Systems and methods for determining sweat rate

Abstract

A system (300) is provided for determining the sweat rate per gland and measuring biomarker concentrations. The system includes a device and a sensor (166). The device receives sweat from the skin and delivers the sweat to the sensor in the form of discrete sweat droplets. The sensor senses each of the counted sweat droplets. The system also includes a processor that counts the number of sweat droplets sensed over a time period. The processor also determines the time interval between successively sensed sweat droplets and receives a measure of the volume of each of the counted sweat droplets. The time interval and volume measure are then used by the processor to identify sweat bursts and rest periods of one or more sweat glands that produce sweat. The identification process necessarily involves assigning sweat bursts and rest periods to the one or more sweat glands, allowing the processor to determine the number of sweat glands involved in sweat production. The sweat rate per gland can then be determined based on the number of sweat droplets, the measure of the volume of each of the counted sweat droplets, and the determined number of sweat glands. A method for determining the sweat rate per gland is also provided.

Description

Technical Field

[0001] This invention relates to systems and methods for determining sweat rate (particularly sweat rate per gland) and measuring biomarker concentrations. Background Technology

[0002] Non-invasive, semi-continuous, and long-term monitoring of biomarkers indicating disease / health status and health level is required for monitoring of conditions such as dehydration, stress, sleep, child health, and perioperative monitoring.

[0003] Sweat, tears, and saliva can all be obtained non-invasively. Sweat is a particularly accessible biofluid and a rich source of information about the physiology and metabolism of an individual.

[0004] Some examples of clinically relevant components of sweat are Na+, Cl- and / or K+ used to monitor dehydration; lactation as an early warning sign of inflammation (which is associated with sepsis); glucose for diabetic patients and newborns; and cortisol associated with sleep apnea and stress monitoring.

[0005] Continuous monitoring of high-risk patients (e.g., those with severe chronic conditions, pre- or post-operative patients, and the elderly) using sweat biomarker monitoring devices can provide higher quality diagnostic information than conventional biomarker sampling, which is typically accomplished by repeatedly drawing multiple blood samples. Such continuous monitoring can occur in hospital settings or elsewhere. Human sweat alone, or a mixture of sweat and sebum, can be an easily accessible source for biomarker measurements in wearable skin devices. For example, cholesterol is an important biomarker associated with an elevated risk of developing cardiovascular disease. Inflammatory markers or cytokines (e.g., interleukins (e.g., TNF-α, IL-6)) play a crucial role in the immune response and detection or disease monitoring of joint damage in rheumatoid arthritis and psoriatic arthritis, as well as in intestinal diseases.

[0006] Examples of biomarkers that can be detected in eccrine / apocrine sweat using suitable capture substances (antibodies, aptamers, molecularly imprinted polymers, etc.) include small molecules (e.g., urea, creatinine, cholesterol, triglycerides, steroid hormones (cortisol), glucose, melatonin), peptides and proteins (including cytokines such as IL-1α, IL-1β, IL-6, TNFα, IL-8 and TGF-βIL-6, cysteine ​​proteases, deoxyribonuclease I, lysozyme, Zn-α2-glycoprotein, cysteine-rich secretory protein-3 and dermcidin), as well as large biomarkers (e.g., hepatitis C virus).

[0007] As reviewed by Mena-Bravo and de Castro in “Sweat: A sample with limited present applications and promising future in metabolomics” (J. Pharm. Biomed. Anal. 90, 139–147 (2014)), results from sweat sensing have been found to be highly variable, and for various biomarkers, values ​​determined from blood and sweat samples appear to lack correlation. Historical research in this area has involved relatively crude sampling techniques, such as collecting large amounts of sweat in bags or textiles. The limitations of such techniques may contribute to this apparent lack of correlation. Therefore, Mena-Bravo and de Castro's review also highlights further key setbacks of conventional sweat sensing techniques in the following areas: difficulty in generating sufficient sweat for analysis, problems with sample evaporation, lack of suitable sampling equipment, the need for trained personnel, and issues related to the normalization of sample volume.

[0008] Efforts have been made to address these issues by enabling wearable sensors to come into contact with sweat almost immediately as it emerges from the skin. A recent example is the wearable patch proposed by Gao et al. in “Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis” (Nature 529, 509-514 (2016)). The patch comprises an array of sensors for measuring Na+, K+, glucose, lactate, and skin temperature. However, this study focuses on developing and integrating the sensors themselves, which, while crucial, does not address the issues associated with sweat sample collection. The latter is primarily accomplished by placing an absorbent pad, several square centimeters in size, between the skin and the sensor. The assumption is that, assuming sufficient sweat is generated (and therefore the test is performed on an individual exercising), the pad will absorb the sweat for analysis, while newly generated sweat will refill the pad and “wash away” the old sweat. However, due to accumulation effects, the time-dependent response of the sensor may not directly reflect the actual levels of biomarkers over time. Sample collection and presentation for published sensors may not be well controlled, making continuous and reliable sensing over long periods difficult. Such patches may also not be designed to handle the minute amounts of sweat produced under normal conditions, i.e., at sub-nanoliter to nanoliter levels per sweat gland per minute.

[0009] An adult at rest generates 100 joules per second (100 watts) of heat. For a person wearing clothes at a temperature of around 22°C, this heat is removed passively, such as through conduction and convection. Under these conditions, the core temperature remains constant. However, when i) a person engages in physical labor or exercise and / or ii) the ambient temperature rises, this conduction / convection process is insufficient to maintain the core temperature. To maintain homeostasis, the body causes vasodilation in the skin to cool the blood and begins to produce sweat, which cools the skin through evaporation.

[0010] People engaged in only light exercise or light labor at ambient temperature produce relatively little sweat, as discussed by Taylor in “Regional variations in transepidermal water loss, eccrine sweat gland density, sweat secretion rates and electrolyte composition in resting and exercising humans” (Extrem Physiol Med 2013; 2:4) and Simmers in “Prolonged and localized sweat stimulation by iontophoretic delivery of the slowly-metabolized cholinergic agent carbachol” (Journal of Dermatological Science 89(2018)40-51). Within the so-called thermoneutral zone (approximately 25°C to 30°C), the core temperature remains very stable, and sweat production is not required to cool the body. This zone is defined for naked men at rest. For clothed individuals at rest, the thermoneutral zone is lower: ranging from approximately 13°C to 22°C. Therefore, when the temperature is in this zone and the person is at rest, sweat production is very low.

[0011] According to Taylor, under resting and thermoneutral conditions, sympathetic nerve discharge (secretion of sweat gland ducts) may not induce measurable sweating because sweat reabsorption may be comparable to its formation rate. Simmers measured sweat rates in people wearing clothes, exposed to air conditioning, and primarily engaged in non-physical labor, and found that a typical sweat rate is approximately 0.3 nl / min / gland (measured values ​​ranged between zero and 0.7 nl / min / gland). When people were resting but at a high temperature of 36°C, the average sweat production rate measured by Taylor was 0.36 mg·cm³.2 ·min -1 When assuming every 1.8m 2 With 2.03 million sweat glands and a sweat density of 1 g / ml (for an average person's skin surface area), the average sweat production rate is approximately 3.2 nl / min / gland. Due to the higher temperatures above the thermoneutral zone, the body needs to cool down, and the actual rate of sweat production increases.

[0012] Therefore, sedentary individuals (such as hospital patients) have the lowest sweat rates, resulting in a significant delay between sweat excretion and biomarker detection, which can hinder timely monitoring and early warning of any impending complications. The concentrations of specific relevant biomarkers are sweat rate dependent, and therefore per-gland sweat rate must be assessed for clinically relevant interpretation. Traditional sweat sensing solutions have limited applications because they require the monitored individual to participate in exercise and tend to use rather complex microfluidics and sensors to determine sweat rate.

[0013] WO2018 / 125695A1 discloses a wearable sweat biosensor device with active sweat sampling. An active method for delivering sweat is described, utilizing the electromechanical effect of electrowetting. The electrowetting plate includes a hydrophobic dielectric layer (e.g., Teflon) covering electrodes. A sweat-coupled "wicking" component made of a hydrophilic material allows sweat from the skin surface to slowly diffuse over time to the electrowetting plate, thus delivering the sweat via the electromechanical effect. This method is very time-consuming and may be ineffective for small sweat volumes due to evaporation. Furthermore, the technique requires mixing sweat received from the skin at different times, which is undesirable for reliable semi-continuous biomarker measurements.

[0014] US2015 / 0112165A1 discloses a method for determining the sweat rate per gland. The method involves using multiple sweat rate sensors to monitor the cumulative change in the dielectric value of a porous material in a corresponding sweat collection chamber. Sodium sensors monitor the sodium concentration of sweat in the corresponding chamber. Sodium ion concentration is correlated with the total sweat flow rate using correlation curves derived from volunteer testing. This method has two main drawbacks: (i) it assumes numerous sweat glands in each surface area during volunteer testing, and (ii) it assumes that the correlation between sodium concentration and sweat rate determined by volunteer testing applies to any particular person / patient. The considerable variability observed between individuals may render the latter assumption unwise, and disease may exacerbate this variability.

[0015] Heikenfeld et al., in “Digital nanoliter to milliliter flow rate sensor with in vivo demonstration for continuous sweat rate measurement” (Lab Chip, 2019, 19, 178), and Yang et al., in “Wearable microfluidics: fabric-based digital droplet flowmetry for perspiration analysis” (Lab on a Chip. 2017, received 14 / 04. DOI: 10.1039 / c6lc01522k), disclosed sweat rate sensors that collect sweat in a chamber located near the skin. Sweat droplets grow from the outlet of the chamber until they are released from the outlet by contacting and transferring to a core opposite the outlet. Immediately before this release, the sweat droplet contacts one of a pair of electrodes mounted on the core. The other electrode is mounted in the chamber. Thus, the electrode is short-circuited due to the connection provided by the sweat in the chamber and the sweat droplet still attached to it. This short-circuiting of the electrode immediately before the sweat droplet is released into the core allows the device to count the sweat droplets. However, this design requires a sweat rate sensor for each chamber. This unfavorably complicates the arrangement. Furthermore, the design may be incompatible with alternative sweat droplet sensing principles.

[0016] WO2019 / 060689A1 discloses a flow rate and analyte sensor for a discrete volume sensing system.

[0017] US2018 / 042585A1 discloses a sweat sensing device with priority sweat data from a subset of sensors.

[0018] US2010 / 179403A1 discloses a method and kit for measuring sweat activity. Summary of the Invention

[0019] This invention is defined by the independent claims. The dependent claims define advantageous embodiments.

[0020] According to one aspect, a system is provided, comprising: a sensor for sensing sweat droplets; a device for receiving sweat from one or more sweat glands and delivering the sweat to the sensor in the form of discrete sweat droplets; and a processor configured to: record sweat droplets sensed by the sensor during a time period; determine time intervals between sweat droplets sensed successively during the time period; and use the time intervals to identify at least one active period and at least one resting period for each of the one or more sweat glands, during the active period, the corresponding sweat gland excretes sweat, and during the resting period, the corresponding sweat gland does not excrete sweat, the active period and the resting period being assigned to the one or more sweat glands.

[0021] The device can sample sweat from the skin and deliver the sweat drop by drop to a sensor. Depending on the device design, the corresponding sweat sample may include sweat from a single sweat gland or sweat from more than one sweat gland. This can complicate the determination of the sweat rate per gland, as the number of sweat glands is ambiguous.

[0022] Sweat glands are known to secrete sweat in a cyclical manner. The active phases of sweat gland secretion, or "sweating bursts," are separated by resting phases where the glands do not secrete sweat. Sweating bursts typically last about 30 seconds, while resting phases can last about 150 seconds.

[0023] This invention is based on the understanding that this periodic behavior of sweat glands can be used to determine the number of sweat glands supplying sweat sensed by a sensor. During a sweat burst, one or more active sweat glands excrete sweat, which is transported to the sensor in the form of a series of discrete sweat droplets. This results in the generation of a series of different sensor signals, i.e., pulses, corresponding to the discrete sweat droplets detected by the sensor. By considering the time intervals between successive sweat droplets (pulses), the active and resting periods of one or more sweat glands can be determined. The process of identifying active and resting periods necessarily involves assigning such active and resting periods to one or more sweat glands. The number of sweat glands can then be determined.

[0024] Therefore, the method relies on determining the sweating burst periods of one or more individual sweat glands. The device can receive sweat from the skin, for example, via one or more chambers. Each chamber can be configured to receive sweat from, for example, up to five sweat glands. In other words, the entrance to each chamber can be sized to span the skin area occupied by the exits of up to five individual sweat glands. For this purpose, the area of ​​each entrance can be, for example, 0.05 mm². 2 Up to 2mm 2 Within the range, for example, 0.75mm 2 Up to 1.5mm2 .

[0025] Any suitable sensor can be used for the purpose of sensing sweat droplets, so that each of the sensed sweat droplets can be recorded / registered. For example, capacitance, conductivity, impedance, optical, and / or biomarker sensors can be used.

[0026] The processor can also be configured to determine the number of sweat glands allocated to the activity period and the rest period.

[0027] The processor may also be configured to: receive a measure of the volume of each sweat droplet in the recorded sweat droplets (e.g., corresponding to the width of a pulse); and determine the sweat rate per gland based on the number of sweat droplets, the measure of the volume of each sweat droplet in the recorded sweat droplets, and the determined number of sweat glands.

[0028] The number of sweat droplets sensed by the sensor over a period of time, the measurement of the volume of each recorded sweat droplet, and the number of sweat glands identified make it possible to calculate the sweat rate per gland.

[0029] The processor can be configured to identify the at least one active period and the at least one resting period based on the measurement of the volume of each sweat droplet in the recorded sweat droplets and the time interval. Taking into account the time interval and volume measurement of each sweat droplet in the recorded sweat droplets allows for the interpretation of sensor signal patterns in which the sensor signal corresponding to the active period of one sweat gland overlaps or interleaves with the sensor signal of another sweat gland.

[0030] The sensor can be configured to sense an indicator of the volume of the sweat droplets. The processor can therefore be configured to receive the sensed indicator. For example, the indicator could be the contact time between each sweat droplet and the sensor, such as the time it takes for the sweat droplet to pass through the sensor, i.e., the pulse width of each sensor signal. The pulse width can be used to determine the volume of the sweat droplet, provided that the speed at which the sweat droplet migrates through the sensor is known or can be estimated.

[0031] The processor can be configured to fit data received from the sensor to a first template model to identify the active and resting periods of each of the one or more sweat glands, the data including at least the time interval and a measure of the volume of each sweat droplet in the recorded sweat droplets.

[0032] Algorithms that fit sensor signal patterns to template models can provide a convenient means of identifying active and resting periods and assigning them to one or more sweat glands.

[0033] The fitting to the first template model may additionally utilize: the number of sweat droplets during the at least one active period, the duration of the at least one active period, and / or the duration of the at least one resting period. Considering one or more of these factors can provide a template model fitting algorithm with the ability to identify active and resting periods and assign them to one or more sweat glands.

[0034] The processor can be configured to evaluate how well the data fits to the first template model. Based on the goodness of fit, the processor can fit at least a portion of the data to another first template model. For example, the data portion that satisfies the goodness-of-fit criterion can be subtracted from the original data, and the remaining data can be fitted to another first template model, thereby enabling iteration to be performed.

[0035] The processor can be configured to, after fitting the data to the first template model, fit at least a portion of the data to a second template model, wherein the first template model is based on at least some of the sweat droplets from a sweat sample consisting of sweat excreted from a single sweat gland, and the second template model is based on at least some of the sweat droplets from another sweat sample consisting of sweat excreted from two or more sweat glands. Such a two-step fitting method can be particularly useful when there is a significant probability of a (other) sweat sample consisting of sweat excreted from two or more sweat glands due to the receipt of sweat from a relatively large area of ​​skin.

[0036] The device can be arranged to deliver sweat droplets of a predetermined volume to the sensor. Using sweat droplets of a predetermined volume increases the ease of assigning signal sensor patterns to one or more sweat glands. In other words, the fitting space can be advantageously limited in size.

[0037] The sensor may include a sensing device for detecting parameters related to the concentration of an analyte, the concentration of which varies with sweat rate, wherein the processor may be configured to use the parameters when allocating the active and rest periods to the one or more sweat glands. Therefore, the sweat rate dependence of the parameters can help resolve any ambiguities encountered when interpreting sensor signal patterns.

[0038] The sensing device can be a conductivity sensor, and the parameter is conductivity. Specifically, a conductivity sensor can help determine the rate of sweat production per gland. This is because the conductivity of sweat can serve as a representative of sodium ion concentration, which is rate-dependent. Furthermore, conductivity can be easily sensed using a relatively simple electrode arrangement.

[0039] The sensor may include a biomarker sensor. A biomarker sensor may be, for example, a lactate sensor. The concentration of a specific relevant biomarker (such as lactate) is sweat rate dependent, and therefore the system's ability to determine the sweat rate per gland can help provide a clinically relevant interpretation of the sensed biomarker concentration.

[0040] For this purpose, the processor can be configured to receive multiple biomarker concentrations from the biomarker sensor during the at least one activity period of the corresponding sweat gland, and to determine the temporal variation of the biomarker concentrations within the at least one activity period.

[0041] Furthermore, in the case of lactic acid, timescales relating changes in the concentration of lactic acid in sweat excreted onto the skin that are related to sweat glands (i.e., due to the active and resting periods of sweat glands) and those related to blood can be used to distinguish the former from the latter source of lactic acid. Therefore, measuring changes in the concentration of lactic acid in sweat over time can lead to a proper distinction between changes in lactic acid concentration originating from sweat glands and those originating from blood.

[0042] A method is also provided, comprising: receiving sweat from one or more sweat glands; delivering the sweat to a sensor in the form of discrete sweat droplets; sensing the sweat droplets using the sensor over a time period; recording the sweat droplets sensed during the time period; determining a time interval between the sweat droplets sensed sequentially during the time period; and using a processor to identify at least one active period and at least one resting period for each of the one or more sweat glands, during which the corresponding sweat gland excretes sweat, and during the resting period, the corresponding sweat gland does not excrete sweat, the active period and the resting period being assigned to the one or more sweat glands.

[0043] The method may further include: determining the number of sweat glands allocated to the activity period and the rest period.

[0044] The method can determine the sweat rate per gland. In this regard, the method may include: receiving and measuring the volume of each sweat droplet in the recorded sweat droplets; and determining the sweat rate per gland based on the number of recorded sweat droplets, the measurement of the volume of each sweat droplet in the recorded sweat droplets, and the determined number of sweat glands.

[0045] The identification of the at least one activity period and the at least one rest period via the processor may be based on the measure of the volume of each sweat droplet in the recorded sweat droplets and the time interval.

[0046] The method may include using the sensor to sense the measure of the volume, wherein receiving the measure of the volume includes receiving the sensed volume measure from the sensor.

[0047] The identification includes fitting data received from the sensor to a first template model, the data including at least the time interval and a measure of the volume of each sweat droplet in the recorded sweat droplets. The fitting may additionally use, for example, the number of sweat droplets during the at least one activity period, the duration of the at least one activity period, and / or the duration of the at least one rest period.

[0048] The method may additionally include evaluating the goodness of fit of the data to the first template model, and optionally, based on the goodness of fit, fitting at least a portion of the data to another first template model.

[0049] The identification may further include, after fitting the data to the first template model, fitting at least a portion of the data to a second template model, wherein the first template model is based on at least some of the sweat droplets from a sweat sample consisting of sweat excreted from a single sweat gland, and the second template model is based on at least some of the sweat droplets from another sweat sample consisting of sweat excreted from two or more sweat glands. Attached Figure Description

[0050] Embodiments of the invention are described in detail and by way of non-limiting example with reference to the accompanying drawings, wherein:

[0051] Figure 1 A first example of a device for delivering sweat droplets to a sensor is shown;

[0052] Figure 2 A second example of a device for delivering sweat droplets to a sensor is shown;

[0053] Figure 3 A third example of a device for delivering sweat droplets to a sensor is shown;

[0054] Figure 4 A fourth example of a device for delivering sweat droplets to a sensor is shown;

[0055] Figure 5 A fifth example of a device for delivering sweat droplets to a sensor is shown;

[0056] Figure 6 A sixth example of a device for delivering sweat droplets to a sensor is shown;

[0057] Figure 7A seventh example of a device for delivering sweat droplets to a sensor is shown;

[0058] Figure 8 An eighth example of a device for delivering sweat droplets to a sensor is shown;

[0059] Figure 9 A ninth example of a device for delivering sweat droplets to a sensor is shown;

[0060] Figure 10 A tenth example of a device for delivering sweat droplets to a sensor is shown;

[0061] Figure 11a A portion of the electrowetting arrangement according to an example is shown;

[0062] Figure 11b A portion of the electrowetting arrangement according to another example is shown;

[0063] Figure 12 An example of a device having multiple chambers is shown, all of which are connected in parallel to a common interconnect.

[0064] Figure 13 A sensor for sensing sweat droplets is shown according to an example;

[0065] Figure 14 Six exemplary sensors for sensing sweat droplets are shown;

[0066] Figure 15 The curves showing the time taken for sweat droplets to pass through the sensor as a function of droplet volume are shown for bundle-shaped sweat samples (dashed line) and hemispherical sweat droplets (solid line).

[0067] Figure 16 A portion of a system for sensing sweat droplets, based on an example, is shown;

[0068] Figure 17 Another example of a device for delivering sweat droplets to a sensor is shown;

[0069] Figure 18 The graph depicting two sweat bursts and two rest periods is shown (top pane), a magnified view of the first sweat burst and the first rest period (middle pane), and a graph showing the sweat rate sensor signal changing over time (bottom pane).

[0070] Figure 19 The graphs depicting two sweat bursts from the first sweat gland and two sweat bursts from the second sweat gland (upper pane) and the graphs showing the change of sweat sensor signal over time (lower pane) are shown.

[0071] Figure 20The graph shows the change of the sweat rate sensor signal over time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers and all sweat droplets overlap each other.

[0072] Figure 21 The graph shows the change of the sweat rate sensor signal over time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers and some of the sweat droplets overlap with each other.

[0073] Figure 22 The graph shows the sweat rate sensor signal changing over time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers and there is some overlap between the signals of the corresponding groups of sensors, but the corresponding sweat droplets do not coalesce with each other.

[0074] Figure 23 A flowchart illustrating a method for determining the rate of sweat production per gland, based on an example, is shown.

[0075] Figure 24 An example of an algorithm for attributing sweat droplets to the gland(s) from which they originate is shown;

[0076] Figure 25 The graph shows the change of the sweat rate sensor signal over time when the sweat rate is relatively high.

[0077] Figure 26 The graphs show the sweat rate sensor signal changing over time when sweat droplets originate from one gland in each chamber (upper pane) and when sweat droplets originate from two glands in each chamber (lower pane);

[0078] Figure 27 The diagram illustrates a schematic representation of the frequency of the electrowetting wave as a function of time when the electrowetting wave is out of sync with the formation of sweat droplets (upper pane) and a related graph of the sweat rate sensor signal as a function of time (lower pane).

[0079] Figure 28 It shows the relationship with Figure 27 The graphs shown are similar, but with more pronounced rises and falls at the beginning and end of the sweat burst, respectively.

[0080] Figure 29 A portion of another exemplary electrowetting arrangement is shown;

[0081] Figure 30 The graphs shown are of the sweat rate sensor signal changing over time for sweat glands that excrete at a defined average rate (top pane) and of the two models showing the change of lactic acid concentration over time (bottom pane).

[0082] Figure 31 A portion of another system for sensing sweat droplets, based on an example, is shown, in which calibration fluid is also supplied to the sensor drop by drop;

[0083] Figure 32 Another system for sensing sweat droplets, based on an example, is shown;

[0084] Figure 33 A first view of a portion of another exemplary device for delivering sweat droplets to a sensor is shown;

[0085] Figure 34 It shows Figure 33 A second view of a portion of the device shown;

[0086] Figure 35 It shows Figure 33 A third view of a portion of the device shown;

[0087] Figure 36 It shows Figure 33 A fourth view of a portion of the device shown;

[0088] Figure 37A It shows Figures 34-36 The diagram shows a plan view of the alternative chamber outlet for the shown outlet design;

[0089] Figure 37B It shows Figures 34-36 A plan view of an alternative chamber outlet for the shown outlet design;

[0090] Figure 38 It shows the use of Figure 33-36 The device shown is being transported with droplets of sweat;

[0091] Figure 39 It shows Figure 35 , 36 Electrical connection to the electrode shown in Figure 38;

[0092] Figure 40 A first view of a portion of yet another exemplary device for delivering sweat droplets to a sensor is shown;

[0093] Figure 41 It shows Figure 40 A second view of a portion of the device shown;

[0094] Figure 42 It shows the use of Figure 40 and Figure 41 The device shown delivers sweat droplets;

[0095] Figure 43 It shows Figure 41 and 42 The electrical connections of the electrodes shown;

[0096] Figure 44 A view is provided of yet another exemplary device for delivering sweat droplets to a sensor; and

[0097] Figure 45 A view of a device with an alternative electrical connection design is provided. Detailed Implementation

[0098] It should be understood that the detailed descriptions and specific examples, while indicating exemplary embodiments of the apparatus, systems, and methods, are intended for illustrative purposes only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the apparatus, systems, and methods of the invention will be better understood from the following description, the appended claims, and the accompanying drawings. It should be understood that the drawings are merely schematic and not drawn to scale. It should also be understood that the same reference numerals are used throughout the drawings to denote the same or similar parts.

