WO2018071895A1

WO2018071895A1 - Autonomous sweat electrolyte loss monitoring devices

Info

Publication number: WO2018071895A1
Application number: PCT/US2017/056750
Authority: WO
Inventors: Robert Beech; Gavi BEGTRUP
Original assignee: Eccrine Systems, Inc.
Priority date: 2016-10-14
Filing date: 2017-10-16
Publication date: 2018-04-19

Abstract

The disclosed invention comprises a wearable sweat sensing device configured to monitor sweat electrolyte concentrations, trends, and ratios under demanding use conditions. The disclosed method includes use of the disclosed device to track fluid and electrolyte gain and loss in order to produce an electrolyte estimate for the device wearer, such as a sweat electrolyte concentration, a sweat electrolyte concentration trend, a sweat rate, or a concentration ratio between a plurality of electrolytes.

Description

AUTONOMOUS SWEAT ELECTROLYTE LOSS MONITORING DEVICES STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] No federal funds were utilized for this invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present application has specification that builds upon U.S. Provisional Application No. 62/408,097, filed October 14, 2016, and PCT/US2016/36038, filed June 6, 2016, the disclosures of which are hereby incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0003] Among the biofluids potentially used for physiological monitoring (e.g., sweat, blood, urine, saliva, tears), sweat has arguably the least predictable sampling rate in the absence of technological solutions. An excellent summary is provided by Sonner, et al. in the 2015 article titled "The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications," Biomicrofluidics 9, 031301, included by reference herein in its entirety. However, with proper application of technology, sweat can be made to outperform other non-invasive or less invasive biofluids in predictable sampling. Many of the drawbacks and limitations of the sweat medium can be resolved by creating novel and advanced interplays of chemicals, materials, sensors, electronics, microfluidics, algorithms, computing, software, systems, and other features or designs, in a manner that affordably, effectively, conveniently, intelligently, or reliably brings sweat sensing and stimulating technology into intimate proximity with sweat as it is generated.

[0004] In particular, sweat sensing devices hold tremendous promise for use in workplace safety, athletic, and military settings. One potential application that can improve personal safety and performance in these settings, is a robust, autonomous wearable sweat electrolyte loss monitor. As disclosed herein, a sweat sensing device is configured to monitor sweat electrolyte concentrations, ratios and trends under demanding use conditions. DEFINITIONS

[0005] Before continuing with the background, a variety of definitions should be made, these definitions gaining further appreciation and scope in the detailed description and embodiments of the disclosed invention.

[0006] "Sweat sensor" means any type of sensor that measures a state, presence, flow rate, solute concentration, solute presence, in absolute, relative, trending, or other ways in biofluid. Sweat sensors can include, for example, potentiometric, amperometric, impedance, optical, mechanical, antibody, peptide, aptamer, or other means known by those skilled in the art of sensing or biosensing.

[0007] "Analyte" means a substance, molecule, ion, or other material that is measured by a sweat sensing device.

[0008] "Electrolyte" means solutes within human body fluids and tissues that include all acids and bases, inorganic salts, and some proteins. Examples of interest include Na⁺, CI^", H⁺, K⁺, NH4⁺, Ca⁺, HC0₃-, and Mg⁺.

[0009] "Measured" can imply an exact or precise quantitative measurement and can include broader meanings such as, for example, measuring a relative amount of change of something. Measured can also imply a binary measurement, such as 'yes' or 'no' type measurements.

[0010] "Chronological assurance" means the sampling rate or sampling interval that assures measurement(s) of analytes in biofluid in terms of the rate at which measurements can be made of new biofluid analytes emerging from the body. Chronological assurance may also include a determination of the effect of sensor function, potential contamination with previously generated analytes, other fluids, or other measurement contamination sources for the measurement(s). Chronological assurance may have an offset for time delays in the body (e.g., a well-known 5 to 30 minute lag time between analytes in blood emerging in interstitial fluid), but the resulting sampling interval (defined below) is independent of lag time, and furthermore, this lag time is inside the body, and therefore, for chronological assurance as defined above and interpreted herein, this lag time does not apply. [0011] As used herein, the term "analyte-specific sensor" is a sensor specific to an analyte and performs specific chemical recognition of the analytes presence or concentration (e.g., ion-selective electrodes, enzymatic sensors, electro-chemical aptamer based sensors, etc.). For example, sensors that sense impedance or conductance of a fluid, such as biofluid, are excluded from the definition of "analyte- specific sensor" because sensing impedance or conductance merges measurements of all ions in biofluid (i.e., the sensor is not chemically selective; it provides an indirect measurement). Sensors could also be optical, mechanical, or use other physical/chemical methods which are specific to a single analyte. Further, multiple sensors can each be specific to one of multiple analytes.

[0012] "Sweat sensor data" means all of the information collected by device sensor(s) and communicated via the device to a user or a data aggregation location.

[0013] "Correlated aggregated sweat sensor data" means sweat sensor data that has been collected in a data aggregation location and correlated with relevant outside information such as time, temperature, weather, location, user profile, other sweat sensor data, or any other relevant data.

[0014] "Operation and compliance warning" means an alert generated by the sweat sensing device and relayed to the system user if a reading indicates a device is not in adequate skin contact.

[0015] This has served as a background for the disclosed invention, including background technical invention needed to fully appreciate the disclosed invention, which will now be summarized.

