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Real-time monitoring of human health can be significantly improved by designing novel electronic skin (E-skin) platforms that mimic the characteristics and sensitivity of human skin. A high-quality E-skin platform that can simultaneously monitor multiple physiological and metabolic biomarkers without introducing skin discomfort or irritation is an unmet medical need. Conventional E-skins are either monofunctional or made from elastomeric films that do not include key synergistic features of natural skin, such as multi-sensing, breathability, and thermal management capabilities in a single patch. Herein, a biocompatible and biodegradable E-skin patch based on flexible gelatin methacryloyl aerogel (FGA) for non-invasive and continuous monitoring of multiple biomarkers of interest is engineered and demonstrated. Taking advantage of cryogenic temperature treatment and slow polymerization, FGA is fabricated with a highly interconnected porous structure that displays good flexibility, passive-cooling capabilities, and ultra-lightweight properties that make it comfortable to wear for long periods of time. It also provides numerous permeable capillary channels for thermal-moisture transfer, ensuring its excellent breathability. Therefore, the engineered FGA-based E-skin can simultaneously monitor body temperature, hydration, and biopotentials via electrophysiological sensors and detect glucose, lactate, and alcohol levels via electrochemical sensors. This work offers a previously unexplored materials strategy for next-generation E-skin platforms with superior practicality.

Expanding our global testing capacity is critical to preventing and containing pandemics1-9. Accordingly, accessible and adaptable automated platforms that in decentralized settings perform nucleic acid amplification tests resource-efficiently are required10-14. Pooled testing can be extremely efficient if the pooling strategy is based on local viral prevalence15-20; however, it requires automation, small sample volume handling and feedback not available in current bulky, capital-intensive liquid handling technologies21-29. Here we use a swarm of millimetre-sized magnets as mobile robotic agents ('ferrobots') for precise and robust handling of magnetized sample droplets and high-fidelity delivery of flexible workflows based on nucleic acid amplification tests to overcome these limitations. Within a palm-sized printed circuit board-based programmable platform, we demonstrated the myriad of laboratory-equivalent operations involved in pooled testing. These operations were guided by an introduced square matrix pooled testing algorithm to identify the samples from infected patients, while maximizing the testing efficiency. We applied this automated technology for the loop-mediated isothermal amplification and detection of the SARS-CoV-2 virus in clinical samples, in which the test results completely matched those obtained off-chip. This technology is easily manufacturable and distributable, and its adoption for viral testing could lead to a 10-300-fold reduction in reagent costs (depending on the viral prevalence) and three orders of magnitude reduction in instrumentation cost. Therefore, it is a promising solution to expand our testing capacity for pandemic preparedness and to reimagine the automated clinical laboratory of the future.

Advancements in wearable bioanalytical microsystems have enabled diurnal and (semi)continuous monitoring of physiologically-relevant indices that are accessible through probing sweat. To deliver an undistorted and physiologically-meaningful interpretation of these readings, tracking the sweat secretion rate is essential, because it allows for calibrating the biomarker readings against variations in sweat secretion and inferring the bodys hydration/electrolyte homeostasis status. To realize an autonomous wearable solution with intrinsically high signal-to-noise ratio sweat rate sensing capabilities, here, we devise a digitized microbubble detection mechanism-delivered by a hybrid microfluidic/electronic system with a compact footprint. This mechanism is based on the intermittent generation of microliter-scale bubbles via electrolysis and the instantaneous measurement of their time-of-flight (and thus, velocity) via impedimetric sensing. In this way, we overcome the limitations of previously proposed sweat rate sensing modalities that are inherently susceptible to non-targeted secretion characteristics (pH, conductivity, and temperature), constrained by volume, or lack system integration for autonomous on-body operation. By deploying our solution in human subject trials, we validate the utility of our solution for seamless monitoring of exercise- and iontophoretically-induced sweat secretion profiles.

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.

The awareness of individuals’ biological status is critical for creating interactive and adaptive environments that can actively assist the users to achieve optimal outcomes. Accordingly, specialized human–machine interfaces—equipped with bioperception and interpretation capabilities—are required. To this end, we devised a multimodal cryptographic bio-human–machine interface (CB-HMI), which seamlessly translates the user’s touch-based entries into encrypted biochemical, biophysical, and biometric indices. As its central component, the CB-HMI features thin hydrogel-coated chemical sensors and inference algorithms to noninvasively and inconspicuously acquire biochemical indices such as circulating molecules that partition onto the skin (here, ethanol and acetaminophen). Additionally, the CB-HMI hosts physical sensors and associated algorithms to simultaneously acquire the user’s heart rate, blood oxygen level, and fingerprint minutiae pattern. Supported by human subject studies, we demonstrated the CB-HMI’s capability in terms of acquiring physiologically relevant readouts of target bioindices, as well as user-identifying and biometrically encrypting/decrypting these indices in situ (leveraging the fingerprint feature). By upgrading the common surrounding objects with the CB-HMI, we created interactive solutions for driving safety and medication use. Specifically, we demonstrated a vehicle-activation system and a medication-dispensing system, where the integrated CB-HMI uniquely enabled user bioauthentication (on the basis of the user’s biological state and identity) prior to rendering the intended services. Harnessing the levels of bioperception achieved by the CB-HMI and other intelligent HMIs, we can equip our surroundings with a comprehensive and deep awareness of individuals’ psychophysiological state and needs.

