Devices, systems, and methods for sweat flow monitoring

Abstract

A device (100) for delivering sweat droplets (112) to a sensor is provided. The device comprises a chamber (102) for filling with sweat. The chamber has an inlet (104) located near the surface of the skin (106) that allows sweat to enter and fill the chamber. The chamber has an outlet (114) from which a sweat droplet protrudes when the chamber has been filled. The device further comprises a fluid transport assembly designed such that the sweat droplet protruding from the outlet can detach from the outlet of the chamber. The sweat droplet is subsequently transported by the fluid transport assembly to the sensor. When the protruding droplet has been released from the outlet, the outlet becomes available for a subsequent sweat droplet to protrude from the outlet when the chamber is further filled. The released sweat droplet is transported via the fluid transport assembly at least as fast as the subsequent sweat droplet protrudes from the outlet, such that the respective sweat droplets do not contact each other before reaching the sensor. Thus, the device supplies sweat to the sensor in a drop-by-drop manner. A system comprising the device and a sensor and a method for delivering sweat droplets to a sensor are also provided.

Description

Technical Field

[0001] The present invention relates to an apparatus for delivering sweat to a sensor, a system including the apparatus and the sensor, and a method for delivering sweat to a sensor. 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 biological fluid 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 + They are used to monitor dehydration, lactation as an early warning sign of inflammation (which is associated with sepsis), glucose in diabetic patients and newborns, and cortisol in relation to 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. This continuous monitoring can occur in a hospital setting or elsewhere. Human sweat alone, or a mixture of sweat and sebum, can be an easily accessible source for biomarker measurements in wearable devices on the skin. 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 important roles 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, pp. 139-147, 2014), it has been found that results from sweat sensing can be highly variable, and for various biomarkers, there appears to be a lack of correlation between values ​​determined from blood and sweat samples. Historical research in this area has involved relatively crude sampling techniques, such as collecting large amounts of sweat using bags or textiles. The limitations of such techniques can contribute to this apparent lack of correlation. Therefore, Mena-Bravo and de Castro's review highlights further key setbacks in conventional sweat sensing techniques, including difficulty in generating sufficient sweat for analysis, problems with sample evaporation, a 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 soon as it appears on the skin. A recent example is a wearable patch proposed by Gao et al. in “Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis” (Nature 529, pp. 509-514, 2016). This patch includes components for measuring Na+. + K + The study utilizes an array of sensors for glucose, lactic acid, and skin temperature. However, the focus of this research is 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 sufficient sweat is produced (hence, the test is conducted on an individual exercising), the pad will absorb the sweat for analysis, and 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 level of the biomarker over time. Sample collection and presentation to the published sensor may not be well-controlled, making continuous and reliable sensing over long periods difficult. Such a patch may also not be designed to handle the minute amounts of sweat produced under normal conditions (i.e., sweat on the order of nanoliters / minute / gland).

[0009] An adult at rest generates heat on the order of 100 joules per second (100 watts). For a person wearing clothing at a temperature of around 22°C, this heat is removed passively, for example, through conduction and convection. In this case, the core temperature remains constant. However, when i) a person engages in physical labor or exercise and / or ii) the ambient temperature rises, these conduction / convection processes become 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] 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, Vol. 2, No. 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, pp. 40-51), the amount of sweat produced by individuals engaging in only light exercise or light labor at ambient temperature is relatively small. Within the so-called thermoneutral zone (approximately 25°C to 30°C), the core temperature remains very stable, and sweating 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: approximately 13°C to 22°C. Therefore, when the temperature is in this zone and a person is at rest, the amount of sweat produced is very low.

[0011] According to Taylor, under resting and thermoneutral conditions, sympathetic nerve discharge (secretion induced by sweat gland coils) may not result in measurable sweating because sweat reabsorption may match its formation rate. Simmers measured sweat production rates in clothed individuals, those exposed to air conditioning, and those primarily engaged in non-physical labor, and found that a typical sweat rate is approximately 0.3 nanoliters / min / gland (measurements range from 0 to 0.7 nanoliters / min / gland). When people were resting but at an elevated 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 an average human skin surface area of ​​2.03 million sweat glands and a sweat density of 1 g / ml, the average sweat production is approximately 3.2 nanoliters / minute / gland. Due to the elevated temperature above the thermoneutral zone, the body needs to cool down, and the actual rate of sweat production increases.

[0012] Therefore, sedentary individuals (e.g., 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 dependent on sweat rate, and therefore the sweat rate of each gland must be assessed for clinically relevant interpretation. Conventional sweat sensing solutions have limited applications because they require the monitored individual to participate in exercise and tend to use rather sophisticated microfluidic devices and sensors to determine sweat rate.

[0013] WO 2018 / 125695 A1 discloses a wearable sweat biosensor with active sweat sampling capability. 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 can be ineffective for small sweat volumes due to evaporation. Furthermore, this technique requires mixing sweat received from the skin at different times, which is undesirable for reliable semi-continuous biomarker measurements.

[0014] US 2015 / 0112165 A1 discloses a method for determining the sweat rate of each gland. This 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 total sweat flow rate using correlation curves derived from volunteer testing. This method has two main drawbacks: (i) it assumes that there are 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] A sweat rate sensor that collects sweat in a chamber located near the skin is disclosed in Heikenfeld et al.'s "Digital nanoliter to milliliter flow rate sensor with in vivo demonstration for continuous sweat rate measurement" (Lab Chip, 2019, Vol. 19, p. 178) and Yang et al.'s "Wearable microfluidics: fabric-based digital droplet flowmetry for perspiration analysis" (Lab on aChip, accepted January 4, 2017, DOI: 10.1039 / c6lc01522k). 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. At the moment 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. Therefore, 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 electrode short-circuiting, occurring just before sweat droplets are released into the core, allows the device to count the sweat droplets. However, this design also requires a sweat rate sensor for each chamber. This makes the arrangement complex and disadvantageous. Furthermore, the design may be incompatible with alternative sweat droplet sensing principles.

