach; Bali, Ahilya; Plaxco, Kevin W.; Heikenfeld, Jason
      Lab on a Chip (2023), 23 (14), 3289-3299CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
      The ability to continually collect diagnostic information from the body during daily activity has revolutionized the monitoring of health and disease. Much of this monitoring, however, has been of phys. "vital signs", with the monitoring of mol. markers having been limited to glucose, primarily due to the lack of other medically relevant mols. for which continuous measurements are possible in bodily fluids. Electrochem. aptamer sensors, however, have a recent history of successful in vivo demonstrations in rat animal models. Herein, we present the first report of real-time human mol. data collected using such sensors, successfully demonstrating their ability to measure the concn. of phenylalanine in dermal interstitial fluid after an oral bolus. To achieve this, we used a device that employs three hollow microneedles to couple the interstitial fluid to an ex vivo, phenylalanine-detecting sensor. The resulting architecture achieves good precision over the physiol. concn. range and clin. relevant, 20 min lag times. By also demonstrating 90 days dry room-temp. shelf storage, the reported work also reaches another important milestone in moving such sensors to the clinic. While the devices demonstrated are not without remaining challenges, the results at min. provide a simple method by which aptamer sensors can be quickly moved into human subjects for testing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhtlKqtLfM&md5=ad2f06f0af80db180aec154b71269850
    21. 21
      Ribet, F.; Stemme, G.; Roxhed, N. Microneedle-Based System for Minimally Invasive Continuous Monitoring of Glucose in the Dermal Interstitial Fluid. In 2018 IEEE Micro Electro Mechanical Systems (MEMS) 2018; pp 408– 411.  DOI: 10.1109/MEMSYS.2018.8346574 .
      There is no corresponding record for this reference.
    22. 22
      Freeman, D. M. E.; Ming, D. K.; Wilson, R.; Herzog, P. L.; Schulz, C.; Felice, A. K. G.; Chen, Y. C.; O’Hare, D.; Holmes, A. H.; Cass, A. E. G. Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes. ACS Sens. 2023, 8 (4), 1639– 1647,  DOI: 10.1021/acssensors.2c02780
      There is no corresponding record for this reference.
    23. 23
      De la Paz, E.; Saha, T.; Del Caño, R.; Seker, S.; Kshirsagar, N.; Wang, J. Non-Invasive Monitoring of Interstitial Fluid Lactate through an Epidermal Iontophoretic Device. Talanta 2023, 254 (November 2022), 124122  DOI: 10.1016/j.talanta.2022.124122
      There is no corresponding record for this reference.
    24. 24
      De la Paz, E.; Barfidokht, A.; Rios, S.; Brown, C.; Chao, E.; Wang, J. Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch. Anal. Chem. 2021, 93 (37), 12767– 12775,  DOI: 10.1021/acs.analchem.1c02887
      24
      Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch
      De la Paz, Ernesto; Barfidokht, Abbas; Rios, Samantha; Brown, Christopher; Chao, Edward; Wang, Joseph
      Analytical Chemistry (Washington, DC, United States) (2021), 93 (37), 12767-12775CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      An effective, noninvasive glucose monitoring technol. could be a pivotal factor for addressing the major unmet needs for managing diabetes mellitus (DM). Here, we describe a skin-worn, disposable, wireless electrochem. biosensor for extended noninvasive monitoring of glucose in the interstitial fluid (ISF). The wearable platform integrates three components: a screen-printed iontophoretic electrode system for ISF extn. by reverse iontophoresis (RI), a printed three-electrode amperometric glucose biosensor, and an electronic interface for control and wireless communication. Prolonged on-body glucose monitoring of up to 8 h, including clin. trials conducted in individuals with and without DM, demonstrated good correlation between glucose blood and ISF concns. and the ability to monitor dynamically changing glucose levels upon food consumption, with no evidence of skin irritation or discomfort. Such successful extended operation addresses the challenges reported for the GlucoWatch platform by using a lower RI c.d. at shorter extn. times, along with a lower measurement frequency. Such a noninvasive skin-worn platform could address long-standing challenges with existing glucose monitoring platforms.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFeltbbJ&md5=ade1e3f59638c656f670a7bb674eb80c