[0099] As mentioned above, conventional sweat analysis techniques tend to be limited to individuals who engage in exercise to induce sufficient sweating for measurement purposes. This is unsuitable for healthcare settings where patients are mostly sedentary and sweat rates are correspondingly relatively low, for example, approximately 0.2 nl / min / gland.

[0100] A problem with conventional sweat sensing devices is the significant time delay between sweat excretion and biomarker measurement at such low sweat rates. Filling the sweat collection chamber used in such devices can take several hours.

[0101] So-called sweat rate-dependent biomarkers require measurement of sweat rate per gland for the biomarker data to be meaningful. However, known systems capable of measuring sweat rate per gland suffer from the drawback of highly complex design. For example, ten or more complex flow sensors may be required to monitor sweat flow in multiple sweat collection chambers. For instance, WO2018 / 125695 discloses a complex system that utilizes numerous sweat rate sensors and sodium biomarker sensors to jointly determine the average sweat rate per gland.

[0102] At low sweat rates, evaporation becomes a confounding factor leading to artificially elevated biomarker concentrations. Evaporation can also inhibit or prevent sweat from reaching the sensor, especially at low sweat rates (approximately 0.2 nl / min / gland) and volumes.

[0103] Another drawback of conventional sweat sensing devices is that electrochemical sensors, typically used for semi-continuous measurements, may require frequent recalibration and offline calibration. This can negatively impact workflow when such devices are used to monitor objects.

[0104] A system is provided for determining the rate of sweat production per gland. The system includes a device and a sensor. The device receives sweat from the skin and delivers the sweat to the sensor in the form of discrete sweat droplets. The sensor senses each of the sweat droplets. The system also includes a processor that records the number of sweat droplets sensed over a time period. The processor also determines the time interval between successively sensed sweat droplets and may optionally receive a measure of the volume of each of the sensed sweat droplets. The time interval and, optionally, the volume measure are then used by the processor to identify sweat bursts and rest periods of one or more sweat glands that produce sweat. The identification process necessarily involves assigning sweat bursts and rest periods to one or more sweat glands, allowing the processor to determine the number of sweat glands involved in sweat production.

[0105] The sweat rate per gland can then be determined based on the number of sweat droplets sensed, the measurement of the volume of each sweat droplet within the sweat droplets, and the identified number of sweat glands.

[0106] The device samples sweat from the skin and delivers the sweat drop by drop to a sensor. Depending on the device design, the corresponding sweat sample can consist of sweat from a single sweat gland or more than one. This can complicate the determination of the sweat rate per gland, as the number of sweat glands is ambiguous.

[0107] Sweat glands are known to secrete sweat in a cyclical manner. The active phases of sweat gland secretion, or "sweat bursts," are separated by resting phases where the glands do not secrete sweat. Sweat bursts typically last about 30 seconds, while resting phases can last about 150 seconds.

[0108] This invention is based on the understanding that this periodic behavior of sweat glands can be used to determine the number of sweat glands supplying sweat sensed by a sensor. During a sweat burst, one or more active sweat glands excrete sweat, which is transported to the sensor in the form of discrete queues of sweat droplets. This results in the generation of a series of different sensor signals, i.e., pulses, corresponding to the generation of discrete sweat droplets detected by the sensor. By taking into account the time interval between successive sweat droplets (pulses) and optionally a measure of the volume of each sensed sweat droplet (e.g., corresponding to the pulse width), the active and resting periods of one or more sweat glands can be determined.

[0109] Measuring the intervals and volumes of each sweat droplet in a count can aid in interpreting sensor signal patterns, where the sensor signal corresponding to an active period of one sweat gland overlaps or intersects with the sensor signal of another sweat gland. The process of identifying active and resting periods necessarily involves assigning such active and resting periods to one or more sweat glands. The number of sweat glands can then be determined.

[0110] The number of sweat droplets sensed by the sensor over a period of time, the measurement of the volume of each sweat droplet in the counted sweat droplets, and the number of sweat glands identified make it possible to calculate the sweat rate per gland.

[0111] This device provides the sensor with a discrete flow of sweat, rather than the continuous flow of sweat used in conventional sweat sensing devices. A fluid delivery assembly allows sweat droplets to be released from the outlet of the chamber and delivered to the sensor. Droplet orientation, and in some examples, migration through the sensor, can be achieved, for example, via interfacial tension methods and / or by the application of pressure, as will be further described below.

[0112] The droplet or discrete flow of sweat offers several unique advantages over continuous flow. The delay between sweat excretion and the actual determination of biomarker concentration can be reduced, for example, from typically 1-2 hours to approximately 10-15 minutes for sedentary subjects. In the case of sensors including biomarker sensors, the ability to process minute amounts of sweat and deliver it to the sensor relatively quickly allows biomarker concentrations to be determined even when the subject is sedentary. Furthermore, when sweat is provided as discrete sweat droplets rather than a continuous flow, the sweat rate can be determined more directly, for example, using simpler sensors.

[0113] Because this device releases sweat droplets from the outlet before delivering them to the sensor, it eliminates the need for sensors in each chamber, as is done in some prior art devices, to sense sweat droplets while they are still attached to most of the sweat collected in the chamber. This allows for greater design flexibility. For example, the device could deliver sweat to a sensor that is spatially removed from the outlet.

[0114] As will be described in more detail below with reference to the accompanying drawings, the fluid delivery assembly may include a surface extending between an outlet and a sensor. The surface may have, for example, a topological and / or chemical gradient, which allows sweat droplets to migrate downwards towards the sensor during use of the device. Alternatively or additionally, electrowetting techniques are used. Such electrowetting techniques use an electric field to achieve a transient change in the wetting properties of the surface, causing sweat droplets to migrate along the surface towards the sensor.

[0115] The fluid delivery assembly may alternatively or additionally apply pressure to the sweat droplets to release them from an outlet and / or deliver the released droplets to the sensor. Pressure may be applied via, for example, a flow of carrier fluid, wherein the sweat droplets flow immiscibly in the direction of the sensor.

[0116] The resulting queue of sweat droplets can be detected and counted using, for example, a simple detector with a pair of electrodes, each sweat droplet passing between the electrodes. Correspondingly, a simple device for measuring sweat rate is provided.

[0117] Figure 1 A portion of the device 100 according to an example is schematically depicted in cross-sectional view. The device 100 includes a chamber 102 having an inlet 104. The inlet 104 receives sweat from the skin 106. Figure 1 As shown, the inlet 104 can be positioned near the surface of the skin 106. Although in Figure 1 A single chamber 102 is depicted, but this is not intended to be limiting, and in other examples, the device 100 may include multiple chambers 102, as will be further described below.

[0118] The inlet 104 is shown as being adjacent to the sweat gland 108. In this configuration, sweat excreted by the sweat gland 108 enters through the inlet 104 and fills the chamber 102. Figure 1 As shown, the device 100 may include a plate 110 attached to the surface of skin 106. In the depicted example, the lower surface of the plate 110 is in direct contact with the surface of skin 106. In this case, the chamber 102 takes the form of an opening defined by the plate 110. The plate 110 may be formed of any suitable material capable of being disposed on the skin, such as a polymer. For example, the plate 110 may have at least a degree of flexibility to allow it to be conformally applied to the surface of skin 106. A more rigid plate 110 is also contemplated, provided that the inlet 104 can receive sweat from skin 106.

[0119] To collect sweat from the subject, the plate 110 can be adhered to the surface of the skin 106, for example, using a suitable biocompatible adhesive. Alternatively, the plate 110 can be held against the surface of the skin 106 by fasteners (e.g., strips) used to attach the plate 110 to the subject's body.

[0120] In this embodiment, each inlet 104 of the plurality of chambers 102 is sized to receive sweat from an average of 0.1 to 1 active sweat gland. This helps the device 100 determine the sweat rate of each sweat gland, as will be explained in more detail below.

[0121] Each inlet 104 can, for example, have a diameter of 0.005 mm. 2Up to 20mm 2 The area between chambers. The inlet area can be selected based on other dimensions of chamber 102 and the number of chambers 102 included in device 100. The basic principles behind the inlet area and dimensions will be discussed in more detail below.

[0122] Preferably, the diameter of the inlet 104 for receiving sweat from the skin 106 is chosen to be relatively small, such as 200-2000 μm, like 300-1200 μm, for example about 360 μm or about 1130 μm. The diameter of the sweat gland outlets on the surface of the skin 106 is typically in the range of about 60 μm to 120 μm. A relatively small inlet 104 can help reduce the probability of two or more sweat glands 108 draining into the same inlet 104, which could complicate the interpretation of sensor signals, as will be explored in further detail below. To compensate for the limited amount of sweat received in the individual chambers 102, the device 100 may include, for example, a plurality of such chambers 102, such as 2 to 50 chambers 102, like 10 to 40 chambers 102, for example about 25 chambers 102.

[0123] Once chamber 102 is filled with sweat, sweat droplets 112 protrude from outlet 114 of chamber 102. Figure 1 In the example shown, outlet 114 is defined by the upper surface of plate 110, and once chamber 102 is filled with sweat, hemispherical sweat droplets 112 are on top of forming outlet 114.

[0124] More generally, the device 100 can be configured such that the formation rate of the sweat droplets 112 is determined by the sweat rate, while the volume of the sweat droplets 112 is determined by the fluid delivery components. This will be explained in further detail.

[0125] The respective areas of the inlet 104 and outlet 114 can be selected to ensure effective filling of the chamber 102 and formation of sweat droplets 112 within the sweat rate range. In some examples, the inlet 104 and outlet 114 have fixed dimensions selected for this purpose. Alternatively, the device 100 can be configurable, allowing at least some dimensions and geometries associated with the formation of sweat droplets 112 to be varied.

[0126] In the preferred example ( Figure 1 In (not shown), chamber 102 is sized to fill with sweat within 10-15 minutes. After chamber 102 is filled, the formation of hemispherical sweat droplets 112 preferably occurs typically within 10 seconds at a relatively low sweat rate (e.g., 0.2 nl / min / gland).

[0127] The diameter of the outlet 114 can be, for example, in the range of 10 μm to 100 μm, such as 15 μm to 60 μm, like about 33 μm, to help control the size of the sweat droplets 112, making their volume uniform and reproducible. With an outlet 114 having such a diameter (e.g., about 33 μm), even at sweat rates as low as 0.2 nl / min / gland, several sweat droplets 112 can be formed during a single sweat burst (typically lasting 30 seconds) of the sweat gland 108. Therefore, sufficient sweat droplets 112 can be generated and delivered to the sensor via the device 100 to reliably estimate the sweat rate.

[0128] Device 100 enables the formation of sweat droplets 112 of relatively uniform size, and can also handle variable volumes of sweat droplets 112. Regarding the latter, the sensor to which device 100 delivers the sweat droplets 112 can be configured to count the sweat droplets 112 and determine the time taken for each sweat droplet 112 to pass through the sensor. This time is linearly related to the a priori known migration speed and the volume of the sweat droplet 112, as will be referred to below. Figure 15 A more detailed explanation.

[0129] As Figure 1 The proportions of the exemplary device 100 shown are indicated by a length 116 (indicated by a double-headed arrow) of approximately 500 μm. More generally, the dimensions of chamber 102, inlet 104, and outlet 114 can be selected based on, for example, the rate of sweating of the object. The volume of chamber 102 can be minimized to reduce filling time. This can help ensure minimal delay between actual sweat excretion and the sensing / monitoring of sweat droplets 112. For example, the volume of chamber 102 can be in the range of 0.1–100 nml, such as 0.5–50 nml, for example 1–20 nml.

[0130] The volume of chamber 102 can be minimized in various ways to minimize the time required for chamber 102 to fill with sweat. Such a modification could be, for example, to the plate 110 that defines chamber 102.

[0131] Figure 2 An example of a chamber 102 tapering from inlet 104 toward outlet 114 is shown. The volume of such a tapering chamber 102 would be smaller than, for example, a cylindrical chamber 102 with the same height and base diameter, such as... Figure 1 The cylindrical chamber of the device 100 shown.

[0132] As illustrated in the diagram. Figure 2 The length dimension 118 of the plate 110 shown is approximately 500 μm. In this example, the tapered chamber 102 has a conical geometry, i.e., a volume of 1 / 3πh[R]. 2 +Rr+r2 The truncated conical shape (h = 50 μm; R = 360 μm; r = 33 μm) is used. For a relatively low sweat rate of 0.2 nl / min / gland, the filling time of the tapered chamber 102 can be approximately 10 minutes, and the formation of sweat droplets 112 may take approximately 12 seconds. In contrast, the filling... Figure 1 The cylindrical chamber 102 shown, with the same height (50 μm) and bottom (360 μm) dimensions, may take approximately 50 minutes to form, and the hemispherical sweat droplets 112 may take more than 3 hours to form.

[0133] In this respect, it should be noted that sweat glands 108 tend to excrete during sweat bursts, followed by a resting period after each sweat burst when glands 108 do not excrete. During a sweat burst, the sweat rate can be approximately six times the average sweat rate. This is because, within a 180-second time window, there is typically a 30-second sweat burst and a typical 150-second resting period, thus creating a factor of six between the average sweat rate and the sweat rate during a sweat burst. In the illustrated example above with a truncated conical chamber 102, the time for the depicted sweat droplets 112 to form during a sweat burst of sweat gland 108 is approximately 12 seconds.

[0134] exist Figure 2 In the example shown, 56% of the surface area of ​​the sweat droplet 112 is in contact with the upper surface of the plate 110. For the purpose of releasing the sweat droplet 112 from the outlet 114 and transporting it to the sensor, the upper surface of the plate 110 can be provided with a gradient, such as a topological and / or chemical gradient, as will be further discussed below regarding the fluid transport assembly. In this respect, it can be said that, in the case of such a topological and / or chemical gradient, the surface area of ​​the sweat droplet 112 required to contact the upper surface of the plate 110 for release from the outlet 114 can depend on the steepness of the chemical and / or topological gradient and the volume of the sweat droplet 112.

[0135] Figure 3 Another example of how the volume of chamber 102 can be minimized is shown. In this example, chamber 102 is divided into compartments, at least some of which are fluidly connected to each other to allow chamber 102 to fill with sweat. Figure 3 As shown, the compartment can be formed by a support 120. Such a support 120 can form part of the plate 110, and in such an example, it can be formed by patterning (e.g., etching) the lower surface of the plate 110. Other suitable ways of forming such a support 120 will be apparent to those skilled in the art.

[0136] Figure 4Another example is illustrated where a porous material 122 (e.g., a glassy material, such as sintered glass) divides the chamber 102 into compartments. The volume of the chamber 102 can be reduced due to the space occupied by the spacers between the pores of the porous material 122. Depending on the shape of the chamber 102 and the extent to which the material separating the pores occupies the chamber 102, the filling time of the chamber 102 can be reduced, for example, by 1-4 minutes.

[0137] The porous material 122 can also serve as a filter for substances such as polymerized proteins that might otherwise clog downstream components of the device 100, such as outlet 114 or the fluid delivery assembly. Furthermore, the porous material 122 can help prevent the device 100 from being contaminated by specific sweat components and impurities. For example, the porous material can be selected to have specific adsorption properties for proteins and other substances that may be desired to be removed from sweat entering or contained within chamber 102. Removing such impurities can be advantageous because it reduces the risk of impurities altering surface properties in the fluid delivery assembly, such as adsorption onto the surfaces of the fluid delivery assembly, such as adsorption onto electrowetting tiles of an electrowetting arrangement (when such an electrowetting arrangement is included in the fluid delivery assembly). Therefore, the porous material can help mitigate the risk that these impurities will impair the hydrophilic / hydrophobic balance required for the release of sweat droplets 112 from outlet 114 and for the migration of sweat droplets 112 to the sensor.

[0138] In examples where the porous material 122 includes or is located near the surface of the skin 106, the porous material 122 may be partially prevented from becoming clogged due to the skin 106 protruding into the chamber 102 due to its incompressibility.

[0139] The diameter of the pores in the porous material 122 can be, for example, in the range of 100 nm to 10 μm. The diameter of the spacers between the pores can also be, for example, in the range of 100 nm to 10 μm, so as to minimize the risk of these spacers themselves blocking the exit of the sweat gland 108. In this respect, the outlet diameter of the sweat gland 108 is typically in the range of about 60 μm to 120 μm.

[0140] It should be noted that, to avoid any doubt, refer to Figure 1-3 The described volume minimization measures can be used in any combination to minimize the volume of chamber 102 so as to facilitate the formation of sweat droplets 112 even at relatively low sweat rates. For example, device 100 may include a tapered chamber 102 that is also divided into compartments, for example by including columnar structures 120 and / or porous materials 122.

[0141] As described above, the device 100 includes a fluid delivery assembly arranged to release sweat droplets 112 protruding from the outlet 114. Therefore, the fluid delivery assembly may include, for example, a structure that separates the sweat droplets 112 (e.g., hemispherical sweat droplets 112) from the outlet 114.

[0142] Due to the intermolecular attraction between water molecules in sweat, the formed sweat droplets 112 can be anchored to the large amount of sweat that has already filled the chamber 102.

[0143] In practice, sweat droplets 112 do not have a single contact angle value, but rather a range from the maximum to the minimum contact angle, which are respectively called the advancing contact angle and the receding contact angle. The difference between the advancing contact angle and the receding contact angle is called contact angle hysteresis.

[0144] These forces resist the movement of sweat droplets 112 from outlet 114. This force causes sweat droplets 112 to remain above the filled chamber 102. A fluid delivery assembly allows these forces to be overcome, such as separating the sweat droplets 112 (and delivering the sweat droplets 112 downstream toward the sensor). The fluid delivery assembly can be configured to allow the sweat droplets 112 to be definitively displaced from the chamber 102. In other words, the separation of sweat droplets 112 ensures a definitive definition of the discrete sweat droplets 112.

[0145] For example, the fluid delivery assembly may be provided with passive and / or active gradients for displacing (i.e., releasing) sweat droplets 112. Passive gradients may include chemical and / or topological gradients. Active gradients may be provided by applied pressure and / or by an electric field from an electrowetting arrangement.

[0146] In some examples, the separation or release of sweat droplets 112 can occur at the moment when the sweat droplets 112 reach a certain diameter. At this diameter, the active and / or passive gradient (e.g., which can be experienced by at least part and preferably the entire sweat droplet 112) can be large enough to overcome the contact angular hysteresis of the sweat droplets 112, allowing the sweat droplets 112 to be released from the outlet 114.

[0147] Figure 5 An example of separating sweat droplets 112 via electrowetting technology is schematically depicted. This can be considered an example of an "active" interfacial tension method, in which a force is actively applied to overcome the contact angular hysteresis of the sweat droplets 112.

[0148] like Figure 5As shown, the upper surface of plate 110 is provided with a series of discrete electrowetting tiles 124. For the purpose of separating and / or conveying aqueous sweat droplets from outlet 114, the electrowetting tiles 124 may include electrodes coated with a hydrophobic material (e.g., a fluoropolymer). The conveying assembly may include an electric field generator (not shown) for sequentially charging and discharging each of the series-connected electrowetting tiles 124. Charging the electrowetting tiles 124 can switch the surface properties of the electrowetting tiles 124 from hydrophobic to hydrophilic, thereby instantly overcoming the contact angular hysteresis of the sweat droplets 112. The sweat droplets 112 can then migrate to the charged electrowetting tiles 124 accordingly. Subsequent discharging of the charged electrowetting tiles 124 and charging of subsequent electrowetting tiles 124 in the series can cause the sweat droplets 112 to migrate to subsequent electrowetting tiles 124, and so on. This sequence can be considered a “wave of electrowetting.”

[0149] exist Figure 5 In the example shown, separation from the outlet 114 can occur when the sweat droplet 112 has grown to a sufficiently large diameter such that it at least partially overlaps with a pair of electrowetting tiles 124. In this case, once the electrowetting wave passes along the electrowetting tiles 124, the sweat droplet 112 spanning the pair of electrowetting tiles 124 will be displaced from the outlet 114 accordingly. In this example, the sweat droplets 112 may not all have a uniform size or volume because the sweat droplets 112 can continue to grow to different degrees during the time interval between when the sweat droplet 112 reaches the necessary diameter and when the electrowetting wave arrives. In this respect, the size of the sweat droplet 112 can be determined by the frequency of the electrowetting wave.

[0150] In an alternative example, the fluid delivery assembly may employ a “passive” gradient to release sweat droplets 112 from outlet 114. In this context, the term “passive” generally refers to the fluid delivery assembly not actively applying force to overcome the contact angular hysteresis of the sweat droplets 112.

[0151] For example, the upper surface of plate 110 may be provided with a chemical and / or topological gradient that allows sweat droplets 112 to separate from outlet 114. The topological gradient may be provided by the inclined upper surface of plate 110 such that when device 100 is oriented for use, the inclined gradient across the diameter of sweat droplets 112 is large enough to overcome contact angular hysteresis.

[0152] Chemical gradients can be provided by surfaces having hydrophilic and hydrophobic portions arranged to provide a wettability gradient along the surface. For example, microfluidic channels functionalized with hydrophobic CH3- portions (towards the skin 106) and hydrophilic OH- portions (towards the sensor) can be used to generate chemical gradients (Morgenthaler et al., Langmuir; 2003; 19(25) pp. 10459-10462).

[0153] A chemical gradient can be provided, for example, at the molecular level, with hydrophilic / hydrophobic water regions, such that the wettability gradient varies substantially continuously along the surface. This chemical gradient can be provided, for example, by grafting polymer chains to functionalize the surface of plate 110. Alternatively or additionally, μm-sized hydrophilic / hydrophobic water regions can be provided on the surface to provide a stepped wettability gradient. Preferably, the regions are arranged to have a gradually varying distribution along the length of the surface in the direction of the sensor.

[0154] When such a passive (chemical and / or topological) gradient is used for the separation of sweat droplets 112, separation can occur when the sweat droplets 112 (e.g., hemispherical sweat droplets 112) reach a specific size. Once the diameter of the sweat droplets 112 is large enough across the diameter to overcome contact angular hysteresis, the sweat droplets 112 will separate from the outlet 114. In this sense, such a gradient may result in each sweat droplet 112 being transported to a sensor having a size / volume similar to each other. After the sweat droplets 112 are separated, viscous drag can also play a role in delaying the movement of the sweat droplets 112 due to the driving force generated by the surface energy gradient.

[0155] exist Figure 5 and 6 In the example shown, the fluid delivery assembly includes another plate 128, which is separated from and opposite the plate 110 defining the chamber 102. The other plate 128 allows for control over the volume of sweat droplets 112. This can be achieved, for example, by separating the other plate 128 from the plate 110 by a defined distance 130. The size of the sweat droplets 112 can increase until they contact the other plate 128. In practice, when the sweat droplets 112 contact the other plate 128, they can be separated by “jumping” to it. This can be considered another example of an interfacial tension method for separating sweat droplets 112 from the outlet 114.

[0156] refer to Figure 6The spacing 130 between plate 110 and another plate 128 can be selected to be large enough to ensure that the diameter of the formed sweat droplets 112 (e.g., hemispherical sweat droplets 112) is large enough before contacting the other plate 128 (i.e., the lower surface of the other plate 128 opposite to the upper surface of plate 110).

[0157] exist Figure 6 In the example shown, the lower surface of the other plate 128 may be provided with a passive (e.g., chemical and / or topological) and / or active (e.g., via applied pressure and / or electric field) gradient for transporting sweat droplets 112 toward the sensor in the direction of arrow 126. After the sweat droplets 112 separate by “jumping” to the other plate 128, the sweat droplets 112 can begin to migrate via the gradient. As briefly described above, the spacing 130 between plate 110 and the other plate 128 can be selected to ensure that the diameter of the formed sweat droplets 112 is large enough before contacting the other plate 128. This can help ensure the immediate migration / transportation of sweat droplets 112 of uniform size.

[0158] like Figure 6 As shown, the lower surface of another plate 128 is provided with an electrowetting tile 124. The electrowetting tile 124 and the electric field generator (not shown) can be similar to those described above. Figure 5 The described layout. However, in Figure 6 In the case of a sweat droplet 112 migrating on another plate 128 via the electrowetting tile 124, the migration of the sweat droplet 112 will occur when the next electrowetting wave reaches the sweat droplet 112 that has already been released onto the other plate 128. Therefore, a sufficiently high electrowetting wave frequency can ensure that sweat droplets 112 of relatively uniform size / volume are delivered / migrated to the sensor. On the other hand, if the frequency of the electrowetting wave is relatively slow, the size / volume of the sweat droplet 112 can be determined by both the electrowetting wave frequency and the interval 130 between plate 110 and the other plate 128, i.e., because the sweat droplet 112 can grow during the time interval between electrowetting waves.

[0159] In a non-limiting example, the fluid delivery assembly can be configured to control the interval 130 between plate 110 and another plate 128. This can be achieved, for example, by a fluid delivery assembly including a mechanism engaging at least one of the plates 110, 128, said mechanism being configured to move at least one of the plates 110, 128 to adjust the interval between the plates 110, 128. The control applied to the mechanism can be manual and / or automatic. With regard to automatic control, the fluid delivery assembly can, for example, control the interval 130 based on the sweat rate of the sweat glands 108. In such an example, the fluid delivery assembly can include a controller configured to control said mechanism to move at least one of the plates 110, 128 based on a determined sweat rate (e.g., a sweat rate detected by a sensor). Thus, the fluid delivery assembly can be configured to control the interval 130 in a dynamic manner.

[0160] At relatively high sweat rates, sweat droplet 112 formation may be too rapid, and uncontrolled sweat droplet aggregation may occur. This can be mitigated by increasing the interval 130, as separating larger sweat droplets 112 onto another plate 128 may take longer.