[0016] WO 2019 / 060689 A1 discloses a flow rate and analyte sensor for a discrete volume distribution system.

[0017] US 2011 / 180571 A1 discloses droplet actuators, modified fluids, and methods. Summary of the Invention

[0018] This invention is defined by the independent claims. The dependent claims define advantageous embodiments.

[0019] According to one aspect, an apparatus for delivering sweat droplets to a sensor is provided, the apparatus comprising: a plurality of chambers, each chamber having an inlet and an outlet, the inlet for receiving sweat from the skin, the outlet being arranged such that sweat droplets form after the chamber is filled with sweat and the sweat liquid protrudes from the outlet; and a fluid delivery assembly arranged to release each sweat droplet protruding from the outlet and deliver each released sweat droplet to the sensor, such that a corresponding outlet can be used to form subsequent sweat droplets as the corresponding chamber is further filled and the subsequent sweat droplets protrude from the corresponding outlet, 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 contact each other.

[0020] This invention is based on the understanding that collecting sweat and supplying it to a sensor in the form of discrete sweat droplets has advantages over using a continuous sweat flow. In particular, when sweat is supplied as discrete sweat droplets rather than a continuous flow, the sweat rate can be determined more directly, for example, using a simpler sensor.

[0021] For this purpose, the device has multiple chambers, each of which collects sweat from the skin via an inlet. Each chamber also has an outlet arranged (e.g., sized) such that sweat droplets protrude from the outlet when the chamber is already filled. A fluid delivery assembly releases sweat droplets from each outlet and delivers the released sweat droplets toward a sensor. As the sweat droplets are delivered toward the sensor, the fluid delivery assembly maintains the sweat droplets in a discrete form. A droplet-by-drop supply of sweat to the sensor is provided because the released sweat droplets are delivered at least as quickly as, and preferably even faster than, subsequent sweat droplets protruding from the outlet. This avoids such subsequent sweat droplets leaning against and coalescing with sweat droplets released from the same chamber during delivery to the sensor.

[0022] Because the device releases the sweat droplets from the outlet before delivering them to the sensor, it eliminates the need for a sensor for each chamber (as is done in some prior art devices) to sense the sweat droplets while they are still attached to a stream of sweat collected in the chamber.

[0023] The multiple chambers allow the device to sample sweat from the skin in a wider range of scenarios than a single chamber could. By arranging the fluid delivery components to release sweat droplets protruding from the respective outlets of the multiple chambers and deliver the sweat droplets to the sensor, the device can thus deliver sweat droplets from multiple chambers to the same sensor (in other words, a common sensor).

[0024] This allows for a physically simpler design than known sweat sensing systems that require sensors for each chamber.

[0025] This device can correspondingly offer greater design flexibility. For example, the device can deliver sweat to a sensor that is spatially removed from the outlet, and any suitable sweat sensing device can be envisioned for sensing sweat droplets supplied by the device to that sweat sensing device.

[0026] The fluid delivery assembly may include a surface for delivering the sweat droplets thereon. The surface may, for example, be provided with alternating hydrophobic and hydrophilic water areas for delivering the sweat droplets. Preferably, the areas are arranged to have a gradually varying distribution along the length of the surface in the direction of the sensor. This can be considered as providing a "chemical gradient" to the surface for releasing sweat droplets from the outlet and / or delivering sweat droplets toward the sensor.

[0027] Alternatively or additionally, the surface may be inclined and arranged such that when the device is oriented for use, sweat droplets are pulled off the inclined surface at least partially due to gravity, and the sweat droplets are released from the outlet and / or transported toward the sensor. This topological gradient can facilitate the release of sweat droplets from the outlet and / or the transport of sweat droplets toward the sensor.

[0028] Chemical gradients and topological gradients can be considered “passive” gradients because these gradients do not require the fluid transport components to actively apply force to overcome the contact hysteresis of sweat droplets, i.e., the force that resists the movement of sweat droplets.

[0029] The fluid delivery assembly may include a series of tiles and an electric field generator. The series of tiles is disposed between the outlet and the sensor. The electric field generator is used to sequentially charge and discharge each tile in the series to release the sweat droplets from the outlet and / or to deliver the sweat droplets toward the sensor. This series of tiles and the electric field generator may be collectively referred to as an "electrowetting arrangement device".

[0030] For the purpose of detaching and / or transporting aqueous sweat droplets from an outlet, the tile may, for example, include electrodes coated with a hydrophobic material (e.g., a fluoropolymer). Charging the tile (also referred to herein as an "electroplated tile") can cause the surface properties of the tile to switch from hydrophobic to hydrophilic, thereby immediately overcoming the contact angular hysteresis of the sweat droplets. The sweat droplets can then migrate onto the charged electrowetting tile. Subsequent discharge of the charged electrowetting tile and charging of subsequent electrowetting tiles in a series can cause sweat droplets to migrate to subsequent electrowetting tiles, etc. This sequence can be considered an "electroplated wave".

[0031] The fluid delivery assembly can be configured to provide a carrier fluid flow for releasing the sweat droplets and / or delivering the sweat droplets to the sensor. For example, when the surface is a contoured surface (where the outlet is provided at the apex of the contoured surface), the fluid delivery assembly can be arranged to direct the carrier fluid flow to the sweat droplets protruding from the outlet at the apex. This configuration can facilitate the detachment of sweat droplets because less energy is required to overcome the droplet inertia caused by contact angular hysteresis.

[0032] In this configuration, the fluid delivery assembly can be considered to apply a pressure gradient. The resulting sweat droplets can, for example, protrude from the outlet into the passage, and thus can at least partially block the passage. The carrier fluid flow driven by the pressure gradient can then release the sweat droplets and transport them along the passage toward the sensor. The carrier fluid is preferably a fluid that is immiscible with the sweat droplets, in order to facilitate the detection of each discrete sweat droplet transported to the sensor by the carrier fluid. Suitable examples of such carrier fluids include oils (e.g., perfluorocarbon oils) that do not absorb moisture (i.e., have relatively low or negligible hygroscopicity).