SUMMARY OF THE INVENTION

[0016] The disclosed invention comprises a wearable sweat sensing device configured to monitor sweat electrolyte concentrations, trends and ratios under demanding use conditions. The accompanying method includes use of the disclosed device to track fluid and electrolyte gain and loss in order to produce an electrolyte estimate, such as a sweat electrolyte concentration, a sweat electrolyte concentration trend, a sweat rate, or a concentration ratio between a plurality of electrolytes. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The objects and advantages of the disclosure will be further appreciated in light of the following detailed descriptions and drawings in which:

[0018] Fig. 1 represents at least a portion of the disclosed invention.

[0019] Fig. 2 depicts at least a portion of an embodiment of the disclosed invention.

[0020] Fig. 3 depicts at least a portion of an embodiment of the disclosed invention having reusable components and disposable components.

[0021] Fig. 4A depicts a cross section of an embodiment of the disclosed invention.

[0022] Fig. 4B depicts a cross section of an embodiment of the disclosed invention.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present disclosure provides a sweat sensing device configured to monitor electrolyte concentrations, trends and ratios while a device wearer is participating in physical activity in order to improve the wearer's safety or physical performance. Any time an individual sweats, s/he loses electrolytes. Under extreme physical conditions, such as intense heat or prolonged physical exertion, individuals can lose sufficient quantities of electrolytes through sweat, so that numerous essential biological processes become impaired. For example, excessive sodium loss, or hyponatremia, can manifest as headaches, nausea, vomiting, muscle spasms, and seizures. Similarly, excessive loss of K⁺, or hypokalemia, can manifest as muscle cramps, heart palpitations, or delirium. Other electrolyte imbalance disorders include alkalosis, hypochloremia, hypocalcemia, hypomagnesemia, and loss of bicarbonates (HCO3 ). Monitoring the loss and replenishment of electrolytes can therefore improve the safety and performance of individuals operating under extreme electrolyte loss conditions.

[0024] Sweat contains a number of electrolytes in varying concentrations, including the following: Na⁺ (10-100 mM), CI^" (10-100 mM), H⁺ (0.1 mM-0.0001 mM), K⁺ (1-24 mM), NH₄ ⁺ (0.5-8 mM), Ca⁺ (~0.5 mM), and Mg⁺. Sweat also includes a variety of other electrolytes in lower concentrations. [0025] The present disclosure applies at least to any type of sweat sensing device that measures sweat, sweat generation rate, sweat chronological assurance, its solutes, solutes that transfer into sweat from skin, a property of or things on the surface of skin, or properties or things beneath the skin. The disclosure applies to sweat sensing devices which can take on forms including patches, bands, straps, portions of clothing or equipment, or any suitable mechanism that reliably brings sweat collecting, and/or sweat sensing technology into intimate proximity with sweat as it is generated.

[0026] Certain embodiments of the invention show sensors as simple individual elements. It is understood that many sensors require two or more electrodes, reference electrodes, or additional supporting technology or features that are not captured in the description herein. Sensors are preferably electrochemical in nature, but may also include electrical, optical, chemical, mechanical, or other known biosensing mechanisms. Sensors can be in duplicate, triplicate, or more, to provide improved data and readings. Sensors may be referenced herein by what the sensor is sensing, for example: an analyte- specific sensor; an impedance sensor; a sweat volume sensor; a sweat rate sensor; or a solute generation rate sensor. Certain embodiments of the disclosed invention show sub-components of what would be sweat sensing devices with more sub-components needed for use of the device in various applications, which are obvious (such as a battery), and for purpose of brevity and focus on inventive aspects, are not explicitly shown in the diagrams or described in the embodiments of the present disclosure.

[0027] Sweat is known to contain a large number of compounds that could be used to indicate an individual's physiological state. In general, determining an individual's physiological state is a significant challenge. Not only is every individual different in terms of how a physiological state may present, but even a simple physiological state or disorder is a complex set of biological processes that does not readily lend itself to reduction. Consequently, a definitive diagnosis of a physiological condition often is not possible. Among the most common substances found in sweat are the following: Na⁺, CI^", K⁺, Ammonium (NEU^"1"), urea, lactate, glucose, serine, glycerol, Cortisol, and pyruvate. In addition to these common sweat analytes, each physiological condition may also have particular sweat analytes that will prove informative for indicating that physiological state. For example, blood creatinine levels have proven useful for indicating hydration levels, which also may prove true for sweat.

[0028] To date, there have been few studies linking sweat analytes or analyte concentrations to physiological states. Among these are studies linking increased sweat chloride levels with cystic fibrosis, or a spike in chloride levels with ovulation. It will likely be necessary to build data across multiple individuals correlating physiological states with sweat sensor readings. By this means, a given physiological state will manifest and a discernible sweat analyte signature will be detectible by a sweat sensing device.

[0029] Further, translation of analyte concentrations and ratios to meaningful physiological information will have to account for a number of variabilities unrelated to differences in concentrations. For example, sweat concentrations of analytes relative to blood or plasma concentrations are known to vary depending on sweat rate, the body location from which a sample is taken, kidney or liver disease or function, external temperatures, and other factors. To develop meaningful physiological information, it will therefore be necessary to develop algorithms and techniques that reflect how the various analyte signatures change in response to these variabilities.