    25. 25
      Tehrani, F.; Teymourian, H.; Wuerstle, B.; Kavner, J.; Patel, R.; Furmidge, A.; Aghavali, R.; Hosseini-Toudeshki, H.; Brown, C.; Zhang, F.; Mahato, K.; Li, Z.; Barfidokht, A.; Yin, L.; Warren, P.; Huang, N.; Patel, Z.; Mercier, P. P.; Wang, J. An Integrated Wearable Microneedle Array for the Continuous Monitoring of Multiple Biomarkers in Interstitial Fluid. Nat. Biomed. Eng. 2022, 6 (11), 1214– 1224,  DOI: 10.1038/s41551-022-00887-1
      25
      An integrated wearable microneedle array for the continuous monitoring of multiple biomarkers in interstitial fluid
      Tehrani, Farshad; Teymourian, Hazhir; Wuerstle, Brian; Kavner, Jonathan; Patel, Ravi; Furmidge, Allison; Aghavali, Reza; Hosseini-Toudeshki, Hamed; Brown, Christopher; Zhang, Fangyu; Mahato, Kuldeep; Li, Zhengxing; Barfidokht, Abbas; Yin, Lu; Warren, Paul; Huang, Nickey; Patel, Zina; Mercier, Patrick P.; Wang, Joseph
      Nature Biomedical Engineering (2022), 6 (11), 1214-1224CODEN: NBEAB3; ISSN:2157-846X. (Nature Portfolio)
      Abstr.: Implementations of wearable microneedle-based arrays of sensors for the monitoring of multiple biomarkers in interstitial fluid have lacked system integration and evidence of robust anal. performance. Here we report the development and testing of a fully integrated wearable array of microneedles for the wireless and continuous real-time sensing of two metabolites (lactate and glucose, or alc. and glucose) in the interstitial fluid of volunteers performing common daily activities. The device works with a custom smartphone app for data capture and visualization, comprises reusable electronics and a disposable microneedle array, and is optimized for system integration, cost-effective fabrication via advanced micromachining, easier assembly, biocompatibility, pain-free skin penetration and enhanced sensitivity. Single-analyte and dual-analyte measurements correlated well with the corresponding gold-std. measurements in blood or breath. Further validation of the technol. in large populations with concurrent validation of sensor readouts through centralized lab. tests should det. the robustness and utility of real-time simultaneous monitoring of several biomarkers in interstitial fluid.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFSgs7rI&md5=63cad1c14626a654e8a3d3d5ae0f8ffa
    26. 26
      Chen, Z.; Lee, J. B. Biocompatibility of SU-8 and Its Biomedical Device Applications. Micromachines 2021, 12 (7). 794 DOI: 10.3390/mi12070794 .
      There is no corresponding record for this reference.
    27. 27
      Kuppusami, S.; Oskouei, R. H. Parylene Coatings in Medical Devices and Implants: A Review. Univ. J. Biomed. Eng. 2015, 3 (2), 9– 14,  DOI: 10.13189/ujbe.2015.030201
      There is no corresponding record for this reference.
    28. 28
      Jiang, X.; Wilkirson, E. C.; Bailey, A. O.; Russell, W. K.; Lillehoj, P. B. Microneedle-Based Sampling of Dermal Interstitial Fluid Using a Vacuum-Assisted Skin Patch. Cell Rep. Phys. Sci. 2024, 5, 101975  DOI: 10.1016/j.xcrp.2024.101975
      There is no corresponding record for this reference.
    29. 29
      Makvandi, P.; Kirkby, M.; Hutton, A. R. J.; Shabani, M.; Yiu, C. K. Y.; Baghbantaraghdari, Z.; Jamaledin, R.; Carlotti, M.; Mazzolai, B.; Mattoli, V.; Donnelly, R. F. Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion; Springer: Singapore, 2021; Vol. 13  DOI: 10.1007/s40820-021-00611-9 .
      There is no corresponding record for this reference.