[0033] Electrowetting arrangements and pressure gradients can be considered as methods to provide “active” release and / or delivery of sweat droplets, as the fluid delivery components actively apply force to overcome the contact angular hysteresis of the sweat droplets.

[0034] The chamber may taper from the inlet toward the outlet. For example, the chamber may have the shape of a truncated cone. In this example, the inlet and outlet may define a wider base and a narrower base of the truncated cone, respectively. This tapering shape can help reduce the volume of the chamber and thus reduce the time required for the chamber to fill with sweat.

[0035] In other examples, the chambers can be cylindrical, with the inlet and outlet located at their respective bases. This allows for higher density chamber arrangements. Devices providing more densely packed chambers with smaller volumes can help reduce the time required to fill the chambers while ensuring sufficient sweat sampling.

[0036] The chamber can be divided into compartments. At least some of these compartments can be fluidly connected to each other to allow the chamber to be filled with sweat. The spacers between the compartments occupy space and thus can help reduce the available volume of the chamber for containing sweat. This can help reduce the time required for the chamber to become filled with sweat.

[0037] The chamber can be divided by multiple pillars. These pillars can, for example, form portions of a plate that also defines the chamber. Alternatively or additionally, a porous material can be used to divide the chamber into fluidly connected compartments. In this case, the pores of the porous material define the compartments. Porous materials can advantageously help filter substances such as proteins from sweat, which could otherwise clog downstream portions of the device.

[0038] The fluid delivery assembly may include an additional surface opposite the outlet, spaced apart from the outlet, such that protruding sweat droplets are released from the outlet upon contact with the additional surface. Therefore, the additional surface can cause the formation of sweat droplets of relatively uniform size / volume, since the size of each droplet is determined by the spacing between the outlet and the additional surface. When the size of each sweat droplet is known a priori in this way, it facilitates the distribution of sweat droplets sensed by sensors to one or more sweat glands. This can help determine the sweat rate of each gland.

[0039] Sweat droplets formed on another surface can be transported to the sensor via another surface. For example, an electrowetting arrangement device can be used for this purpose by arranging a series of the aforementioned electrowetting tiles on another surface. The frequency of the electrowetting wave provided by the electric field generator can be higher than the frequency at which sweat droplets are released onto the other surface. In this way, uniformly sized sweat droplets can be transported to the sensor at clearly defined intervals between successive sweat droplets.

[0040] In a more detailed example, the fluid delivery assembly can be configured to control the spacing between the additional surface and the outlet based on a metric of sweat rate, for example, provided by the sensor. At relatively high sweat rates, increasing the spacing can mitigate the rapid and uncontrolled formation of sweat droplets, as it takes longer for larger sweat droplets to detach and reach the additional surface. At relatively low sweat rates, decreasing the spacing can be used to increase the number of (smaller) sweat droplets formed on the additional surface.

[0041] When using an electrowetting arrangement device, the electric field generator can be configured to adjust the frequency of the electrowetting wave in response to a measure of sweat rate.

[0042] The fluid delivery assembly can be arranged to fluidly connect the respective outlets of each of the plurality of chambers to the sensor in parallel. By connecting each chamber to the sensor in parallel (rather than serially), fully formed migrating sweat droplets from one chamber will not pass through the outlet of another chamber on their path toward the sensor. In this way, the parallel arrangement effectively prevents such fully formed sweat droplets from colliding with partially formed sweat droplets growing from the outlet of a downstream chamber. Furthermore, the parallel arrangement avoids fully formed migrating sweat droplets being obstructed (e.g., trapped) by the outlet of a downstream chamber. Therefore, the associated complexities in interpreting sensor data can be avoided.

[0043] The plurality of chambers may be arranged in groups, with a subset of the plurality of chambers belonging to each group, wherein the fluid delivery assembly includes: a first interconnect for each group; a first branch for fluidly connecting each chamber of the respective group to the first interconnect; second interconnects for every two or more groups; and a second branch for fluidly connecting the first interconnects to a corresponding second interconnect, wherein each of the second interconnects is fluidly connected to the sensor.

[0044] The fluid delivery assembly may further include, for example, a third interconnect for every two or more of the second interconnects; and a third branch for fluidly connecting the two or more second interconnects to a corresponding third interconnect, wherein the third interconnect is fluidly connected to the sensor.

[0045] This branching structure enables the efficient delivery of numerous sweat droplets collected from various skin locations toward the sensor.

[0046] In one embodiment, the device includes at least one first track within which the chamber is defined; and a second track, each of the at least one first track being fluidly coupled to the second track. The second track is arranged to deliver sweat droplets received from the at least one first track toward the sensor.

[0047] Therefore, the purpose of the second track is to collect sweat droplets from at least one of the first tracks and transport each sweat droplet downstream toward the sensor. This arrangement can help provide a relatively dense arrangement of lower-volume chambers (e.g., cylindrical chambers), which reduces the time required for filling.

[0048] The at least one first track can be, for example, multiple first tracks. Therefore, the collection unit can be defined by multiple first tracks and second tracks.

[0049] More generally, the entrance to each chamber can be defined by an opening of the chamber near the skin that receives sweat from the skin.

[0050] In one embodiment, each inlet of the plurality of chambers is sized to receive an average of 0.1 to 1 active sweat glands. This can help determine the sweat rate of each sweat gland using the device.

[0051] Each inlet can, for example, have a diameter of 0.005 mm. 2 Up to 20mm 2 The inlet area is determined by the dimensions of the chambers and the number of chambers included in the device. The fundamental principles behind inlet area and size will be discussed in more detail below.

[0052] According to another aspect, a sweat monitoring system is provided, comprising: a sensor for sensing sweat droplets; and means as defined above for delivering sweat droplets to the sensor. The sensor may, for example, include at least one of the following: a capacitive sensor, an impedance sensor, a conductivity sensor, an optical sensor, an electrochemical sensor, and a sweat biomarker sensor. The sweat biomarker sensor itself may, for example, include an electrochemical sensor.

