Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis

In the paper

“Wearable sensor technologies are essential to the realization of personalized medicine through continuously monitoring an individual's state of health1–12.”

What the sources say

• Partly supported

  The paper’s Abstract describes skin-integrated sensors for physiological-status monitoring, and its ECG, EMG and EEG demonstrations show that they can measure an individual’s signals. It does not establish that wearable sensors are essential to personalized medicine or demonstrate continuous health monitoring; it notes that long-term use requires further work (Abstract; page unavailable). (LLM, conf=0.84)

  cites [1] Kim, D. H. et al. Epidermal electronics. Science 333, 838–843 (2011) sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [2] Lipomi, D. J. et al. Skin-like pressure and strain sensors based on transparent elastic films of carbon nanotubes. Nature Nanotechnol. 6, 788–792 (2011) source
• ?Not checked — no full text of the sourcecites [3] Takei, K. et al. Nanowire active-matrix circuitry for low-voltage macroscale artificial skin. Nature Mater. 9, 821–826 (2010) source
• ?Not checked — no full text of the sourcecites [4] Wu, W. et al. Piezoelectricity of single-atomic-layer MoS2 for energy conversion and piezotronics. Nature 514, 470–474 (2014) source
• Partly supported

  The Abstract (p. 1) says flexible chemical and biological sensors could enable wearable monitoring systems. It does not establish that wearable sensors are essential to personalized medicine or that they continuously monitor an individual's health; those claims are stronger and more specific than the paper's proposed application. (LLM, conf=0.86)

  cites [5] McAlpine, M. C., Ahmad, H., Wang, D. & Heath, J. R. Highly ordered nanowire arrays on plastic substrates for ultrasensitive flexible chemical sensors. Nature Mater. 6, 379–384 (2007) sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [6] Kaltenbrunner, M. et al. An ultra-lightweight design for imperceptible plastic electronics. Nature 499, 458–463 (2013) source
• Partly supported

  The Abstract says skin-mounted sensors can provide clinical-quality health monitoring for continuous use and that continuous physiological monitoring is needed to treat many medical conditions. It does not say wearable sensors are essential to the realization of personalized medicine; that part overstates what the paper supports. (LLM, conf=0.85)

  cites [7] Xu, S. et al. Soft microfluidic assemblies of sensors, circuits, and radios for the skin. Science 344, 70–74 (2014) sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [8] Wang, C. et al. User-interactive electronic skin for instantaneous pressure visualization. Nature Mater. 12, 899–904 (2013) source
• ?Not checked — no full text of the sourcecites [9] Liang, J., Li, L., Niu, X., Yu, Z. & Pei, Q. Elastomeric polymer light-emitting devices and displays. Nature Photon. 7, 817–824 (2013) source
• ?Not checked — no full text of the sourcecites [10] Kim, D. H., Ghaffari, R. & Rogers, J. A. Flexible and stretchable electronics for biointegrated devices. Annu. Rev. Biomed. Eng. 14, 113–128 (2012) source

In the paper

“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 state14–18.”

What the sources say

• Supported

  The Abstract describes this device as a sodium-selective sweat sensor, and the Conclusions discuss a sensor array for other ions as a future possibility. The paper therefore supports its use as an example of a previously reported single-analyte sweat sensor; the citation need not establish that this device also lacked on-site processing or calibration. (LLM, conf=0.90)

  cites [14] Schazmann, B. et al. A wearable electrochemical sensor for the real-time measurement of sweat sodium concentration. Anal. Methods 2, 342–348 (2010) source
• ?Not checked — no full text of the sourcecites [15] Jia, W. et al. Electrochemical tattoo biosensors for real-time noninvasive lactate monitoring in human perspiration. Anal. Chem. 85, 6553–6560 (2013) source
• ?Could not verify

  The Introduction describes limitations of earlier sweat-collection methods, but does not say that previously reported biosensors were restricted to one analyte or lacked on-site processing and calibration. It instead describes BIOTEX’s multiparametric patch; the sensor and control-electronics sections discuss calibration before trials and signal processing, without establishing the claimed either-or limitation of prior devices. (LLM, conf=0.76)

  cites [16] Coyle, S. et al. BIOTEX—biosensing textiles for personalised healthcare management. IEEE Trans. Inf. Technol. Biomed. 14, 364–370 (2010) sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [17] Bandodkar, A. J. et al. Epidermal tattoo potentiometric sodium sensors with wireless signal transduction for continuous non-invasive sweat monitoring. Biosens. Bioelectron. 54, 603–609 (2014) source
• ?Not checked — no full text of the sourcecites [18] Rose, D. P. et al. Adhesive RFID sensor patch for monitoring of sweat electrolytes. IEEE Trans. Biomed. Eng. 62, 1457–1465 (2015) source

In the paper

“sweat lactate can potentially serve as a sensitive marker of pressure ischaemia22;”

What the sources say

• Supported

  The “Potential applications for sweat lactate measurements” section (page not provided) calls sweat lactate “potentially a very useful early warning indicator of pressure ischemia.” This supports the claim’s tentative wording. (LLM, conf=0.93)

  cites [22] Derbyshire, P. J., Barr, H., Davis, F. & Higson, S. P. Lactate in human sweat: a critical review of research to the present day. J. Physiol. Sci. 62, 429–440 (2012) source

In the paper

“Sampling human sweat, which is rich in physiological information13, could enable non-invasive monitoring.”

