Wearable sensor technologies are essential to the realization of personalized medicine through continuously monitoring an individual's state of health 1-12 . Sampling human sweat, which is rich in physiological information 13 , could enable non-invasive monitoring. Previously reported sweat-based and other noninvasive 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 [14] [15] [16] [17] [18] . 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 plasticbased 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. Wearable electronics are devices that can be worn or mated with human skin to continuously and closely monitor an individual's activities, without interrupting or limiting the user's motions [1][2][3] [4] [5] [6] [7] [8] [9] . Thus wearable biosensors could enable real-time continuous monitoring of an individual's physiological biomarkers [10] [11] [12] . At present, commercially available wearable sensors are only capable of tracking an individual's physical activities and vital signs (such as heart rate), and fail to provide insight into the user's health state at molecular levels. Measurements of human sweat could enable such insight, because it contains physiologically and metabolically rich information that can be retrieved non-invasively 13 . Sweat analysis is currently used for applications such as disease diagnosis, drug abuse detection, and athletic performance optimization 13 . For these applications, the sample collection and analysis are performed separately, failing to provide a real-time profile of sweat content secretion, while requiring extensive laboratory analysis using bulky instrumentation 19 . Recently, wearable sweat sensors have been developed, with which a variety of biosensors have been used to measure analytes of interest (Supplementary Table 1) 14-18 . Given the multivariate mechanisms that are involved in sweat secretion, an attractive strategy would be to devise a fully integrated multiplexed sensing system to extract the complex information available from sweat. Here we present a wearable flexible integrated sensing array (FISA) for simultaneous and selective screening of a panel of biomarkers in sweat (Fig. 1a) . Our solution bridges the existing technological gap between signal transduction (electrical signal generation by sensors), conditioning (here, amplification and filtering), processing (here, calibration and compensation) and wireless transmission in wearable biosensors by merging commercially available integrated-circuit technologies, consolidated on a flexible printed circuit board (FPCB), with flexible and conforming sensor technologies fabricated on plastic substrates. This approach decouples the stringent mechanical requirements at the sensor level and electrical requirements at the signal conditioning, processing and transmission levels, and at the same time exploits the strengths of the underlying technologies. The independent and selective operation of individual sensors is preserved during multiplexed measurements by employing highly specific surface chemistries and by electrically decoupling the operating points of each sensor's interface. This platform is a powerful tool with which to advance largescale and real-time physiological and clinical studies by facilitating the identification of informative biomarkers in sweat. As illustrated in Fig. 1a , the FISA allows simultaneous and selective measurement of a panel of metabolites and electrolytes in human perspiration as well as skin temperature during prolonged indoor and outdoor physical activities. By fabricating the sensors on a mechanically flexible polyethylene terephthalate (PET) substrate, a stable sensorskin contact is formed, while the FPCB technology is exploited to incorporate the critical signal conditioning, processing, and wireless transmission functionalities using readily available integrated-circuit components (Fig. 1b) . The panel of target analytes and skin temperature was selected to facilitate an understanding of an individual's physiological state (see Supplementary Information for selection of the target analytes). For example, excessive loss of sodium and potassium in sweat could result in hyponatremia, hypokalemia, muscle cramps or dehydration 20 ; sweat glucose is reported to be metabolically related to blood glucose 21 ; sweat lactate can potentially serve as a sensitive marker of pressure ischaemia ; and skin temperature is clinically informative of a variety of diseases and skin injuries such as pressure ulcers 23, 24 . Additionally, skin temperature measurements are needed to compensate for and eliminate the influence of temperature variation in the readings of the chemical sensors through a built-in signal processor. Figure 1c illustrates the schematic of the multiplexed sensor array (each electrode is 3 mm in diameter) for sweat analysis; fabrication processes are detailed in Methods and Extended Data Fig. 1 . Here,
A mechanically flexible and fully integrated wearable sensor array was demonstrated in REF for in situ perspiration analysis.
Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis
Nature
Nature
Computer Science Medicine