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      Autonomous sweat extraction and analysis applied to cystic fibrosis and glucose monitoring using a fully integrated wearable platform

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          Significance

          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. Through devising an electrochemically enhanced, programmable, and miniaturized iontophoresis interface, integrated in a wearable sensing platform, we demonstrated a method for periodic sweat extraction and in situ analysis. The system can be programmed to induce sweat with various secretion profiles, which in combination with the in situ analysis capability allow us to gain real-time insight into the sweat-secretion and gland physiology. 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.

          Abstract

          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.

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          Most cited references19

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          An ultra-lightweight design for imperceptible plastic electronics.

          Electronic devices have advanced from their heavy, bulky origins to become smart, mobile appliances. Nevertheless, they remain rigid, which precludes their intimate integration into everyday life. Flexible, textile and stretchable electronics are emerging research areas and may yield mainstream technologies. Rollable and unbreakable backplanes with amorphous silicon field-effect transistors on steel substrates only 3 μm thick have been demonstrated. On polymer substrates, bending radii of 0.1 mm have been achieved in flexible electronic devices. Concurrently, the need for compliant electronics that can not only be flexed but also conform to three-dimensional shapes has emerged. Approaches include the transfer of ultrathin polyimide layers encapsulating silicon CMOS circuits onto pre-stretched elastomers, the use of conductive elastomers integrated with organic field-effect transistors (OFETs) on polyimide islands, and fabrication of OFETs and gold interconnects on elastic substrates to realize pressure, temperature and optical sensors. Here we present a platform that makes electronics both virtually unbreakable and imperceptible. Fabricated directly on ultrathin (1 μm) polymer foils, our electronic circuits are light (3 g m(-2)) and ultraflexible and conform to their ambient, dynamic environment. Organic transistors with an ultra-dense oxide gate dielectric a few nanometres thick formed at room temperature enable sophisticated large-area electronic foils with unprecedented mechanical and environmental stability: they withstand repeated bending to radii of 5 μm and less, can be crumpled like paper, accommodate stretching up to 230% on prestrained elastomers, and can be operated at high temperatures and in aqueous environments. Because manufacturing costs of organic electronics are potentially low, imperceptible electronic foils may be as common in the future as plastic wrap is today. Applications include matrix-addressed tactile sensor foils for health care and monitoring, thin-film heaters, temperature and infrared sensors, displays, and organic solar cells.
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            User-interactive electronic skin for instantaneous pressure visualization.

            Electronic skin (e-skin) presents a network of mechanically flexible sensors that can conformally wrap irregular surfaces and spatially map and quantify various stimuli. Previous works on e-skin have focused on the optimization of pressure sensors interfaced with an electronic readout, whereas user interfaces based on a human-readable output were not explored. Here, we report the first user-interactive e-skin that not only spatially maps the applied pressure but also provides an instantaneous visual response through a built-in active-matrix organic light-emitting diode display with red, green and blue pixels. In this system, organic light-emitting diodes (OLEDs) are turned on locally where the surface is touched, and the intensity of the emitted light quantifies the magnitude of the applied pressure. This work represents a system-on-plastic demonstration where three distinct electronic components--thin-film transistor, pressure sensor and OLED arrays--are monolithically integrated over large areas on a single plastic substrate. The reported e-skin may find a wide range of applications in interactive input/control devices, smart wallpapers, robotics and medical/health monitoring devices.
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              A skin-inspired organic digital mechanoreceptor.

              Human skin relies on cutaneous receptors that output digital signals for tactile sensing in which the intensity of stimulation is converted to a series of voltage pulses. We present a power-efficient skin-inspired mechanoreceptor with a flexible organic transistor circuit that transduces pressure into digital frequency signals directly. The output frequency ranges between 0 and 200 hertz, with a sublinear response to increasing force stimuli that mimics slow-adapting skin mechanoreceptors. The output of the sensors was further used to stimulate optogenetically engineered mouse somatosensory neurons of mouse cortex in vitro, achieving stimulated pulses in accordance with pressure levels. This work represents a step toward the design and use of large-area organic electronic skins with neural-integrated touch feedback for replacement limbs.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                2 May 2017
                17 April 2017
                17 April 2017
                : 114
                : 18
                : 4625-4630
                Affiliations
                [1] aStanford Genome Technology Center, Stanford School of Medicine , Palo Alto, CA 94304;
                [2] bDepartment of Electrical Engineering and Computer Sciences, University of California, Berkeley , CA 94720;
                [3] cBerkeley Sensor and Actuator Center, University of California, Berkeley , CA 94720;
                [4] dMaterials Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, CA 94720;
                [5] eThe Stanford Cystic Fibrosis Center, Center for Excellence in Pulmonary Biology, Stanford School of Medicine, Palo Alto, CA 94305;
                [6] fDepartment of Electrical Engineering, Stanford University, Stanford, CA 94305
                Author notes
                3To whom correspondence may be addressed. Email: cmilla@ 123456stanford.edu , ajavey@ 123456berkeley.edu , or krhong@ 123456stanford.edu .

                Contributed by Ronald W. Davis, February 14, 2017 (sent for review December 15, 2016; reviewed by Maneesh Jain and Andre Marziali)

                Author contributions: S.E., W.G., C.M., A.J., and R.W.D. designed research; S.E., W.G., E.W., Z.A.D., H.Y.Y.N., S.C., S.P.R., H.M.F., K.C., Z.S., S.T., C.M., A.J., and R.W.D. performed research; S.E., W.G., E.W., C.M., A.J., and R.W.D. contributed new reagents/analytic tools; S.E., W.G., E.W., C.M., A.J., and R.W.D. analyzed data; and S.E., W.G., E.W., C.M., A.J., and R.W.D. wrote the paper.

                Reviewers: M.J., Cirina; and A.M., University of British Columbia.

                1S.E. and W.G. contributed equally to this work.

                2Present address: Department of Electrical Engineering, University of California, Los Angeles, CA 90095.

                Article
                PMC5422810 PMC5422810 5422810 201701740
                10.1073/pnas.1701740114
                5422810
                28416667
                80b2f55f-6430-46d7-9aad-87335d4b48e1

                Freely available online through the PNAS open access option.

                History
                Page count
                Pages: 6
                Funding
                Funded by: National Institutes of Health
                Award ID: HG000205
                Funded by: National Science Foundation (NSF) 100000001
                Award ID: NASCENT
                Funded by: U.S. Department of Energy (DOE) 100000015
                Award ID: DE-AC02-05CH11231
                Categories
                Physical Sciences
                Engineering
                Biological Sciences
                Physiology

                personalized medicine,wearable,biosensors,noninvasive,iontophoresis

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