[0053] The sensor may include a channel sized such that each sweat droplet forms a meniscus across the cross-section of the channel at the head and tail of the sweat droplet. The sweat droplet may correspondingly conform to the shape of the channel. This can (e.g., compared to a scenario where a sweat droplet passing through the sensor retains its original hemispherical shape) help the sensor determine changes in the volume of the sweat droplet.

[0054] The sensor may further include: a plurality of series of tiles arranged in the channel, each series extending in the direction in which sweat droplets are conveyed through the channel; an electric field generator for sequentially charging and discharging each tile in each series to convey the sweat droplets through the channel, wherein the respective series of tiles are sufficiently close to each other in a direction perpendicular to the direction in which the sweat droplets are conveyed through the channel such that, depending on the volume of the sweat droplets, one or more series convey the sweat droplets through the sensor; and a plurality of sensor modules, each sensor module arranged to sense the sweat conveyed by the respective series of the plurality of series.

[0055] Each corresponding series of tiles can be considered an electrowetting path. Depending on the volume of the sweat droplets, the sweat droplets can be distributed across multiple electrowetting paths. For example, larger sweat droplets can be distributed across two or more corresponding tiles in an electrowetting path, while smaller sweat droplets can be confined to a single electrowetting path. A sensor module is provided for each electrowetting path to sense the sweat droplets being transported and the time taken for the droplets(s) to pass through the sensor module(s). This allows for better differentiation of sweat droplets based on their size / volume.

[0056] According to another aspect, a method for delivering sweat droplets to a sensor is provided, the method comprising: filling a plurality of chambers with sweat received from skin, each chamber having an outlet, the filling continuing until one or more sweat droplets protrude from one or more outlets of the chambers respectively; releasing the one or more protruding sweat droplets; and delivering the one or more released sweat droplets to the sensor, such that each outlet is configured to form a subsequent sweat droplet as the respective chamber is further filled and the subsequent sweat droplet protrudes from the respective outlet, wherein the released sweat droplets are delivered at least as quickly as the subsequent sweat droplets protruding from the outlet of the respective chamber, such that sweat droplets from the same chamber do not contact each other, i.e., do not contact each other upstream of the sensor. Attached Figure Description

[0057] Embodiments of the invention are described in detail with reference to the accompanying drawings and by way of non-limiting examples, wherein:

[0058] Figure 1 A first example of a device for delivering sweat droplets to a sensor is shown;

[0059] Figure 2 A second example of a device for delivering sweat droplets to a sensor is shown;

[0060] Figure 3 A third example of a device for delivering sweat droplets to a sensor is shown;

[0061] Figure 4 A fourth example of a device for delivering sweat droplets to a sensor is shown;

[0062] Figure 5 A fifth example of a device for delivering sweat droplets to a sensor is shown;

[0063] Figure 6 A sixth example of a device for delivering sweat droplets to a sensor is shown;

[0064] Figure 7 A seventh example of a device for delivering sweat droplets to a sensor is shown;

[0065] Figure 8 An eighth example of a device for delivering sweat droplets to a sensor is shown;

[0066] Figure 9 A ninth example of a device for delivering sweat droplets to a sensor is shown;

[0067] Figure 10 A tenth example of a device for delivering sweat droplets to a sensor is shown;

[0068] Figure 11a A portion of the electrowetting arrangement equipment according to an example is shown;

[0069] Figure 11b A portion of the electrowetting arrangement device according to another example is shown;

[0070] Figure 12 An example of a device having multiple chambers is shown, all of which are connected in parallel to a common interconnect.

[0071] Figure 13 A sensor for sensing sweat droplets is shown according to an example;

[0072] Figure 14 Six exemplary sensors for sensing sweat droplets are shown;

[0073] Figure 15 The graph shows the time taken for a sweat droplet to pass through the sensor as a function of droplet volume for a bundle-shaped sweat sample (dashed line) and a hemispherical sweat droplet (solid line);

[0074] Figure 16 A portion of a system for sensing sweat droplets, based on an example, is shown;

[0075] Figure 17 Another example of a device for delivering sweat droplets to a sensor is shown;

[0076] Figure 18 The diagram shows a graph depicting two sweat bursts and two rest periods (top pane), a magnified view of the first sweat burst and the first rest period (middle pane), and a graph of the sweat rate sensor signal as a function of time (bottom pane).

[0077] Figure 19 The graph depicts two sweat bursts from the first sweat gland and two sweat bursts from the second sweat gland (top pane), and a graph of the sweat sensor signal as a function of time (bottom pane).

[0078] Figure 20 The graph shows the sweat rate sensor signal as a function of time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers, but all the sweat droplets just overlap each other.

[0079] Figure 21 The graph shows the sweat rate sensor signal as a function of time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers and some of the sweat droplets in the respective sweat droplets overlap each other.

[0080] Figure 22 The graph shows the sweat rate sensor signal as a function of time when sweat droplets originating from two sweat glands excrete sweat into their respective chambers and there is some overlap between the corresponding sets of sensor signals, but the corresponding sweat droplets do not coalesce with each other.

[0081] Figure 23 A flowchart illustrating a method for determining the sweat rate of each gland, based on an example, is shown.

[0082] Figure 24 An example of an algorithm for attributing sweat droplets to the gland(s) from which they originate is shown;

[0083] Figure 25 A graph of the sweat rate sensor signal as a function of time is shown when the sweat rate is relatively high;

[0084] Figure 26 The graph shows the sweat rate sensor signal as a function of time when the sweat droplets originate from one gland per chamber (top pane) and when the sweat droplets originate from two glands per chamber (bottom pane).

[0085] Figure 27 The diagram schematically depicts a graph of the frequency of the electrowetting wave as a function of time, the sweat rate as a function of time (top pane), and a graph of the associated sweat rate sensor signal as a function of time (bottom pane) when the electrowetting wave and the sweat droplet formation are out of sync.