    30. 30
      Jiang, X.; Lillehoj, P. B. Microneedle-Based Skin Patch for Blood-Free Rapid Diagnostic Testing. Microsyst. Nanoeng. 2020, 6 (1), 96  DOI: 10.1038/s41378-020-00206-1
      30
      Microneedle-based skin patch for blood-free rapid diagnostic testing
      Jiang, Xue; Lillehoj, Peter B.
      Microsystems & Nanoengineering (2020), 6 (1), 96CODEN: MNIACT; ISSN:2055-7434. (Nature Research)
      Rapid diagnostic tests are one of the most commonly used tests to detect and screen for infectious diseases in the developing world. While these tests are simple, inexpensive, and readily available, they rely on finger-prick blood sampling, which requires trained medical personnel, poses risks of infection, and can complicate cooperation in young children, asymptomatic individuals, and communities with blood taboos. Here, we report a novel microneedle-based skin patch for the rapid detection of protein biomarkers in dermal interstitial fluid. Sample collection is facilitated by a hydrophilic hollow microneedle array that autonomously exts. and transports interstitial fluid to an antibody-based lateral flow test strip via surface tension for colorimetric antigen detection. We employ a simple gold enhancement treatment to enhance the detection sensitivity of this colloidal gold-based lateral flow assay and elucidate the underlying mechanism of this enhancement mechanism through exptl. investigation. For proof-of-concept, this device was used to detect Plasmodium falciparum histidine-rich protein 2, a biomarker for malaria infection, which could be detected at concns. as low as 8 ng/mL. Each test can be completed in <20 min and requires no equipment. To the best of our knowledge, this work is the first demonstration of a microneedle-based lateral flow assay for rapid protein detection in dermal interstitial fluid. In addn. to its simplicity, minimally invasive nature, and low cost, this diagnostic device can be readily adapted to detect other protein biomarkers in interstitial fluid, making it a promising tool for point-of-care testing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1OrurbM&md5=18ac3696e43fcfd617d8aeb97b034e07
    31. 31
      Parolo, C.; Sena-Torralba, A.; Bergua, J. F.; Calucho, E.; Fuentes-Chust, C.; Hu, L.; Rivas, L.; Álvarez-Diduk, R.; Nguyen, E. P.; Cinti, S.; Quesada-González, D.; Merkoçi, A. Tutorial: Design and Fabrication of Nanoparticle-Based Lateral-Flow Immunoassays. Nat. Protoc. 2020, 15 (12), 3788– 3816,  DOI: 10.1038/s41596-020-0357-x
      31
      Tutorial: design and fabrication of nanoparticle-based lateral-flow immunoassays
      Parolo, Claudio; Sena-Torralba, Amadeo; Bergua, Jose Francisco; Calucho, Enric; Fuentes-Chust, Celia; Hu, Liming; Rivas, Lourdes; Alvarez-Diduk, Ruslan; Nguyen, Emily P.; Cinti, Stefano; Quesada-Gonzalez, Daniel; Merkoci, Arben
      Nature Protocols (2020), 15 (12), 3788-3816CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
      A review. Lateral-flow assays (LFAs) are quick, simple and cheap assays to analyze various samples at the point of care or in the field, making them one of the most widespread biosensors currently available. They have been successfully employed for the detection of a myriad of different targets (ranging from atoms up to whole cells) in all type of samples (including water, blood, foodstuff and environmental samples). Their operation relies on the capillary flow of the sample throughout a series of sequential pads, each with different functionalities aiming to generate a signal to indicate the absence/presence (and, in some cases, the concn.) of the analyte of interest. To have a user-friendly operation, their development requires the optimization of multiple, interconnected parameters that may overwhelm new developers. In this tutorial, we provide the readers with: (i) the basic knowledge to understand the principles governing an LFA and to take informed decisions during lateral flow strip design and fabrication, (ii) a roadmap for optimal LFA development independent of the specific application, (iii) a step-by-step example procedure for the assembly and operation of an LF strip for the detection of human IgG and (iv) an extensive troubleshooting section addressing the most frequent issues in designing, assembling and using LFAs. By changing only the receptors, the provided example procedure can easily be adapted for cost-efficient detection of a broad variety of targets.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFGqtb7I&md5=60908ae715c25c21320ff448726e38df
    32. 32
      Schmook, F. P.; Meingassner, J. G.; Billich, A. Comparison of Human Skin or Epidermis Models with Human and Animal Skin in In-Vitro Percutaneous Absorption. Int. J. Pharm. 2001, 215 (1–2), 51– 56,  DOI: 10.1016/S0378-5173(00)00665-7
      32
      Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption
      Schmook, F. P.; Meingassner, J. G.; Billich, A.