[0161] At relatively low sweat rates, the number of sweat droplets 112 delivered to the sensor can be relatively low. This problem can be mitigated by reducing the spacing 130 to increase the number of (smaller) sweat droplets 112 formed on the other plate 128.

[0162] Figure 7 An example of separating sweat droplets 112 using a fluid delivery assembly is shown, wherein the upper surface of plate 110 and the lower surface of another plate 128 are provided with passive gradients, such as chemical and / or topological gradients. In this regard, arrows 126A and 126B indicate the directions of the gradients provided on the upper surface of plate 110 and the lower surface of the other plate 128 for delivering sweat droplets 112 toward the sensor.

[0163] Alternatively or additionally, the separation of the defined sweat droplets 112 can be achieved by applying a pressure gradient to the sweat droplets 112 protruding from the outlet 114 via the fluid delivery assembly. This can be considered an example of providing an active gradient to overcome the contact angular hysteresis of the sweat droplets 112, as the fluid delivery assembly actively applies pressure / force to the sweat droplets 112 to overcome the contact angular hysteresis of the sweat droplets 112.

[0164] For example, a pressure gradient can be applied by contacting the protruding sweat droplets 112 with the flow phase of a carrier fluid. The carrier fluid is preferably a fluid immiscible with the sweat droplets 112. Therefore, since mixing of the sweat droplets 112 with the carrier fluid is substantially prevented, the sensor can be able to detect each discrete sweat droplet 112 carried thereon by the carrier fluid. Suitable examples of such carrier fluids include oils that do not absorb moisture (i.e., have relatively low or negligible hygroscopicity), such as oxycyte (artificial blood). Oxycyte is a perfluorocarbon compound commonly used as a blood substitute.

[0165] In this example of separating sweat droplets 112 by the flow of the carrier fluid, as previously described, another plate 128 can be provided opposite the plate 110 defining the chamber 102. Sweat droplets 112 can form and grow until they contact the other plate 128, thus blocking the passage defined by the space between the respective plates 110, 128. The sweat droplets 112 can then be displaced by the flow of the carrier fluid. In this way, relatively uniformly sized sweat droplets 112 can be provided; their size is determined by the distance 130 between the plates 110, 128, as previously described. Figure 6 The flow of the carrier fluid can also help deliver sweat droplets 112 to the sensor.

[0166] In cases where, for example, the flow of the carrier fluid is insufficient to separate sweat droplets 112, the fluid delivery assembly can be configured to induce pulses or peaks in the flow rate, which can provide sufficient pressure to release the sweat droplets 112 from the outlet 114. For example, a piezoelectric pump can be used to induce such peaks in the flow rate of the carrier fluid. This can be achieved directly by changing the pump's pulse frequency.

[0167] Figure 8 An example device 100 is schematically depicted, wherein the fluid delivery assembly is configured to provide an active gradient, for example, via an electric field applied in the context of an electrowetting arrangement. Furthermore, the plate 110 defining the outlet 114 has a corrugated (upper) surface 132, wherein the outlet 110 of the chamber 102 is disposed at the apex 134 of the corrugated surface 132.

[0168] When the fluid delivery assembly applies pressure to the sweat droplets 112 via the flow of carrier fluid (as indicated by arrow 136), the flow can be directed to the protruding sweat droplets 112 at the top 134 of the wavy surface 132. Figure 8As shown, chamber 102 may include a narrower neck region extending to the apex 134 of the wavy-shaped surface 132. This structure can facilitate the separation of sweat droplets 112 because less energy is required to overcome droplet inertia caused by contact angular hysteresis. This is especially true if the wavy-shaped surface is hydrophobic.

[0169] This structure can be considered a passive support structure and may be referred to as a "rod" structure, wherein the outlet 114 is positioned on the top of the rod, which defines the neck of the chamber 102. As described above, this structure can aid in the separation of sweat droplets 112, particularly when utilizing an active pressure gradient. Therefore, this support structure can be advantageously used in the context of an active pressure gradient between plate 110 and another plate 128, as described above regarding... Figure 7 Described.

[0170] The wavy "rod" structure can be manufactured in any suitable manner. For example, it can be manufactured using micromachining techniques such as deep reactive ion etching (DRIE), lithography, plating and molding (LIGA), wet etching, fused deposition modeling (FDM), projection micro-stereolithography, and direct-write additive manufacturing (KS Teh. Additive direct-write microfabrication for MEMS:Areview.Front.Mech.Eng.2017;12(4):490–509).

[0171] After the sweat droplets 112 separate, they are transported to a sensor, such as a sweat rate sensor and / or a biomarker sensor, via a fluid delivery assembly. For example, the sensor may include a unit through which the sweat droplets 112 can be transported. In such an example, the fluid delivery assembly enables the sweat droplets 112 to be transported or migrated to and through the sensor.

[0172] The released sweat droplets 112 are delivered at least as quickly as subsequent sweat droplets 112 protrude from the outlet 114. Preferably, the migration of sweat droplets 112 is faster than the formation (i.e., protrusion) of subsequent sweat droplets 112. This is to ensure a defined sweat droplet 112, i.e., to ensure that a series of discrete sweat droplets 112 are delivered to the sensor.

[0173] In other words, the fluid delivery component can maintain the discrete droplet characteristics of sweat droplets 112 by ensuring rapid delivery / migration relative to the formation of sweat droplets 112. This may be superior to continuous sweat flow in terms of reducing or avoiding the diffusion of components (e.g., biomarkers) between sweat samples collected at different time points, especially at low sweat rates.

[0174] The concentration of biomarkers in each sweat droplet 112 can be determined primarily or solely by the size / volume of the sweat droplet 112, leading to relatively simple measurements, as will be discussed in this paper. Figure 15 Further described. Therefore, when a series of discrete sweat droplets 112 are delivered to a sensor configured to detect the concentration of a biomarker in the corresponding sweat droplet 112, the biomarker concentration over time can be determined, where the likelihood of error related to the diffusion of the biomarker between sweat samples taken at different time points is smaller. Otherwise, such a cumulative effect could lead to a measured biomarker concentration lower than the actual concentration in sweat sampled during a specific time period. Thus, device 100 can provide a means to overcome key drawbacks of conventional continuous sweat monitoring.

[0175] Sweat glands 108 operate in a periodic manner. During a sweat burst, sweat glands 108 typically excrete for about 30 seconds, followed by a rest period of approximately 150 seconds. By means of the discrete flow of sweat droplets 112 supplied to the sensor by the fluid delivery component, even during the sweat burst of sweat glands 108, the device 100 can be applied to determine detailed information about the concentration of biomarkers changing over time. Sweat gland bursts can be detected accordingly, which can have various advantages, including the ability to determine lactic acid concentrations, as will be referred to below. Figure 29 and 30 A more detailed description.

[0176] The relatively rapid delivery of sweat droplets 112 to the sensor via the fluid delivery assembly can also help mitigate / minimize the problem of sweat evaporation as it migrates to the sensor. In the most severe cases, this evaporation can prevent sweat droplets 112 from reaching the sensor. Ensuring minimal evaporation of sweat droplets 112 at low sweat rates / volumes is particularly important.

[0177] Similar to the above description of the separation of sweat droplets 112, the fluid delivery assembly can be provided with passive and / or active gradients for delivering the separated sweat droplets 112 to the sensor. Therefore, the delivery of sweat droplets 112 can be via interfacial tension techniques and / or by applying pressure, as will be further described below.

[0178] A significant advantage associated with passive gradients is that no power needs to be supplied to the fluid delivery components to deliver discrete sweat droplets 112 to the sensor.

[0179] When a chemical gradient is used, the length of the chemical gradient trajectory is limited by two factors: firstly, the finite range of a lower contact angle of approximately 20° and an upper contact angle of 170° at a hydrophilic / hydrophobic balance; and secondly, the size of the transported / migrated sweat droplets 112. Smaller sweat droplets 112 require a steeper gradient than larger ones. In particular, because the relatively small length of the sweat droplets 112 effectively limits their exposure to the gradient, relatively small sweat droplets 112 require a steeper gradient to initiate their movement.

[0180] For example, depending on the size of the sweat droplets 112, a delivery distance of 5-10 mm is achievable and, in principle, sufficient for the operation of the device 100.

[0181] To minimize the contact angle hysteresis of sweat droplets 112, chemical gradients can be formed in various ways. As described above regarding the separation of sweat droplets 112 via chemical gradients, for example, a stepped chemical gradient can be employed. Preferably, the domains are arranged to have a gradually varying distribution along the length of the surface in the direction of the sensor. This stepped gradient can be made, for example, by hydrophobic water formed from nanopillars and hydrophilic water formed from silanoxyl-based materials. In practice, chemical gradients can result in contact angles between about 15° and about 166°, which is typical for superhydrophilicity and superhydrophobicity.

[0182] In an alternative example, the chemical gradient can be provided at the molecular level with hydrophilic / hydrophobic water zones, such that the wettability gradient varies substantially continuously along the surface. Such a chemical gradient can be provided, for example, by grafting polymer chains to functionalize the surface of plate 110, as discussed above with respect to the separation of sweat droplets 112.

[0183] These embodiments are supported by the theory of a chemical wettability gradient that determines the movement of droplets along a solid surface at alternating contact angles. As previously described, such alternating contact angles can be created by changing the chemical composition of the solid surface, thereby achieving chemical anisotropy on the surface. The resulting wettability gradient alters the surface tension at the liquid-solid interface. Since sweat droplets 112 tend to minimize their surface energy, they move from a less wettable region (larger water contact angle) to a more wettable region (smaller water contact angle).

[0184] A sweat droplet 112 placed on a surface with a horizontal chemiwetting gradient is subjected to two main reaction forces: driving force and viscous drag. The driving force is generated by the surface energy gradient that promotes the motion of the sweat droplet 112, while the viscous drag is opposite to the motion of the sweat droplet 112. Contact angular hysteresis acts as a drag on movement, attempting to hold the sweat droplet in its static position. The sweat droplet 112 accelerates under the resultant force of these opposing forces.

[0185] An estimate of the velocity of a sweat droplet 112, achievable via a chemical wetting gradient, has been obtained from a theoretical model. The model estimates, for a 4° hysteresis water droplet with a diameter of 100 μm (size ≈ 0.26 nm) and a hydrophobic contact angle of 150°, that, assuming a linear chemical gradient, the minimum wetting gradient can be dcosθ / dx = 0.83 mm. -1 This is to overcome the hysteresis and thus initiate droplet motion. Considering the air-water surface tension of 0.072 N / m and the dynamic viscosity of water of 8.8871 x 10⁻⁶, -4 Pas., in this specific example, the theoretical model also predicts droplet velocities that vary in the range of 0.6–10 cm / s.

[0186] Figure 9 An exemplary device 100 is schematically depicted, wherein the fluid delivery assembly is provided with a passive topological gradient. In this example, the topological gradient is provided by an inclined surface 138. The inclined surface 138 is inclined toward, i.e., ascends toward, the outlet 114, such that when the device 100 is oriented for use, for example, horizontally as shown, sweat droplets 112 are delivered downward along the inclined surface 138 in the direction of the sensor.

[0187] exist Figure 9 In the example shown, the inclined surface 138 corresponds to the upper surface of the plate 110. The inclination angle 140 relative to the horizontal plane 142 is chosen to be large enough to overcome the contact angular hysteresis of the sweat droplets 112.

[0188] Although Figure 9 The inclined surface 138 shown has a linear (topological) gradient, but alternative types of inclined surfaces can be expected. In this respect, Figure 10 A device 100 is schematically depicted having an inclined surface 138 in the form of a ramp, the ramp having portions with different inclination angles.

[0189] Although Figure 9 and 10 The inclined surface 138 is shown as the outer surface or outer surface of the plate 110, but this is not intended to be limiting. Preferably, the inclined channel or internal passage provided within the plate 110 includes the inclined surface 138.

[0190] More generally, and although in Figure 1-10 The cross-sectional representation provided is not visible, but the pathway for delivering sweat droplets 112 toward the sensor, included in the fluid delivery assembly, can be at least partially and preferably completely closed in order to minimize the evaporation of sweat droplets 112.

[0191] The tilted surface 138 can be formed in any suitable manner, such as by applying various micromachining techniques, such as deep reactive ion etching (DRIE), photolithography, electroplating and molding (LIGA), spraying with or without wet etching, fused deposition modeling (FDM), projection microstereolithography and direct-write additive manufacturing, etc.

[0192] In fact, the passive migration of sweat droplets 112 can be achieved through a combination of the aforementioned chemical and topological gradients.

[0193] Alternatively, the fluid delivery assembly may be provided with an active gradient, such as a pressure gradient, to deliver the sweat droplets 112. For example, a pressure gradient may be applied by bringing the sweat droplets 112 into contact with a flow of carrier fluid, as previously described with respect to the separation of the sweat droplets 112.

[0194] In an example where the carrier fluid and the sweat droplets 112 are immiscible with each other, the sensor can be able to detect each discrete sweat droplet 112 carried thereon by the carrier fluid. Suitable examples of such carrier fluids include oils that do not absorb moisture (i.e. have relatively low or negligible hygroscopicity), such as artificial blood.

[0195] The fluid delivery assembly may include a plate 110 opposite another plate 128. In such an example, sweat droplets 112 can form and grow until they contact the other plate 128, whereupon the sweat droplets 112 can block the passage defined by the space between the respective plates 110, 128. The sweat droplets 112 can then be displaced by the flow of a carrier fluid driven by a pressure gradient (e.g., a constant flow of the carrier fluid). In this way, relatively uniformly sized sweat droplets 112 can be delivered to the sensor, the size of which is determined by the distance 130 between the plates, as previously discussed. Figure 5 As described.

[0196] In cases where, for example, the flow of the carrier fluid is insufficient to separate sweat droplets 112, the fluid delivery assembly can be configured to induce pulses or peaks in the flow rate, which can provide sufficient pressure to release the sweat droplets 112 from the outlet 114. For example, a piezoelectric pump can be used to induce such peaks in the flow rate of the carrier fluid. This can be achieved directly by changing the pump's pulse frequency.

[0197] The fluid delivery assembly may include, for example, a reservoir (not shown) for the carrier fluid, thereby enabling a continuous supply of the carrier fluid during operation of the device 100. Preferably, the fluid delivery assembly may be connected to an external reservoir for the carrier fluid, which is not included in the device 100 itself, because a relatively large volume of carrier fluid, such as 1 liter or more, would be required for continuous 24-hour operation over several days (e.g., 7 days).

[0198] In a non-limiting example, the carrier fluid (e.g., oil) can be circulated by a pump included in the fluid delivery assembly, as previously described. Sweat can be separated from the carrier fluid after sensing and delivered to a waste container (not shown) for collecting the sweat. Separation of sweat from the carrier fluid can be aided when sweat is immiscible with it. In this way, the carrier fluid can be recycled, which also reduces the required volume of carrier fluid. The waste container can, for example, have the capacity to hold milliliters of sweat.

[0199] As previously mentioned Figure 5 and 6 The fluid delivery assembly described herein may include an electrowetting tile 124 (the term "electrowetting tile" is an alternative to the term "electrowetting electrode") and an electric field generator for separating and delivering sweat droplets 112. The electrowetting tile 124 and the electric field generator may at least partially constitute an electrowetting arrangement 144, an example of which is shown in [example missing]. Figure 11a and 11b The diagram is used to represent this.

[0200] For conveying water-based sweat droplets 112, each of the tiles 124 includes a coating of a hydrophobic material (such as a chloropolymer, for example, Parylene C, or a fluoropolymer, for example, ...). The electrodes and the electric field generator for charging / discharging the electrowetting tile 124. Parylene can also be used as a hydrophobic material, and layered coatings of various substances can be used, such as sputtering tantalum pentoxide onto the electrodes, coating with parylene, and finally coating with... In practice, the electrowetting arrangement 144 can be operated by an applied electric field that makes the electrowetting tile 124 charged and thus switches it from hydrophobic to hydrophilic, as previously described.

[0201] The electrowetting device 144 may require control electronics and a power source to actively deliver sweat droplets 112. Figure 11a An example is shown where the electrowetting arrangement 144 can still be implemented in a relatively simple way.

[0202] In this example, multiple electrowetting waves can be generated using only 3 to 8 controlled local voltages. These electrowetting waves enable the transport / migration of sweat droplets 112 over the desired (e.g., the entire) length of the fluid transport assembly, so that the sweat droplets 112 are transported to the sensor and optionally pass through the sensor.

[0203] Figure 11a An electrowetting arrangement 144, including a planar two-dimensional electrode design, is shown. For simplicity, Figure 11aThe diagram illustrates the connection of fifteen electrowetting tiles 124. However, those skilled in the art will understand that the electrowetting arrangement 144 can be scaled up to include, for example, one hundred or more electrowetting tiles 124.

[0204] Figure 11a Three configurations are shown: each first line 146 connects one of the electrowetting tiles numbered 1 to 5 to the corresponding external connection pad 148a-e; each second line 150 connects one of the electrowetting tiles numbered 1 to 5 to the corresponding electrowetting tiles numbered 6 to 10; and each third line 152 connects one of the electrowetting tiles numbered 6 to 10 to the corresponding electrowetting tiles numbered 11 to 15. Figure 11a The obvious variations in line thickness (146, 150, and 152) are solely for guiding the reader's eye.

[0205] The electrowetting arrangement 144 can be operated by applying a series of charge-discharge actions from the first pad 148a to the second pad 148b, to the third pad 148c, to the fourth pad 148d, and finally to the fifth pad 148e, for example, with each action spaced apart by, for example, one-tenth of a second. In this way, an electrowetting wave can propagate from the electrowetting tile 1 to the electrowetting tile 15. This sequence can be repeated so that the electrowetting wave repeatedly sweeps across the array 124 of electrowetting tiles. The sequence can also be reversed so that the electrowetting wave propagates from the electrowetting tile 15 toward the tile 1. The frequency at which the electrowetting wave travels along the array can at least partially determine the size / volume of the sweat droplets 112, as previously discussed regarding... Figure 5 Described.

[0206] Although Figure 11a The illustration shows an electrowetting arrangement 144 with a two-dimensional electrode design, but the same principle applies to three-dimensional designs, such as those using vertical interconnect access (VIA) connections.

[0207] However, Figure 11a The electrical wiring shown in the same plane allows for a single structure within that plane, thus avoiding VIAs on other layers. Therefore, this design can be manufactured relatively inexpensively. The disadvantage of this wiring design is the use of a fairly large surface area, and the limitations on the structure of the electrowetting path. For example, Figure 11a The design shown may not support paths with branches, such as... Figure 12 The branch structure shown.

[0208] exist Figure 11b In the alternative example shown, the parallel electrowetting paths are linear. Note that the numbering direction of the electrowetting tiles is... Figure 11b relative to Figure 11aIt is in reverse. The electrowetting wave advances from 1 to 15, and there is an outlet for chamber 102 at tile 1. The reason for the reverse numbering is that a sweat rate sensor can be provided on the side of tile 15.

[0209] because Figure 11b The wiring pattern shown, and the corresponding electrowetting paths, can converge, for example, to power a single sweat rate sensor. Figure 11b It also shows that multiple chambers 102 can be solved using in-plane design.

[0210] More generally, using the electrowetting device 144 to transport / migrate sweat droplets 112 can provide relatively rapid migration and precise control over the transport (e.g., speed) of the sweat droplets 112. In principle, the propagation of the electrowetting wave can be applied to transport sweat droplets 112 over relatively long distances. This latter advantage also applies to examples where the fluid transport assembly applies pressure to the sweat droplets 112, but an energy source is required in both cases.

[0211] When electrowetting is used for the migration of sweat droplets 112, the gradient length is between the two electrowetting tiles 124, and therefore a much stronger force than that of a chemical gradient can be achieved. However, the choice of migration principle can depend on the application intended for use in device 100. As mentioned above, the migration of sweat droplets 112 via a chemical gradient does not require an energy source.

[0212] Although Figure 1-10 A single chamber 102 is shown from which sweat droplets 112 are delivered to the sensor, but the device 100 may include multiple chambers 102, and the fluid delivery assembly releases sweat droplets 112 protruding from the respective outlets 114 of the chamber 102 and delivers the respective sweat droplets 112 to the sensor.

[0213] In such an example, the fluid delivery component can deliver the corresponding sweat droplets 112 by means of an interfacial tension method and / or via applied pressure, as previously described.

[0214] The fluid delivery assembly can fluidly connect the respective outlets of each of the multiple chambers 102 to the sensor in parallel. By connecting each chamber 102 to the sensor in parallel rather than in series, fully formed migrating sweat droplets 112 from one chamber 102 will not pass through the outlet 114 of another chamber 102 on their path toward the sensor. In this way, the parallel arrangement effectively prevents such fully formed sweat droplets 112 from colliding with partially formed sweat droplets 112 growing from the outlet 114 of a downstream chamber 102. Furthermore, the parallel arrangement avoids fully formed migrating sweat droplets 112 being obstructed, for example, trapped, by the outlet 114 of a downstream chamber 102.

[0215] Figure 12The device 100 is schematically depicted, wherein corresponding sweat droplets 112 from a plurality of chambers 102 are delivered via an arrangement of paths defining branching structures. The plurality of chambers 102 are arranged into groups 154. A subset of the plurality of chambers belongs to each group. The groups 154 may be spatially separated from each other such that each group 154 ​​is supplied with sweat from skin regions 106, which are spatially removed from the corresponding skin regions of the chambers 102 supplying the other groups 154.

[0216] like Figure 12 As shown, the first branch 156 fluidly connects each chamber 102 of the corresponding group 154 ​​to the first interconnect 158. In this respect, such a first interconnect 158 ​​can be provided for each group 154. The second branch 160 fluidly connects the first interconnect 158 ​​to the corresponding second interconnect 162. Figure 12 As shown, such a second interconnection can be provided for every two or more groups. The second interconnection can be fluidly connected to the sensor. Figure 12 (Not shown in the image).

[0217] Optionally, the third branch 164 fluidly connects two or more of the second interconnects to the corresponding third interconnects, which in Figure 12 The asterisk (*) indicates the location of the sweat droplets 112. The sensor can receive sweat droplets 112 from each of the multiple chambers 102 via this third interconnect.

[0218] For example, the above-mentioned interfacial tension method can be used along... Figure 12 The corresponding branch of the illustrated device 100 delivers sweat droplets 112. This allows the sweat droplets 112 to be delivered to the sensor from the corresponding chamber 102 at a relatively high speed. The migration speed of the sweat droplets 112, which is at least as fast as the formation of the sweat droplets 112 and preferably significantly faster in this example than the formation of the sweat droplets 112, can result in the necessary series of discrete sweat droplets 112 being delivered to the sensor, as previously described.

[0219] Since no chamber 102 in this branched structure is located downstream of any other chamber 102, the risk of migrating sweat droplets 112 colliding with sweat droplets 112 formed from the portion protruding from the corresponding outlet 114 is effectively eliminated. The coalescence of fully formed and partially formed sweat droplets 112 can be difficult because it is hard to determine the corresponding contributions of fully formed and partially formed sweat droplets 112 to the volume of the coalesced sweat droplets 112. Therefore, by eliminating this risk of collision, the branched structure can help reduce the ambiguity associated with sweat sampling when determining the sweat rate per gland.

[0220] This branching structure also prevents fully formed, migrating sweat droplets 112 from being obstructed, for example, trapped, by the outlet 114 of the downstream chamber 102. Furthermore, the branching structure allows for the delivery of a relatively large number of sweat droplets 112 using a relatively compact device 100.

[0221] The branched structure means that the number of sensors (e.g., sweat rate sensors) can be kept to a minimum, as sweat droplets 112 originating from multiple chambers 102 are directed to the same destination. This can represent a key advantage over known solutions that employ sensors for each sweat collection chamber.

[0222] Fully formed migrating sweat droplets 112 originating from different chambers 102 can collide with each other before reaching the sensor. For example, for a device 100 having one hundred chambers 102 and an average of 0.1 sweat glands 108 per chamber 102, an average of nine chambers 102 will produce sweat droplets 112 originating from a single sweat gland 108, and an average of about zero to one chamber 102 will produce sweat droplets 112 originating from two sweat glands 108.

[0223] As briefly mentioned above, due to the increased size / volume of the coalesced sweat droplets passing through the sensor, collisions of fully developed sweat droplets 112 originating from a single gland 108 can be detected relatively directly. This is especially true considering that most of the sweat droplets 112 delivered to the sensor will not have already combined with other sweat droplets, thus providing a baseline. The sensor to which the device 100 delivers the sweat droplets 112 can be configured to count the sweat droplets 112 and determine the time taken for each sweat droplet 112 to pass through the sensor. This time is linearly related to the volume of the sweat droplet 112 by a priori known migration velocity, as will be referenced below. Figure 15 A more detailed explanation follows. The issue of sweat droplets 112 originating from the two sweat glands 108 will be discussed further below.

[0224] Preferably, each sweat droplet 112 travels the same distance from the outlet 114 of the chamber 102 that forms it to the end of the fluid delivery assembly. Figure 12 The design shown can effectively deliver one hundred sweat droplets 112. Smaller and larger branching structures are also anticipated. The branching structure can also be optimized according to the specific application of the device 100 and, in particular, according to the density of active sweat glands 108 on the skin 106.

[0225] The aforementioned electrowetting tiles 124 and domains used to provide a stepped chemical gradient are, for example, particularly suitable for forming branched structures. Branched structures are also compatible with the use of pressure gradients. In this case, it is possible to... Figure 12Pressure is applied upstream of chamber 102 as depicted. However, the applied pressure can be limited to avoid hindering sweat excretion.