[0086] 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.

[0087] Figure 29 A portion of another exemplary electrowetting arrangement device is shown;

[0088] Figure 30The graph (top pane) shows a sweat rate sensor signal as a function of time for sweat glands that excrete at a defined average rate, and the graph (bottom pane) shows two models of lactic acid concentration as a function of time.

[0089] Figure 31 A portion of another system for sensing sweat droplets, according to an example, is shown, in which calibration fluid is also supplied to the sensor drop by drop;

[0090] Figure 32 Another system for sensing sweat droplets, according to an example, is shown;

[0091] Figure 33 A first view of a portion of another exemplary device for delivering sweat droplets to a sensor is shown;

[0092] Figure 34 It shows Figure 33 A second view of a portion of the device shown;

[0093] Figure 35 It shows Figure 33 A third view of a portion of the device shown;

[0094] Figure 36 It shows Figure 33 A fourth view of a portion of the device shown;

[0095] Figure 37A It shows Figures 34-36 The diagram shows a plan view of the alternative chamber outlet for the shown outlet design;

[0096] Figure 37B It shows Figures 34-36 A plan view of an alternative chamber outlet for the shown outlet design;

[0097] Figure 38 It shows the use of Figure 33-36 The device shown delivers sweat droplets;

[0098] Figure 39 It shows Figure 35 , Figure 36 and Figure 38 The electrical connections of the electrodes shown;

[0099] Figure 40 A first view of a portion of yet another exemplary device for delivering sweat droplets to a sensor is shown;

[0100] Figure 41 It shows Figure 40 A second view of a portion of the device shown;

[0101] Figure 42 It shows the use of Figure 40 and Figure 41 The device shown delivers sweat droplets;

[0102] Figure 43 It shows Figure 41 and Figure 42 The electrical connections of the electrodes shown;

[0103] Figure 44 A view is provided of yet another exemplary device for delivering sweat droplets to a sensor; and

[0104] Figure 45 A view of a device with an alternative electrical connection design is provided. Detailed Implementation

[0105] It should be understood that the detailed descriptions and specific examples, while indicating exemplary embodiments of the apparatus, system, and method, 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, system, and method of the invention will be better understood from the following description, claims, and 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 indicate the same or similar parts.

[0106] As mentioned above, conventional sweat analysis techniques tend to be limited to people who exercise in order 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 nanoliters / minute / gland.

[0107] 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.

[0108] So-called sweat rate-dependent biomarkers require measuring the sweat rate of each gland in order for the biomarker data to be meaningful. However, known systems capable of measuring the sweat rate of each gland suffer from the drawback of high design complexity. 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 collectively determine the average sweat rate of each gland.

[0109] 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 (on the order of 0.2 nanoliters / minute / gland) and volumes.

[0110] Another drawback of conventional sweat sensing devices is that they may require frequent recalibration and offline calibration, especially for electrochemical sensors typically used for semi-continuous measurements. This can negatively impact workflow when such devices are used to monitor objects.

[0111] An apparatus is provided for delivering sweat droplets to a sensor. The apparatus includes a chamber for filling with sweat. The chamber has an inlet located near the skin surface, allowing sweat to enter and fill the chamber. The chamber has an outlet from which sweat droplets protrude when the chamber has been filled. The apparatus also includes a fluid delivery assembly designed such that the sweat droplets protruding from the outlet can become detached from the outlet of the chamber. The sweat droplets are then delivered by the fluid delivery assembly to the sensor. Once the protruding droplets have been released from the outlet, the outlet becomes available for subsequent sweat droplets to protrude from the outlet as the chamber is further filled. The released sweat droplets are delivered via the fluid delivery assembly at least as quickly as the subsequent sweat droplets protruding from the outlet, such that the corresponding sweat droplets do not come into contact with each other before reaching the sensor. Therefore, the apparatus supplies sweat to the sensor droplet-by-drop.

[0112] This device provides a discrete flow of sweat to the sensor, rather than a continuous flow of sweat used in conventional sweat sensing devices. A fluid delivery assembly causes sweat droplets to be released from the outlet of the chamber and delivered to the sensor. The migration of droplets toward the sensor, and in some examples, through the sensor itself, can be achieved, for example, via interfacial tension methods and / or by applying pressure, as well as migration through the sensor in some examples, which will be described further below.

[0113] Droplet or discrete sweat streams offer several unique advantages over continuous streams. The delay between sweat excretion and the actual determination of biomarker concentrations can be reduced; for example, for sedentary subjects, this delay is typically reduced from 1-2 hours to approximately 10-15 minutes. In cases where the sensor includes a biomarker sensor, the ability to process minute amounts of sweat and deliver them relatively quickly to the sensor allows for the determination of biomarker concentrations even when the subject is sedentary. Furthermore, when sweat is provided as discrete sweat droplets rather than a continuous stream, the sweat rate can be determined more directly, for example, using simpler sensors.

[0114] Because this device releases sweat droplets from the outlet before delivering them to the sensor, it eliminates the need for a sensor in each chamber (as in some prior art devices) to sense the sweat droplets while they are still attached to a stream of 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.

[0115] As will be described in more detail below with reference to the accompanying drawings, the fluid delivery assembly may include a surface extending between the outlet and the sensor. This surface may have, for example, a topological gradient and / or a chemical gradient, which, during use of the device, causes sweat droplets to migrate downwards toward the sensor. Alternatively or additionally, electrowetting techniques are used. Such electrowetting techniques use an electric field to achieve an instantaneous change in the wetting properties of the surface, thereby causing sweat droplets to migrate along the surface toward the sensor.

[0116] 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 a sensor. Pressure may be applied via, for example, a carrier fluid flow in which the sweat droplets flow immiscibly in the direction of the sensor.

[0117] The resulting queue of sweat droplets can be detected and counted using, for example, a simple detector with a pair of electrodes, each droplet passing between the electrodes. This provides a simple means of measuring sweat rate.