[0030] Specific to determining an individual's electrolyte status, a sweat sensing device can be configured to accurately measure electrolyte loss amounts, trends and ratios. Electrolyte loss is a key component of a larger picture that constitutes an individual's overall electrolyte status, which includes at least the following three basic factors: 1) electrolyte inputs through an individual's diet; 2) electrolyte redistribution within the individual's body; and 3) electrolyte loss.

[0031] At a basic level, electrolyte inputs are those electrolytes consumed through food or fluids, and which are absorbed from the digestive tract for use throughout the body. Absorption is a complicated process that may be affected by the amount of food or fluids consumed, the existing levels or ratios of electrolytes in the body, the activity taking place during absorption, circulation levels to the digestive tract, the kinetics of absorption of the different electrolytes, and other factors. [0032] Electrolyte redistribution is a continual process by which the body manages electrolyte concentrations in extracellular fluid by moving electrolytes among various repositories in the body. These repositories include intracellular fluid, extracellular fluid, interstitial fluid, plasma volume, and certain tissues, such as skeletal repositories of calcium. Electrolytes move among the different repositories based on osmotic and hydrostatic pressure gradients, may be controlled by selectively permeable membranes, or may respond to homeostatic control mechanisms triggered by extracellular fluid concentrations of particular electrolytes.

[0033] Electrolyte loss may be through urine excretion, sweat excretion, or gastrointestinal tract excretion. Electrolyte loss amounts are influenced by homeostasis feedback loops, which control electrolyte retention and excretion processes, as well as water retention and excretion processes. Additionally, electrolyte loss is complicated by individual factors, such as the health of key organs, e.g., the kidneys, or the relative dysfunction in the body's homeostasis mechanisms. A non-exhaustive list of potential considerations that may inform sweat electrolyte loss include the following: sweat rate, hydration status, electrolyte intake during monitoring period, exercise intensity, body temperature, environmental conditions, heat acclimation, fitness level, routine daily electrolyte intake, BMI, body location of device, phenotype, sex, age, medical conditions, and pharmaceutical use.

[0034] The disclosed invention provides accurate measurements of sweat electrolyte loss, which is a key element of the equation for determining a device wearer's electrolyte condition. Generally, sweat electrolyte loss and sweat rate are highly correlated, therefore, the disclosed device can be configured with sweat rate sensors, e.g., volumetric sweat rate sensors, ISEs, or micro-thermal flow rate sensors, as well as algorithms capable of determining sweat rate, as disclosed in PCT/US2016/36038 and U.S. 15/653,494, which are hereby incorporated by reference herein in their entirety.

[0035] Various studies in eccrinology have characterized the variance in molarity of Na⁺, CI^" and K⁺ with sweat rate. See Fig. 4, Sato, K., et ah, "Biology of sweat glands and their disorders," J. of the Am. Academy of Dermatology, p. 552, 20/4/Apr. 1989. Na⁺ and CI^" enter sweat in the secretory coil of the eccrine sweat gland, and at negligible sweat rates, are isotonic with interstitial fluid concentrations of Na⁺ and CI^". Bovell, Journal of Local and Global Health Science, p. 9, 2015:5. With the initiation of sweating, CI^" is pumped into the lumen of the gland, where its negative electrical potential pulls in Na⁺. The Na⁺ and CI^" combine to form NaCl, which creates an osmotic gradient that draws water into the lumen. As the newly created sweat moves out of the secretory coil, Na⁺, with CI^" in tow, is reabsorbed through the duct and re-enters the interstitial fluid.

[0036] At lower sweat rates, 0.0 to 0.4 μ1/οηι²/ιηϊη, relatively more of the Na⁺ and CI^" are reabsorbed by the duct so that sweat reaching the skin has lower concentrations of Na⁺ and CI^". Amano, T., et al, "Determination of the maximum rate of eccrine sweat glands' ion readsorption using galvanic skin conductance to local sweat rate relationship," Eur. J. Appl. Physiology, p. 4, DOI 10.1007/s00421- 015-3275-9. Initially, between 0.2 and 0.4 μΕ/οπι²/πιϊη sweat rate, the Na⁺ gland reabsorption rate is at is maximum (around 85%), which translates to Na+ concentration of 10-15 mM. Sato, K., et al, "Biology of sweat glands and their disorders," J. of the Am. Academy of Dermatology, p. 552, 20/4/Apr. 1989, p. 552; Buono, M., et al, "Na⁺ secretion rate increases proportionally more than the Na+ reabsorption rate with increases in sweat rate," J. Appl. Physiology, 105:1044-1048, 2008. As sweat rate increases, the amount and speed of Na⁺ flowing through the duct overwhelms the reabsorption mechanism, so that at sweat rates above 0.4

the duct absorbs a significantly lower percentage of Na⁺, down to about 65% of Na⁺ at a sweat rate of 0.8 μυοηι²/ιηϊη. Buono, M., et al. As a result, Na⁺ concentrations show a linear increase with increases in sweat rate in the range of about 20 mEq/L for a 0.4 μ]_,/αιι²/ιηίη sweat rate, to 60 mEq/L for a 1.5 xL /cm²/min sweat rate. Allen, J., et al, "Influence of acclimatization on sweat sodium concentration," /. of Applied Physiology, 30/5/May 1971, at 710; Bovell, at 11 ; see also, Buono, p. 1025. (0.25 μΙ7αη²/ιηϊη sweat rate correlated to 20 mM/L Na⁺, 0.9

sweat rate correlated to 55 mM/L Na⁺). CI^" concentrations roughly correspond to Na⁺ levels for various sweat rates, but are usually 20 mM less. Sato, K., et al For individuals that acclimatize to warmer environments, or who engage in physical conditioning, the body's ability to reabsorb Na⁺ improves, and sweat profiles for these individuals will tend to have sweat Na⁺ concentrations about 15 mM lower than for unconditioned individuals. Allen, J., et al, at 710.