      International Journal of Pharmaceutics (2001), 215 (1-2), 51-56CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)
      For the study of in-vitro skin penetration of candidate drugs, excised animal skin is frequently used as a replacement for human skin. Reconstructed human skin or epidermis equiv. have been proposed as alternatives. We compared the penetration properties of human, pig and rat skin with the Graftskin LSE (living skin equiv.) and the Skinethic HRE (human reconstructed epidermis) models using four topical dermatol. drugs (salicylic acid, hydrocortisone, clotrimazole and terbinafine) with widely varying polarity. In agreement with published data, pig skin appeared as the most suitable model for human skin: the fluxes through the skin and concns. in the skin were of the same order of magnitude for both tissues, with differences of at most two- or fourfold, resp. Graftskin LSE provided an adequate barrier to salicylic acid, but was very permeable for the more hydrophobic compds. (e.g. about 900-fold higher flux and 50-fold higher skin concns. of clotrimazole as compared to human skin), even more than rat skin. In the case of the Skinethic HRE, we found similar concns. of salicylic acid as in human skin and an approx. sevenfold higher flux. In contrast, the permeation of hydrophobic compds. through the epidermal layer was vastly higher than through split-thickness human skin (up to a factor of about 800). To conclude, currently available reconstituted skin models cannot be regarded as generally useful for in-vitro penetration studies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsleltLc%253D&md5=0e9495996adaaed4ab6115c9493cf892
    33. 33
      Waghule, T.; Singhvi, G.; Dubey, S. K.; Pandey, M. M.; Gupta, G.; Singh, M.; Dua, K. Microneedles: A Smart Approach and Increasing Potential for Transdermal Drug Delivery System. Biomed. Pharmacother. 2019, 109 (September 2018), 1249– 1258,  DOI: 10.1016/j.biopha.2018.10.078
      There is no corresponding record for this reference.
    34. 34
      Dragatin, C.; Polus, F.; Bodenlenz, M.; Calonder, C.; Aigner, B. Secukinumab Distributes into Dermal Interstitial Fluid of Psoriasis Patients as Demonstrated by Open Flow Microperfusion. Exp. Dermatol. 2016, 25, 151– 164,  DOI: 10.1111/exd.12863
      There is no corresponding record for this reference.
    35. 35
      Lönsmann Poulsen, H. Interstitial Fluid Concentrations of Albumin and Immunoglobulin g in Normal Men. Scand. J. Clin. Lab. Invest. 1974, 34 (2), 119– 122,  DOI: 10.1080/00365517409050824
      There is no corresponding record for this reference.