[0118] 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, which will be further described below.

[0119] The entrance 104 is shown adjacent to the sweat gland 108. In this configuration, sweat excreted by the sweat gland 108 enters through the entrance 104 and fills the chamber 102. Figure 1As 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 (e.g., a polymer) that can be applied to the skin. 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 is capable of receiving sweat from skin 106.

[0120] 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 means of fasteners (e.g., strips) used to attach the plate 110 to the subject's body.

[0121] 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 can help determine the sweat rate of each sweat gland using the device 100, which will be explained 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, for example, 200-2000 μm, for example, 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 that two or more sweat glands 108 excrete into the same inlet 104, which can 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, for example, 2 to 50 chambers 102, for example, 10 to 40 chambers 102, for example, about 25 chambers 102.

[0123] When 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 when chamber 102 is filled with sweat, hemispherical sweat droplets 112 are formed on top of 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 inlet 104 and outlet 114 can be selected to ensure effective filling of chamber 102 and formation of sweat droplets 112 within the sweat rate range. In some examples, inlet 104 and outlet 114 have fixed dimensions selected for this purpose. Alternatively, device 100 can be configurable, enabling changes to at least some of the dimensions and geometries associated with the formation of sweat droplets 112.

[0126] In the preferred example (in) Figure 1 In (not shown), chamber 102 is sized to be filled with sweat within 10-15 minutes. Preferably, the process of forming hemispherical sweat droplets 112 after filling chamber 102 occurs typically within 10 seconds at a relatively low sweat rate (e.g., 0.2 nanoliters / minute / gland).

[0127] The diameter of the outlet 114 can be, for example, in the range of 10 μm to 100 μm, or, for example, in the range of 15 μm to 60 μm, or, for example, approximately 33 μm, to help control the size of the sweat droplets 112 so that their volume is uniform and reproducible. With an outlet 114 having this diameter (e.g., approximately 33 μm), even at sweat rates as low as 0.2 nanoliters / minute / gland, a number of 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] The device 100 enables the formation of relatively uniformly sized sweat droplets 112, and can also handle variable volumes of sweat droplets 112. Regarding the latter, the sensor to which the device 100 delivers the sweat droplets 112 can be configured to both count the sweat droplets 112 and determine the time taken for each droplet 112 to pass through the sensor. This time is linearly related to the previously known migration velocity and the volume of the sweat droplet 112, as will be discussed below. Figure 15 To provide a more detailed explanation.

[0129] As a response Figure 1The scale of the exemplary device 100 shown is indicated by a length 116 (indicated by a double-headed arrow) of approximately 500 μm. More generally, the dimensions of the 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 range from 0.1 to 100 nanoliters, for example, from 0.5 to 50 nanoliters, for example, from 1 to 20 nanoliters.

[0130] The volume of chamber 102 can be minimized in various ways so as to minimize the time required for chamber 102 to be filled with sweat. Such a modification can be, for example, a 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 this tapering chamber 102 will be smaller than, for example, a cylindrical chamber 102 with the same height and base diameter (e.g., Figure 1 The volume of 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., it has 1 / 3πh[R] 2 +Rr+r 2 The volume is a truncated cone shape (h = 50 μm; R = 360 μm; r = 33 μm). For a relatively low sweat rate of 0.2 nanoliters / minute / gland, the filling time of this tapering chamber 102 can be approximately 10 minutes, and the formation of sweat droplets 112 takes approximately 12 seconds. In contrast, the filling... Figure 1 The cylindrical chamber 102, which has the same height (50 μm) and base (360 μm) dimensions, takes about 50 minutes to form, and the hemispherical sweat droplets 112 take more than 3 hours to form.

[0133] It should be noted that sweat glands 108 tend to excrete during sweat bursts, followed by a resting period after each sweat burst. 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 the sweat rate during a sweat burst is six times the average sweat rate. In the above illustrative example of the chamber 102 with a truncated conical shape, 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 may be provided with a gradient (e.g., a topological gradient and / or a chemical gradient), which will be further discussed below regarding the fluid transport assembly. At this point, it can be said that, in the case of such a topological gradient 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 gradient and / or the topological gradient, as well as 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 be filled with sweat. Figure 3 As shown, the compartment can be formed by a pillar 120. Such a pillar 120 can form part of the plate 110, and in this example, it can be formed by patterning (e.g., etching) the lower surface of the plate 110. Other suitable ways of forming such a pillar 120 will be apparent to those skilled in the art.

[0136] Figure 4 Another example is schematically depicted 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 is reduced by 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 aggregated proteins that could otherwise clog downstream components of the device 100, such as outlet 114 or the fluid delivery assembly. Additionally, the porous material 122 can help prevent the device 100 from being contaminated by certain 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 the chamber 102. Removing such impurities can be advantageous because it reduces the risk of impurities altering surface properties in the fluid delivery assembly (e.g., due to adsorption onto the surface of the fluid delivery assembly, such as onto the electrowetting tiles of an electrowetting arrangement device (when such an electrowetting arrangement device 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 comprises or is located near the surface of the skin 106 and is an incompressible glassy material, the porous material 122 may prevent blockage due to the skin 106 protruding into the cavity 102, in part 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 outlet 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, references may be used in any combination. Figure 1-3 The described volume minimization measures aim to minimize the volume of chamber 102, thereby facilitating the formation of sweat droplets 112 even at relatively low sweat rates. For example, device 100 may include a tapered chamber 102, which is also divided into compartments, for example by including columnar structures 120 and / or porous materials 122.

[0141] As noted above, the device 100 includes a fluid delivery assembly arranged to release sweat droplets 112 protruding from the outlet 114. Thus, the fluid delivery assembly may include, for example, a structure that allows the sweat droplets 112 (e.g., hemispherical sweat droplets 112) to detach 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 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. The fluid delivery assembly allows these forces to be overcome, enabling the sweat droplets 112 to detach (and transport downstream towards 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 detachment 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 sweat droplets 112 (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 the electric field of the electrowetting arrangement device.