[0037] Similar examination of K⁺ molarity as it changes with sweat rate reveals an analyte that can function as a reference for a number of sweat applications, including the determination of sweat rate. Unlike Na⁺ and CI^", the rate of K⁺ excretion by the sweat gland does not accelerate with sweat rate increase, and K⁺ is not reabsorbed by the duct in significant amounts. As a result, K⁺ concentration remains relatively steady throughout the range of sweat rates. At negligible sweat rates, K⁺ concentration in the secretory coil corresponds to plasma concentrations of about 3-4 mM. Baker, L., et al, "Comparison of regional patch collection vs. whole body washdown for measuring sweat sodium and potassium loss during exercise," J. Appl. Physiology, 107: 887-895, 2009. At very low sweat rates, K⁺ tends to enter sweat at increased levels, i.e., up to 9 mM, before settling to a concentration of about 6 mM. Sato, K., et al; Bovell, at 11. It is expected that the loss amounts trends and ratios for other electrolytes of interest will also display dependence on sweat rate, which may be characterized and detected by sweat sensing devices of the disclosed invention.

[0038] With reference to Fig. 1, a representative sweat sensing device 100 to which the present disclosure applies is placed on or near skin 12. The sweat sensing device may be fluidically connected to skin or regions near skin through microfluidics or other suitable techniques. Device 100 may be in wired communication 152 or wireless communication 154 with a reader device 150, which could be a smart phone, tablet computer, or other portable electronic device, or for some devices, the device and reader device can be combined. The reader device may also be in communication with computer network that can provide access to database information capable of informing device function. In a preferred embodiment, communication 152 or 154 is not constant and could be a data upload to the device at the initiation of use, and periodic data downloads from the device during use. [0039] The sweat sensing device's data aggregation capability may include collecting all of the sweat sensor data generated by the sweat sensing device or communicated to the device. The aggregated sweat sensor data could be de-identified from individual wearers, or could remain associated with an individual wearer. Such data can also be correlated with outside information, such as the time, date, medications, drug sensitivity, medical condition, activity performed by the individual, motion level, fitness level, mental and physical performance during the data collection, body orientation, the proximity to significant health events or stressors, age, sex, health history, or other relevant information. The reader device or companion transceiver can also be configured to correlate speed, location, environmental temperature or other relevant data with the sweat sensor data. The data collected could be made accessible via secure website portal to allow sweat system users to perform safety, compliance and/or care monitoring of target individuals. The sweat sensor data monitored by the user includes real-time data, trend data, or may also include aggregated sweat sensor data drawn from the system database and correlated to a particular user, a user profile (such as age, sex, or fitness level), weather condition, activity, combined analyte profile, or other relevant metric. Trend data, such as a target individual's hydration level over time, could be used to predict future performance, or the likelihood of an impending physiological event. Such predictive capability can be enhanced by using correlated aggregated data, which would allow the user to compare an individual's historical analyte and external data profiles to a real-time situation as it progresses, or even to compare thousands of similar analyte and external data profiles from other individuals to the real-time situation. Sweat sensor data may also be used to identify wearers that are in need of additional monitoring or instruction, such as the need to drink additional water, or to adhere to a drug regimen.

[0040] The disclosed sweat sensing device includes computing and data storage capability sufficient to operate the device, which incorporates the ability to conduct communication among system components, to perform data aggregation, and to execute algorithms capable of generating notification messages. The device may have varying degrees of onboard computing capability (i.e., processing and data storage capacity). For example, all computing resources could be located onboard the device, or some computing resources could be located on a disposable portion of the device and additional processing capability located on a reusable portion of the device. Alternatively, the device may rely on portable, fixed or cloud-based computing resources.

[0041] Because the sweat sensing device could produce potentially sensitive physiological data, some database fields will be routinely encrypted. A preferred encryption method is the Advanced Encryption Standard. The device will access a random 128-bit encryption and decryption key that will be generated and stored by a companion reader device when needed for data transmission. In addition, because some sweat sensor data may repeat frequently, additional protection will be provided by introducing a random initialization vector before the encryption of each value. This will prevent observable patterns from emerging in the encrypted sweat sensor data. Other encryption methods and steps may be required and will be applied according to best practices, as known to those skilled in the art.

[0042] With reference to Fig. 2, an autonomous sweat sensing device for determining electrolyte loss as disclosed herein is placed on skin 12. The device 200 includes a reusable component 202 and a disposable component 204. The disposable component may contain a wicking collector 230 or microfluidic channel (not shown) which will be in fluidic communication with the skin 12 while the device is in use. The wicking collector transports sweat from the skin to a plurality of analyte-specific sensors 222, 224, 226, 228 arranged in an array. Said analyte-specific sensors may include, for example, ion-selective sensors for Na⁺, CI^", K⁺, and H⁺. Sensors can be screen printed or suspension material ISEs, as disclosed in U.S. Provisional Application No. 62/526810, filed June 29, 2017. In other embodiments, the device may use a combination of screen printed and suspension material ISEs, e.g., the reference electrode could be a suspension material configuration, while the ion selective sensors are ionophore polymers that are screen printed on electrodes.