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 In2O3 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.

Wearable piezoresistive sensors are being developed as electronic skins (E-skin) for broad applications in human physiological monitoring and soft robotics. Tactile sensors with sufficient sensitivities, durability, and large dynamic ranges are required to replicate this critical component of the somatosensory system. Multiple micro/nanostructures, materials, and sensing modalities have been reported to address this need. However, a trade-off arises between device performance and device complexity. Inspired by the microstructure of the spinosum at the dermo epidermal junction in skin, a low-cost, scalable, and high-performance piezoresistive sensor is developed with high sensitivity (0.144 kPa-1 ), extensive sensing range ( 0.1-15 kPa), fast response time (less than 150 ms), and excellent long-term stability (over 1000 cycles). Furthermore, the piezoresistive functionality of the device is realized via a flexible transparent electrode (FTE) using a highly stable reduced graphene oxide self-wrapped copper nanowire network. The developed nanowire-based spinosum microstructured FTEs are amenable to wearable electronics applications.

Mechanical deformation of human skin provides essential information about human motions, muscle stretching, vocal fold vibration, and heart rates. Monitoring these activities requires the measurement of strains at different levels. Herein, we report a wearable wide-range strain sensor based on conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). A bioinspired bilayer structure was constructed to enable a wide-range strain sensing (1%~100%). Besides, hydrogel was chosen as the biological- and mechanical-compatible interface layer with the human skin. Finally, we demonstrated that the strain sensor is capable of monitoring various strain-related activities, including subtle skin deformation (pulse and phonation), mid-level body stretch (swallowing and facial expressions), and substantial joint movement (elbow bending).

Gelatin methacryloyl (GelMA) is a widely used hydrogel with skin-derived gelatin acting as the main constituent. However, GelMA has not been used in the development of wearable biosensors, which are emerging devices that enable personalized healthcare monitoring. This work highlights the potential of GelMA for wearable biosensing applications by demonstrating a fully solution-processable and transparent capacitive tactile sensor with microstructured GelMA as the core dielectric layer. A robust chemical bonding and a reliable encapsulation approach are introduced to overcome detachment and water-evaporation issues in hydrogel biosensors. The resultant GelMA tactile sensor shows a high-pressure sensitivity of 0.19 kPa-1 and one order of magnitude lower limit of detection (0.1 Pa) compared to previous hydrogel pressure sensors owing to its excellent mechanical and electrical properties (dielectric constant). Furthermore, it shows durability up to 3000 test cycles because of tough chemical bonding, and long-term stability of 3 days due to the inclusion of an encapsulation layer, which prevents water evaporation (80% water content). Successful monitoring of various human physiological and motion signals demonstrates the potential of these GelMA tactile sensors for wearable biosensing applications.

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.

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, R 2 ∼ 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.

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.

Embedding microfluidic architectures with microneedles enables fluid management capabilities that present new degrees of freedom for transdermal drug delivery. To this end, fabrication schemes that can simultaneously create and integrate complex millimeter/centimeter-long microfluidic structures and micrometer-scale microneedle features are necessary. Accordingly, three-dimensional (3D) printing techniques are suitable candidates because they allow the rapid realization of customizable yet intricate microfluidic and microneedle features. However, previously reported 3D-printing approaches utilized costly instrumentation that lacked the desired versatility to print both features in a single step and the throughput to render components within distinct length-scales. Here, for the first time in literature, we devise a fabrication scheme to create hollow microneedles interfaced with microfluidic structures in a single step. Our method utilizes stereolithography 3D-printing and pushes its boundaries (achieving print resolutions below the full width half maximum laser spot size resolution) to create complex architectures with lower cost and higher print speed and throughput than previously reported methods. To demonstrate a potential application, a microfluidic-enabled microneedle architecture was printed to render hydrodynamic mixing and transdermal drug delivery within a single device. The presented architectures can be adopted in future biomedical devices to facilitate new modes of operations for transdermal drug delivery applications such as combinational therapy for preclinical testing of biologic treatments.

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications.

Homeostasis of ionized calcium in biofluids is critical for human biological functions and organ systems. Measurement of ionized calcium for clinical applications is not easily accessible due to its strict procedures and dependence on pH. pH balance in body fluids greatly affects metabolic reactions and biological transport systems. Here, we demonstrate a wearable electrochemical device for continuous monitoring of ionized calcium and pH of body fluids using a disposable and flexible array of Ca(2+) and pH sensors that interfaces with a flexible printed circuit board. This platform enables real-time quantitative analysis of these sensing elements in body fluids such as sweat, urine, and tears. Accuracy of Ca(2+) concentration and pH measured by the wearable sensors is validated through inductively coupled plasma-mass spectrometry technique and a commercial pH meter, respectively. Our results show that the wearable sensors have high repeatability and selectivity to the target ions. Real-time on-body assessment of sweat is also performed, and our results indicate that calcium concentration increases with decreasing pH. This platform can be used in noninvasive continuous analysis of ionized calcium and pH in body fluids for disease diagnosis such as primary hyperparathyroidism and kidney stones.