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

[0147] Figure 5 An example of detachment of 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 detaching from 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 of electrowetting tiles 124. Charging of the electrowetting tiles 124 can cause the surface properties of the electrowetting tiles 124 to switch from hydrophobic to hydrophilic, thereby immediately overcoming the contact angular hysteresis of the sweat droplets 112. The sweat droplets 112 can correspondingly migrate to the charged electrowetting tiles 124. Subsequent discharge 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 an “electroplastic wave.”

[0149] exist Figure 5 In the example shown, detachment 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, as the electrowetting wave propagates along the electrowetting tiles 124, the sweat droplet 112 spanning the pair of electrowetting tiles 124 will correspondingly shift from the outlet 114. In this example, the sweat droplets 112 may not all have a uniform size or volume, as they may continue to grow to different degrees during the time interval between when they reach 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 gradient and / or topological gradient that allows sweat droplets 112 to exit 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 create chemical gradients (Morgenthaler et al., Langmuir; 2003; Vol. 19, No. 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 domains 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 (e.g., chemical and / or topological) gradient is used for the detachment of sweat droplets 112, detachment can occur when the sweat droplets 112 (e.g., hemispherical sweat droplets 112) reach a certain size. The sweat droplets 112 will detach from the outlet 114 when the diameter of the sweat droplets 112 becomes large enough across the diameter to overcome contact angular hysteresis. In this sense, such a gradient can cause each sweat droplet in the sweat droplets 112 to be transported to a sensor with a similar size / volume relative to each other. After the sweat droplets 112 detach, viscous drag can also play a role in delaying the movement of the sweat droplets 112 due to the driving force created by the surface energy gradient.

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

[0156] refer to Figure 6The spacing 130 between plate 110 and the other 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 additional plate 128 may be provided with a passive (e.g., chemical and / or topological) gradient and / or an 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 detach by “jumping” to the additional plate 128, they can begin to migrate via the gradient. As briefly described above, the spacing 130 between plate 110 and the additional plate 128 can be selected to ensure that the diameter of the formed sweat droplets 112 is large enough before contacting the additional plate 128. This can help ensure the immediate migration / transportation of uniformly sized sweat droplets 112.

[0158] like Figure 6 As shown, the lower surface of the additional 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 this case, the migration of sweat droplets 112 on the other plate 128 via the electrowetting tile 124 means that when the next electrowetting wave reaches the sweat droplets 112 that have already been released onto the other plate 128, the migration of sweat droplets 112 will occur. 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 low, the size / volume of the sweat droplets 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 sweat droplets 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 for engaging at least one of the plates 110, 128, configured to move at least one of the plates 110, 128 to adjust the interval between the plates 110, 128. The control applied to this 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 this example, the fluid delivery assembly can include a controller configured to control the mechanism to move at least one of the plates 110, 128 according to a determined sweat rate (e.g., the 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, there is a risk that sweat droplets 112 may form too quickly, and uncontrollable sweat droplet aggregation may occur. This can be mitigated by increasing the interval 130, as it takes longer for larger sweat droplets 112 to detach and reach the other plate 128.

[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 interval 130 to increase the number of (smaller) sweat droplets 112 formed on the additional plate 128.

[0162] Figure 7 An example of detaching 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 gradients 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 defined detachment of the 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 bringing the protruding sweat droplets 112 into contact with a carrier fluid flow. The carrier fluid is preferably a fluid that is immiscible with the sweat droplets 112. Therefore, since mixing of the sweat droplets 112 with the carrier fluid is substantially prevented, the sensor is able to detect each discrete sweat droplet 112 transported 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. Oxycyte is a perfluorocarbon compound commonly used as a blood substitute.

[0165] In this example where the carrier fluid flow causes the sweat droplet 112 to detach, as previously described, an additional plate 128 can be provided opposite the plate 110 defining the chamber 102. The sweat droplet 112 can form and grow until it contacts the additional plate 128, thus blocking the passage defined by the space between the respective plates 110, 128. The carrier fluid flow can then displace the sweat droplet 112. 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 carrier fluid flow can further facilitate the delivery of sweat droplets 112 to the sensor.

[0166] In cases where the carrier fluid flow is insufficient to dislodge 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 outlet 114. For example, a piezoelectric pump can be used to induce such a flow rate peak in 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 device. Furthermore, a plate 110 defining an outlet 114 has a contoured (upper) surface 132, wherein the outlet 110 of the chamber 102 is disposed at a vertex 134 of the contoured surface 132.

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

[0169] This structure can be considered a passive support structure and can 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 facilitate the detachment 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 As described.

[0170] The contoured "rod" structure can be fabricated in any suitable manner. For example, micromachining techniques such as deep reactive ion etching (DRIE), photolithography, electroplating and molding (LIGA), wet etching, fused deposition modeling (FDM), projection micro-stereolithography, and direct-write additive manufacturing can be used. (KS Teh. Additive direct-write microfabrication for MEMS: A review. Front. Mech. Eng., 2017, Vol. 12, No. 4, pp. 490-509.)

[0171] After the sweat droplet 112 detaches, it is 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 droplet 112 can be transported. In this example, the fluid delivery assembly enables the transport or migration of the sweat droplet 112 to and through the sensor.

[0172] The released sweat droplets 112 are transported at least as quickly as subsequent sweat droplets 112 protrude from 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, that is, to ensure that a queue of discrete sweat droplets 112 is 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 is 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, making the measurement relatively simple and direct, as will be discussed in this article. Figure 15As will be described further. Therefore, when a queue of discrete sweat droplets 112 is fed to a sensor configured to detect the concentration of a biomarker in the corresponding sweat droplet 112, the biomarker concentration as a function of time can be determined, where the likelihood of errors associated with the diffusion of biomarkers between sweat samples taken at different time points is smaller. Otherwise, such a cumulative effect would cause the concentration of the biomarker being measured to be lower than the actual concentration in sweat sampled during a specific time period. Therefore, device 100 can provide a means to overcome key drawbacks of conventional continuous sweat monitoring.