[0043] Some embodiments may include a wicking pump 232 in fluidic communication with the collector 230 to facilitate sweat flow across the sensors. Other embodiments may include a plurality of secondary sensors, including volumetric sweat rate, micro-thermal flow rate, GSR, sweat conductivity, impedance or capacitance sensors for skin contact measurement, or a temperature sensor (not shown). In other embodiments, the device may include additional analyte-specific sensors, such as electrochemical aptamer-based sensors or amperometric sensors, that are capable of measuring biomarker concentrations, e.g., biomarkers indicative of dehydration or stress. The disposable component 202 will be fluidically connected to the reusable component 204, and in some embodiments will be electrically connected to the reusable component. The device will be secured to the wearer's skin by various means, including a removable adhesive layer, an elastic band or strap, a clothing element, such as a compression sleeve, etc. (not shown), so long as adequate fluidic contact is maintained between the device and skin.

[0044] With reference to Fig. 3, an exterior view of a sweat sensing device 300 of the disclosed invention is depicted secured to a wearer's skin 12 by a flexible strap 302. The reusable component 304 will be configured to communicate outputs with the wearer by various means. For example, the device may include one or more lighted indicators 355, 356, 357, which can be the same color or a plurality of different colors, e.g., one red, one yellow, and one green light. Alternately, LED lights may be configured as a readable display, or the device may include a liquid crystal display (not shown). In some embodiments, the device may include auditory alerts and signals that communicate device outputs. In other embodiments, the device may include haptic output signals. The different output means may also be used in combination to facilitate communication with the wearer in various applications or contexts.

[0045] The device will also be configured to receive inputs from a device user or wearer. In addition to input communications from a reader device, the device may also include components that allow direct inputs from a device user. For example, the device may include at least one button 379 which relays inputs from the user. In another example embodiment, the light indicators 355, 356, 357 may be co- located with input buttons to allow inputs from the user. In other embodiments, the device may include a touch screen, an optical input component 370, such as a camera or laser scanner, that is configured to read a bar code, QR code, or other visual input. Some embodiments may include near field communications capability, such as an RFID communications system, Bluetooth™, Blue Robin™, Listnr™, and other embodiments may communicate via cellular or wireless internet. These inputs can be used to inform the device about the wearer's electrolyte status prior to, at the beginning of, or during device use. Inputs may also improve device function during use by providing information about electrolyte and fluid intake, electrolyte or fluid loss through non-sweat means (such as urinary excretion), or other relevant information.

[0046] For an example use scenario, the electrolyte loss monitor 300 would be secured to an endurance runner's bicep by the flexible strap 302. The wearer would use a smartphone to initialize the device, which could include entering or downloading from a database information about the wearer's recent fluid and food intake, fluid loss, recent training, weather conditions, or other relevant inputs. Once the device is initialized, the wearer would begin running and would begin to sweat. The device would measure electrolyte concentrations in the wearer's sweat at chronologically assured sampling intervals. The device would process the sweat electrolyte data, producing, for example, sweat electrolyte concentration, concentration trend information, or ratios of concentrations among the various monitored electrolytes. Using an algorithm, the device would then determine an electrolyte loss estimate as compared to a baseline value for the wearer reflecting an expected or normal concentration, trend, or ratio, where said baseline reflects relevant characteristics of a wearer profile, which may include information such as the individual's skin temperature, sweat rate, heart rate, age, sex, initial hydration state, body mass index, transdermal evaporative fluid loss, kidney health, fitness level, heat acclimation level, fluid adsorption rate capacity, and recent physical activity, or comparisons to another person or persons with similar relevant characteristics; or external factors, such as altitude, air temperature, and humidity. Depending on the electrolyte loss estimate, the device would then communicate the results to the wearer, for example by auditory alert, a haptic signal, a light signal, or a combination of these.

[0047] The device outputs and physical input components as described may be used by the wearer in real time to inform the wearer's electrolyte status. For example, the device could display a green light indicating only water is required to be consumed at that time. The wearer would press the green indicator button, turning off the alert, and causing the device to run an algorithm to record fluid intake of a standard amount, such as 8 fluid ounces. In another example, the device may display a red light indicating an urgent need for a coded or recommended amount of electrolyte replenishment. The wearer would then place a package of the coded or recommended electrolyte dose, such as a commercial electrolyte replenishment gel, drink, or chew, over the optical scanner. The scanner would read the package' s bar code, causing the device to turn off the light indicator, and to run an algorithm to record the electrolyte intake. Some embodiments may include an RFID communications system, which is able to interact with an RFID tag placed on the electrolyte packaging. In another scenario, the wearer may press an input button 379 that informs the device that a fluid loss event, such as urination or vomiting, has occurred during device use. The device can then update its electrolyte status model to account for the lost fluids and electrolytes, as input by the wearer.