[0226] In some examples, the sensor can count discrete sweat droplets 112 supplied to it via the fluid delivery assembly of device 100. This makes it possible to determine the sweat rate, as will be described further below.

[0227] For this purpose, any suitable sensing principle can be employed. An advantage associated with the ability of device 100 to generate a series of discrete sweat droplets 112 is that relatively simple sensors can be used to detect each droplet 112, thereby enabling the estimation of the sweat rate.

[0228] For example, the capacitive sensing principle can be particularly useful for counting sweat droplets 112. Because the dielectric change between air and sweat droplets 112 (approximately 99% water) is relatively large (approximately 80 times), this sensing principle also allows for estimating the time it takes for sweat droplets 112 to pass through the detector (i.e., between the plates of a capacitor). The time taken for sweat droplets 112 to pass through the sensor can indicate the volume of the sweat droplets 112, as shown by... Figure 15 Further discussion is needed.

[0229] Figure 13 A sensor 166 is shown that counts sweat droplets 112 supplied to it via device 100. (As shown) Figure 13 As shown, sensor 166 includes a unit 168 through which sweat droplets 112 pass. Unit 168 may, for example, employ the sweat droplet 112 delivery principle described above with respect to the fluid delivery assembly of device 100. In this respect, Figure 13 In the example shown, unit 168 includes an electrowetting tile 124 (coated with a hydrophobic coating (not shown)) to deliver sweat droplets 112 through unit 168. In a non-limiting example, unit 168 may be integrated with the fluid delivery assembly of device 100. Alternatively, unit 168 may be a portion of a port that can be connected to an end of the fluid delivery assembly defining device 100.

[0230] Figure 13 The exemplary sensor shown includes a pair of electrodes 170. One or both of the electrodes 170 may come into direct contact with sweat droplets 112 passing through unit 168. Alternatively, direct contact between one or both of the electrodes 170 and the passing sweat droplets 112 may be prevented, for example, by a suitable coating, layer, etc. Figure 13 The electrodes 170 shown are opposite each other, but alternative relative positioning of the electrodes 170 can be expected, as referenced. Figure 14 As described.

[0231] When air occupies the gap between electrodes 170 (i.e., there are no sweat droplets 112 between electrodes 170), the relative permittivity between electrodes 170 is approximately 1. When sweat droplets 112 pass between electrodes 170, the relative permittivity increases to approximately 80, since sweat droplets 112 are approximately 99% water. This large difference means that sweat droplets 112 can be easily detected, and therefore, this sensor 166 can be used to directly count sweat droplets 112.

[0232] because Figure 13 The capacitance of the capacitor shown is relatively small due to the geometry of electrodes 170 and unit 168, allowing it to be connected to a preamplifier circuit that uses an electrical AC signal 172 and feeds a response signal to the rest of the electronics to record the passage of sweat droplets 112 and measure the time it takes for the sweat droplets 112 to pass between electrodes 170. Through the use of operational amplifier 174 and resistor 176, the small current can be converted into a measurable voltage, which is then read by subsequent readout electronics (such as...). Figure 13 As shown, the leakage current of the capacitor is minimized by using voltmeter 178. To further reduce noise, the sensor can be shielded and a preamplifier added, for example. Many alternative sensor circuit designs will be apparent to those skilled in the art.

[0233] As an alternative to or supplement to the aforementioned capacitive sensor, sensor 166 may include a conductivity sensor for counting sweat droplets 112. In this regard, if it is also desired to measure the ion concentration in the sweat droplets 112, sensor 166 including a conductivity unit may be particularly suitable. Thus, the conductivity unit can count the sweat droplets 112, measure the time taken for each sweat droplet 112 to pass through the unit, and enable the measurement of ion concentration.

[0234] A conductivity sensor may include two electrodes 170, to which a sweat droplet 112 may directly contact. Conductivity can be measured while the sweat droplet 112 is passing between the electrodes 170. Various sensor arrangements for implementing such a conductivity sensor are contemplated, as will be referenced. Figure 14 A more detailed explanation.

[0235] Any suitable electrical scheme can be used to measure conductivity. Typically, an AC signal is used to probe conductivity. A voltage can be applied at a frequency of, for example, approximately 100 to 10000 Hz. This helps prevent electrolytic effects that might otherwise interfere with the measurement. Such an electrical scheme may also include electronics for recording the passage of sweat droplets 112 through sensor 166 and measuring the time spent therethrough. Many alternative electrical schemes will be apparent to those skilled in the art.

[0236] The variation in conductivity of sweat droplets 112 can originate from variations in the concentration of dissolved salts (particularly sodium chloride). Sodium chloride is the primary compound determining the variation in conductivity in sweat. The concentration of sodium chloride in sweat varies between 0.06 g / 100 mL and 0.76 g / 100 mL, a variation of approximately 12-fold. This means that such variations in sodium chloride concentration are directly measurable.

[0237] As briefly mentioned above, sensor 166 allows for the measurement of ion concentration in sweat droplets 112. For this measurement to be clinically interpretable, a reliable estimate of the sweat rate per gland is required. Therefore, it may be necessary to determine the number of sweat glands 108 supplying sweat to the respective chambers 102. Measuring the ion concentration allows for the determination of this number of sweat glands 108, as will be further described below.

[0238] Figure 14 Several examples of sensor 166 are schematically depicted. Figure 14 Example AC illustrates how sensor 166 and, in particular, electrode 170 can be arranged relative to the fluid delivery assembly of device 100.

[0239] Figure 14 Example A illustrates a fluid delivery assembly in which a chemical gradient 180 delivers sweat droplets 112 to and through electrodes 170 of sensor 166. In this example, sweat droplets 112, for example having an approximately hemispherical shape, are delivered via the chemical gradient and detected by sensor 166 as they pass between a pair of electrodes 170. The sweat droplets 112 may come into contact with the electrodes 170, or may be prevented from making contact due to, for example, an insulating coating applied to the electrodes 170, as previously described.

[0240] Figure 14 Example B is the same as Example A, except that the chemical gradient 180 is replaced by an electrowetting tile 124. In this example, sweat droplets 112 are delivered to and through sensor 166 by an electrowetting wave employed by the fluid delivery assembly to achieve the migration of sweat droplets 112 from the chamber(s) 102 from which they originate.

[0241] Figure 14 Example C is the same as Example B, except that the electrowetting tile 182 is used to transport sweat droplets 112 through the sensor 166 and detect sweat droplets 112 together with the electrode 170. In this case, the dual-function electrode 182 is coated with an insulating coating, such as a hydrophobic coating, to enable its sweat droplet 112 transport function.

[0242] Figure 14Example D illustrates a sensor 166 with a unit 168 in the form of a rectangular channel. An electrowetting tile 124 is mounted in the unit 168, and the electrodes 170 of the sensor 166 are arranged perpendicular to the electrowetting tile 124. In this example, the channel size can be selected such that sweat droplets 112 contact the wall of the unit 168, thereby forming menisci at the head and tail of the sweat droplets 112 on the cross-section of the unit 168 (e.g., a square, rectangular, triangular, circular, etc.). In this example, direct contact between the electrodes 170 and the sweat droplets 112 can be prevented, for example, by a suitable insulating coating or otherwise. The resulting “bundled” sweat droplets 112 through the unit 168 can help estimate the volume of the sweat droplets 112, as referenced... Figure 15 A more detailed description.

[0243] Figure 14 Example E is the same as Example D, except that the electrodes 170 of the sweat sensor 166 are mounted adjacent to each other; the electrodes 170 are all opposite the electrowetting tile 124.

[0244] Figure 14 Example F is the same as Example E, except that a gradient (e.g., chemical gradient 180 and / or pressure gradient) is provided in a channel within unit 168. If a pressure gradient is provided along the length of the channel, a chemical gradient or electrowetting tile is not required to transport sweat droplets 112 through unit 168.

[0245] When capacitive sensing is employed, all examples of AF can be expected to have or not have a barrier to prevent direct contact between sweat droplets 112 and electrode 170 (but in example C, one of the electrodes 182 is isolated, as previously described).

[0246] When conductivity sensing is employed, examples A, B, D, E, and F can be expected, and in this case, no insulating material is applied to electrode 170 (e.g., coated) on electrode 170.

[0247] Many alternative sensor arrangements are conceivable. For example, the sensor 166 can be provided by dividing the electrowetting tile 124 into two separate components. One component can take the form, for example, an outer edge coated with an insulating material and a central portion not connected to the outer edge. This concentric electrode structure can alternatively include corresponding uncoated electrodes for conductivity measurement.

[0248] Sweat droplets 112 delivered from device 100 to sensor 166 may have different sizes / volumes. This may be due to size variations of the sweat droplets 112 formed at outlets 114 of chamber(s)(s)102. Such size / volume variations may also be due to merging or coalescence of sweat droplets 112 during delivery to the sensor.

[0249] The volume of the sweat droplets 112 can be determined by measuring the time it takes for the sweat droplets 112 to pass through the sensor 166. The sweat rate can then be determined based on the number of sweat droplets 112 sensed (i.e. counted) by the sensor during a given time period and the volume of the sweat droplets 112.

[0250] Sweat droplets 112 can be conveyed through sensor 166 in substantially the same form or shape (e.g., hemispherical) as they take in the fluid delivery assembly upstream of sensor 166. Alternatively, sweat droplets 112 can be fed into channel 168, such as cylindrical, cubic, or prismatic channel 168, to reshape sweat droplets 112 as described above. Figure 13 Briefly described. Therefore, the hemispherical sweat droplet 112 can be formed, for example, cylindrical or bundle-shaped, depending on the shape of the cross-section of the channel 168. The sensor 166 can be arranged to sense the reshaped sweat droplet 112 as it passes through the channel 168.

[0251] In the case of the interfacial tension method, the gradient or electrowetting tile 124 can extend to more than one wall of the channel 168, and in the case of a cylindrical channel 168, can cover most of the circumference. This can help avoid obstruction of transport through the channel 168 by the relatively small surface area of ​​the gradient or electrowetting tile 124 relative to the surface area of ​​the channel not covered by the gradient or electrowetting tile 124.

[0252] The time it takes for a sweat droplet 112 to pass through the sensor 166 varies with the volume of the sweat droplet 112, depending on the shape of the cross-section of the channel 168 formed by the sweat droplet 112 as it passes through the sensor 166. This is in Figure 15 The diagram is shown below. Figure 15 Curves showing the time taken for sweat droplets 112 to pass through sensor 166 as a function of the volume of sweat droplets 112 are provided for bundle-shaped sweat samples (dashed line 184) and hemispherical sweat samples (solid line 186).

[0253] exist Figure 15 In a non-limiting example, the migrating sweat droplet 112 has a velocity of 700 μm / s, and the sensor 166 has a length of 60 μm in the downstream direction. The time taken for the sweat droplet 112 to pass through the sensor 166 is defined as the time from when the sweat droplet 112 begins to overlap with the sensor 166 (e.g., electrode 170 of the sensor 166) until the overlap ends.

[0254] For a hemispherical sweat droplet 112, the time it takes for the sweat droplet 112 to pass through the sensor 166 is approximately equal to: (the diameter of the sweat droplet 112 plus the length of the sensor) / (the migration speed of the sweat droplet 112).

[0255] For a bundle of sweat droplets 112 that has already formed a rectangular prism channel 168, the time it takes for the sweat droplets 112 to pass through the sensor 166 is approximately equal to: (the length of the sweat droplets 112 plus the length of the sensor) / (the migration speed of the sweat droplets 112).

[0256] like Figure 15 As shown, the time taken for a hemispherical sweat droplet 112 to pass through the sensor 166 is less sensitive to the volume of the sweat droplet 112 than it is for cylindrical or bundled sweat droplets 112. For example, a hemispherical sweat droplet 112 may take approximately 1.14 times longer than a similarly shaped sweat droplet 112 by half its volume to pass through the sensor 166. However, a cylindrical or bundled sweat droplet 112 will take approximately twice as long as a similarly shaped sweat droplet 112 by half its volume to pass through the sensor 166.

[0257] Therefore, the sensor 166 including channel 168 can improve the ability of sensor 166 to determine the volume change of sweat droplet 112, and channel 168 is sized such that sweat droplet 112 forms a meniscus across the cross section of unit 168 at the head and tail of sweat droplet 112.

[0258] For reference, in the case of hemispherical sweat droplets... Figure 15 The volume range spanned by the curve corresponds to a sweat droplet diameter of 70 to 140 μm, and in the case of bundled droplets, it corresponds to a sweat droplet length of 40 to 340 μm.

[0259] When the bundled sweat droplets 112 pass through the sensor 166 and a gradient (e.g., a chemical gradient) is used to transport the sweat droplets 112, the migration speed will increase with the increase of the length of the sweat droplets 112. This increased migration speed can offset the improved sensitivity of the sweat droplet 112 volume to the time it takes for the sweat droplets 112 to pass through the sensor 166, as described above.

[0260] When the electrowetting tile 124 is used to transport bundled sweat droplets 112 through the sensor 166, sweat droplets 112 with a length shorter than, for example, about 70 μm can be prevented from passing through the sensor 166 because the sweat droplets 112 are too short to overlap with the paired adjacent electrowetting tiles 124. On the other hand, since the force generated by a single charged electrowetting tile 124 may be insufficient to move such large sweat droplets 112, it may hinder the transport of sweat droplets 112 that are, for example, about 140-200 μm long.

[0261] Figure 16 A sensor 166 is shown, comprising a channel 168 as described above for shaping sweat droplets 112. A plurality of electrowetting paths 188 are provided in the channel 168, the electrowetting paths 188 being spatially separated from each other in a direction perpendicular to the direction of flow through the sensor 166, such that sweat droplets 112 are conveyed through the sensor 166 by one or more of the electrowetting paths 188 according to their volume. Each electrowetting path 188 includes a plurality of electrowetting tiles 124 for conveying sweat droplets 112 from the fluid delivery assembly to and through the sensor 166.

[0262] The corresponding electrowetting waves provided to the electrowetting path 188 can be substantially simultaneous with each other, so that sweat droplets 112 spanning more than one electrowetting path 188 are transported synchronously by these electrowetting paths 188.

[0263] When relatively large sweat droplets 112 are delivered to sensor 166 via the fluid delivery assembly, the sweat droplets 112 may initially enter channel 168. Upon initial entry into channel 168, the shape of the sweat droplets 112 can change from hemispherical to bundle-like, depending on the shape of the cross-section of the inlet portion of channel 168, as previously described. Figure 16 In the non-limiting example shown, the height of the passage of the fluid delivery component upstream of channel 168 can be, for example, about 150 μm, and the channel 168 of sensor 166 can have, for example, a height of about 30 μm.

[0264] Then, depending on the volume of the sweat droplets 112, the sweat droplets 112 can be distributed on multiple electrowetting paths 188. Figure 16 In the non-limiting example shown, four electrowetting paths 188 are provided in channel 168. Relatively small sweat droplets 112 may be primarily retained on the electrowetting tile 124 of one of the four electrowetting paths 188. Larger sweat droplets 112 may be distributed on the corresponding electrowetting tiles 124 of two, three, or all four electrowetting paths 188.

[0265] Essentially simultaneous electrowetting waves can subsequently deliver one or more sweat droplets 112 through sensor 166. Figure 16 In the specific example shown, the sweat droplets 112 first encounter four electrowetting tiles 124 after entering the channel 168 simultaneously. Figure 16Each of the four electrowetting tiles 124 on the left (with an increasing width in the transport direction) is charged to generate this electrowetting wave. Subsequently, these four electrowetting tiles 124 will discharge, for example, after 0.1 seconds, and immediately charge simultaneously, for example, the four center electrowetting tiles 124 adjacent to the initially charged and discharged electrowetting tiles 124, for another 0.1 seconds. After the four center electrowetting tiles 124 have discharged, the next set of electrowetting tiles 124 will immediately charge simultaneously, and so on.

[0266] In this way, the electrowetting waves simultaneously applied to each electrowetting path 188 can cause one or more sweat droplets 112 to be transported through the sensor 166, i.e., in Figure 16 From left to right in the middle.

[0267] Sensor 166 may include sensor module 190 for each electrowetting path 188 to sense one or more sweat droplets 112 being transported and the time spent therein. Therefore, sensor 166 can accommodate the migration of relatively small and relatively large sweat droplets 112. Because a corresponding sensor module 190 is provided for each electrowetting path 188, sweat droplets 112 transported to sensor 166 via device 100 can be better distinguished by their size / volume, while enabling electrowetting to be used to transport sweat droplets 112 through channel 168.

[0268] For example, multiple sensor modules 190 connected in parallel can be considered to provide a linear difference from the diameter of the sweat droplets 112. For example, if the sweat droplets 112 are separated on two sensor modules 190, then sweat droplets 112 with twice the diameter will be separated on four sensor modules 190 and will therefore be detected by twice the number of sensor modules 190.

[0269] exist Figure 16 In the non-limiting example shown, each sensing module 190 includes a pair of electrodes 170 that allow for capacitance- and / or conductivity-based sensing of sweat droplets 112, as previously described. Alternatively or additionally, alternative sensing principles, such as optical and / or biomarker detection techniques, may be considered for the sensing module 190.

[0270] The electrowetting device 144 can be designed to facilitate the migration of relatively small sweat droplets 112 between pairs of electrowetting tiles 124 used in the fluid delivery assembly and / or sensor 166. For example, adjacent electrowetting tiles 124 can be formed to interlock with each other, for example via a pair of electrowetting tiles 124 with corresponding adjacent surfaces having complementary zigzag profiles. For example, such an interlocking pair of electrowetting tiles 124 can each have increased overlap with the sweat droplets 112 relative to a pair of electrowetting tiles 124 with corresponding adjacent flat profiles. Thus, the interlocking electrowetting tiles 124 can help deliver relatively small sweat droplets 112 to and / or through the sensor 166.

[0271] In the case of relatively large sweat droplets 112, the electrowetting tile 124 can widen in a direction perpendicular to the conveying direction, thereby increasing the contact force between the relatively large sweat droplets 112 and the electrowetting tile 124. When on an uncharged electrowetting tile 124, relatively small sweat droplets 112 can still take the form of, for example, hemispherical sweat droplets 112, and can still overlap with adjacent electrowetting tiles 124, especially when interlocked electrowetting tiles 124 are used, as previously described.

[0272] Furthermore, several smaller sweat droplets 112 can be "pinched" from a single relatively large sweat droplet 112. This can be done, for example, via the reference above. Figure 12 The branching structure described herein is used to achieve this. In such an example, a stepwise approach can be used to break down relatively large sweat droplets 112 into smaller sweat droplets 112 before they reach the interconnect. The branching structure, which fluidly connects chamber 102 in parallel to sensor 166, can help reduce or eliminate the possibility that such smaller sweat droplets 112 may be interfered with by other sweat droplets 112 being transported via the branching structure.

[0273] In some examples, sensor 166 may include an optical sensor for sensing sweat droplets 112. Such an optical sensor may be an alternative to the previously described capacitance and conductivity sensors, or may be included in addition to the previously described capacitance and conductivity sensors.

[0274] The optical sensor can sense the sweat droplets 112 in any suitable manner. For example, the optical sensor may include a light source for delivering a light beam along the path taken by the sweat droplets 112 and a corresponding optical detector for sensing the light beam. The light beam can be deflected as the meniscus of the sweat droplets 112 passes through it. The sweat droplets 112 can be detected by the accompanying changes in transmitted light sensed by the optical detector.

[0275] Alternatively or additionally, an optical sensor can be configured to detect the absorption of light by components in sweat. Sweat can have a specific spectral fingerprint derived from the spectral properties of each component of the sweat. Therefore, the optical sensor can, for example, refer to such a spectral fingerprint to sense sweat droplets 112.

[0276] In other examples, sensor 166 may include a biomarker sensor. The biomarker sensor enables the detection of the biomarker concentration in each sweat droplet 112 and allows for the counting of sweat droplets 112. The biomarker sensor also enables the determination of the time it takes for sweat droplets 112 to pass through the biomarker sensor, thereby deriving a measure of the volume of the sweat droplets 112. Therefore, the biomarker sensor can advantageously implement several functions, which can simplify a system including device 100 and the biomarker sensor, particularly because the system does not need to include additional sensor types.

[0277] The biomarker sensor can sense specific biomarkers, i.e., chemical biomarkers, and has a sufficiently fast response to determine the biomarker concentration in sweat droplets 112 that have passed through the biomarker sensor. In this respect, the response time of the biomarker detector can be shorter than the time it takes for sweat droplets 112 to pass through the biomarker sensor.

[0278] Specific components in sweat have concentrations that depend on the sweat rate. Detecting such components using biomarker sensors allows for the precise determination of the sweat rate per gland.

[0279] If the response time of a biomarker sensor is limited by the diffusion of the relevant biomarker from most of the sweat droplets 112 to the sensor's surface, the size of the channel 168 in which the biomarker sensor is located can be chosen to be as small as possible, thereby minimizing the distance the biomarker needs to travel to diffuse. According to Einstein's diffusion equation, the diffusion distance is proportional to the square root of time. Therefore, for example, when the height of the channel 168 is reduced by a factor of two, the time required for diffusion can be reduced by a factor of four, allowing the biomarker sensor to respond much faster (when the diffusion of the relevant biomarker to the biomarker sensor is a rate-limiting step).

[0280] Figure 17 The illustrated device 100 has a fluid delivery assembly including an electrowetting tile 124. Via Figure 17 The size / volume of the sweat droplets 112 delivered by the device 100 shown can depend on the time interval between electrowetting waves.

[0281] As briefly noted above, sweat gland 108 operates in a cyclical manner. Sweat gland 108 typically secretes sweat for approximately 30 seconds during a burst phase, followed by a rest period of approximately 150 seconds. Sweat bursts can vary between 20 and 40 seconds, or even between 10 and 50 seconds (Chen et al., “In vivo single human sweat gland activity monitoring using coherent anti-Stokes Raman scattering and two-photon excited autofluorescence microscopy”, British Journal of Dermatology (2016), 174, pp. 803-812).

[0282] During the sweat burst phase, at a sweat rate of 1.2 nl / min / gland, approximately 0.24 nl of sweat droplets 112 can be formed every 12 seconds. Assuming the sweat droplets 112 have a hemispherical shape, the height of the sweat droplets 112 will be approximately 50 μm, and the diameter will be approximately 100 μm. When applied to collecting sweat from sedentary individuals, the upper limit of the average sweat rate can be expected to be approximately 5 nl / min / gland. In this case, the volume of the hemispherical sweat droplets 112 will be approximately 6 nl, and their diameter will be 285 μm.

[0283] A sweat sensing system, including device 100 and sensor 166, can be configured to provide an alarm, such as an audio and / or visual alarm, when the sweat rate exceeds a threshold indicating proximity to that upper limit. Such a high sweat rate may itself require clinical intervention. As previously mentioned, the sweat burst and rest periods can be approximately 30 seconds and approximately 150 seconds, respectively. If the rest period at the same average sweat rate is reduced, the sweat rate during the sweat burst will decrease.

[0284] When the fluid delivery assembly uses the electrowetting device 144 to deliver sweat droplets 112, several factors can be considered. For the sweat droplets 112 to be delivered, the formed sweat droplets 112 should cover one electrowetting tile 124 and partially cover subsequent electrowetting tiles 124 in the series. Typically, for hemispherical droplets with a diameter of 100 μm, electrowetting tiles 124 with a length of 60 μm (in the delivery direction) can be used, for example, with a 10 μm spacing (in the delivery direction) between adjacent electrowetting tiles 124.

[0285] The aforementioned electrowetting tile 124 is sized to accommodate sweat droplets 112 with a diameter of 100 μm, but not to accommodate larger sweat droplets 112 that will cover more of the electrowetting tile 124. In such cases, the area of ​​the electrowetting tile 124 that exhibits transient hydrophilicity when charged may be too small for the sweat droplets 112 to migrate to subsequent electrowetting tiles 124 in the series.

[0286] However, for example in Figure 17 In the case of the device 100 shown, the problem associated with relatively large sweat droplets 112 can be solved by adjusting the time interval of the separate continuous electrowetting waves.

[0287] For example, instead of a 12-second interval between consecutive electrowetting waves, an electrowetting wave can be initiated every second. In this case, at a sweat rate of 0.2 nl / min / gland, the diameter of the hemispherical sweat droplet 112 formed in one second could be approximately 42 μm, which may be too small to overlap with two adjacent electrowetting tiles 124 portions, and therefore, migration of the sweat droplet 112 will not begin. However, after six subsequent electrowetting waves, the sweat droplet 112 will have grown to a diameter of 77 μm, allowing it to overlap with two adjacent electrowetting tiles 124 portions, and the release of the sweat droplet 112 from the outlet 114 and the migration of the sweat droplet 112 can occur.

[0288] At a sweat rate of 5 nl / min / gland, after one second, the diameter of the hemispherical sweat droplet 112 will be 124 μm, and the sweat droplet 112 can almost overlap with two adjacent electrowetting tiles 124 (the two electrowetting tiles 124 and the gap between them can correspond to a length of 130 μm). Therefore, the diameter of the sweat droplet 112 is sufficient for the sweat droplet 112 to migrate. Therefore, when the electrowetting wave is activated every second, a dynamic range from 0.2 nl / min / gland to 5 nl / min / gland can be accommodated. The number of sweat droplets 112 counted by the sensor 166 and the time it takes for each sweat droplet to pass through the sensor 166 can then be used to calculate the sweat rate during the sweat burst period of the sweat gland 108.

