A skin patch integrating swellable microneedles and electrochemical test strips for glucose and alcohol measurement in skin interstitial fluid
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ABSTRACT:
SUBMITTER: Zheng M
PROVIDER: S-EPMC10487322 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Project description:Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.
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Project description:Though monitoring blood glucose (BG) is indispensable for regulating diabetes, the frequent pricking of the finger by the commonly used fingertip blood collection causes discomfort and poses an infection risk. Since glucose levels in skin interstitial fluid (ISF) correlate with blood glucose levels, monitoring glucose in the skin ISF can be a viable alternative. With this rationale, the present study developed a biocompatible porous microneedle capable of rapid sampling, sensing, and glucose analysis in ISF in a minimally invasive manner, which can improve patient compliance and detection efficiency. The microneedles contain glucose oxidase (GOx) and horseradish peroxidase (HRP), and a colorimetric sensing layer containing 3,3',5,5'-tetramethylbenzidine (TMB) is on the back of the microneedles. After penetrating rat skin, porous microneedles harvest ISF rapidly and smoothly via capillary action, triggering the production of hydrogen peroxide (H2O2) from glucose. In the presence of H2O2, HRP reacts with TMB contained in the filter paper on the back of microneedles, causing an easily visible color shift. Further, a smartphone analysis of the images quickly quantifies glucose levels in the 50-400 mg/dL range using the correlation between color intensity and glucose concentration. The developed microneedle-based sensing technique with minimally invasive sampling will have great implications for point-of-care clinical diagnosis and diabetic health management.
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Project description:Bacterial infection is a major threat to global public health, and can cause serious diseases such as bacterial skin infection and foodborne diseases. It is essential to develop a new method to rapidly diagnose clinical multiple bacterial infections and monitor food microbial contamination in production sites in real-time. In this work, we developed a 4-mercaptophenylboronic acid gold nanoparticles (4-MPBA-AuNPs)-functionalized hydrogel microneedle (MPBA-H-MN) for bacteria detection in skin interstitial fluid. MPBA-H-MN could conveniently capture and enrich a variety of bacteria within 5 min. Surface enhanced Raman spectroscopy (SERS) detection was then performed and combined with machine learning technology to distinguish and identify a variety of bacteria. Overall, the capture efficiency of this method exceeded 50%. In the concentration range of 1 × 107 to 1 × 1010 colony-forming units/mL (CFU/mL), the corresponding SERS intensity showed a certain linear relationship with the bacterial concentration. Using random forest (RF)-based machine learning, bacteria were effectively distinguished with an accuracy of 97.87%. In addition, the harmless disposal of used MNs by photothermal ablation was convenient, environmentally friendly, and inexpensive. This technique provided a potential method for rapid and real-time diagnosis of multiple clinical bacterial infections and for monitoring microbial contamination of food in production sites.
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Project description:Malignant melanoma (MM) is the most aggressive form of skin cancer. The delay in treatment will induce metastasis, resulting in a poor prognosis and even death. Here, a two-step strategy for on-site diagnosis of MM is developed based on the extraction and direct visual quantification of S100A1, a biomarker for melanoma. First, a swellable microneedle is utilized to extract S100A1 in skin interstitial fluid (ISF) with minimal invasion. After elution, antibody-conjugated magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) are introduced. A high expression level of S100A1 gives rise to a robust binding between MMPs and PMPs and reduces the number of free PMPs. By loading the reacted solution into the device with a microfluidic particle dam, the quantity of free PMPs after magnetic separation is displayed with their accumulation length inversely proportional to S100A1 levels. A limit of detection of 18.7 ng mL-1 for S100A1 is achieved. The animal experiment indicates that ISF-based S100A1 quantification using the proposed strategy exhibits a significantly higher sensitivity compared with conventional serum-based detection. In addition, the result is highly comparable with the gold standard enzyme-linked immunosorbent assay based on Lin's concordance correlation coefficient, suggesting the high practicality for routine monitoring of melanoma.
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Project description: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.
| S-EPMC6197253 | biostudies-literature
Project description:Hollow microneedles are an emerging technology for delivering drugs and therapeutics, such as vaccines and insulin, into the skin. Although the benefits of intradermal drug delivery have been known for decades, our understanding of fluid absorption by skin tissue has been limited due to the difficulties in imaging a highly scattering biological material such as skin. Here, we report the first real-time imaging of skin tissue at the microscale during intradermal injections through hollow microneedles, using optical coherence tomography. We show that skin tissue behaves like a deformable porous medium and absorbs fluid by locally expanding rather than rupturing to form a single fluid filled cavity. We measure the strain distribution in a cross section of the tissue to quantify local tissue deformation, and find that the amount of volumetric expansion of the tissue corresponds closely to the volume of fluid injected. Mechanically restricting tissue expansion limits fluid absorption into the tissue. Our experimental findings can provide insights to optimize the delivery of drugs into skin for different therapeutic applications, and to better model fluid flow into biological tissue.