[0048] Some embodiments of the disclosed device may include a galvanic skin response (GSR) sensor, a sweat conductivity sensor and a volumetric sweat rate sensor, all of which can be used in conjunction with contemporaneous ISE-derived sweat ion measurements to provide improved sweat ion concentration and sweat rate data. For example, with reference to Fig. 4 A, a top view of a first layer 400a of a device of the disclosed invention is depicted. The sweat sensing device is configured to be worn on skin 12 and secured by a flexible strap, band, or sleeve 402 made from neoprene, spandex, elastic or other suitable material capable of holding the device against skin comfortably while preventing excessive movement of the device relative to the skin. The depicted layer of the device comprises a water impermeable substrate 470a, which carries a plurality of electrodes 420 (four are shown) for sensing galvanic skin response ("GSR"). One or more of these electrodes 420 can also be configured to include a temperature sensor (not shown). These sensors pass through the substrate and contact the wearer's skin 12 when the device is worn. This layer also includes a reference electrode 422, comprised of a reference chamber 423 for containing a fumed silica matrix mixed with a reference electrolyte compound, e.g., KC1, a fill port 438 for replenishing the reference electrolyte, a salt bridge chamber 425 containing a fumed silica matrix mixed with a salt bridge compound, e.g., MgS0₄, and a port 436 to allow the reference electrode to be in fluid communication with ISE sensors that are configured on a second layer (depicted in Fig. 4B). As depicted, this port 436 will is located upstream of the ISEs on the second layer, however, in some embodiments, the port will be located downstream of the ISEs. The first layer also includes an inlet 432 for transporting sweat collected from the skin 12 to the microfluidic channel that is also configured on the second layer.

[0049] Said second layer 400b of the device is depicted in Fig. 4B. As with the first layer, this layer also comprises a water impermeable substrate 470b. The first layer and second layer are not necessarily arranged in the depicted order relative to the wearer's skin, i.e., in some embodiments, the second layer can be located closer to the skin than the first layer. The substrate houses a microfluidic channel 430 that is configured to receive sweat from the skin and convey the sweat sample to a plurality of sensors. Some embodiments may use a microfluidic textile or wick rather than the channel as shown. The sensors include a plurality of ion selective electrodes 428 (six are shown), one or more sweat conductivity sensors 426, and a plurality of volumetric sweat rate sensor electrodes or switches 424. The channel 430 is cut into the substrate, or the entire part will be injection molded and sensor electrodes added afterward. The channel has a volume, e.g., several nL. Some embodiments will include air traps or air bubble venting components to prevent air bubbles from interfering with measurements taken by electrodes or other sensors. During operation, sweat enters the channel 430 via the inlet 432, and moves through the channel in the direction of the arrow 14. Once sweat reaches the port 436, it enters fluidic communication with the reference electrode, and then progresses to contact the sweat conductivity sensor 426, where the total electrolyte content of the sweat sample will be measured. As sweat continues to fill the channel 430, the sweat sample will move across the ISEs 428, which work in conjunction with the reference to measure sweat concentrations of electrolytes, such as Na⁺, CI^", K⁺, Mg⁺, etc.. Then sweat will contact the volumetric sweat rate switches 424 that are arranged along the channel at known intervals from each other, so that the channel volumes between switches are determined, e.g., 1-5 nL. The rate at which additional switches are closed by the sweat sample, coupled with the volume of the channel section that is filled with sweat, provides a sweat rate value. Because of space limitations on the wearable device, volumetric sweat rate channels have limited operational lifespans that may not cover an entire application period. For example, at moderately high sweat rates, i.e., 10 nL/min/gland, a device as disclosed having a sweat collection area of about 2 cm² would operate for about 2 hours. The channel design can be modified to facilitate individual applications by varying channel geometry (length, cross section, path geometry), inner surface treatments, or switch spacing. Some embodiments include a sweat collecting pump or reservoir (not shown), or include a drain 434 to pass sweat out of the device.

[0050] The substrate is configured to allow the GSR electrodes 420 to pass through the second layer and, when the device is assembled, contact the printed circuit board layer (not shown), so that the electrodes facilitate electrical communication between the skin 12 and device electronics. The device also may include additional layers (not shown), including a printed circuit board layer for carrying electronics, communication, and processing capability, a battery, a water impermeable cover, among other components.

[0051] By combining contemporaneous ISE electrolyte measurements, GSR, sweat conductivity, volumetric sweat rate, and skin temperature on a single device, the disclosed invention provides a number of advantages over existing capabilities. Chief among these advantages is the ability to foster redundancy and feedback loops among device sensors to improve the quality of information derived from a device wearer's sweat. As disclosed in US Application No. 15/653,494, incorporated herein by reference in its entirety, contemporaneous GSR, sweat conductivity and volumetric sweat rate measurements provide redundancy to sweat rate calculations. The disclosed invention can provide an additional layer of redundancy through use of ISEs. Because sweat concentrations of Na⁺ and CI^" are highly dependent on sweat rate, ISE-derived concentrations for these electrolytes can be correlated to a sweat rate through a look-up table, a database, or other means. Together, these four sensor modalities can provide a composite sweat rate estimate, for example, by calculating a weighted average of the four estimates, or by using the estimates to create a profile. Comparisons between volumetric sweat rate, GSR-derived sweat rate, conductivity-derived sweat rate, and ISE-derived sweat rate can therefore be built to provide a calibrated profile for an individual over multiple uses, or for a device over a single use.