[0289] exist Figure 17 In the case of the illustrated device 100, where the electrowetting tile 124 is provided on the upper surface of the plate 110, different sweat rates may cause sweat droplets 112 of different sizes to be delivered to the sensor 166. However, this may not pose a problem because the sensor 166 can both count the number of sweat droplets 112 delivered thereto and determine the time taken for each sweat droplet 112 to pass through it. The latter is proportional to the volume of the sweat droplet 112. Therefore, the sweat rate can be precisely assessed according to the sweat gland 108.

[0290] More generally, when the electrowetting device 144 is used to deliver sweat droplets 112 to and through the sensor 166, the velocity of the electrowetting wave can be determined by the charging / discharging frequency of the corresponding electrowetting tiles 124 in the series by the electric field generator. The switching frequency can be, for example, about 10 Hz. In the case where the length of the previously described electrowetting tile 124 is 60 μm and the gap between adjacent electrowetting tiles 124 is 10 μm, the sweat droplet 112 can move 70 μm in 0.1 seconds in each “step.” Therefore, in this case, the delivery speed of the sweat droplet 112 can be 700 μm per second.

[0291] Figure 18 The diagram shows graphs depicting two sweat bursts 192A, 192B and two rest periods 194A, 194B (upper pane), an enlarged view of the first sweat burst 192A and the first rest period 194A (middle pane), and graphs showing the sensor signal changing over time (lower pane).

[0292] In the upper pane, the sweat rate is shown as a function of time. This example shows two 30-second bursts 192A and 192B, and two 150-second rest periods 194A and 194B. The middle pane shows a magnified view of the first sweat burst 192A of sweat gland 108, where the sweat rate during the burst period is 1.2 nl / min / gland. In the lower pane, the sweat rate sensor signal over time is depicted for the first sweat burst 192A.

[0293] The delay 196 between the start of the first sweat burst 192A and the first sweat droplet 112 recorded by sensor 166 is significant. The delay 196 can be attributed to the time required for the first sweat droplet 112 of the burst to form (i.e., to protrude from outlet 114) and the time required for the fluid delivery assembly to deliver the sweat droplet 112 to sensor 166.

[0294] exist Figure 18 In the example shown, the time taken for the first sweat droplet 112 to form the first sweat burst 192A is 6 seconds. In other words, it takes 6 seconds for the sweat droplet 112 to grow to a sufficiently large diameter to overlap with the electrowetting tile 124 defining the outlet 114 of the chamber 102, so that the electrowetting wave separates the sweat droplet 112 from the outlet 114, as previously described. In this respect, Figure 18 It describes a situation where the sweat rate is relatively low.

[0295] Furthermore, in this non-limiting example, the distance between chamber 102 and sensor 166 is 5 mm. At a migration speed of 700 μm per second, it takes approximately 7 seconds to transport the fully formed sweat droplet 112 to sensor 166.

[0296] Figure 18 The diagram shows the corresponding sweat droplets 112 sensed by sensor 166 every 6 seconds during the first sweat burst 192A. Thus, for the first sweat burst 192A, sensor 166 records five sweat droplets 112, which has a duration of 30 seconds.

[0297] The sweat droplet 112 can have a hemispherical shape with a diameter of 77 μm, and the sensor 166 has a length of 60 μm in the transport direction. When the transport speed of the sweat droplet 112 is 700 μm per second, the time taken for the sweat droplet 112 to pass through the sensor 166 is 0.196 seconds.

[0298] In corresponding Figure 17 and 18 In the example, the sweat rate at the beginning and end of sweat bursts 192A and 192B is faster than the (1 second) period of the electrowetting wave. However, during the rise and fall of the sweat bursts 192A and 192B, the sweat droplets 112 can vary in size, so that the time taken for the sweat droplets 112 to pass through the sensor 166 can vary accordingly.

[0299] In this regard, it should be noted that the velocity of 700 μm per second represents the average velocity of the sweat droplets 112 when they are transported via electrowetting waves. However, every 0.1 seconds, subsequent electrowetting tiles 124 in the series are charged by an electric field generator, and therefore the sweat droplets 112 can be considered to move in steps. As the sweat droplets 112 are thus transported through the sensor 166, two characteristics can be measured for each step: the time of ramp-up output by the sensor 166 and the time of constant output by the sensor 166. Based on these measurements, the average time for the sweat droplets 112 to pass through the sensor can be derived.

[0300] In an alternative, non-limiting example, the electrowetting tile 124 is alternatively arranged on the lower surface of another plate 128 positioned opposite the outlet 114. In such an example, the size / volume of the sweat droplets 112 can depend on the distance 130 between the outlet 114 and the other plate 128, and therefore the size / volume of the sweat droplets 112 can be independent of the time interval between electrowetting waves, as previously described. In this case, the number of sweat droplets 112 counted within a specific time interval is sufficient to definitively assess the sweat rate, since the volume of the sweat droplets 112 is known a priori.

[0301] After the sweat droplet 112 protrudes from the outlet 114 to the point where it contacts the lower surface of the other plate 128, an electrowetting wave can propel the sweat droplet 112 toward the sensor 166 along a series of electrowetting tiles 124. The distance 130 between the outlet 114 and the other plate 128 alone also determines the size / volume of the hemispherical sweat droplet 112, allowing the frequency at which the electrowetting wave can be applied (e.g., 0.1 waves per second) to be faster than the frequency at which the sweat droplet 112 forms. This ensures that consecutive sweat droplets 112 remain separated from each other. This example may be suitable, for instance, when the sweat rate is relatively high, such as when the system is used to monitor sweat bursts in athletes participating in intensive exercise. During the ascent and descent of sweat bursts 192A, 192B, the formation of sweat droplets 112 takes longer than, for example... Figure 17 In the example shown, more time is taken. Therefore, the time it takes for sweat droplets 112 formed during such upslope and downslope periods to reach sensor 166 will be longer than in the case where sweat droplets 112 are formed at the maximum value of sweat bursts 192A, 192B.

[0302] For example, the dynamic sweat rate measurement range can be improved by dynamically changing the frequency of the electrowetting wave based on the determined sweat rate. In other words, the wave generator can be configured to adjust the frequency of the electrowetting wave based on sweat rate feedback provided by sensor 166.

[0303] In the example where a gradient (e.g., chemical and / or topological gradient) is used to release sweat droplets 112 from outlet 114, the sweat droplets 112 may all have similar size / volume, as previously referenced. Figure 5 Described.

[0304] The ability to determine the rate of sweat per gland without relying on data from volunteer testing represents a key objective, as such data ignores potentially significant inter-individual variability. To this end, a system for determining the rate of sweat per gland is provided. The system includes a sensor 166 for sensing sweat droplets 112 and a means 100 for receiving sweat from one or more sweat glands 108 and delivering the sweat as discrete sweat droplets 112 to the sensor 166. The means 100 may be, for example, a means 100 of the type described above. The sensor 166 may be, for example, a sensor of the type previously described (capacitive, conductive, impedance, electrochemical, optical, and / or biomarker sensors).

[0305] The system includes a processor configured to count the number of sweat droplets 112 sensed by sensor 166 over a time period and to determine the time interval between successively sensed sweat droplets 112 during that time period. The processor also receives a measurement of the volume of each of the counted sweat droplets 112.

[0306] The processor is also configured to use time intervals and a measure of the volume of each of the counted sweat droplets 112 to identify active (i.e., sweat burst) periods (during which one or more sweat glands 108 are excreting sweat) and resting periods (during which one or more sweat glands 108 are not excreting sweat) of one or more sweat glands 108. The process of identifying sweat bursts 192A, 192B and resting periods 194A, 194B of one or more sweat glands 108 also involves assigning active periods 192A, 192B and resting periods 194A, 194B to one or more sweat glands 108.

[0307] The processor then determines the number of sweat glands 108 assigned to the active and rest periods, and subsequently determines the sweat rate of each sweat gland based on the number of sweat gland droplets 112, a measure of the volume of each of the counted sweat gland droplets 112, and the determined number of sweat glands 108.

[0308] Therefore, the system determines the sweat rate per gland by distributing sweat droplets 112 to specific sweat glands 108 based on the intermittent sweat excretion behavior of the sweat glands 108. The system is also physically simpler than conventional sweat sensing systems because the device 100 can deliver sweat droplets 112 from several chambers 102 to a common sensor 166, as previously described (see example...). Figure 12 ).

[0309] This system also consumes less energy than, for example, sweat sensing systems that monitor continuous sweat flow. This is because such conventional systems can employ relatively energy-intensive thermal sweat rate sensors that include a pair of temperature probes and a heater. In contrast, the sensor 166 of this system can simply include a pair of electrodes for sensing the passage of each sweat droplet 112 between them.

[0310] Furthermore, measuring sweat rate via discretized sweat flow allows for more accurate measurement of sweat velocity, especially at relatively low sweat rates. In contrast, flow rate sensors in conventional systems where sweat is transported as a continuous flow can be relatively more difficult to accurately determine sweat velocity, particularly at low rates. The aforementioned type of thermal sweat rate sensor may struggle to accurately measure low flow rates, for example, due to thermal diffusion. Other known techniques, such as sensing cumulative changes in dielectric properties, may also have relatively low accuracy and may require additional sensors, such as sodium sensors, to establish the per-gland sweat rate.

[0311] By fluidly connecting the respective chambers 102 in parallel to the sensor 166 via a fluid delivery assembly, the sweat droplets 112 can be supplied to the common sensor 166 in a manner that avoids collisions between fully formed and partially formed sweat droplets 112. Furthermore, impedance at the outlet 114 of the downstream chamber 102 can be avoided. The sensor 166 may, for example, include a pair of electrodes 170 for use as capacitance, impedance, and / or conductivity sensors, as previously described.

[0312] When a sweat droplet 112 passes between two electrodes 170 (i.e., through sensor 166), the electrical properties (dielectric / conductivity) between the electrodes 170 change, and the sensing electronics can record this change, thereby enabling the processor to count each sweat droplet 112 that passes through sensor 166.

[0313] Furthermore, the sensing electronics can also record the time it takes for the sweat droplet 112 to pass through the sensor 166. For example, the processor can use the time it takes for the sweat droplet 112 to pass through the sensor 166 and the known velocity at which the sweat droplet 112 is transported through it to calculate the volume of the sweat droplet 112. The migration velocity may depend to some extent on the size / volume of the sweat droplet 112, but this can be easily determined a priori. The processor can, for example, apply an appropriate correction factor via a lookup table to account for any size dependence of the sweat droplet 112 on the velocity transported through the sensor 166.

[0314] If two fully developed sweat droplets 112 collide and merge, the time taken for the coalesced sweat droplets 112 to pass through the sensor 166 can be approximately twice as long as, for example, for sweat droplets 112 that have not yet merged, depending on the shape of the sweat droplets 112 within the sensor 166, as previously discussed. Figure 15 This means that the larger volume of sweat droplets 112 can be directly and definitively attributed to the coalescence of two fully formed sweat droplets 112.

[0315] Figure 17The illustrated device 100 has a chamber 102 in the shape of a truncated cone. In a first non-limiting example (Example 1), the chamber 102 has a circular inlet 104 with a diameter of 360 μm and a circular outlet 114 with a diameter of 33 μm. In a second specific non-limiting example (Example 2), the chamber 102 has a circular inlet 104 with a diameter of 1130 μm and a circular outlet 114 with a diameter of 33 μm.

[0316] Assuming the density of active sweat glands on the skin 106 is 100 active sweat glands 108 per square centimeter, then for Example 1 and Example 2, the average number of sweat glands 108 in contact with the inlet 104 is 0.1 glands and 1 gland, respectively.

[0317] The probability of a plurality of glands 108 that coincide with the inlet 104 of the device 100 in the first and second examples can be calculated using a Poisson distribution. The results are shown in Table 1.

[0318]

[0319] Table 1

[0320] Px is the probability that X sweat glands 104 come into contact with the entrance 104 of the chamber 102.

[0321] As an illustrative example, device 100 is arranged to collect sweat from four collection areas on skin 106. For this purpose, device 100 includes twenty-five [unclear symbols] in each collection area. Figure 17 The chamber 102 is of the type shown. In this example, each inlet 104 of the chamber 102 has a diameter of 360 mm (Example 1), resulting in an area of ​​0.1 mm² for each inlet 104. 2 .

[0322] Of the twenty-five chambers 102 (each collection area), there will typically be twenty-two or twenty-three chambers 102 that do not receive sweat from any sweat gland 108. In some special cases, there will be chambers 102 that collect sweat from two or more sweat glands 102 (with a probability of approximately 1 / 200).

[0323] In each of the twenty-five chambers 102 (each collection area), approximately two to three chambers 102 will receive sweat from a sweat gland 108. The sweat droplets 112 collected from each of these two to three chambers 102 can be sensed by a sensor 166. However, the question remains regarding the number of sweat glands 108 that contribute to the formation of sweat droplets 112.

[0324] Furthermore, when the subject is in a sedentary state, the sweat rate of each gland 108 can vary from 0.2 nl / min to 1 nl / min, and when the subject engages in vigorous exercise, the sweat rate of each gland 108 can increase to 5 nl / min or even 10 nl / min. In addition, the number of active sweat glands 108 can increase according to the level of neural stimulation, which is in turn controlled by core body temperature. From an anatomical perspective, sweat glands 108 can also have different sizes, which may lead to variability in the sweat rate during the sweat burst phases 192A and 192B.

[0325] The aforementioned system addresses these issues by using the periodic behavior of sweat glands 108 to determine the number of contributing sweat glands 108. This, in turn, enables the measurement of the average sweat rate of each gland. Furthermore, the system allows for the establishment of variations in sweat rate among sweat glands 108, as will be explained below.

[0326] If the chamber 102 does not receive sweat from any sweat gland 108, no sweat droplets 112 will be correspondingly delivered to the sensor 166.

[0327] When chamber 102 receives sweat from a single sweat gland 108, the sweat gland 108 can exhibit an average sweat rate of 0.2 nl / min, with a sweat rate of approximately 1.2 nl / min during sweat bursts 192A and 192B (assuming typical bursts 192A and 192B last approximately 30 seconds, and rest phases 194A and 194B last approximately 150 seconds). After chamber 102 has been filled with sweat excreted by the corresponding sweat gland 108, for example, this may take approximately 1 to 10 minutes, then sweat droplets 112 can protrude from outlet 114, as... Figure 17 It is depicted schematically in the middle.

[0328] Sweat glands 108 that are relatively close to each other can receive nerve impulses that activate them simultaneously. However, the time taken for metabolism required for the pumping effect of sweat gland cells may vary between sweat glands 108, so partially overlapping cycles may occur.

[0329] In at least some examples (such as) Figure 12In the example shown, the distance between each of the chambers 102 and the sensor 166 can be the same. Since the sweat glands 108 excrete simultaneously into their respective chambers 102, this could cause a synchronized sweat burst to be detected. One way to address this is to change the distance between the respective chambers 102 and the sensor 166. However, it is unknown whether the sweat glands 108 excreting into each chamber 102 will perform a simultaneous sweat burst. Furthermore, since the distances between the respective chambers 102 and the sensor 166 are different, asynchronous sweat bursts of the respective sweat glands 108 may overlap simultaneously. Identification performed by the processor allows for the explicit determination of the sweat rate per gland, regardless of whether there is overlap between sensor signals corresponding to different sweat glands 108. Therefore, consider a typical cycle of 30 seconds of excretion followed by a 150-second rest period.

[0330] Figure 19 The graphs show the changes in sweat rate over time (upper pane) and sensor signal over time (lower pane) when the corresponding sweat glands 108 have sweat bursts 192A, 192B, 198A, and 198B at different times relative to each other.

[0331] exist Figure 19 In the illustrated case, one sweat gland 108 supplies the first chamber 102, and different sweat glands 108 supply the second chamber 102. By analyzing, for example, data from sensor 166, sweat droplets 112 originating from the respective sweat glands 108 can be distinguished from each other. Specifically, the possibility that time periods 200, 202, and 204 correspond to rest periods can be ruled out, as these time periods 200, 202, and 204 are significantly shorter than the typical rest period of approximately 150 seconds as previously described. Since time periods denoted as 194A and 206A have the typical duration of rest periods, these time periods can be correspondingly identified as rest periods 194A and 206A of the respective sweat glands 108.

[0332] Even if the first two sweat bursts 192A and 198A are incorrectly attributed to the first sweat gland 108, and the latter two sweat bursts 192B and 198B are incorrectly attributed to the second sweat gland 108, the average sweat rate for each sweat gland determined by the processor remains correct. Furthermore, in cases where the sweat burst 198A of the second sweat gland 108 happens to follow the sweat burst 192A of the first sweat gland 108, making it unlikely that the obtained sensor 166 data would be interpreted as a single, long sweat burst from a single sweat gland 108, this erroneous assignment is likely insignificant since the determined sweat rate does not change during the sweat burst period.

[0333] The sweat rate dependence of a specific biomarker may occur only during the (active) sweat burst phase of sweat gland 108, and obviously not during the resting phase. Specifically, the primary sweat production and reabsorption that leads to sweat excretion onto skin 106 may occur only during the sweat burst phase. The ratio of the original sweat gland rate to the reabsorption rate of the sweat rate-dependent biomarker may change solely according to the sweat rate. Therefore, the duration of the sweat burst does not affect the sweat rate. However, slope rise and fall will affect the sweat rate, as will be discussed further below.

[0334] exist Figure 20 In the case shown, the sweat droplets 112 originate from two sweat glands 108 that excrete sweat into the corresponding chambers 102, but the sweat droplets 112 completely overlap each other. This has the following effect: the time taken for each aggregated sweat droplet 112 to pass through the sensor 166 (as shown in...) Figure 20 (As shown by the width of the signal from each sensor) from a single sweat droplet 112 in 0.196 seconds (see above) Figure 18 The time was increased to 0.224 seconds.

[0335] exist Figure 6 In the example shown, a series of electrowetting tiles 124 are provided on the lower surface of another plate 128 opposite the outlet 114, and all sweat droplets 112 are formed with the same size / volume, which is determined by the distance 130 between the outlet 114 and the other plate 128, as previously described. Since the sweat droplets 112 are formed with a priori known size / volume, the size of the coalesced sweat droplets 112, determined by the time it takes for these sweat droplets 112 to pass through the sensor, clearly points to the pattern in the sensor signal induced by the two sweat glands 108.

[0336] exist Figure 17 In an alternative scenario to the illustrated example, where a series of electrowetting tiles 124 are provided on the upper surface of plate 110, and no additional plate is used to separate sweat droplets 112 from outlet 114, the sensor signal pattern may initially appear to point to a single sweat gland 108 excreting at twice the sweat rate, rather than the actual situation of two sweat glands 108 excreting at the same sweat rate. However, the interpretation of a single sweat gland 108 can be ruled out, as the time between detected consecutive sweat droplets 112 should be correspondingly shorter, which is not... Figure 20 The situation in the middle.

[0337] exist Figure 21In the illustrated case, sweat droplets 112 originate from two sweat glands 108 that excrete sweat into their respective chambers 102, but some sweat droplets 112 produced by the respective sweat glands 108 overlap with each other. In this case, signals 208 and 210 corresponding to the first two sweat droplets 112 sensed by sensor 166 are assigned to the first sweat gland 108. Signals 216 and 218 for the last two sweat glands 112 are assigned to the second sweat gland 108. The remaining signals 212, 214, and 215 correspond to the aggregated sweat droplets 112 originating from the respective sweat droplets 112 of the two sweat glands 108.

[0338] exist Figure 6 In the example shown, it is clear that since the device 100 delivers sweat droplets 112 of the same size / volume to the sensor 166, the aggregated sweat droplets 112 must belong to the corresponding sweat glands 108.

[0339] However, in Figure 17 In the example shown, there are possibilities to consider: (a) two sweat bursts, each resulting in five sweat droplets 112 shifted in time during sensing, and (b) one sweat burst from the first gland forming seven sweat droplets 112 and one shorter sweat burst from the second gland forming three droplets. In the latter case, the burst would have a length of 42 seconds, and the second burst would have a length of 18 seconds, which is unlikely. More importantly, both possibilities (a) and (b) could lead to the determination of the same average sweat rate for each gland, since the average sweat rate for each gland is the same during the sweat burst period in both cases.

[0340] With a series of electrowetting tiles 124 provided on the plate 110, where sweat droplets 112 can be formed of variable size, at first glance, Figure 21 The data pattern shown could also originate from a single sweat gland 108 with relatively slow ascent and descent. However, this can be ruled out because the time between successive sensor signals should also change, which is not the case in this example.

[0341] exist Figure 22In the illustrated case, the sweat droplets 112 originate from two sweat glands 108 that excrete sweat into their respective chambers 102. Signals 222a-222e are assigned to the first sweat gland 108, while signals 223a-223e are assigned to the second sweat gland. There is some overlap between the sensor signals of the corresponding groups, but the corresponding sweat droplets 112 do not coalesce. This sensor signal pattern can be attributed to each sweat gland 108 producing a time-shifted set of five sweat droplets 112. An alternative explanation would require highly unstable behavior of one sweat gland 108, which is physiologically unlikely, namely, the oscillating sweat rate during a sweat burst. The latter can be correspondingly ruled out.

[0342] exist Figure 17 In the example shown, and with an electrowetting wave generated per second, at a relatively low sweat rate (e.g., 0.2 nl / min / gland), sweat droplets 112 can migrate toward sensor 166 approximately every 6 seconds, and within a single sweat burst lasting 30 seconds, five sweat droplets 112 will form. This can be followed by a rest period of approximately 150 seconds during which no sweat droplets 112 will form. This pattern can then be repeated. Two of these patterns will occur when both sweat glands 108 are active. Note that this discussion is limited to two chambers 102, each receiving sweat from a corresponding sweat gland 108. The case where chamber 102 receives sweat from more than one sweat gland 108 will also be discussed below.

[0343] When the corresponding sensor signal patterns of two sweat glands 108 do not overlap, the processor can directly identify the corresponding patterns, and the sweat rate of each sweat gland can be directly derived from the data pattern, for example, as shown in the reference above. Figure 19 In the described scenario, the sweat droplets 112 of an individual sweat gland 108 can be distinguished by considering the periodic behavior of the sweat gland 108 (sweating bursts and resting periods). Even if the sweat bursts are improperly distributed, it may not affect the average sweat rate of each identified gland, as previously described.

[0344] More generally, the processor can be configured to search for the periodic behavior of one or more sweat glands 108 and identify which sweat droplet 112 originates from which sweat gland 108 or which sweat glands 108. This allows the processor to determine the number of sweat glands and the sweat rate per gland.

[0345] Figure 23 A flowchart of a method 224 for determining the rate of sweat per gland is shown. Method 224 includes receiving sweat 226 from one or more sweat glands and delivering the sweat as discrete sweat droplets 228 to a sensor. Steps 226 and 228 can be implemented, for example, by the device 100 described above.

[0346] In step 230, sweat droplets are sensed using a sensor over a time period. For example, step 230 can be implemented using the sensor 166 described above. In step 232, sweat droplets are counted over a time period. At 234, the time interval between successively sensed sweat droplets during that time period is determined. The time interval may correspond to the period between the sensor signal returning to the baseline and the subsequent increase in the sensor signal from the baseline. At step 236, a measure of the volume of each of the counted sweat droplets is received from the sensor, for example, as previously described.

[0347] In step 238, active (i.e., sweat burst) periods (during which one or more sweat glands are excreting sweat) and resting periods (during which one or more sweat glands are not excreting sweat) of one or more sweat glands are identified, and the active and resting periods are assigned to one or more sweat glands. This identification and assignment uses time intervals and measures of the volume of each of the counted sweat droplets, as previously referenced. Figure 19-22 Described.

[0348] In step 240, the number of sweat glands allocated to active and rest periods is determined. Then, in step 242, the sweat rate per gland is determined. This determination of the sweat rate per gland uses the number of sweat droplets, a measure of the volume of each of the counted sweat droplets, and the determined number of sweat glands.

[0349] Steps 232 to 242 can be implemented, for example, using the processor of the system described above.

[0350] Figure 24 An example of algorithm 243 is shown, which can be used to identify sweat burst periods and rest periods of one or more sweat glands and assign sweat burst periods and rest periods to one or more sweat glands. In other words, it can be employed, for example, by the system's processor. Figure 24 The algorithm 243 shown implements step 238 of method 224.

[0351] In block 244 of algorithm 243, sensor signals, i.e., data patterns, are received from the sensor over a defined time period (e.g., 10 minutes). In block 246, the received data is fitted to a template model. Specifically, the fitting considers: the number of sensor signals (i.e., pulses) sensed within the time period, the width of each sensor signal (i.e., pulse width) (which may be a measure of the volume of each sensed sweat droplet), and the time interval between successive sensor signals. The model fitting also considers physiologically plausible sweat bursts and rest periods.

[0352] In box 248, the goodness of fit between the received data and the template model is determined. In box 250, at least some data is identified as suitable for sweat rate determination based on it. This identification can be based on the goodness of fit of the identified data reaching or exceeding a predetermined threshold. In box 252, the ratio of the original received data corresponding to the identified data is determined, and if the ratio is sufficiently high, the algorithm terminates at box 256. On the other hand, if the ratio is below a predetermined value, such as 80%, a new fit is performed in box 254, and boxes 246 to 252 are repeated, i.e., iteration is performed.

[0353] In a specific example, the algorithm begins with the following template: (i) the number of sweat droplets in a sweat burst, (ii) the pulse duration, (iii) the time it takes for sweat droplets to pass through the sensor, (iv) the duration of the sweat burst period, and (v) the duration of the rest period.