    36. 36
      Wang, Z.; Luan, J.; Seth, A.; Liu, L.; You, M.; Gupta, P.; Rathi, P.; Wang, Y.; Cao, S.; Jiang, Q.; Zhang, X.; Gupta, R.; Zhou, Q.; Morrissey, J. J.; Scheller, E. L.; Rudra, J. S.; Singamaneni, S. Microneedle Patch for the Ultrasensitive Quantification of Protein Biomarkers in Interstitial Fluid. Nat. Biomed. Eng. 2021, 5 (1), 64– 76,  DOI: 10.1038/s41551-020-00672-y
      36
      Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid
      Wang, Zheyu; Luan, Jingyi; Seth, Anushree; Liu, Lin; You, Minli; Gupta, Prashant; Rathi, Priya; Wang, Yixuan; Cao, Sisi; Jiang, Qisheng; Zhang, Xiao; Gupta, Rohit; Zhou, Qingjun; Morrissey, Jeremiah J.; Scheller, Erica L.; Rudra, Jai S.; Singamaneni, Srikanth
      Nature Biomedical Engineering (2021), 5 (1), 64-76CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)
      Abstr.: The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and anal. Here we report the use of a microneedle patch for fast in vivo sampling and on-needle quantification of target protein biomarkers in interstitial fluid. We used plasmonic fluor-an ultrabright fluorescent label-to improve the limit of detection of various interstitial fluid protein biomarkers by nearly 800-fold compared with conventional fluorophores, and a magnetic backing layer to implement conventional immunoassay procedures on the patch and thus improve measurement consistency. We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum-a challenging site for biomarker detection-and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids. Microneedle patches for the minimally invasive collection and anal. of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXmvVKnu7g%253D&md5=954d96d02accd13f64e33c0213c22f29
    37. 37
      Kolluru, C.; Williams, M.; Yeh, J. S.; Noel, R. K.; Knaack, J.; Prausnitz, M. R. Monitoring Drug Pharmacokinetics and Immunologic Biomarkers in Dermal Interstitial Fluid Using a Microneedle Patch. Biomed. Microdevices 2019, 21 (1), 14  DOI: 10.1007/s10544-019-0363-3
      37
      Monitoring drug pharmacokinetics and immunologic biomarkers in dermal interstitial fluid using a microneedle patch
      Kolluru Chandana; Williams Mikayla; Prausnitz Mark R; Yeh Jihee Stephanie; Knaack Jennifer; Noel Richard K
      Biomedical microdevices (2019), 21 (1), 14 ISSN:.
      Minimally invasive point-of-care diagnostic devices are of great interest for rapid detection of biomarkers in diverse settings. Although blood is the most common source of biomarkers, interstitial fluid (ISF) is an alternate body fluid that does not clot or contain red blood cells that often complicate analysis. However, ISF is difficult to collect. In this study, we assessed the utility of a microneedle patch to sample microliter volumes of ISF in a simple and minimally invasive manner. We demonstrated the use of ISF collected in this way for therapeutic drug monitoring by showing similar vancomycin pharmacokinetic profiles in ISF and serum from rats. We also measured polio-specific neutralizing antibodies and anti-polio IgG in ISF similar to serum in rats immunized with polio vaccine. These studies demonstrate the potential utility of ISF collected by microneedle patch in therapeutic drug monitoring and immunodiagnostic applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjps1akug%253D%253D&md5=7b1779972527b501fbb3be98cdd527f5
    38. 38
      Xu, M.; Liu, Y.; Chen, H.; Hu, W.; Li, Y.; Zhang, Y.; Wang, Q.; Ma, T. Rapid Detection of Antibodies in Skin Interstitial Fluid via Fluorescent Testing Using Antigen-Modified Porous Microneedles. Colloids Surf., A 2024, 693 (April), 133987  DOI: 10.1016/j.colsurfa.2024.133987
      There is no corresponding record for this reference.
    39. 39
      Rafidi, H.; Rajan, S.; Urban, K.; Shatz-Binder, W. Effect of Molecular Size on Interstitial Pharmacokinetics and Tissue Catabolism of Antibodies. MAbs 2022, 14 (1), 2085535  DOI: 10.1080/19420862.2022.2085535
      There is no corresponding record for this reference.
    40. 40
      Tiwari, T. S. P.; Moro, P. L.; Acosta, A. M. Pinkbook: Tetanus | CDC. Centers Dis. Control Prev. 2021, 315– 328
      There is no corresponding record for this reference.
    41. 41
      Hanvatananukul, P.; Prasarakee, C.; Sarachai, S.; Aurpibul, L.; Sintupat, K.; Khampan, R.; Saheng, J.; Sudjaritruk, T. Seroprevalence of Antibodies against Diphtheria, Tetanus, and Pertussis among Healthy Thai Adolescents. Int. J. Infect. Dis. 2020, 96, 422– 430,  DOI: 10.1016/j.ijid.2020.04.088
      There is no corresponding record for this reference.
