Wearable technologies for personalized monitoring require sensors that track biomarkers often present at low levels. Cortisol-a key stress biomarker-is present in sweat at low nanomolar concentrations. Previous wearable sensing systems are limited to analytes in the micromolar-millimolar ranges. To overcome this and other limitations, we developed a flexible field-effect transistor (FET) biosensor array that exploits a previously unreported cortisol aptamer coupled to nanometer-thin-film In 2 O 3 FETs. Cortisol levels were determined via molecular recognition by aptamers where binding was transduced to electrical signals on FETs. The physiological relevance of cortisol as a stress biomarker was demonstrated by tracking salivary cortisol levels in participants in a Trier Social Stress Test and establishing correlations between cortisol in diurnal saliva and sweat samples. These correlations motivated the development and on-body validation of an aptamer-FET array-based smartwatch equipped with a custom, multichannel, self-referencing, and autonomous source measurement unit enabling seamless, real-time cortisol sweat sensing.

Active biofluid management is central to the realization of wearable bioanalytical platforms that are poised to autonomously provide frequent, real-time, and accurate measures of biomarkers in epidermally-retrievable biofluids (e.g., sweat). Accordingly, here, a programmable epidermal microfluidic valving system is devised, which is capable of biofluid sampling, routing, and compartmentalization for biomarker analysis. At its core, the system is a network of individually-addressable microheater-controlled thermo-responsive hydrogel valves, augmented with a pressure regulation mechanism to accommodate pressure built-up, when interfacing sweat glands. The active biofluid control achieved by this system is harnessed to create unprecedented wearable bioanalytical capabilities at both the sensor level (decoupling the confounding influence of flow rate variability on sensor response) and the system level (facilitating context-based sensor selection/protection). Through integration with a wireless flexible printed circuit board and seamless bilateral communication with consumer electronics (e.g., smartwatch), contextually-relevant (scheduled/on-demand) on-body biomarker data acquisition/display was achieved.

Recent advances in microelectronics, microfluidics, and electrochemical sensing platforms have enabled the development of an emerging class of fully integrated personal health monitoring devices that exploit sweat to noninvasively access biomarker information. Despite such advances, effective sweat sampling remains a significant challenge for reliable biomarker analysis, with many existing methods requiring active stimulation (e.g., iontophoresis, exercise, heat). Natural perspiration offers a suitable alternative as sweat can be collected with minimal effort on the part of the user. To leverage this phenomenon, we devised a thin hydrogel micropatch (THMP), which simultaneously serves as an interface for sweat sampling and a medium for electrochemical sensing. To characterize the performance of the THMP, caffeine and lactate were selected as two representative target molecules. We demonstrated the suitability of the sampling method to track metabolic patterns, as well as to render sample-to-answer biomarker data for personal monitoring (through coupling with an electrochemical sensing system). To inform its potential application, this biomarker sampling and sensing system is incorporated within a distributed terminal-based sensing network, which uniquely capitalizes on the fingertip as a site for simultaneous biomarker data sampling and user identification.

To render high-fidelity wearable biomarker data, understanding and engineering the information delivery pathway from epidermally retrieved biofluid to a readout unit are critical. By examining the biomarker information delivery pathway and recognizing near-zero strained regions within a microfluidic device, a strain-isolated pathway to preserve biomarker data fidelity is engineered. Accordingly, a generalizable and disposable freestanding electrochemical sensing system (FESS) is devised, which simultaneously facilitates sensing and out-of-plane signal interconnection with the aid of double-sided adhesion. The FESS serves as a foundation to realize a system-level design strategy, addressing the challenges of wearable biosensing, in the presence of motion, and integration with consumer electronics. To this end, a FESS-enabled smartwatch was developed, featuring sweat sampling, electrochemical sensing, and data display/transmission, all within a self-contained wearable platform. The FESS-enabled smartwatch was used to monitor the sweat metabolite profiles of individuals in sedentary and high-intensity exercise settings.

To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals’ drug transcourse profiles (semi)continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target’s redox signature. However, the target’s redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy—centering on engineering the molecule–surface interactions—to simultaneously mitigate biofouling and create an “undistorted potential window” within which the target drug’s voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays, R2 ∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.

Therapeutic drug monitoring is essential for dosing pharmaceuticals with narrow therapeutic windows. Nevertheless, standard methods are imprecise and involve invasive/resource-intensive procedures with long turnaround times. Overcoming these limitations, we present a microneedle-based electrochemical aptamer biosensing patch (μNEAB-patch) that minimally invasively probes the interstitial fluid (ISF) and renders correlated, continuous, and real-time measurements of the circulating drugs’ pharmacokinetics. The μNEAB-patch is created following an introduced low-cost fabrication scheme, which transforms a shortened clinical-grade needle into a high-quality gold nanoparticle-based substrate for robust aptamer immobilization and efficient electrochemical signal retrieval. This enables the reliable in vivo detection of a wide library of ISF analytes—especially those with nonexistent natural recognition elements. Accordingly, we developed μNEABs targeting various drugs, including antibiotics with narrow therapeutic windows (tobramycin and vancomycin). Through in vivo animal studies, we demonstrated the strong correlation between the ISF/circulating drug levels and the device’s potential clinical use for timely prediction of total drug exposure.

Wearable electroenzymatic sensors enable monitoring of clinically informative biomolecules in epidermally retrievable biofluids. Conventional wearable enzymatic sensors utilize Prussian Blue (a redox mediator) to achieve selectivity against electroactive interferents. However, the use of Prussian Blue presents fundamental challenges including: 1) the susceptibility of the sensor response to dynamic concentration variation of ionic species and 2) the poor operational stability due to the degradation of its framework. As an alternative wearable electroenzymatic sensor development methodology to bypass the aforementioned limitations, a mediator‐free sensing interface is devised, comprising of a coupled platinum nanoparticle/multiwall carbon nanotube layer and a permselective membrane. The interface is adapted to develop sensors targeting glucose, lactate, and choline (as examples of informative metabolites and nutrients), showing high degrees of sensitivity, selectivity (against a wide panel of naturally present and diverse interfering species), stability (<6.5% signal drift over 20 h operation), and reliability of sensing operation in sweat samples. By integration within a readout board, a wireless sample‐to‐answer system is realized for on‐body sweat biomarker analysis. This methodology can be adapted to target a wide panel of biomarkers in various biofluids, introducing a new sensor development direction for personal health monitoring.

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