| S-EPMC6137045 | biostudies-literature
Project description:Background: Fluid in lymphedema tissue appears histologically as spaces around vessels and between dermal skin fibers. Lipedema is a painful disease of excess loose connective tissue (fat) in limbs, almost exclusively of women, that worsens by stage, increasing lymphedema risk. Many women with lipedema have hypermobile joints suggesting a connective tissue disorder that may affect vessel structure and compliance of tissue resulting in excess fluid entering the interstitial space. It is unclear if excess fluid is present in lipedema tissue. The purpose of this study is to determine if fluid accumulates around vessels and between skin fibers in the thigh tissue of women with lipedema. Methods: Skin biopsies from the thigh and abdomen from 30 controls and 80 women with lipedema were evaluated for dermal spaces and abnormal vessel phenotype (AVP): (1) rounded endothelial cells; (2) perivascular spaces; and (3) perivascular immune cell infiltrate. Women matched for body mass index (BMI) and age were considered controls if they did not have lipedema on clinical examination. Data were analyzed by analysis of variance (ANOVA) or unpaired t-tests using GraphPad Prism Software 7. p < 0.05 was considered significant. Results: Lipedema tissue mass increases beginning with Stage 1 up to Stage 3, with lipedema fat accumulating more on the limbs than the abdomen. AVP was higher in lipedema thigh (p = 0.003) but not abdomen skin compared with controls. AVP was higher in thigh skin of women with Stage 1 (p = 0.001) and Stage 2 (p = 0.03) but not Stage 3 lipedema versus controls. AVP also was greater in the thigh skin of women with lipedema without obesity versus lipedema with obesity (p < 0.0001). Dermal space was increased in lipedema thigh (p = 0.0003) but not abdomen versus controls. Dermal spaces were also increased in women with lipedema Stage 3 (p < 0.0001) and Stage 2 (p = 0.0007) compared with controls. Conclusion: Excess interstitial fluid in lipedema tissue may originate from dysfunctional blood vessels (microangiopathy). Increased compliance of connective tissue in higher stages of lipedema may allow fluid to disperse into the interstitial space, including between skin dermal fibers. Lipedema may be an early form of lymphedema. ClinicalTrials.gov: NCT02838277.
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Project description:Blood sampling is a common practice to monitor health, but it entails a series of drawbacks for patients including pain and discomfort. Thus, there is a demand for more convenient ways to obtain samples. Modern analytical techniques enable monitoring of multiple bioanalytes in smaller samples, opening possibilities for new matrices, and microsampling technologies to be adopted. Interstitial fluid (ISF) is an attractive alternative matrix that shows good correlation with plasma concentration dynamics for several analytes and can be sampled in a minimally invasive and painless manner from the skin at the point-of-care. However, there is currently a lack of sampling devices compatible with clinical translation. Here, to tackle state-of-the-art limitations, a cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes is presented. The fluid is volume-metered, dried, and stably stored into analytical-grade paper within the microfluidic device. The obtained sample can be mailed to a laboratory, quantitatively analyzed, and provide molecular insights comparable to blood testing. In a human study, the possibility to monitor various classes of molecular analytes is demonstrated in ISF microsamples, including caffeine, hundreds of proteins, and SARS-CoV-2 antibodies, some being detected in ISF for the first time.
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Project description:The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and analysis. 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 analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.
| S-EPMC8020465 | biostudies-literature
Project description:Individuals with diabetes can benefit considerably from continuous blood glucose monitoring. To address this challenge, a proof-of-concept was performed for continuous glucose monitoring (CGM) based on an enzymeless porous nanomaterial (pNM)-modified microneedle electrode array (MNEA). The pNM sensing layer was electrochemically deposited on MNs by applying a fixed negative current of -2.5 mA cm-2 for 400 s. The pNM-modified MNEA was packed using a biocompatible Nafion ionomer. The fabricated MNEAs were 600 × 100 × 150 µm in height, width, and thickness, respectively. The surfaces of the modified MNs were characterized by scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The fabricated MNEAs showed a wide dynamic range (1-30 mM) in phosphate-buffered saline (PBS) and in artificial interstitial fluid (ISF), with good sensitivities (PBS: 1.792 ± 0.25 µA mM-1 cm-2, ISF: 0.957 ± 0.14 µA mM-1 cm-2) and low detection limits (PBS: 7.2 µM, ISF: 22 µM). The sensor also showed high stability (loss of 3.5% at the end of 16 days), selectivity, and reproducibility (Relative standard deviations (RSD) of 1.64% and 0.70% for intra- and inter-assay, respectively) and a good response time (2 s) with great glucose recovery rates in ISF (98.7-102%).
| S-EPMC7824010 | biostudies-literature