[0354] In this example, each portion of the dataset that is sufficiently similar to the template model is subtracted from the original received data. The goodness of fit can be used to control how much of the received (i.e., real) data might deviate from the model. If wide pulses are partially removed by such subtraction, the remaining pulses are retained in the dataset. Such remaining pulses can, for example, be subsequently assigned to another sweat gland.

[0355] Each part of the dataset, similar to this template, can be subtracted again, and the process repeated. Further iteration of the algorithm may not be necessary, as the overlap of sweat droplets originating from the four glands is highly improbable.

[0356] The size of the remaining dataset is assessed, and if, for example, it is greater than 5% to 20% of the original dataset, a new iteration begins with new values ​​for the fitted parameters. In this way, both non-overlapping and overlapping data patterns can be reliably evaluated, making it possible to determine the average sweat rate for each gland.

[0357] In an example where the device 100 (e.g., the fluid delivery assembly described above) is configured to deliver sweat droplets of a predetermined volume to a sensor, the fitting parameter space can be correspondingly limited. For example, when using... Figure 6 In the illustrated device 100, the volume of each sweat droplet 112 released from the outlet 114 of the chamber 102 is defined by the distance 130 between the outlet 114 and the opposing surfaces of the other plate 128, as previously described. By providing sweat droplets 112 with defined (e.g., uniform) volumes in this way, the identification step 238 described above can be implemented more directly, i.e., compared to when the volume of the (unaggregated) sweat droplets 112 is not prior known.

[0358] For example, when Figure 17When the illustrated device 100 is used to deliver sweat droplets 112 to sensor 166, the sweat droplets 112 can have different sizes / volumes, especially during the rising and falling phases of a sweat burst. This may require a more complex implementation of step 238, such as using a more complex model with variable pulse times. Alternatively, a template that ignores the edges of the sweat burst (i.e., the rising and falling phases) in the analysis can be used.

[0359] It should be noted that when more than three sweat glands 108 supply sweat droplets 112 to the same sensor 166, the resulting pattern analysis may become more difficult to interpret. For this reason, the size of each inlet 104 and the number of chambers 102 of each sensor 166 can be limited (e.g., limited to twenty-five), such that only two to three chambers 102 are supplied by active sweat glands, as previously described with reference to Table 1.

[0360] To increase the amount of data, more than one device 100 can be combined into a single wearable patch. For example, a single patch may include four devices 100, each having twenty-five chambers 102. The number of devices 100 and therefore the number of chambers 102 can vary, for example, depending on the required accuracy, because sampling sweat from a larger number of sweat glands can lead to a reduction in the variation of the average sweat rate for each identified gland.

[0361] Figure 20 This illustrates a highly improbable scenario where corresponding sweat droplets 112 from sweat eruptions originating from different sweat glands 108 completely overlap, resulting in only one sensor signal pattern. When sweat droplets 112 of a predetermined volume are delivered from device 100 to sensor 166, sweat droplets 112 with a sensing volume larger than the predetermined volume must be caused by the aggregation of sweat droplets 112 originating from the corresponding sweat gland 108, as previously described.

[0362] However, in Figure 17 In the case of the device shown, larger sweat droplets 112 may be caused by the coalescence of sweat droplets 112 or a higher sweat rate (recall in this example, the diameter of the hemispherical sweat droplets can vary between 77 μm and 124 μm, depending on the sweat rate per gland).

[0363] When the corresponding sweat gland 108 simultaneously exhibits a sweat burst and the generated sweat droplets 112 are detected simultaneously, the volume of the aggregated (hemispherical) sweat droplets 112 at the lowest average sweat rate of 0.2 nl / min / gland can have a diameter of approximately 97 μm. At first glance, this might be attributed to the fact that a single sweat gland 108 excretes sweat at an average sweat rate of 2.5 nl / min / gland. However, since aggregated sweat droplets 112 at the low sweat rate (0.2 nl / min / gland) can be detected every 6 seconds, while single droplets 112 at a higher sweat rate (2.5 nl / min / gland) can be detected every second, a distinction can be made between sweat droplet aggregation and the relatively high sweat rate. This information is included in the algorithm described above.

[0364] It is known that the excretion cycle of sweat glands 108 can vary. For example, this could mean that the duration of the rest period can vary. Therefore, taking into account this variability in the rest period, the algorithm can evaluate sensor signal patterns, and in particular, the intervals between sensor signals.

[0365] It should also be noted that as the sweat rate increases, more sweat glands 108 may become active. The algorithm can take into account such sweat gland 108 activation. In this regard, for example, it can be done per cm 2 The system is configured based on the assumption of one hundred active sweat glands. This relatively high estimate can account for the activation of an additional 108 sweat glands at an elevated sweat rate.

[0366] Even when the sweat rate is relatively high (e.g., 5 nl / min / gland), Figure 6 The exemplary device 100 shown can also provide clearly defined separation of sweat droplets 112. By generating an electrowetting wave every second, sweat droplets 112 are delivered to the sensor every second, and 30 sweat droplets 112 will form within a 30-second sweat burst. During subsequent rest periods, for example, during a subsequent 150-second period, no sweat droplets 112 will form. Since each incremental step of the electrowetting wave can last 0.1 seconds, the sweat droplets 112 can be clearly separated from each other, as previously described. Therefore, the same analytical methods can be applied when the sweat rate is relatively low. Figure 25 The graph shows the change of the sweat rate sensor signal over time when the sweat rate is relatively high.

[0367] exist Figure 25In the example shown, the average sweat rate is 5 nl / min / gland, the sweat burst lasts for 30 seconds, and the rest period lasts for 150 seconds. The delay between the start of the burst and the first sensor signal is attributed to the time taken to form sweat droplets 112 (in this case, 1 second during the sweat burst) and the time taken to transport the sweat droplets 112 to the sensor 166 (in this case, 7 seconds, because the migration speed is 700 μm per second, and the distance between the chamber 102 and the sensor 166 is 5 mm). As described above, 30 sweat droplets 112 are formed during the 30-second sweat burst. In this case, the width of each sensor signal is 0.26 seconds (the hemispherical sweat droplet 112 has a diameter of 124 μm; the width of the sensor 166 is 60 μm; the combined length of 184 μm is divided by the migration speed of 700 μm per second).

[0368] As illustrated above with respect to Example 1, the probability that two sweat glands 108 will excrete sweat into the same chamber 102 could be 1 / 200. Although chamber 102 is less likely to receive sweat than a single sweat gland 108, the improbability of two sweat glands 108 excreting sweat into the same chamber 102 can still have some influence on the determination of the average sweat rate of each gland. Two methods are anticipated for determining whether two sweat glands 108 (or more) are excreting into a common chamber 102 based on sensor signal patterns.

[0369] As a first example, the system includes four devices 100, each having twenty-five chambers 102. A sweat rate sensor 166 is provided for each of the four devices 100. Therefore, the system has a total of one hundred chambers 102. The area of ​​each inlet 104 is 0.1 mm². 2 In the case of no sweat gland 108 excreting into chamber 102 (P0), the probability (P1) is 90.5%, the probability (P1) of one sweat gland 108 excreting into chamber 102 is 9%, and the probability (P≥2) of two or more sweat glands 108 excreting into chamber 102 is 0.5% (see Table 1 above). Therefore, the occurrence of two or more glands will be 1 / 18 compared to the occurrence of a single gland.

[0370] If a requirement is set that no more than four of the one hundred chambers 102 can receive sweat from two or more sweat glands 108, then, using probability theory, the risk of violating this requirement is approximately 3 in 10,000. Conversely, if a requirement is set that at least four chambers 102 receive sweat from a single sweat gland 108, the risk of violating this requirement is approximately 3 in 1,000. Therefore, such boundary requirements help ensure a sufficient number of single sweat gland 108 events are provided to establish a baseline sensor signal pattern corresponding to a single sweat gland 108 excreting into a single chamber 102. Once this baseline is established, sensor signal patterns generated by two sweat glands 108 excreting into one chamber 102 can then be identified.

[0371] In principle, the requirement that four chambers 102 receive sweat from a single sweat gland 108 can, for example, be relaxed to two chambers 102 receiving sweat from a single sweat gland 108. In this case, the probability of violating this requirement would be 9 in 10,000.

[0372] Figure 26 The diagram shows the sweat rate sensor signal versus time when sweat droplets 112 originate from one sweat gland 108 (upper window pane) in each chamber 102 and when sweat droplets 112 originate from two sweat glands 108 (lower window pane) in each chamber 102. It should be noted that the latter case is different from... Figure 19-21 The situation described in the text is significantly different. Figure 19-21 In this process, the sweat droplets 112 originate from two sweat glands 108 that excrete sweat into the corresponding chambers 102.

[0373] about Figure 26 In the lower pane, if the sweat rate of a sweat gland 108 corresponds to... Figure 26 The sensor signal pattern in the upper pane suggests that one of the two sweat glands 108 excreting into the same chamber 102 may be located near the sweat gland 108 excreting into a single chamber 102. This is based on the assumption that sweat glands 108 located locally in each other can excrete sweat at similar or identical rates. At first glance, the sensor signal pattern depicted in the lower pane could be attributed to a single gland excreting sweat into chamber 102 at a sweat rate of 0.4 nl / min / gland. However, the aforementioned baseline of a single gland can rule out this interpretation.

[0374] It should be noted that, such as Figure 26The two sweat glands 108 depicted in the lower pane, excreting into the common chamber 102, are shown as simultaneously bursting with sweat. This is likely reasonable, as the respective sweat glands 108 can be relatively close to each other, and nerve impulses can arrive at both sweat glands 108 simultaneously and with the same intensity. However, when the corresponding sweat bursts of the two sweat glands 108 are asynchronous, the sweat droplet 112 pattern can result in, for example, a 6-second interval between sensor signals at the start and end of a sweat burst, and a 3-second interval during a sweat burst (see, for example...). Figure 22 This will immediately point to two asynchronous sweat glands, which can be directly identified.

[0375] It can be done Figure 24 The algorithm shown analyzes droplet pattern events of two sweat glands 108 excreting into a common chamber 102. Except in box 246, the algorithm initially fits the data pattern to a model template based on the excretion of a single sweat gland 108 into chamber 102 (“lowest sweat gland droplet 112 count”), and then fits the data pattern to a second template model based on the excretion of two sweat glands 108 into chamber 102 (“twice as high sweat gland droplet 112 count”).

[0376] Sweat droplets 112 can be sensed, and their contact time with sensor 166 can be determined using, for example, capacitance and / or conductivity sensors, as previously described. In particular, conductivity sensors can help determine the rate of sweat per gland.

[0377] The conductivity of the sweat droplets 112 can be determined in part by the ion concentration in the sweat droplets 112. The sodium ion concentration in sweat can vary depending on the sweat flow rate, ranging from 0.06 to 0.76 g / 100 mL. The measured conductivity of the sweat droplets 112 can be used as a representative of the sodium ion concentration. Alternatively, a specific electrochemical sensor for sodium can be used, provided that the sensor's response is fast enough to sense the sodium concentration of the passing sweat droplets 112.

[0378] The following three scenarios can be considered: one sweat gland 108 excretes sweat into the chamber 102 at a rate of 5 nl / min / gland; two sweat glands 108 excrete sweat into the chamber 102, for example, simultaneously, with each sweat gland 108 excreting at a rate of 2.5 nl / min / gland; and three sweat glands 108 excrete sweat into the chamber 102, for example, simultaneously, with each sweat gland 108 excreting at a rate of 1.67 nl / min / gland.

[0379] A sweat rate sensor that relies solely on counting sweat droplets 112 and determining the time it takes for each droplet 112 to pass through sensor 166 may not be able to distinguish between these cases, because the sensor signal pattern will be the same in each case. To determine the sweat rate per gland, an algorithm of the type described above can be used, or alternatively, a sensing device can be used to detect parameters related to the concentration of an analyte that varies with the sweat rate. For example, a conductivity sensor can be used for this purpose, in which case the parameter is conductivity and the analyte is sodium ions.

[0380] When a conductivity sensor is used, the measured ion concentration gradually decreases from the first case to the second case to the third case due to the sweat rate dependence of ion concentration (and sodium ion concentration). This difference in ion concentration between the corresponding cases can be directly detected. Due to the aforementioned dominance of the case where only a single sweat gland 108 excretes into chamber 102, it is not necessary to know the relationship between ion concentration and sweat rate a priori. This dominance can be used to determine the baseline ion concentration of a single sweat gland 108, allowing the various cases outlined above to be distinguished from each other.

[0381] Therefore, and more generally, the step of identifying one or more sweat glands 108 can also be based on the measured concentration of the analyte, for example, via conductivity measurement.

[0382] Another pair of cases can also be considered: one sweat gland 108 excretes sweat into the chamber 102 at a rate of 5 nl / min / gland; and two sweat glands 108 excrete sweat into the chamber 102, for example, synchronously, with each sweat gland 108 excreting at a rate of 5 nl / min / gland.

[0383] In the first case of this pair of scenarios, the sweat rate sensor can sense 112 sweat droplets per second, and in the second case, the sweat rate sensor can sense 112 sweat droplets every half second.

[0384] This could lead to the sensor signal pattern being interpreted as indicating that in the first case, only one sweat gland 108 excretes into chamber 102, and in the second case, two sweat glands 108 excrete into the same collection chamber 102. However, an alternative interpretation would be that in the first case, only one sweat gland 108 excretes into chamber 102, and in the second case, also one sweat gland 108 excretes into chamber 102, but at twice the sweat rate of the first case.

[0385] Although the second scenario seems unlikely, since local sweat glands 108 do not physiologically tend to exhibit such significantly different sweat rates, a clear explanation can be obtained by detecting parameters (e.g., conductivity) related to the concentration of the analyte, whose concentration varies with the sweat rate. In this specific illustrative example, the first explanation would result in equal ion concentrations measured under the corresponding conditions, while the second explanation would result in different ion concentrations measured; therefore, only one of these explanations can be consistent with the measured parameter.

[0386] Another pair of cases can also be considered: one sweat gland 108 excretes sweat into chamber 102 at a rate of 5 nl / min / gland; and two sweat glands 108 excrete sweat asynchronously into the same chamber 102, each sweat gland 108 excreting sweat at a rate of 2.5 nl / min / gland.

[0387] When the two sweat glands 108 excrete into their respective chambers 102, the accidental coalescence of sweat droplets 112 from the two chambers 102 will increase the time it takes for the coalesced sweat droplets 112 to pass through the sensor 166 (approximately 1.14 times longer in the case of hemispherical sweat droplets 112; approximately 2 times longer in the case of bundled sweat droplets 112, as previously described), and the measured parameters (e.g., ion concentration) will be the same as for a single sweat droplet 112. This means that such accidental coalescence of sweat droplets 112 from their respective chambers 102 can be directly identified.

[0388] When two sweat glands 108 excrete asynchronously into the same chamber 102, the factors considered are different. When the corresponding sensor signal patterns do not overlap, the excretion of a single sweat gland 108 can be directly identified, and the sweat droplets 112 can all have similar ion concentrations.

[0389] On the other hand, when sweat bursts from two glands 108 excreted into the same chamber 102 overlap, the sensor signal pattern may cause the signals at the beginning and end of the sweat burst to be more widely spaced than the signals during the sweat burst (see, for example...). Figure 22 This will immediately point to two asynchronous sweat glands, which can be directly identified. As additional evidence of the presence of two sweat glands 108 instead of one that excretes into chamber 102, parameter measurements, such as measurements of ion concentration, as previously described, may also be considered.

[0390] When sweat droplets 112 are transported via electrowetting, the onset of the electrowetting wave may not be synchronized with the onset of the sweat burst. This problem exists in... Figure 17The illustrated example is significant, where an electrowetting tile 124 is provided on the upper surface of a plate 110 defining a chamber 102. Sweat droplets 112 with a different size / volume during the rising and falling phases of a sweat burst compared to the intervening period of the sweat burst can be detected. As previously described, an electrowetting wave can be initiated every second. A sweat burst can begin at some point during that second, such that the size / volume of the first sweat droplet 112 delivered to the sensor 166 can be smaller than that of subsequent sweat droplets 112 formed throughout the entire second between consecutive electrowetting waves. The latter can be considered “fully formed” sweat droplets 112, while smaller sweat droplets 112 generated during the rising or falling phases of the sweat burst can be considered “partially formed.”

[0391] To reiterate, in Figure 17 In the example shown, at a low sweat rate, sweat droplets 112 may be too small to overlap with the two electrowetting tiles 124 that partially define the outlet 114. Therefore, the sweat droplets 112 cannot be delivered to the sensor 166. However, after six electrowetting waves, and assuming an average sweat rate of 0.2 nl / min / gland, the sweat droplets 112 may have become large enough to partially overlap with the two electrowetting tiles 124.

[0392] However, if only 0.5 seconds are available for the formation of sweat droplets 112 during the first electrowetting cycle, the total time for the growth of sweat droplets 112 can be 5.5 seconds, and such sweat droplets 112 can be correspondingly smaller than the sweat droplets 112 formed during the entire 6 seconds. In another example with an average sweat rate of 5 nl / min / gland, the formed sweat droplets 112 can begin to overlap with the electrowetting tiles 124 that partially define the outlet 114 after approximately 0.2 seconds.

[0393] Therefore, the sweat droplets 112 formed in the portion that migrates to the sensor can be substantially smaller than the fully formed sweat droplets 112.

[0394] Figure 27 A schematic diagram is shown depicting the sweat rate over time as a function of the frequency of the electrowetting wave 260 (upper pane) and the associated sweat rate sensor signal over time (lower pane) when the electrowetting wave 260 and the sweat droplet 112 are asynchronous. In the depicted example, the average sweat rate is 5 nl / min / gland, and the sweat burst 192A begins 0.2 seconds before the electrowetting wave 260, such that the first sweat droplet 112 forms in only 0.2 seconds before being delivered to the sensor 166. This is reflected in the shorter time (0.19 seconds) that the first sweat droplet 112 takes to pass through the sensor 166 compared to the entire second (0.26 seconds) during which sweat droplets 112 form between consecutive electrowetting waves 260.

[0395] The final sweat droplet 112 takes 0.8 seconds to form, and this is reflected in the fact that the time it takes for the sweat droplet 112 to pass through the sensor 166 (0.25 seconds) is shorter than the time it takes for the sweat droplet 112 to form during the entire second of the electrowetting wave 260 (0.26 seconds).

[0396] Figure 28 It shows the relationship with Figure 27 The graphs shown are similar, but with more pronounced rises and falls at the beginning and end of the sweat burst, respectively. So far, it has been assumed that the slope is rapid relative to the 1-second cycle of the electrowetting arrangement 144. However, here we assume the rise and fall take approximately 5 seconds. In this case, the sweat rate during the rise and fall is smaller than in the middle of the sweat burst.

[0397] Based on the above regarding Figure 27 For a similar reason, the sweat droplets 112 formed during ascent / descent have a smaller size compared to those formed in the middle of an upslope. However, this results in unique sensor signal patterns, such as Figure 28 As shown in the lower pane. The algorithm discussed above can identify such patterns or ignore such initiation effects. The latter could involve considering only pulses with pulse widths that meet or exceed a predetermined threshold pulse width.

[0398] from Figure 28 As can be seen, there are missing sensor signals at the beginning and end of the sweating process, as indicated by the arrows. At these extreme start and end points of the ascent and descent phases, respectively, the sweat rate can be so small that the formed sweat droplets 112 do not partially overlap with the two electrowetting tiles 124 that partially define the outlet 114. Correspondingly, there is no migration of the partially formed sweat droplets 112, and therefore no sensor signal is recorded.

[0399] At the start of a sweat burst, sweat droplets 112 can be large enough to be transported only after the second pass of the electrowetting wave. In this example, the first and second sensed sweat droplets 112 take the same amount of time to pass through sensor 166 (0.2 seconds). The increasing time taken for sweat droplets 112 to pass through sensor 166 indicates that subsequent sweat droplets 112 sensed by sensor 166 become increasingly larger during the upswing. In the middle of the burst, the time taken for sweat droplets 112 to pass through sensor 166 is constant (0.26 seconds).

[0400] As the slope descends, the rate of sweating decreases, and the size of the sweat droplets 112 decreases accordingly, as can be seen from the shorter time it takes for the sweat droplets 112 to pass through the sensor 166.

[0401] Although it can be expected that the first and last sweat droplets 112 take the same amount of time to pass through sensor 166, during ascent, the first sweat droplet 112 forms within 2 seconds, and during descent, the last sweat droplet 112 forms within 1 second. Therefore, the contact time of the first sweat droplet 112 is longer than that of the last sweat droplet. Some sweat droplets 112 formed during descent are too small to reach sensor 166 and may migrate in subsequent sweat bursts. These partial sweat droplets 112 can combine with newly formed sweat received during subsequent sweat bursts, meaning that no sensor signal is lost during ascent in these subsequent sweat bursts.

[0402] The above considerations can be combined with Figure 6 In contrast to the case of the illustrated device 100, the initiation of sweat droplet 112 delivery is not determined by the frequency of the applied electrowetting wave, and therefore the sweat droplets 112 can all have similar (predetermined) sizes. During the rising or falling phase, the sweat droplets 112 can appear more slowly, and the intervals between successive sweat droplets 112 can be larger than those between consecutive sweat droplets 112 generated in the middle of the burst. If larger sweat droplets 112 are sensed, these will be caused by the aggregation of sweat droplets 112 originating from different sweat glands 108 excreted into the respective chambers 102.

[0403] As a second example, the system includes three devices 100, each device 100 having three chambers 102. A sweat rate sensor 166 is provided for each of the three devices 100. Thus, the system has a total of nine chambers 102. Each chamber 102 has a circular inlet 104 with a diameter of 1130 μm and a circular outlet 114 with a diameter of 33 μm (see Example 2 above).

[0404] The area of ​​each inlet 104 is 1 mm². 2 In the case of no sweat gland 108 excreting into chamber 102 (P0), the probability is 36.8%, the probability is 36.8% for one sweat gland 108 excreting into chamber 102 (P1), the probability is 18.4% for two sweat glands 108 excreting into chamber 102 (P2), the probability is 6.1% for three sweat glands 108 excreting into chamber 102 (P3), and the probability is 1.9% for four or more sweat glands 108 excreting into chamber 102 (P≥4) (see Table 1 above).

[0405] In the case of a collection area served by a device 100 having three chambers 102, there will typically be a chamber 102 that does not supply sweat from sweat glands 108, a chamber 102 that supplies sweat from one sweat gland 108, and a chamber 102 that supplies sweat from two or more sweat glands 108.

[0406] As previously described, sensor signal patterns generated by one or more sweat glands 108 can be appropriately distinguished, allowing the determination of the average sweat rate for each gland. However, in this case, the occurrence of two or more sweat glands 108 excreting sweat into the same chamber 102 may be more frequent compared to the example described above. A potential drawback is that, in very rare cases, four or five sweat glands 108 may excrete sweat into the same chamber 102. This could result in particularly complex overlapping data patterns, but with the aid of appropriate criteria in the algorithm, the results can be declared invalid, and the patch can be replaced accordingly.

[0407] More generally, the area of ​​each inlet 104 can be, for example, 0.05 mm². 2 Up to 2mm 2 Within a range, such as 0.75mm 2 Up to 1.5mm 2 This ensures that (one or more) chambers 102 receive sweat from sweat glands 108, but not every chamber 102 receiving sweat from so many sweat glands 108 would make interpreting sensor signal patterns overly complicated.

[0408] In the example with nine chambers 102 (each chamber having an inlet diameter of 1130 μm), the algorithm described above can be used, but the physical design of the system can be simpler than, for example, a system with one hundred chambers 102.

[0409] In an example with one hundred chambers 102 (each with an inlet diameter of 360 μm), the physical design of the system may be more complex, but the algorithm can be simplified by focusing on the data patterns corresponding to a given chamber 102 supplied by a single sweat gland 108. Less likely data patterns can be discarded.

[0410] From a manufacturing perspective, it may be realistic to provide each chamber 102 with its own sweat rate sensor 166 (e.g., a capacitance or conductivity sensor) because such sensors are relatively simple to design. In this case, the algorithm can be used solely for the purpose of distinguishing between one or more glands 108 that have excreted into a particular chamber 102.

[0411] Those skilled in the art will understand that more chambers 102 can be employed to handle variations in the sensed data. In this example, one hundred sweat glands per cm are used. 2The density of sweat glands should be considered for interpretive purposes only. For different average sweat gland densities 108, the size and number of chambers 102 can be adapted to optimize the results. For example, when the device 100 is applied to skin locations with relatively few active sweat glands 108, the skin surface area used for sampling can be correspondingly increased to obtain sufficiently meaningful data.

[0412] Lactic acid is an important biomarker because it is produced by cells in the event of hypoxia. Elevated blood lactate levels are an indicator of shock. There are four types of shock: hypovolemic shock, obstructive shock, cardiogenic shock, and distributive shock. One cause of distributive shock is sepsis. Shock and sepsis are life-threatening and serious conditions.

[0413] Therefore, an inconspicuous measurement of lactic acid concentration in sweat is highly desirable. However, there are two complicating factors when correlating lactic acid concentration in sweat with that in blood: (i) the concentration of lactic acid in sweat is sweat rate-dependent, and (ii) lactic acid is secreted by the sweat gland cells themselves. Furthermore, it is known that the transfer of biomarkers from blood to sweat can take up to approximately 10 minutes in the human body, but this is an acceptable delay from a clinical point of view.

[0414] To date, this disclosure has provided a solution to the first complex case (i). Regarding the second complex case (ii), it is further noted that the majority (90-95%) of lactic acid excreted into the skin in sweat may originate from the sweat glands themselves, with the remainder (5-10%) originating from the blood. Lactic acid originating from the sweat gland cells themselves and lactic acid originating from the blood should be distinguished in some way.