[0052] In addition to redundancy, such comparisons of ISE-derived sweat rate to GSR/conductivity/volumetric sweat rate can be used to mitigate shortcomings in ISE measurements, and vice versa. For example, a characteristic of the disclosed design is that GSR and sweat conductivity sensors will measure new sweat at an earlier time than the ISEs, resulting in the need to synchronize measurements among the different sensor modalities, so that measurements of the same sweat sample are compared. The device may also account for the relative position of the ISEs, since those ISEs closer to the inlet 432 will see new sweat earlier than the downstream ISEs. In addition, sweat will tend to pool over the ISEs, especially during periods of decreased or ceased sweating. While it pools over the ISEs, old and new sweat will tend to mix in the chamber 430 in the vicinity of the ISEs, so changes in ISE concentration registered by the device during such periods will primarily be due to mixing of old and new sweat. As a result, while the ISEs are measuring more or less continuously, the chronologically assured data will be much more limited, and will be related to sweat rate, the surface area of the ISE electrode, and the channel volume. Because GSR is the most responsive modality to sweat initiation, rate change, and cessation, GSR readings will be used to indicate the time sweating initiates, decreases, or stops altogether. Similarly, the timing of changes in the measurements by other sensors, such as sweat rate, sweat conductivity, or skin temperature, can also be used to improve ISE measurement quality. ISE measurements during periods of decreasing or ceased sweat rate can then be corrected, weighted less, or discarded to account for sensor response lag, and more responsive sensor modalities, i.e., GSR, can be weighted more or used exclusively to inform sweat rate and ion concentration.

[0053] Another aspect of ISE measurement of sweat ion concentrations is the need to take measurements at chronologically assured intervals. Sweat rate measurements from the other sensor modalities, combined with the known volume of the channel 430 can be used to assess whether the sweat sample contacted by an ISE is new sweat, old sweat (i.e., sweat that has already been measured) or a mixture of old and new sweat. For example, volumetric sweat rate measurements, combined with the channel volume near the ISE could be used to set a chronologically assured sampling interval, so that the ISE only measures ion concentration when the sweat sample is predominately, or all, new sweat. Alternately, the device could use sweat rate and channel volume to determine a sweat sample's relative mix of old and new sweat, and by comparison with previous readings, determine the ion concentration of the new component of such a mixed sweat sample. Another solution is to intersperse reference ISEs, e.g., CI^" ISEs, among the ISE sensor suite to measure the amount of mixing that is taking place. During periods of decreased sweat rate, concentration changes along the channel will likely be from sample mixing, and should be detected by the reference ISEs.

[0054] Similarly, since GSR readings are comprised of three components (sweat rate, sweat ion content (conductivity), and skin contact resistance), ISE measurements of ion content can be used to inform GSR measurements. For example, ISE ion measurements could be mapped to a GSR change to determine the relative contribution of sweat rate change or skin contact resistance change. ISE measurements could also calibrate GSR measurements to correct for large person-to-person and use-to- use variabilities in the GSR skin contact resistance component. For example, when a sweat sensing device is first activated and taking measurements on a wearer, the device may compare ISE ion concentration, sweat conductivity, and GSR changes throughout the three GSR sweating regimes. The device could then correlate Na⁺/Cl^" concentrations to GSR/sweat conductivity readings for each regime, and by extension, a calculated sweat rate. Then, during subsequent sweating cycles, the device could measure Na⁺/Cl^" concentration changes, sweat conductivity change, and GSR change to calculate a sweat rate based on the calibrated relationship among the sensor modalities in the appropriate sweat regime. This composite sweat rate may then be compared to the sweat rate developed by the volumetric sensor. [0055] Because of their overlapping and complimentary attributes, the four sensor modalities can be used in concert to provide improved electrolyte loss measurements through the use of continuous feedback loops. For example, the interpretation of instantaneous sweat rate and ion concentration readings from the four modalities can be refined and updated as additional data is acquired. If at time tO, a device wearer begins to sweat, and at tl, the GSR, and sweat conductivity sensors begin measurements. Sweat rate measurement for tl will necessarily be a rough estimate, based only on the two sensor modalities. At t2, ISEs and volumetric sweat rate sensors take their first reading. From this point, the ISEs, GSR and sweat conductivity measurements can be taken more or less continually, while volumetric sweat rate will be periodic, based on sweat traveling in the channel to the subsequent switch. At t3, sweat reaches the second volumetric switch, and a new sweat rate estimate is determined. Not only can the device compare the different sensor modalities to develop a composite sweat rate, but the device can also reach back to refine previous ISE measurements based on the chronologically assured sampling interval indicated by the sweat rate. The corrected ISE measurements from time t2 can then be used to improve sweat rate and ion concentration measurements taken at t3. During periods of decreasing sweat rate, such refinements will be especially important.