• Also stated in: § Abstract · plain

  “Measurements of human sweat could enable such insight, because it contains physiologically and metabolically rich information that can be retrieved non-invasively13.”

What the sources say

• Supported

  The Introduction describes sweat as a source of biomarkers and blood solutes accessible non-invasively. Section V explains that many blood solutes enter sweat quickly enough for continuous physiological monitoring, supporting the claim that sweat sampling could provide useful physiological information. (LLM, conf=0.92)

  cites [13] Sonner, Z. et al. The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications. Biomicrofluidics 9, 031301 (2015) source

In the paper

“The two-electrode system is a common strategy for low-current electrochemical sensing34,35.”

What the sources say

• ?Not checked — no full text of the sourcecites [34] Kudo, H. et al. A flexible and wearable glucose sensor based on functional polymers with Soft-MEMS techniques. Biosens. Bioelectron. 22, 558–562 (2006) source
• Partly supported

  The Results and Discussion section describes this tattoo glucose sensor using an Ag/AgCl electrode as a combined counter/reference electrode alongside a working electrode (page unavailable). It does not say that this two-electrode configuration is a common or standard strategy for low-current electrochemical sensing; its discussion of lower current density concerns glucose extraction by reverse iontophoresis, not the sensing configuration. (LLM, conf=0.85)

  cites [35] Bandodkar, A. J. et al. Tattoo-based noninvasive glucose monitoring: a proof-of-concept study. Anal. Chem. 87, 394–398 (2015) sourceExperimental — accuracy not yet measured

In the paper

“These trends are probably caused by increased blood serum [Na+] and [K+] with dehydration and increased neural stimulation, a conclusion in agreement with previous ex situ sweat analyses33.”

What the sources say

• Partly supported

  The Results report higher serum Na+ and K+ during dehydration, and the Discussion proposes greater extracellular Na+ and sympathetic nervous activity as possible explanations for higher sweat Na+. The Discussion’s concluding mechanism emphasizes Na+ and Cl−, aldosterone, and sympathetic activity; it does not identify increased serum K+ as a specific cause. The Experimental procedures describe sweat collected from a forearm patch and analyzed after collection, consistent with ex situ analysis. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [33] Morgan, R. M., Patterson, M. J. & Nimmo, M. A. Acute effects of dehydration on sweat composition in men during prolonged exercise in the heat. Acta Physiol. Scand. 182, 37–43 (2004) sourceExperimental — accuracy not yet measured

In the paper

“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).”

• Also stated in: § Abstract · plain

  “Here we present a wearable flexible integrated sensing array (FISA) for simultaneous and selective screening of a panel of biomarkers in sweat (Fig. 1a).”

In the paper

“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.”

In the paper

“The use of Prussian blue dye as a mediator minimizes the reduction potentials to approximately 0 V (versus Ag/AgCl) (Extended Data Fig. 2a), and thus eliminates the need for an external power source to activate the sensors.”

In the paper

“The pad could absorb about 10 μl of sweat, which was sufficient to provide stable sensor readings.”

In the paper

“Sweat [Na+] increases and [K+] decreases in the beginning of perspiration, in line with the previous ex situ studies from the collected sweat samples28,29.”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Cage, G. W., Wolfe, S. M., Thompson, R. H. & Gordon, R. S. Jr. Effects of water intake on composition of thermal sweat in normal human volunteers. J. Appl. Physiol. 29, 687–690 (1970) source
• ?Not checked — no full text of the sourcecites [29] Patterson, M. J., Galloway, S. D. R. & Nimmo, M. A. Variations in regional sweat composition in normal human males. Exp. Physiol. 85, 869–875 (2000) source

In the paper

“Importantly, the entire system is mechanically flexible, thus delivering a practical wearable sensor technology that can be used for prolonged indoor and outdoor physical activities.”

In the paper

“This conditioning process was important to minimize the potential drift further.”

In the paper

“No apparent difference is observed for glucose concentration at different power output settings, a finding consistent with the response of blood glucose to graded, short-term exercise30.”

What the sources say

• ?Not checked — no full text of the sourcecites [30] Messonnier, L. A. et al. Lactate kinetics at the lactate threshold in trained and untrained men. J. Appl. Physiol. 114, 1593–1602 (2013) source

In the paper

“Extended Data Fig. 6a–d show that Na+ and K+ sensors had a relative standard deviation of ~1% in sensitivity while glucose and lactate sensors had a relative standard deviation of ~5% in sensitivity.”

In the paper

“Although temperature has a minimal effect on the potentiometric sensors, it greatly influences the performance of the enzymatic sensors.”

In the paper

“After the power is raised, the sweat rate visibly increases, followed by a sharp increase in skin temperature and sweat [Na+] as well as a slight increase in [K+] (in three of the seven subjects, [K+] remained stable).”