[0415] Sweat gland cells are innervated by nerves, and nerve impulses activate the sweat glands. During activation, metabolism causes interstitial fluid to be pumped into the coiled tubular portion of the sweat gland. Metabolism requires energy and therefore consumes oxygen. When neural activity is relatively high, the rate of sweat production increases and requires a greater amount of oxygen. It is conceivable that oxygen consumption could cause the sweat glands to switch to an alternative (anaerobic) pathway, thereby producing lactic acid.

[0416] However, given that sweat glands produce sweat in bursts (lasting about 30 seconds) followed by rest periods (lasting about 150 seconds), it is reasonable to assume that sweat gland cells produce lactic acid in a similar cyclical manner with periods of about 180 seconds.

[0417] Furthermore, clinically relevant increases in blood lactate concentrations can have significantly different timescales, approximately several hours (e.g., 1–3 hours). These different timescales, associated with sweat gland-related and blood-related changes in lactate concentrations secreted into the skin, can be used to distinguish the former's lactate origin from the latter. Therefore, measuring the time-varying lactate concentration in sweat can lead to a proper distinction between changes in lactate concentration originating from sweat glands and changes in lactate concentration originating from the blood.

[0418] For this purpose, the above-described apparatus, system, and method can be effectively applied to measure the lactic acid concentration in sweat over time. In a brief summary of the above embodiments, sweat produced by sweat glands 108 is transformed into individual sweat droplets 112 through chamber 102 (defined by plate 110). These sweat droplets 112 then migrate toward sensor 166 via fluid transport components, such as using interfacial tension methods (employing topological and / or chemical gradients or electrowetting techniques) or pressure methods.

[0419] In this particular case, sensor 166 may include a lactate sensor (but if the interest lies in the concentration of another biomarker that changes over time, sensor 166 may include a biomarker specific to that particular biomarker). When each sweat droplet 112 comes into contact with (e.g., passes through) the detection surface of the lactate sensor, the lactate concentration in the sweat droplet 112 can be detected.

[0420] If the lactate sensor responds quickly enough, it can further sense the time it takes for sweat droplets 112 to pass through its detection surface. If the lactate sensor's response time is not fast enough, other sensors, such as capacitance, impedance, conductivity, and / or optical detectors, can be used, as previously described.

[0421] In the various examples described in detail above, the fluid delivery assembly is arranged to deliver sweat droplets at a rate of 700 μm per second. When the length of the lactic acid sensor in the delivery direction of the sweat droplet 112 is, for example, about 60 μm, the time taken for each sweat droplet 112 to pass through the lactic acid sensor can be about 0.19 seconds to 0.29 seconds when the sweat droplet 112 is hemispherical, and the time taken for each sweat droplet 112 to pass through the lactic acid sensor can be 0.15 seconds to 0.57 seconds when the sweat droplet 112 is formed into a bundle of sweat droplets 112 by the channel 168 of the sensor 166, as previously referenced. Figure 15 As stated above.

[0422] Since the response time of conventional electrochemical lactic acid sensors can be as fast as 1 to 2 seconds, and typically varies between 1 second and 90 seconds, measures can be taken to reduce the migration rate of sweat droplets 112 on the detection surface of sensor 166. However, it should be noted that the transport rate of sweat droplets 112 should not be reduced to the extent that sweat droplets 112 originating from the same chamber 102 are generated.

[0423] In the first example, sweat droplets 112 can be transported across the detection surface of the lactate sensor via a chemical gradient. As the sweat droplets 112 are transported across the lactate sensor, the migration velocity can be reduced by employing a chemical gradient with "lower power" than that used by fluid transport components upstream (and in some cases downstream) of the lactate sensor. This can be achieved by providing a smaller local hydrophilic-hydrophobic change per unit length in the migration direction consistent with the lactate sensor.

[0424] In the second embodiment, sweat droplets 112 can be delivered through the detection surface of the lactic acid sensor by using an electrowetting device 144. Figure 29 A portion of an exemplary electrowetting arrangement 144 is shown. The migration of electrowetting-driven sweat droplets 112 can be achieved by charging and discharging a series of electrowetting tiles 124, as previously described. Figure 29 In the example shown, electrowetting waves are generated on electrowetting tiles 124 numbered 1 to 8. Figure 29 The connection scheme shown in the upper pane can result in a new electrowetting wave being generated for every eight tiles.

[0425] Therefore, the following connection scheme can be used to deliver sweat droplets 112 through a series of electrowetting tiles 124 marked 1 to 32 at a constant speed. For example... Figure 29 As shown in the upper pane (connection scheme A), tile 1 is connected to tiles 9, 17, and 25; tile 2 is connected to tiles 10, 18, and 26; tile 3 is connected to tiles 11, 19, and 27; tile 4 is connected to tiles 12, 20, and 28; tile 5 is connected to tiles 13, 21, and 29; tile 6 is connected to tiles 14, 22, and 30; tile 7 is connected to tiles 15, 23, and 31; and tile 8 is connected to tiles 16, 24, and 32.

[0426] Electrowetting waves can be generated by, for example, performing the following sequence with a generator: charging tile 1 (and all connected tiles); waiting 0.1 seconds; discharging tile 1 (and all connected tiles) while simultaneously charging tile 2 (and all connected tiles); waiting 0.1 seconds; discharging tile 2 (and all connected tiles) while simultaneously charging tile 3 (and all connected tiles); waiting 0.1 seconds; discharging tile 3 (and all connected tiles) while simultaneously charging tile 4 (and all connected tiles); waiting 0.1 seconds; discharging tile 4 (and all connected tiles) while simultaneously charging tile 4 (and all connected tiles); waiting 0.1 seconds; discharging tile 4 (and all connected tiles) while simultaneously charging tile 4 (and all connected tiles). Discharge tile 5 (and all connected tiles) and charge tile 6 (and all connected tiles) simultaneously; wait 0.1 seconds; discharge tile 5 (and all connected tiles) and charge tile 6 (and all connected tiles) simultaneously; wait 0.1 seconds; discharge tile 6 (and all connected tiles) and charge tile 7 (and all connected tiles) simultaneously; wait 0.1 seconds; discharge tile 7 (and all connected tiles) and charge tile 8 (and all connected tiles) simultaneously; wait 0.1 seconds; discharge tile 8 (and all connected tiles); wait 1 second and repeat the cycle.

[0427] Using this connection scheme, a new electrowetting wave is generated every eight tiles. Furthermore, the electrowetting waves all have the same velocity, one tile per 0.1 seconds. The electrowetting tiles 124 can, for example, all have a length of 60 μm in the transport direction, and each pair of adjacent electrowetting tiles 124 can be separated from each other by 10 μm in the transport direction. Therefore, each sweat droplet 112 can travel 70 μm every 0.1 seconds, which corresponds to a sweat droplet 112 velocity of 700 μm per second. Since the 1-second time interval is continuously cycled, the frequency of occurrence of the electrowetting wave in this specific example is 1 Hz.

[0428] exist Figure 29 In the case of the connection scheme shown in the upper pane, the corresponding electrowetting waves generated by every eight tiles are effectively combined to form an electrowetting wave over the entire length of a series of electrowetting tiles 124. For clarity, the connection is drawn in two dimensions, but in practice, a three-dimensional VIA can be used to create the connection. The latter also applies to the electrowetting arrangement 144 shown in Figure 11.

[0429] exist Figure 29 The lower pane shows a different connection scheme (connection scheme B), which is designed to provide a slower migration rate of sweat droplets 112 through the lactic acid sensor compared to the upstream and downstream portions of the electrowetting device 144. This is to accommodate the relatively slow response of the lactic acid sensor (e.g., an electrochemical lactic acid sensor), as described above.

[0430] Figure 29Connection scheme B shown in the lower pane is similar to that shown in the upper pane, but tile 1 is also connected to tile labeled A, tile 4 is also connected to tile labeled B, and tile 8 is also connected to tile labeled C. Tiles A, B, and C are localized for the lactic acid sensor. Note that black dot 274 indicates an electrical connection, but intersection 276 without a black dot means there is no electrical connection.

[0431] Tile 1 (together with connected tiles (including tile A)) is charged with a 0.1-second delay, and tile 1 (together with connected tiles) is discharged while tile 2 is charged simultaneously, and so on. Due to the localized connection scheme, tile B is charged 0.4 seconds after tile A, and tile C is charged 0.4 seconds after tile B. Therefore, the localized migration speed of the lactic acid sensor is relatively... Figure 29 The connection scheme A shown in the upper pane is reduced by a factor of four.

[0432] Therefore, the local velocity of the lactic acid sensor is one tile every 0.4 seconds, instead of one tile every 0.1 seconds. Thus, in this example, the local average velocity of sweat droplets 112 passing through the lactic acid sensor is 175 μm per second. The frequency of the applied electrowetting wave can still be 1 Hz, minimizing the risk of uncontrolled collisions of sweat droplets 112 within the region of the lactic acid sensor (i.e., due to sweat droplets 112 catching up with each other). It should be noted that sweat droplets 112 with intervals less than 0.4 seconds will coalesce on tile A, but this will not cause problems, as a resolution of one second is usually sufficient. Furthermore, the contact time with the lactic acid sensor can be increased if the detection surface of the lactic acid sensor spans the same area as tile AC, for example, if the detection surface of the lactic acid sensor is opposite the electrowetting tile AC.

[0433] As described above, when the migration speed is 700 μm per second, the time it takes for each sweat droplet 112 to pass through the lactic acid sensor can be approximately 0.19 to 0.29 seconds when the sweat droplet 112 is hemispherical, and 0.15 to 0.57 seconds when the sweat droplet 112 is a bundle of sweat droplets. However, when using an electrowetting wave that delivers the sweat droplet 112 four times slower (e.g., connection scheme B), the shortest time for the sweat droplet 112 to pass through the lactic acid sensor can be extended to 0.60 seconds. Furthermore, when the detection surface spans three electrowetting tiles 124, the total contact time between the sweat droplet 112 and the sensor can be 1.80 seconds. This is longer than the shortest response time of a conventional lactic acid sensor.

[0434] It should be noted that the connection scheme may allow the local stepping duration of sensor 166 to be neither equal to nor greater than one second, because there is a risk that sweat droplets 112 in this locality may be captured by sweat droplets 112 transported by an electrowetting wave with a period of 1 second, and thus cause uncontrolled collisions of sweat droplets 112.

[0435] Repeating the three local sections (A, B, and C) can further extend the time it takes for sweat droplets 112 to pass through sensor 166. For example, connecting four consecutive groups of these three tiles in configuration B (ABC AB CABC AB C) can increase the time it takes for sweat droplets 112 to pass through sensor 166 to 2.40 seconds. If the area of ​​the detection surface is simultaneously increased to span these 12 tiles, the contact time can be increased to 9.60 seconds. Note that after this local deceleration through sensor 166, the speed can be increased again downstream of sensor 166 by applying the first connection scheme A. Of course, by further repeating the three local tiles (A, B, and C), the contact time with sensor 166 can be further increased. For example, with 10 repetitions and ensuring that the detection surface of sensor 166 spans these tiles, a contact time of approximately 60 seconds can be achieved. Although increasing the period of the electrowetting wave from 1 second to 2 seconds seems at first glance to provide a means of increasing the contact time with sensor 166, it would also cause the growth of sweat droplets 112, requiring the use of larger tiles, which would offset the increase in contact time.

[0436] A system has been established where the contact time between each sweat droplet 112 and the lactic acid sensor can be matched with the response time of the lactic acid sensor, allowing the system to measure the lactic acid concentration of each sweat droplet 112. Depending on the sweat rate, typically 5 to 30 sweat droplets from each spurt of sweat gland 108 can be delivered to the lactic acid sensor. Therefore, the lactic acid concentration over time can be determined.

[0437] As briefly described above, on the timescale of sweating, there can be a nearly constant contribution from lactic acid derived from the blood, and there can also be a contribution from the variation of lactic acid produced by sweat gland cells. For example, lactic acid derived from the blood can remain almost unchanged over a 3-minute period, while lactic acid produced by sweat glands can change according to the 3-minute cycle of the sweat glands.

[0438] The apparatus, system, and method of this disclosure enable close monitoring of changes in lactic acid concentration in sweat over time. In other words, this disclosure allows for observation of the dynamics of lactic acid production in sweat glands with a relatively high degree of detail / resolution. The dynamics of lactic acid production in sweat glands during a sweating outburst may differ from the nearly constant lactic acid concentration in sweat that originates solely from blood.

[0439] Therefore, by using, for example, suitable filtration techniques, the corresponding timescale can be determined, and the lactate concentration in sweat derived from blood lactate can be determined. In this way, a reliable correlation can be established between blood lactate levels and sweat lactate levels. It may be shown that finding an exact correlation is not necessary, but the trend of increasing or decreasing lactate concentration over time should be correlated between blood and sweat. At the very least, this disclosure makes it possible to investigate lactate kinetics, which is a prerequisite for verifying the possibility of a timescale-based distinction between changes in lactate concentration derived from sweat glands and those derived from blood.

[0440] Figure 30 The upper pane provides a graph showing the change in the sweat rate sensor signal over time during a 30-second sweat burst. In this example, there is one sweat gland excreting at an average sweat rate of 0.4 nl / min / gland. Figure 30 The bottom left and bottom right panes provide two seemingly plausible models for altering lactic acid concentrations based on sweat gland metabolism. Both the bottom left and bottom right panes indicate a baseline lactic acid concentration of 278 in blood-derived sweat. This baseline level is virtually constant during a 30-second time period, but can increase, for example, in the presence of an impending infection.

[0441] Figure 30 The model shown in the lower left pane illustrates that during a sweat gland burst, sweat gland cells produce increasingly higher concentrations of lactic acid until a certain maximum is reached, after which the concentration decreases again.

[0442] Figure 30 The model shown in the lower right pane reveals that lactic acid concentration increases with each sweat burst and decreases only slowly during subsequent rest periods due to backdiffusion into the tissues. With each subsequent sweat burst, lactic acid concentration increases further, eventually reaching a final maximum after multiple sweat bursts, and the sweat glands become inactive for an extended period despite further neural stimulation.

[0443] It is worth noting that the baseline lactate concentration changes slowly only over several hours, and this baseline lactate concentration can be considered almost constant within 10 sweat bursts (equivalent to a time period of approximately 30 minutes). Therefore, random deviations between sweat bursts can be attributed to variations in the lactate sensor response rather than actual concentration changes. Thus, such observations can be used to indicate when the lactate sensor should be calibrated, for example, to trigger online calibration of the lactate sensor, as will be discussed below. Figure 31 Further description.

[0444] More generally, sensor 166 may include a biomarker sensor for determining the concentration of a biomarker present in sweat. As previously described, device 100 may supply sweat droplets 112 to the biomarker sensor. In this regard, a biomarker sensor may be provided as an alternative to, or in addition to, a capacitive, impedance, conductivity, and / or optical sensor intended to be used as a sweat rate sensor. When a biomarker sensor is provided in addition to such a sweat rate sensor, the biomarker sensor may be connected in series with the sweat rate sensor or in a separate microfluidic loop connected in parallel.

[0445] To reiterate, the biomarker sensor itself can be used to sense each sweat droplet 112 and measure the time it takes for the sweat droplet to pass through the detection surface of the biomarker sensor. This is due to the relatively high sensitivity of the biomarker sensor, as such a biomarker sensor is typically needed to sense relatively low (e.g., sub-millimolar) concentrations of biomarkers (e.g., glucose). Therefore, the biomarker sensor can be sensitive enough to count the sweat droplets 112 and measure the contact time between each sweat droplet 112 and the sensor 166. Thus, in some examples, the system can be implemented using only the biomarker sensor, as previously described. Omitting the additional sweat flow rate sensor can advantageously reduce system complexity and also save energy, thereby extending the operational life of the sweat patch that includes the system or at least a portion of the system.

[0446] The biomarker sensor should respond quickly enough to changes in biomarker concentration to measure biomarker concentration continuously as discrete sweat droplets 112 pass through the biomarker. Typically, electrochemical sensors for semi-continuous monitoring are based on enzymatic conversion steps that may involve more than one hundred conversions per second per enzyme. Response times of one second have been reported (see, for example, the lactate sensing example above). Therefore, an electrochemical sensor can respond quickly enough for application in this system.

[0447] However, biomarker sensors may require frequent calibration and / or perfusion. This is due to several reasons, including: gradual chemical degradation of the biomarker sensor, drift associated with electronic components, changes in environmental conditions (such as higher or lower temperatures and humidity, changes in atmospheric pressure, exposure to relatively high concentrations of the target analyte of interest), harsh storage and operating conditions (such as when the biomarker sensor is dropped or bumped against a hard surface or immersed in liquid), and manufacturing variations from one sensor to another.

[0448] When this system is used to monitor objects, offline calibration of biomarker sensors can have a negative workflow impact. Therefore, the system can be configured to allow online calibration, as will now be described.

[0449] In the example, the system includes a reservoir for storing calibration fluid for a biomarker sensor and a dosing device for supplying the calibration fluid dropwise to the biomarker sensor.

[0450] Various methods can be envisioned for implementing the dropwise supply of calibration fluid to a biomarker sensor (electrochemical biomarker sensor). The calibration fluid contains dissolved calibration components required for calibrating the biomarker at a known concentration. The reservoir can be filled, for example, before first use by irreversibly opening a valve, thereby connecting the reservoir fluid to the rest of the system. This "breaker" is commonly used in infusion techniques as a device to irreversibly open such a sealed fluid container.

[0451] In addition to the calibration components, the calibration fluid may also include additional components, for example, for stabilizing the obtained biomarker sensor readings. These additional components may include, for example, proteins also present in sweat. While such proteins may be present in sweat at varying concentrations and thus affect sensor measurements to varying degrees, they may be present in calibration fluids at constant and relatively high concentrations. This can cause the additional components to saturate the absorption and interactions of the biomarker sensor, resulting in a more stable sensor output that is essentially or solely controlled by the concentration of the biomarker(s) of interest.

[0452] like Figure 31 As shown, the dosing device 278 can be configured to inject a calibration fluid droplet into a conduit 280, which delivers the calibration fluid droplet to a biomarker sensor (not visible). Chemical and / or topological (i.e., passive) gradients of the type discussed above regarding the fluid delivery assembly can, for example, be used to deliver the calibration fluid droplet to the biomarker sensor.

[0453] The dosing device 278 may, for example, include a valve for controlling the injection of calibration fluid droplets from the reservoir 282 into the conduit 280. The valve controls the injection of the calibration fluid droplets, switching from a closed state to an open state and back whenever calibration fluid droplets are supplied to the biomarker sensor. The calibration fluid droplets can then be delivered to the biomarker sensor via the conduit 280.

[0454] like Figure 31As shown, conduit 280 meets passage 284, which delivers sweat droplets 112 to sensor 166. As previously described, passage 284 may, for example, be provided between plate 110 and another plate 128. In this respect, the conduit can be considered part of a fluid delivery assembly. Similar to sweat droplets 112, calibration fluid droplets may be delivered to the biomarker sensor along the chemical and / or topological gradients indicated by arrows 126A and 126B.

[0455] Alternatively, calibration fluid droplets can be delivered to the biomarker sensor via electrowetting tiles 124 of the electrowetting arrangement 144. In such an example, the dosing device 278 includes a valve for injecting calibration fluid droplets from the reservoir 282 into the conduit 280. However, in an alternative example, the dosing device also includes the electrowetting tiles 124, and the electrowetting wave can cause calibration fluid droplets to migrate from the reservoir 282 toward the biomarker sensor via the electrowetting tiles 124.

[0456] The electrowetting tiles 124 in conduit 280 can encounter the electrowetting tiles 124 of the fluid delivery assembly. For example, an electric field generator can provide electrowetting waves to the electrowetting tiles 124 of conduit 280 between electrowetting waves used for delivering sweat droplets 112. In this way, calibration fluid droplets can reach the electrowetting tiles 124 shared by both conduit 280 and passage 284 of the fluid delivery assembly before being delivered to the biomarker sensor by another electrowetting wave provided by a series of electrowetting tiles 124 along passage 284.

[0457] More generally, the system is configured to control the timing of delivering calibration fluid droplets to the biomarker sensor such that the calibration fluid droplets do not overlap with migrating sweat droplets 112. Thus, the system distinguishes between calibration fluid droplets and sweat droplets 112 by timing the amount of calibration fluid droplets delivered relative to the sweat droplets 112.

[0458] In another example, calibration fluid droplets can be delivered to the biomarker sensor via a pressure gradient. The pressure gradient can be provided by storing the calibration fluid in reservoir 282 at a pressure above atmospheric pressure (e.g., about 3-4 bar). Therefore, the pressure at the sensor 166 side of the valve of the dosing device 278 can be lower than the pressure in reservoir 282, for example, about atmospheric pressure. This pressurization can be achieved, for example, using pressurized air.

[0459] When the valve is open, the calibration droplet can be forced by pressure into the pathway 284 (via conduit 280) leading to the biomarker sensor.

[0460] Figure 32A non-limiting example of a sweat sensing system 300 is schematically depicted. Sweat is collected by various chambers 102, but only a single chamber 102 is shown for clarity. In this example, sweat enters chamber 102 via inlet 104, and hemispherical sweat droplets 112 are formed and protrude from outlet 114. The sweat droplets 112 may contact another plate 128 opposite outlet 114 after growing to a certain size / volume and be separated onto the other plate 128. In this example, the other plate 128 is provided with a series of electrowetting tiles 124 for conveying the sweat droplets 112 to sensor 166, as previously referenced. Figure 6 Described.

[0461] In this case, the fluid delivery assembly includes the components mentioned above. Figure 12 The branching structure is described, but for clarity, Figure 32 Only the path for fluidly connecting chamber 102 to sensor 166 is shown. It should also be noted that, for simplicity, [the following is omitted as it is not explicitly stated]. Figure 32 The electrowetting arrangement 144 used in the system is shown in only a limited number of electrowetting tiles 124.

[0462] Figure 32 The fluid delivery assembly of the system 300 shown includes another plate 128 and sidewalls that at least partially define a closed passage for minimizing the evaporation of sweat droplets 112 as they migrate to the sensor 166.

[0463] In this example, the distance 130 between outlet 114 and the lower surface of another plate 128 is typically 150 μm. This distance 130 defines the size / volume of sweat droplets 112, as previously described. After the electrowetting wave begins at tile 1, sweat droplets 112 are transported in the direction of sensor 166.

[0464] Sensor 166 includes a channel 168, which is sized such that each sweat droplet 112 forms a meniscus across the cross-section of the channel 168 at its head and tail, as previously described. In this respect, in this example, the height of the channel (approximately 30 μm) is reduced relative to the height of the passage (approximately 150 μm).

[0465] Multiple electrowetting paths 188 (including electrowetting tiles labeled A1, B1, C1; A2, B2, C2; A3, B3, C3; and A4, B4, C4, respectively) are provided in channel 168. Sensor 166 includes multiple sensor modules 190; each of the sensor modules 190 is arranged to sense sweat delivered by a corresponding one or more electrowetting paths 188.

[0466] Each sensor module in the corresponding sensor module 190 may, for example, include a sweat rate sensor and / or a biomarker sensor. For this purpose, channel 168 may be provided with electrodes and / or biomarker sensing surfaces, for example, mounted on one or more surfaces of channel 168. The sweat rate sensor enables the counting of the number of sweat droplets 112 passing through channel 168 and the sensing of the time taken for each sweat droplet 112 to pass through sensor 166. The sweat rate sensor may, for example, include a capacitive sensor, an impedance sensor, a conductivity sensor, and / or an optical sensor. One or more biomarker sensors determine the biomarker concentration of each sweat droplet 112, but the biomarker sensor itself may also enable the counting of the number of sweat droplets 112 and / or the sensing of the time taken for each sweat droplet 112 to pass through sensor 166, as previously described.

[0467] Alternatively, system 300 may include in Figure 31 Another sensor 166 downstream of the sensor 166 shown (in) Figure 31 (Not visible in the image). In this regard, the sweat rate sensor and the biomarker sensor can be provided at different locations along the migration path of the sweat droplets 112, for example. Electrowetting tiles 124, labeled 17 to 24, can deliver the sweat droplets 112 to such additional downstream sensors and / or waste containers.

[0468] In the area defined by tiles A1-4, B1-4, and C1-4, the migration speed of sweat droplets can be determined via the above-mentioned... Figure 28 The described electrical connection scheme is slowed down.

[0469] Electrowetting tiles 124, marked I to IV, are activated at regular intervals between electrowetting waves passing along electrowetting tiles marked 1 to 24, thereby causing a droplet of calibration fluid to be delivered to electrowetting tile 124 marked 13. The calibration fluid droplet can then migrate to sensor 166, such as a biomarker sensor, via subsequent electrowetting waves passing along electrowetting tiles marked 1 to 24. The concentration of a known biomarker in the calibration fluid droplet can then be measured, and, if necessary, a correction to the measured biomarker concentration in sweat droplet 112 can be applied accordingly.

[0470] Although Figure 12 The device 100 shown can help prevent collisions between fully developed sweat droplets 112 and underdeveloped sweat droplets 112, but alternative devices 100 are proposed that can increase the density of the collection chambers 102 near the skin 106.

[0471] For a person who is sedentary, filling a chamber 102 with a height of, for example, 25 μm could take several hours. However, a device 100 that provides more chambers 102 with a smaller volume can help reduce the time required to fill the chambers 102. For this purpose, Figure 33 A portion of the device 100 with increased chamber 102 density is shown.