[0056] Embodiments of the disclosed invention can also include a means to determine if the sweat sensing device is being worn by an individual, and whether it is in proper skin contact to allow accurate sweat sensing device readings, as disclosed in PCT/US 15/55756, which is incorporated herein in its entirety. This may be accomplished through the GSR electrodes or by use of capacitive sensor electrodes, as are commonly used in consumer wearable health monitoring devices and mobile computing devices. If impedance electrode contact with the skin is, or becomes inadequate, this can be detected as an increase in impedance and the device can send an alert signal to the user or another device. Similarly, capacitance sensors may be placed on selected locations on the skin-facing side of the device, and could convey information about the distance between the device and the skin. Inadequate contact can indicate that the device has been removed by the user, or has become detached from the skin for other reasons. [0057] The sweat sensing device's skin contact sensor(s) may also continuously or near-continuously monitor the adequacy of skin contact during device operation. Inadequate skin contact can affect sensor readings in a number of ways, for example, air bubbles can enter the microfluidic channel. If an air bubble contacts an ISE, sweat conductivity sensor, or volumetric sweat rate switch, the sensor can record an inaccurate measurement. Sensors that rely on contact with the skin, such as GSR, temperature, and certain ISE configurations, can also provide inaccurate measurements if skin contact is insufficient. During times of poor or no skin contact, the device may avoid taking measurements, or may, via algorithm, account for the poor or no skin contact when interpreting or weighting the measurements. The device may also communicate to the wearer or user to inform them of the inadequacy or absence of skin contact and to advise corrective action. Alternately, the device may track periods during which the device is out of contact with skin and discard any collected data, or extrapolate previous measurements to bridge gaps in device use.

[0058] This has been a description of the disclosed invention along with a preferred method of practicing the disclosed invention.

Claims

AUTONOMOUS SWEAT ELECTROLYTE LOSS MONITORING DEVICES WHAT IS CLAIMED IS:

1. A sweat sensing device capable of monitoring sweat electrolyte loss and configured to be worn on an individual's skin, comprising:

a plurality of primary sensors for measuring at least one electrolyte concentration in a sweat sample;

a reference electrode;

at least one secondary sensor;

a fluid management component, where said component allows fluidic communication between the skin and the sensors; and

at least one user interface component, where said component includes at least one of the following: an output component; and an input component.

2. The device of claim 1, where the device is fully disposable.

3. The device of claim 1, where the device is at least partially reusable.

4. The device of claim 1, where the user interface component is at least one of the following: one or more lights; a visual display; a sound generating component; a haptic component; a touchscreen; one or more buttons; an optical scanner; and a camera.

5. The device of claim 1, where the primary sensors are capable of measuring at least one of the following electrolytes: Na⁺; CI^"; H⁺; K⁺; NH₄ ⁺; Ca⁺; HCCV; and Mg⁺.

6. The device of claim 1, where the secondary sensor is at least one of the following: volumetric sweat rate; micro-thermal sweat flow rate; galvanic skin response; sweat conductivity; and skin temperature.

7. A method of using the device of claim 1 to monitor an individual's electrolyte levels, the method comprising: taking at least one measurement of at least one sweat electrolyte with a primary sensor;

taking at least one measurement with a secondary sensor;

receiving input from a device user relevant to at least one of the following: the individual's hydration status; the individual's electrolyte status; the individual's fluid intake; the individual's fluid output; the individual's electrolyte intake; and the individual's electrolyte output;

using said measurements and input to develop at least one of the following electrolyte estimates: a sweat electrolyte concentration; a sweat electrolyte concentration trend; a sweat rate; and a concentration ratio between a plurality of electrolytes; and

communicating an output to a device user.

8. The method of claim 7, further comprising comparing the electrolyte estimate to a baseline value, where said baseline value reflects at least one of the following: a profile for the individual; a profile for one or more persons with similar relevant characteristics to the individual; and external information.

9. The method of claim 8, where said baseline value reflects at least one of the following: the individual's skin temperature; the individual's sweat rate; the individual's heart rate; the individual's age; the individual's sex; the individual's initial hydration state; the individual's body mass index; the individual's transdermal evaporative fluid loss; the individual's kidney health; the individual's fitness level; the individual's heat acclimation level; the individual's recent physical activity; relevant characteristics of another person or persons; altitude; air temperature; and humidity.

10. The method of claim 7, where the measured electrolyte is at least one of the following: Na⁺; CI^"; H⁺; K⁺; NH₄ ⁺; Ca⁺; HCO3-; and Mg⁺.

11. The method of claim 7, further comprising developing the electrolyte estimate using one of the following: a sweat rate measurement; a sweat conductivity measurement; a sweat a sweat onset time; a sweat cessation time; a sweat rate change time; a sweat conductivity change time; and a skin temperature change time.

12. The method of claim 7, where said output is at least one of the following: the electrolyte estimate; a recommendation to consume an amount of fluid; and a recommendation to consume an amount of electrolyte.

13. The method of claim 7, where said input is acquired from a fluid or electrolyte product package.

14. The method of claim 7, further comprising developing a sweat rate profile using the following: a volumetric sweat rate measurement; a sweat conductivity sweat rate estimate; a GSR sweat rate estimate; and a primary sensor sweat rate estimate.

15. The method of claim 7, further comprising using a sweat rate measurement to determine a chronologically assured sampling rate for primary sensor measurements.

16. The method of claim 15, further comprising using the chronologically assured sampling rate to refine a primary sensor measurement.

17. The method of claim 7, further comprising associating a primary sensor measurement of a sweat sample with a secondary sensor measurement of the sweat sample.

18. The method of claim 7, further comprising using a primary sensor measurement to determine the relative contribution of sweat rate change and skin contact resistance change to a contemporaneous GSR measurement.