A flexible and wearable microsensor array is described for simultaneous multiplexed monitoring of heavy metals in human body fluids. Zn, Cd, Pb, Cu, and Hg ions are chosen as target analytes for detection via electrochemical square wave anodic stripping voltammetry (SWASV) on Au and Bi microelectrodes. The oxidation peaks of these metals are calibrated and compensated by incorporating a skin temperature sensor. High selectivity, repeatability, and flexibility of the sensor arrays are presented. Human sweat and urine samples are collected for heavy metal analysis, and measured results from the microsensors are validated through inductively coupled plasma mass spectrometry (ICP-MS). Real-time on-body evaluation of heavy metal (e.g., zinc and copper) levels in sweat of human subjects by cycling is performed to examine the change in concentrations with time. This platform is anticipated to provide insightful information about an individual's health state such as heavy metal exposure and aid the related clinical investigations.

Printed electronics and sensors enable new applications ranging from low-cost disposable analytical devices to large-area sensor networks. Recent progress in printed carbon nanotube electronics in terms of materials, processing, devices, and applications is discussed on page 4397 by A. Javey and co-workers. The research challenges and opportunities regarding the processing and system-level integration are also discussed for enabling of practical applications.

Printing technologies offer large-area, high-throughput production capabilities for electronics and sensors on mechanically flexible substrates that can conformally cover different surfaces. These capabilities enable a wide range of new applications such as low-cost disposable electronics for health monitoring and wearables, extremely large format electronic displays, interactive wallpapers, and sensing arrays. Solution-processed carbon nanotubes have been shown to be a promising candidate for such printing processes, offering stable devices with high performance. Here, recent progress made in printed carbon nanotube electronics is discussed in terms of materials, processing, devices, and applications. Research challenges and opportunities moving forward from processing and system-level integration points of view are also discussed for enabling practical applications.

Wearable sensor technologies are essential to the realization of personalized medicine through continuously monitoring an individual's state of health. Sampling human sweat, which is rich in physiological information, could enable non-invasive monitoring. Previously reported sweat-based and other non-invasive biosensors either can only monitor a single analyte at a time or lack on-site signal processing circuitry and sensor calibration mechanisms for accurate analysis of the physiological state. Given the complexity of sweat secretion, simultaneous and multiplexed screening of target biomarkers is critical and requires full system integration to ensure the accuracy of measurements. Here we present a mechanically flexible and fully integrated (that is, no external analysis is needed) sensor array for multiplexed in situ perspiration analysis, which simultaneously and selectively measures sweat metabolites (such as glucose and lactate) and electrolytes (such as sodium and potassium ions), as well as the skin temperature (to calibrate the response of the sensors). Our work bridges the technological gap between signal transduction, conditioning (amplification and filtering), processing and wireless transmission in wearable biosensors by merging plastic-based sensors that interface with the skin with silicon integrated circuits consolidated on a flexible circuit board for complex signal processing. This application could not have been realized using either of these technologies alone owing to their respective inherent limitations. The wearable system is used to measure the detailed sweat profile of human subjects engaged in prolonged indoor and outdoor physical activities, and to make a real-time assessment of the physiological state of the subjects. This platform enables a wide range of personalized diagnostic and physiological monitoring applications.

The awareness of individuals' biological status is critical for creating interactive and adaptive environments that can actively assist the users to achieve optimal outcomes. Accordingly, specialized human-machine interfaces--equipped with bioperception and interpretation capabilities--are required. To this end, we devised a multimodal cryptographic bio-human-machine interface (CB-HMI), which seamlessly translates the user's touch-based entries into encrypted biochemical, biophysical, and biometric indices. As its central component, the CB-HMI features thin hydrogel-coated chemical sensors and inference algorithms to noninvasively and inconspicuously acquire biochemical indices such as circulating molecules that partition onto the skin (here, ethanol and acetaminophen). Additionally, the CB-HMI hosts physical sensors and associated algorithms to simultaneously acquire the user's heart rate, blood oxygen level, and fingerprint minutiae pattern. Supported by human subject studies, we demonstrated the CB-HMI's capability in terms of acquiring physiologically relevant readouts of target bioindices, as well as user-identifying and biometrically encrypting/decrypting these indices in situ (leveraging the fingerprint feature). By upgrading the common surrounding objects with the CB-HMI, we created interactive solutions for driving safety and medication use. Specifically, we demonstrated a vehicle-activation system and a medication-dispensing system, where the integrated CB-HMI uniquely enabled user bioauthentication (on the basis of the user's biological state and identity) prior to rendering the intended services. Harnessing the levels of bioperception achieved by the CB-HMI and other intelligent HMIs, we can equip our surroundings with a comprehensive and deep awareness of individuals' psychophysiological state and needs. [ABSTRACT FROM AUTHOR]