    42. 42
      Broder, K. R.; Cortese, M. M.; Iskander, J. K.; Kretsinger, K.; Slade, B. A.; Brown, K. H.; Mijalski, C. M.; Tiwari, T.; Weston, E. J.; Cohn, A. C.; Srivastava, P. U.; Moran, J. S.; Schwartz, B.; Murphy, T. V. Preventing Tetanus, Diphtheria, and Pertussis among Adolescents: Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) PsycEXTRA Dataset, American Psychological Association (APA), 2006.
      There is no corresponding record for this reference.
    43. 43
      Havers, F. P.; Moro, P. L.; Hunter, P.; Hariri, S.; Bernstein, H. Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccines: Updated Recommendations of the Advisory Committee on Immunization Practices ─ United States, 2019. MMWR. Morb. Mortal. Wkly. Rep. 2020, 69 (3), 77– 83,  DOI: 10.15585/mmwr.mm6903a5
      There is no corresponding record for this reference.
    44. 44
      Kadam, L.; Patel, K.; Gautam, M.; Thorat, S.; Kale, P.; Ghule, A. K.; Gairola, A.; Rao, H.; Shinde, Y.; Shaligram, U.; Gairola, S. Development and Validation of Magnetic Bead Pentaplex Immunoassay for Simultaneous Quantification of Murine Serum IgG Antibodies to Acellular Pertussis, Diphtheria and Tetanus Antigens Used in Combination Vaccines. Methods 2019, 158 (September 2018), 33– 43,  DOI: 10.1016/j.ymeth.2019.01.015
      There is no corresponding record for this reference.
    45. 45
      Dalton, E. L.; Velasquez, B. J. Cupping Therapy: An Alternative Method of Treating Pain. Public Health – Open J. 2017, 2 (2), 59– 63,  DOI: 10.17140/phoj-2-122
      There is no corresponding record for this reference.
    46. 46
      Kim, S.; Lee, M. S.; Yang, H. S.; Jung, J. H. Enhanced Extraction of Skin Interstitial Fluid Using a 3D Printed Device Enabling Tilted Microneedle Penetration. Sci. Rep. 2021, 11 (1), 14018  DOI: 10.1038/s41598-021-93235-3
      There is no corresponding record for this reference.
    47. 47
      Heinemann, L. Finger Pricking and Pain: A Never Ending Story. J. Diabetes Sci. Technol. 2008, 2 (5), 919– 921,  DOI: 10.1177/193229680800200526
      There is no corresponding record for this reference.
    48. 48
      Robb, S. S. All the Adverse Effects of Drawing Blood. IRB Ethics Hum. Res. 1985, 7 (3), 7– 9,  DOI: 10.2307/3563629
      There is no corresponding record for this reference.
    49. 49
      Causey, K.; Fullman, N.; Sorensen, R. J. D.; Galles, N. C.; Zheng, P.; Aravkin, A.; Danovaro-Holliday, M. C.; Martinez-Piedra, R.; Sodha, S. V.; Velandia-González, M. P.; Gacic-Dobo, M.; Castro, E.; He, J.; Schipp, M.; Deen, A.; Hay, S. I.; Lim, S. S.; Mosser, J. F. Estimating Global and Regional Disruptions to Routine Childhood Vaccine Coverage during the COVID-19 Pandemic in 2020: A Modelling Study. Lancet 2021, 398 (10299), 522– 534,  DOI: 10.1016/S0140-6736(21)01337-4
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssensors.4c00956.

    • Design of the MN array and characterization of MN penetration in porcine skin; overview of the ISF sampling procedure; characterization of ISF extraction from human skin and fluid transport through the patch; skin patch test results for the detection of SARS-CoV-2 neutralizing antibodies; characterization of ISF volume extracted by the patch (Figures S1–S5). Demographics of volunteers whose samples were collected and analyzed; comparison of MN- and vacuum-assisted ISF sampling techniques (Tables S1, S2) (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.