[0472] The device 100 includes at least one first track; one of the first tracks, track 406A, is in Figure 33 As can be seen in the image. Each of at least one first track includes a plurality of chambers 102 for receiving sweat from the surface of the skin 106. Each of at least one first track is fluidly coupled to a second track 408.

[0473] In this example, chamber 102 can be cylindrical, as this increases the density of chamber 102.

[0474] exist Figure 33 In the example shown, the chambers 102 of the first track 406A are all defined by a plate 110. After one or more chambers 102 are filled with sweat, one or more sweat droplets 112 may protrude from one or more corresponding outlets 114, as previously described.

[0475] At least some of the first tracks (e.g., each) may extend perpendicularly to the second track 408. Figure 33 In the example shown, the first track extends parallel to the y-axis, and the second track 408 extends parallel to the x-axis.

[0476] exist Figure 33 In the example shown, sweat droplets 112 are delivered along the first track 406A and the second track 408 in the direction of the sensor via an electrowetting assembly including electrode 124B, which will be explained in more detail below. Alternative designs for the fluid delivery assembly are also contemplated, such as those using the carrier fluid described above.

[0477] exist Figure 33 In the non-limiting example shown, each first track 406A includes six cylindrical chambers 102, but alternative numbers (and shapes) of chambers 102 are contemplated, such as two, three, four, five, seven, eight or more.

[0478] like Figure 33 As shown, each of the chambers 102 is oriented parallel to the z-axis and is defined by a plate 110.

[0479] The plate 110 is positioned against the skin 106, and the inlet 104 of the cylindrical chamber 102 is located at the sampling site on the skin 106. As shown, the outlet 114 of each cylindrical chamber 102 exits onto the first track 406A.

[0480] Both the first track 406A and the second track 408 may include two physical boundaries: (i) a plate 110 defining the outlet 114, and (ii) another plate 128. The first and second tracks do not necessarily have sidewalls. Spacers may, for example, define the distance between the collection plate 110 and the other plate 128.

[0481] The device 100 may include a conductive layer 402, such as an indium tin oxide layer, disposed beneath a hydrophobic layer 404 that is in direct contact with the first track 406A. The conductive layer 402 may serve as a ground electrode.

[0482] Another plate 128 may include a hydrophobic layer 124A in direct contact with the first track 406A. Adjacent to the hydrophobic layer 124A is at least one dielectric layer 124C, such as one, two, or more dielectric layers 124C. The electrode 124B of the electrowetting assembly is positioned adjacent to at least one dielectric layer 124C. Therefore, at least one dielectric layer 124C is disposed between the electrode 124B and the hydrophobic layer 124A.

[0483] In the first track 406A, each outlet 114 is aligned with the electrode 124B of the electrowetting assembly, except for the outlet 114 furthest from the second track 408, which has an unaligned electrode.

[0484] In the second track 408, there may be no chamber 102, and therefore no outlet 114. Thus, in such an example, the second track 408 may only be used to deliver sweat droplets 112 to at least one sensor (in...). Figure 33 (Not visible in the middle).

[0485] Figure 34 A plan view of a portion of the collection plate 110 is shown. Figure 35 A portion of another plate 128 is shown, specifically illustrating the electrode 124B of the electrowetting assembly.

[0486] Figure 36 It shows Figure 34 and 35 The overlay of the plan view provided in the document. Figure 38 It shows Figure 36 The coverage diagram shows that two sweat droplets 112 are transported along the first tracks 406A and 406C.

[0487] Figure 37A It shows Figures 34-36The diagram shows a plan view of the alternative chamber outlet 114 design. In this example, the radius of outlet 114 is reduced to minimize the length of the contact line between the sweat droplet 112 and outlet 114. Therefore, the risk of fully developed sweat droplets 112 getting stuck in the outlets 114 of other collection chambers 102 can be reduced.

[0488] This can be achieved, alternatively or additionally, by utilizing an outlet 114 that is eccentrically positioned relative to the corresponding relative electrode 124B, such as Figure 37B As shown.

[0489] More generally, for the device 100 of this example, collisions between fully developed sweat droplets 112 and incompletely developed sweat droplets 112 can be largely prevented, which would otherwise result in an incorrectly defined volume of sweat droplets 112.

[0490] As previously described, electrode 124B can be used to generate an electrowetting wave by sequentially charging / discharging electrode 124B. Electrodes 124B can be electrically coupled to each other, such as... Figure 39 As shown, and therefore in this example, only five electrical connections 410 may be needed to charge / discharge the electrode 124B in order to continuously move the electrowetting wave on the first and second tracks 406A-D; 408. Thus, the complexity of the electrowetting assembly can be reduced, for example, relative to an electrowetting assembly in which each electrode 124B is charged / discharged individually.

[0491] Multiple VIA412s can be used, for example, vias, to provide... Figure 39 The relatively simple assembly shown contains five electrical connections 410 for the interface connector. Alternatively, to reduce the number of VIA 412, each electrode 124B can, for example, be adapted with a passive electrical bandwidth filter; for the same number (in Figure 39 In the example shown, all electrodes 124B (numbered "1", "2", "3", "4", or "5") have the same bandwidth. In the latter case, five different AC frequencies can be used on a single power line to sequentially activate electrodes 124B to create an electrowetting wave.

[0492] Although the square electrode 124B is in Figure 35 , 36 The examples shown in 38 and 39 are obvious, but this is not intended to be limiting. Figure 40 and 41 A plan view of an alternative example employing hexagonal electrode 124B is shown. In this way, the density of chamber 102 / outlet 114 can be increased.

[0493] exist Figure 40 and 41In the example shown, an electrowetting wave is induced by charging / discharging electrodes 124B numbered 1 to 5 in the first tracks 406A-J. A second electrowetting wave in the second track 408 is induced by sequentially charging / discharging electrodes 124B numbered 1 to 4.

[0494] Figure 42 It shows the use of Figure 40 and 41 The device 100 shown delivers sweat droplets 112. Figure 43 It shows Figure 41 and 42 The electrical connection of electrode 124B is shown. Similar to the reference above. Figure 39 The example described, Figure 43 The electrode 124B shown in the example (e.g., most of the electrodes 124B) can be connected using VIA412.

[0495] Figure 43 A portion of the device 100 shown may be referred to as a “collection unit”. The collection unit in the example includes ten first tracks 406A-J with a total of sixty outlets 114. Twenty electrodes 124B and fifteen VIAs 412 (three of the depicted electrodes 124B and two of the depicted VIAs 412 come from subsequent collection units) are located in the first track 408.

[0496] Figure 44 An exemplary device 100 is depicted, which can be considered a "serpentine route and collection unit," comprising three collection units, for example... Figure 43 The three collection units shown. Arrow 416 points to (one or more) sensors (in...) Figure 44 (Not visible in the middle), and arrow 418 points to the starting point of the second track 408.

[0497] Various alternative "serpentine route and collection unit" components can be anticipated, for example, by combining five collection units in a row and four collection units in a column. The number and arrangement of collection units can be freely chosen.

[0498] Note that the tiles used for gradual electrowetting are well-suited for creating “serpentine routes and collection units”, making the exemplary device 100 easy to implement in practice, for example, using a relatively small amount of VIA412, as previously described.

[0499] Figure 45A device 100 with an alternative electrical connection design is shown. By connecting the electrode 124B to the conductive path diagonally relative to tracks 406A-L, 408, the number of vias can be significantly reduced. For example, connecting several units in a top-to-bottom zigzag pattern (by switching the diagonal orientation by 90 degrees) means that only a few vias may be needed at the top and bottom of the device 100. In this example, the first track 406 and the second track 408 can be electrically connected, while... Figure 39 , 43 In the example shown in 44, the first track 406 and the second track 408 have different electrical connections.

[0500] It is worth noting the time it takes for the sweat droplet 112 to travel from the outlet 114, which is furthest from the sensor, to the sensor. For this calculation, it can be assumed that the sensor is placed... Figure 44 At the end of the serpentine component shown, there are a total of approximately 240 electrodes 124B. With the electrowetting wave stepping from one electrode to the next in 0.5 seconds, the travel time can be approximately 2 minutes. When using a step time of 0.1 seconds, the travel time can be 24 seconds.

[0501] In a non-limiting example, each first track contains six outlets 114, and each outlet 114 may correspond to a sweat gland 108 that excretes sweat into the chamber 102. Therefore, a sweat gland 108 associated with a given outlet 114 may or may not be present. Assuming a cylindrical chamber 102 with a diameter of 30 μm, and assuming the sweat gland 108 exits onto a skin 106 with a diameter of 40 μm (which may be precisely aligned with or barely contact the chamber 102), the chamber 102 can access a nearly circular skin surface with a diameter of 110 μm. This constitutes approximately 9.5 × 10⁻⁶. 3 μm 2 The skin surface area. For the first orbital with six chambers 102, this corresponds to approximately 5.7 × 10⁴ μm. 2 The total area accessible to collect sweat is near the skin surface. When a person (e.g., a patient) is in a sedentary state, every cm... 2 Skin 106 may have approximately 7 to 10 active glands. This can be considered the minimum number of active sweat glands 108 to be monitored to obtain a sufficiently reliable average sweat rate for each gland. Therefore, the minimum skin surface area to be evaluated for sweat monitoring can be set to 1 cm. 2 However, people in a highly active state or patients trying to cool their bodies can typically have up to one hundred active glands per cm. 2The more active the gland 108, the more droplet collisions are likely to occur between fully developed and incompletely developed droplets. Therefore, to determine the number of collisions between fully developed and incompletely developed sweat droplets 112, 100 active glands per cm were used. 2 Further explanation is needed.

[0502] Therefore, 1754 first orbitals may be needed to approach 1 cm. 2 The skin surface is used for sweat collection. The number of active glands can vary between body locations and can even differ from person to person. These figures will be used for further explanation below; however, those skilled in the art will understand that other figures may also be used, for example, depending on body location, and thus the device 100 and method can be adapted accordingly.

[0503] Considering there are one hundred active glands per cm 2 And an accessible skin surface for collecting sweat through six chambers 102 in each first track, 5.7 x 10 4 μm 2 On average, there are 0.057 active glands in the represented accessible skin surface area. Using the Poisson distribution formula:

[0504] PX = [ <x>x / x!]*exp(- <x>)

[0505] Where Px is the probability that x active sweat glands exist in the skin surface area accessible by the first orbit. <x>Let x be the average number of active sweat glands in a specific area of ​​the skin surface, and let x! be the factorial of x. The following probabilities can be determined:

[0506] P0 = 0.9446

[0507] P1 = 0.0538

[0508] P2 = 0.0015

[0509] These are the probabilities of sweat being sprayed onto the first track by no active sweat glands, one active sweat gland, and two active sweat glands, respectively. These numbers are rounded, but eight decimal places are used in subsequent calculations. It is possible that two or more active sweat glands contribute to the formation of sweat droplets in the first track, and there is a considerable probability that a fully developed sweat droplet will collide with an incompletely developed sweat droplet. For further calculations, it can be assumed that the worst-case scenario is that the probability of two or more active sweat glands occurring is equal to the collision probability between a fully developed and an incomplete sweat droplet.

[0510] To calculate the factor between the probability of a non-collision droplet on the first orbit and the probability of a fully developed sweat droplet colliding with an incompletely developed sweat droplet, the following probabilities are evaluated:

[0511] P>1=1–(P0+P1)=0.00156

[0512] P>2=1–(P0+P1+P2)=0.00003

[0513] These are the probabilities of having more than one sweat gland and more than two active sweat glands in each first track, respectively. Again, these numbers are rounded, but eight decimal places are used in subsequent calculations.

[0514] The ratio between the probability of having one active sweat gland and the probability of having more than one active sweat gland is:

[0515] P1 / (1-(P0+P1)=34.4

[0516] Therefore, in approximately one out of 34 measurements, the sweat droplet might have a size varying within the range of one to two fully formed sweat droplets. This equates to 2.9% of the measurements yielding indeterminate droplet sizes. Using the subtraction algorithm described above, a residual of 2.9% is acceptable. Furthermore, larger sweat droplets (a merged fully formed sweat droplet plus an incompletely formed sweat droplet) can still be identified as a single fully formed sweat droplet plus some unidentified sweat droplets, thus reducing the already acceptable residual.

[0517] In the first consideration, a given sweat droplet with a fully developed droplet size can be attributed to: the merging of two incompletely developed sweat droplets with the size of a fully developed sweat droplet; or the merging of three incompletely developed sweat droplets with the size of a fully developed sweat droplet. However, this may be impossible because incompletely developed droplets cannot be transported by the first track (of the electrowetting component).

[0518] Among further considerations, a given sweat droplet of the size of two fully developed sweat droplets can be attributed to: two merged fully developed sweat droplets; or a fully developed sweat droplet merged with two droplets of a total size equal to that of a fully developed sweat droplet. The latter configuration requires three active sweat glands to spray sweat onto a single first track. The ratio between the probability of one active sweat gland and the probability of more than two active sweat glands is:

[0519] P1 / (1-(P0+P1+P2)=1820

[0520] This can result in even smaller residuals.

[0521] Note that the size of fully developed sweat droplets can vary, as droplets may reach full development just before or after passing through the electrowetting wave. Since the sweat rate sensor can count not only the number of sweat droplets but also the elapsed time (which has a relationship with the sweat droplet size), the precise sweat volume of each droplet remains determinable. Based on the above analysis, one out of 35 measurements might incorrectly identify the sweat droplet size. However, most signals represent the correct sweat droplet size, and acceptable residuals can be achieved using the algorithm described above.

[0522] It should also be noted that fully developed sweat droplets can collide with another fully developed sweat droplet on a second orbit, fortunately, this is likely to be relatively easy. For example, when two fully developed sweat droplets collide, they form aggregated droplets with twice the volume, which can be easily identified by sweat rate sensors, as previously described. This can be achieved, for example, by examining the pulse width, which can be a priori well-defined for sweat droplets of twice the size. In fact, since most sweat droplets can be single / non-aggregated, a baseline size for such sweat droplets can be established.

[0523] Calculation of chamber surface area

[0524] A typical surface area can include approximately 0.1 to 1 active gland. This helps the device determine the sweat rate of each sweat gland, as previously described.

[0525] Depending on body position, per cm 2 The skin contains 50 to 600 glands.

[0526] In a sedentary state, approximately 10% of these sweat glands constitute active sweat glands. For individuals engaging in strenuous exercise and / or exposed to relatively high temperatures, active sweat glands may approach 100%. Therefore, the number of active glands is expressed as per cm². 2 A variation of 5 to 600 glands per millimeter of skin area. This is equivalent to... 2 The skin area ranges from 0.05 to 6 active glands.

[0527] The following provides the calculation of the desired surface area.

[0528] <![CDATA[Active gland per mm 2 > 0.05 0.1 6 Number of glands per surface area 0.1 <![CDATA[2mm 2 ]]> <![CDATA[1mm 2 ]]> <![CDATA[0.0167mm 2 ]]> 1 <![CDATA[20mm 2 ]]> <![CDATA[10mm 2 ]]> <![CDATA[0.167mm 2 ]]>

[0529] Table 2. Skin Surface Area

[0530] In some examples, these surface areas can be assigned to a single chamber.

[0531] The chamber filling time may, for example, have a maximum value of approximately one minute but not exceeding 30 to 60 minutes. In the latter case, the time between two determinations may be too long, so that clinical relevance may be controversial depending on the application. Preferably, to cover all applications, the chamber filling time may be approximately a few seconds to a few minutes.

[0532] For a single gland, the rate of sweat production at rest is approximately 0.2 nl / min, which is equal to 3.3 × 10⁻⁶. 3 μm 3 per second. For an exerciser, this can reach 5 nl / min for a single gland. In special cases, the sweat rate may be even higher, such as 5 nl / min, which equals 8.25 × 10⁻⁶. 4 μm 3 per second.

[0533] To calculate the chamber filling time, we introduce an exemplary chamber height of 10 μm. The filling time is equal to the chamber volume divided by the sweat rate.

[0534]

[0535] Table 3. Chamber filling time

[0536] Clearly, the filling time of the cavities in a sedentary state may not meet the maximum filling time requirements for all sweat gland surface area densities. Therefore, the cavity volume should be smaller, with the range defined in the table below.

[0537]

[0538] Table 4. Filling time of small chambers

[0539] In this case, the maximum filling time is approximately one minute.

[0540] For analytical purposes, at least 5 to 10 active glands can be measured, as the sweat rate of each gland may vary.

[0541] For example, considering (i) 0.1 active glands per mm 2 (ii) The average number of active glands to be measured requires a sampling depth of 100 mm. 2 (1cm 2 The table below shows the calculations for various sweat gland densities, representing the skin surface area.

[0542] <![CDATA[Active gland per mm 2 > 0.05 0.1 6 The average total skin area of ​​5 active glands <![CDATA[1cm 2 ]]> <![CDATA[0.5cm 2 ]]> <![CDATA[0.00835cm 2 ]]> The average total skin area of ​​10 active glands <![CDATA[2cm 2 ]]> <![CDATA[1cm 2 ]]> <![CDATA[0.0167cm 2 ]]>

[0543] Table 5. Skin surface area to be sampled

[0544] For patients who are sedentary, with minimal glandular activity, it may require at least 1cm. 2 The skin area.

[0545] A suitable surface area for a relatively small chamber can be approximately 0.0078 mm². 2 This results in a diameter of 100 μm. A suitable diameter range is between 50 and 200 μm.

[0546] The number of these small chambers can be approximately 12,800 (100 mm). 2 / 0.0078mm 2 The appropriate range is between 3200 and 51200.

[0547] The device can be designed with individual small chambers that all enter the electrowetting path, for example, as in Figures 33 to 45 In the example shown.

[0548] Alternatively, the device can be designed with multiple individual small chambers, and sweat droplets converge toward a single path, for example, as in Figure 12 In the example shown, for instance, all 100 small chambers exit via a single path. Therefore, conceptually, the 100 small chambers can be viewed as a single collection container.

[0549] Finally, in another alternative, the chamber can have a diameter of 0.0167 mm. 2 Up to 20mm 2 Surface area within the range, for example, in Figure 12 In the design shown, each chamber constitutes a single chamber. In this case, only the two smallest chambers (see Table 3) can meet the maximum filling time criterion, resulting in filling times of 0.0167 and 0.167 mm. 2 The surface area between them.

[0550] For individuals exercising only at a rate of at least 5 nl / min / gland, with a 1 mm [unclear] 2 and 10mm 2 The surface area of ​​the chamber between them can meet this standard. 20mm 2 The maximum chamber size may be outside the standard filling size, but may be suitable for people who sweat >5 nl / min / gland.

[0551] The apparatus, systems, and methods disclosed herein can be applied to non-invasive, semi-continuous, and prolonged monitoring of biomarkers indicating health and well-being, such as for monitoring dehydration, stress, sleep, child health, and perioperative monitoring. In addition to their general applicability to subject monitoring, these apparatus, systems, and methods can be specifically used to provide early warning of sudden deterioration in patients in general wards and intensive care units, or to investigate sleep disorders. Currently, measurements can be performed only on a sampling basis when patients visit a physician; however, it should be noted that this disclosure can also be usefully applied to performing such sampling measurements.

[0552] Those skilled in the art, through studying the accompanying drawings, the disclosure, and the claims, will be able to understand and implement other variations of the disclosed embodiments when practicing the claimed invention. In the claims, the word "comprising" does not exclude other elements or steps, and the words "a" or "an" do not exclude multiple. Measures recited in mutually different dependent claims can be advantageously combined. No reference numerals in the claims should be construed as limiting the scope.< / x> < / x> < / x>

Claims

1. A system (300) for use in determining sweat rate, comprising: Sensor (166) for sensing sweat droplets; Device (100) for receiving sweat from one or more sweat glands and delivering the sweat to the sensor in the form of discrete sweat droplets; as well as The processor is configured as follows: Record the sweat droplets sensed by the sensor during a time period; Determine the time interval between sweat droplets sensed successively during the time period; and The time interval is used to identify at least one active period and at least one resting period for each of the one or more sweat glands, during which the corresponding sweat gland excretes sweat and during the resting period, the corresponding sweat gland does not excrete sweat, the active period and the resting period being assigned to the one or more sweat glands.

2. The system (300) according to claim 1, wherein, The processor is also configured to determine the number of sweat glands allocated to the activity period and the rest period.

3. The system (300) according to claim 2, wherein, The processor is also configured to: A measurement of the volume of each sweat droplet within the recorded sweat droplets; and The rate of sweat per gland is determined based on the number of sweat droplets recorded, the measurement of the volume of each sweat droplet in the recorded sweat droplets, and the number of sweat glands identified.

4. The system (300) according to claim 3, wherein, The processor is configured to identify the at least one activity period and the at least one rest period based on the measurement of the volume of each sweat droplet in the recorded sweat droplets and the time interval.

5. The system (300) according to claim 3, wherein, The sensor (166) is configured to sense an indicator of the volume of the sweat droplets, and the processor is configured to receive the sensed indicator.

6. The system (300) according to any one of claims 3-5, wherein, The processor is configured to fit data received from the sensor to a first template model to identify the active and resting periods of each of the one or more sweat glands, the data including at least the time interval and a measure of the volume of each sweat droplet in the recorded sweat droplets.

7. The system (300) according to claim 6, wherein, The fitting to the first template model additionally uses: the number of sweat droplets during the at least one activity period, the duration of the at least one activity period, and / or the duration of the at least one rest period.

8. The system (300) according to claim 6, wherein, The processor is configured to evaluate the goodness of fit of the data to the first template model.

9. The system (300) according to claim 8, wherein, The processor is configured to fit at least a portion of the data to another first template model based on the goodness of the fit.

10. The system (300) according to claim 6, wherein, The processor is configured to: after fitting the data to the first template model, fit at least a portion of the data to a second template model, wherein the first template model is based on at least some of the sweat droplets from a sweat sample consisting of sweat excreted from a single sweat gland, and the second template model is based on at least some of the sweat droplets from another sweat sample consisting of sweat excreted from two or more sweat glands.

11. The system (300) according to any one of claims 1-5, wherein, The device (100) is arranged to deliver sweat droplets of a predetermined volume to the sensor (166).

12. The system (300) according to any one of claims 1-5, wherein, The sensor (166) includes a sensing device for detecting parameters related to the concentration of an analyte, the concentration of which varies with the rate of sweating, wherein the processor is configured to use the parameters when allocating the active period and the rest period to the one or more sweat glands.

13. The system (300) according to claim 12, wherein, The sensing device is a conductivity sensor, and the parameter is conductivity.

14. The system (300) according to any one of claims 1-5, wherein, The sensor (166) includes a biomarker sensor.

15. The system (300) according to claim 14, wherein, The processor is configured to receive multiple biomarker concentrations from the biomarker sensor during the at least one activity period of the corresponding sweat gland, and to determine the temporal variation of the biomarker concentrations within the at least one activity period.

16. The system (300) according to any one of claims 1-5, wherein, The device (100) includes a plurality of chambers (102), each of the chambers having an inlet (104) and an outlet (114), the inlet being for receiving sweat from the skin, and the outlet being arranged such that after the chamber is filled with sweat, sweat droplets form and protrude from the outlet. as well as A fluid delivery assembly is arranged to release each sweat droplet protruding from the outlet and deliver each released sweat droplet to the sensor, such that the corresponding outlet can be used for the formation and protrusion of subsequent sweat droplets after further filling of the corresponding chamber, wherein the fluid delivery assembly is arranged to deliver the released sweat droplets at least as quickly as the subsequent sweat droplets protruding from the corresponding outlet, such that sweat droplets from the same chamber do not come into contact with each other.

17. The system (300) according to claim 16, wherein, The device (100) includes: At least one first track (406A, 406b, 406C, 406D), in which the chamber is defined; and A second track (408), each of the at least one first track being fluidly coupled to the second track, wherein the second track is arranged to deliver sweat droplets received from the at least one first track toward the sensor, and wherein the fluid delivery assembly includes: A series of tiles (124), wherein the tiles (124) are provided along at least one first track (406A, 406b, 406C, 406D) and along a second track (408); and An electric field generator is used to sequentially charge and discharge each of the series of tiles in order to release each of the sweat droplets from the corresponding outlet and to direct each of the sweat droplets toward the sensor.

18. The system (300) according to claim 17, wherein, The tiles are provided in pairs, each pair comprising a first tile provided along the at least one first track and a second tile provided along the second track, the first tile being electrically connected to the second tile.

19. A method (224) for use in determining sweat rate, comprising: Receives (226) sweat from one or more sweat glands; The sweat is delivered (228) to the sensor in the form of discrete sweat droplets; The sensor is used to sense (230) the sweat droplets during a certain period of time; Record (232) the sweat droplets sensed during the said time period; Determine (234) the time interval between sweat droplets sensed successively during the said time period; and Using a processor, the time interval is used to identify (238) at least one active period and at least one resting period for each of the one or more sweat glands, during which the corresponding sweat gland excretes sweat and during which the corresponding sweat gland does not excrete sweat, the active period and the resting period being assigned to the one or more sweat glands.

20. The method of claim 19, further comprising: Determine (240) the number of sweat glands to which the activity period and the rest period are allocated.

21. The method (224) according to claim 20, further comprising: A measure of the volume of each sweat droplet in the sweat droplets recorded by the receiver (236); and The per-gland sweat rate is determined based on the number of recorded sweat droplets, the measurement of the volume of each sweat droplet in the recorded sweat droplets, and the number of sweat glands identified. (242) 22. The method (224) according to claim 21, wherein, The processor is used to identify (238) the at least one activity period and the at least one rest period based on the measure of the volume of each sweat droplet in the recorded sweat droplets and the time interval.

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