Successful commercialization of wearable diagnostic sensors necessitates stability in detection of analytes over prolonged and continuous exposure to sweat. Challenges are primarily in ensuring target disease specific small analytes (i.e. metabolites, proteins, etc.) stability in complex sweat buffer with varying pH levels and composition over time. We present a facile approach to address these challenges using RTILs with antibody functionalized sensors on nanoporous, flexible polymer membranes. Temporal studies were performed using both infrared spectroscopic, dynamic light scattering, and impedimetric spectroscopy to demonstrate stability in detection of analytes, Interleukin-6 (IL-6) and Cortisol, from human sweat in RTILs. Temporal stability in sensor performance was performed as follows: (a) detection of target analytes after 0, 24, 48, 96, and 168 hours post-antibody sensor functionalization; and (b) continuous detection of target analytes post-antibody sensor functionalization. Limit of detection of IL-6 in human sweat was 0.2 pg/mL for 0–24 hours and 2 pg/mL for 24–48 hours post-antibody sensor functionalization. Continuous detection of IL-6 over 0.2–200 pg/mL in human sweat was demonstrated for a period of 10 hours post-antibody sensor functionalization. Furthermore, combinatorial detection of IL-6 and Cortisol in human sweat was established with minimal cross-talk for 0–48 hours post-antibody sensor functionalization.
In this work, we demonstrate a robust, dual marker, biosensing strategy for specific and sensitive electrochemical response of Procalcitonin and C-reactive protein in complex body fluids such as human serum and whole blood for the detection of sepsis. Enhanced sensitivity is achieved by leveraging the physicochemical properties of zinc oxide at the electrode-solution interface. Characterization techniques such as SEM, EDAX, AFM, FTIR and fluorescence microscopy were performed to ensure a suitable biosensing surface. The characteristic biomolecular interactions between the target analyte and specific capture probe is quantified through unique frequency signatures using non-faradaic electrochemical impedance spectroscopy (EIS). The developed biosensor demonstrated a detection limit of 0.10 ng mL −1 for PCT in human serum and whole blood with an R 2 of 0.99 and 0.98 respectively. CRP demonstrated a detection limit of 0.10 μg mL −1 in human serum and whole blood with an R 2 of 0.90 and 0.98 respectively. Cross-reactivity analysis demonstrated robust selectivity to PCT and CRP with negligible interaction to non-specific biomolecules. The novel aspect of this technology is the ability to fine-tune individual biomarkers response owing to the optimal frequency tuning capability. The developed biosensor requires an ultra-low sample volume of 10 μL without the need for sample dilution for rapid analysis. We envision the developed dual marker biosensor to be useful as a sepsis-screening device for prognostic monitoring.
This work presents the viability of passive eccrine sweat as a functional biofluid toward tracking the human body's inflammatory response. Cytokines are biomarkers that orchestrate the manifestation and progression of an infection/inflammatory event. Hence, noninvasive, real-time monitoring of cytokines can be pivotal in assessing the progression of infection/inflammatory event, which may be feasible through monitoring of host immune markers in eccrine sweat. This work is the first experimental proof demonstrating the ability to detect inflammation/infection such as fever, FLU directly from passively expressed sweat in human subjects using a wearable "SWEATSENSER" device. The developed SWEATSENSER device demonstrates stable, real-time monitoring of inflammatory cytokines in passive sweat. An accuracy of >90% and specificity >95% was achieved using SWEATSENSER for a panel of cytokines (interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α) over an analytical range of 0.2-200 pg mL −1 . The SWEATSENSER demonstrated a correlation of Pearson's r > 0.98 for the study biomarkers in a cohort of 26 subjects when correlated with standard reference method. Comparable IL-8 levels (2-15 pg mL −1 ) between systemic circulation (serum) and eccrine sweat through clinical studies in a cohort of 15 subjects, and the ability to distinguish healthy and sick (infection) cohort using inflammatory cytokines in sweat provides pioneering evidence of the SWEATSENSER technology for noninvasive tracking of host immune response biomarkers. Such a wearable device can offer significant strides in improving prognosis and provide personalized therapeutic treatment for several inflammatory/infectious diseases.
Background More than 1.2 million people in the United States are affected by inflammatory bowel disease (IBD). Inflammatory bowel disease has a natural course characterized by alternating periods of remission and relapse. Currently, disease flares are unpredictable as they occur in a random way. Further, current testing methods and practices lack the ability for real-time tracking of flares. There exists no technology that can be utilized for continuous monitoring of biomarkers, as most of these rely on samples such as blood, feces, and testing methods by which continuous monitoring is not feasible. Cytokines play a key role in IBD; the development, recurrence, and exacerbation of the inflammatory process are orchestrated by their levels in time and space. Cytokines are also present in sweat. We hypothesize that demonstrating real-time continuous monitoring of interleukin-1β (IL-1β) and C-reactive protein (CRP) may help create an enabling technology to track inflammation in IBD patients and identify flare-ups and assess efficacy of therapy. Methods A multiplexed SWEATSENSER was used for noninvasive continuous monitoring of interleukin-1β and C-reactive protein in human eccrine sweat. Impedance spectroscopy was used to measure the sensor response. Sweat was collected using an FDA-approved PharmChek patch from 26 healthy human subjects to determine the levels of the 2 study inflammatory markers. Correlation analysis was performed for preclinical validation of the SWEATSENSER with ELISA as the reference method. On-body continuous monitoring measurements were performed on 20 human subjects using EnLiSense’s SWEATSENSER wearable device for real-time monitoring studies. Results The sensor device can detect interleukin-1β and C-reactive protein in sweat over a dynamic range of 3 log orders. Pearson correlation of r = 0.99 and r = 0.95 was achieved for IL-1β and CRP, respectively, for the SWEATSENSER with ELISA. Bland-Altman results further confirmed a good agreement (mean bias of –0.25 and –3.9 pg/mL for IL-1β and CRP, respectively) of the device with the reference method, demonstrating applicability of the device for real-time monitoring. Continuous on-body measurements were performed in 20 healthy human subjects for the detection of IL-1β to establish the preclinical utility of the sensor device. The continuous on-body measurements in healthy cohort reported a mean IL-1β concentration of ~28 pg/mL. Stable measurements for over continuous 30 hours was reported by the device. Conclusion This work demonstrates the first proof-of-feasibility of multiplexed cytokine and inflammatory marker detection in passively expressed eccrine sweat in a wearable form-factor that can be utilized toward better management of inflammatory bowel disease. This is a first step toward demonstrating a noninvasive enabling technology that can enable baseline tracking of an inflammatory response. Furthermore, this is the first study to report and quantify the presence of CRP in human eccrine sweat.
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