In the paper

“Parylene is used as an insulating layer to ensure reliable sensor reading by preventing electrical contact of the metal lines with skin and sweat.”

In the paper

“Both [Na+] and [K+] stabilize as the cycling continues.”

In the paper

“Figure 2h illustrates that with the increase of temperature, the uncompensated sensor readouts can lead to substantial overestimation of the actual concentration of the given glucose and lactate solutions; however, the temperature compensation allows for accurate and consistent readings.”

In the paper

“Sweat analyte levels on the wrist follow similar trends but with concentrations different from those obtained at the forehead (Extended Data Fig. 9).”

In the paper

“During the exercise, the heart rate, oxygen consumption (VO2), and pulmonary minute ventilation were measured using external monitoring instruments, and were found to increase proportionally with increasing power output as shown in Fig. 3c.”

In the paper

“On the other hand, a substantial increase in sweat [Na+] and a smaller increase in sweat [K+] (no clear increase in [K+] was observed in two out of six subjects) were observed in dehydration trials (without water intake) after 80 min when subjects had lost a large amount of water (~2.5% of body weight) (Fig. 4d and e).”

In the paper

“With continued perspiration, the skin temperature rises at about 400 s because of muscle heat conductance to skin and then remains stable, while the concentration of both lactate and glucose in sweat decrease gradually.”

In the paper

“A linear relationship between current and analyte concentrations with sensitivities of 2.35 nA μM−1 for glucose sensors and 220 nA mM−1 for lactate sensors was observed.”

In the paper

“The sensor–FPCB interface allows for convenient replacement of the fresh sensor arrays for subsequent use.”

In the paper

“With the cessation of exercise, these physiological responses decrease and then remain stable.”

In the paper

“The sensors could be used without pre-conditioning (with a small drift of ~2–3 mV h−1).”

In the paper

“The current sensing signal paths were capable of measuring current levels as low as 1 nA, which was much lower than the minimum signal in our measurements (tens of nanoamperes).”

In the paper

“An increase in temperature was observed when the ‘smart headband’ or ‘smart wristband’ was worn owing to the use of the plastic substrate on skin.”

In the paper

“This platform enables a wide range of personalized diagnostic and physiological monitoring applications.”

In the paper

“For example, excessive loss of sodium and potassium in sweat could result in hyponatremia, hypokalemia, muscle cramps or dehydration20;”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Speedy, D. B., Noakes, T. D. & Schneider, C. Exercise-associated hyponatremia: a review. Emerg. Med. 13, 17–27 (2001) source

In the paper

“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 instrumentation19.”

What the sources say

• ?Not checked — no full text of the sourcecites [19] Boysen, T. C., Yanagawa, S., Sato, F. & Sato, K. A modified anaerobic method of sweat collection. J. Appl. Physiol. 56, 1302–1307 (1984) source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“The convection and non-uniform distributions of solution temperature could result in noticeable noise in the signal measurements.”

In the paper

“This platform could be exploited or reconfigured for in situ analyses of other biomarkers within sweat and other human fluid samples to facilitate personalized and real-time physiological and clinical investigations.”

In the paper

“During on-body tests, the newly generated sweat would refill the pad and ‘rinse away’ the old sweat.”

In the paper

“On the other hand, the silicon integrated-circuit technology does not provide sufficiently large active areas nor the intimate skin contact required to achieve stable and sensitive on-body measurements.”

In the paper

“In this case, because the subject had a lower sweat rate at the wrist29, the sensors were activated at a later time.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Patterson, M. J., Galloway, S. D. R. & Nimmo, M. A. Variations in regional sweat composition in normal human males. Exp. Physiol. 85, 869–875 (2000) source

In the paper

“Monitoring hydration status is of the utmost importance to athletes because fluid deficit impairs endurance performance and increases carbohydrate reliance32.”

What the sources say

• ?Not checked — no full text of the sourcecites [32] Barr, S. I. Effects of dehydration on exercise performance. Can. J. Appl. Physiol. 24, 164–172 (1999) source

In the paper

“We believe that this wearable platform may enable new fundamental physiology studies through further on-body evaluation.”

In the paper

“To ensure the fidelity of sensor readings, the data collection of each channel took place when a sufficient sweat sample was present, as shown by stabilization of sensor readings within the physiologically relevant range (see Methods).”

In the paper

“The power output was calibrated and monitored through the ergometer.”

In the paper

“All subjects gave written, informed consent before participation in the study.”

In the paper

“The on-body evaluation of the FISA was performed in compliance with the protocol that was approved by the institutional review board at the University of California, Berkeley (CPHS 2014-08-6636).”

In the paper

“Although this may result in a small error in measuring the actual skin temperature, it should be noted that this does not have an impact on the measurement of the electrolytes and metabolites, owing to the on-board temperature calibration.”

In the paper

“The sensor arrays were calibrated, and the subjects’ foreheads and wrists were cleaned with alcohol swabs and gauze before sensors were worn on-body.”