[0175] Sweat glands 108 operate in a cyclical manner. During a sweat burst, sweat glands 108 typically excrete for 30 seconds, followed by a rest period of approximately 150 seconds. By means of a discrete flow of sweat droplets 112 supplied to the sensor by a fluid delivery component, even during the sweat burst of sweat glands 108, the device 100 can be applied to determine detailed information regarding the concentration of biomarkers as a function of 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 Figure 30 A more detailed description.

[0176] Delivering sweat droplets 112 relatively quickly to the sensor via a 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 detachment of sweat droplets 112, the fluid delivery assembly may be provided with passive and / or active gradients for delivering the detached sweat droplets 112 to the sensor. Therefore, sweat droplets 112 can be delivered via interfacial tension technology 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 employed, the length of the 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, a delivery distance of 5-10 mm is achievable, and in principle, depending on the size of the sweat droplets 112, the device 100 is actually sufficient to achieve such a delivery distance.

[0181] To minimize the contact angle hysteresis of the sweat droplets 112, chemical gradients can be formed in various ways. As described above regarding the removal of sweat droplets 112 via chemical gradients, a stepped chemical gradient can be employed, for example. 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, from hydrophobic water formed by nanopillars and hydrophilic water formed by silanoxyl-based materials. In practice, chemical gradients can yield contact angles between approximately 15° and approximately 166°, which is typical for both superhydrophilicity and superhydrophobicity.

[0182] In an alternative example, a chemical gradient can be provided at the molecular level with hydrophilic / hydrophobic water layers, 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, as discussed above regarding the detachment of sweat droplets 112.

[0183] These embodiments are supported by the theory of chemical wettability gradients that manage 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 regions with smaller wettability (larger water contact angle) to regions with more wettability (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 created 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, thus attempting to hold the sweat droplet in its static position. The sweat droplet 112 accelerates under the resultant force of these opposing forces.

[0185] Estimates of the velocity of sweat droplets 112 achievable via a chemical wetting gradient have been obtained from a theoretical model. The model estimates that for a 4° hysteresis water droplet with a diameter of 100 μm (approximately 0.26 nanoliters) and a hydrophobic contact angle of 150°, 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 × 10⁻⁶, -4 Pas., in this particular 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 (i.e., ascends) toward the outlet 114 such that when the device 100 is oriented (e.g., horizontally as shown) for use, 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 anticipated. In this respect, Figure 10 A device 100 is schematically depicted having an inclined surface 138 in the form of a slope, the portion of which has a different inclination angle.

[0189] Although Figure 9 and Figure 10 The inclined surface 138 is shown as the outer surface or external 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 the pathway included in the fluid delivery assembly for delivering sweat droplets 112 toward the sensor... Figure 1-10 The cross-sectional representation provided is not visible, but the pathway can be at least partially closed 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, for example 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.

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

[0193] Alternatively, the fluid delivery assembly may be provided with an active gradient (e.g., 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 carrier fluid flow, as previously described regarding the detachment of the sweat droplets 112.

[0194] In an example where the carrier fluid and sweat droplets 112 are immiscible with each other, the sensor is able to detect each discrete sweat droplet 112 carried 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.

[0195] The fluid delivery assembly may include a plate 110 opposite another plate 128. In this example, sweat droplets 112 can form and grow until they come into contact with 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 a carrier fluid flow (e.g., a constant carrier fluid flow) driven by a pressure gradient. In this way, relatively uniformly sized sweat droplets 112 can be delivered to the sensor, their size determined by the distance 130 between the plates, as previously discussed. Figure 5 As described.

[0196] In cases where the carrier fluid flow is insufficient to dislodge 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 outlet 114. For example, a piezoelectric pump can be used to induce such a flow rate peak in 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 can be connected to an external reservoir for the carrier fluid, which is not itself included in the device 100, because a relatively large volume (e.g., 1 liter or more) of carrier fluid 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. After sensing, sweat can be separated from the carrier fluid and delivered to a waste container (not shown) for collecting sweat. Separation of sweat from the carrier fluid can be facilitated when sweat is immiscible. In this way, the carrier fluid can be recirculated, which also reduces the required volume of carrier fluid. The waste container may, for example, have the capacity to hold milliliters of sweat.

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

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

[0201] The electrowetting device 144 requires control electronics and a power source to actively deliver sweat droplets 112. Figure 11a An example of an electrowetting arrangement device 144 that can still be implemented in a relatively simple manner is shown.

[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, i.e., allowing the sweat droplets 112 to be transported to the sensor and optionally transported through the sensor.

[0203] Figure 11a An electrowetting arrangement device 144, including a planar two-dimensional electrode design, is shown. For simplicity, Figure 11a The connection of fifteen electrowetting tiles 124 is shown. However, those skilled in the art will understand that the electrowetting arrangement device 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 thickness of the lines 146, 150, and 152 are merely used to guide the reader's eye.

[0205] The electrowetting arrangement device 144 can be operated by applying a sequence 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 propagates along the array can at least partially determine the size / volume of the sweat droplets 112, as previously discussed regarding... Figure 5 As described.

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

[0207] However, Figure 11aThe electrical wiring shown in the diagram allows for a single structure within a single plane, thus avoiding VIA routing to other layers. Therefore, manufacturing this design can be relatively inexpensive. The disadvantages of this wiring design are: it uses a fairly large surface area, and the structure of the electrowetting path is limited. For example, Figure 11a The design shown may not support paths with branches, for example, Figure 12 The branch structure shown.

[0208] exist Figure 11b In the alternative example shown, the parallel electrowetting paths are wired. It should be noted that in... Figure 11b The numbering direction of the electrowetting tiles in the middle is relative to Figure 11a It is reversed. The electrowetting wave advances from 1 to 15, and there is an outlet for chamber 102 at tile 1. The reason for the reversed 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 arrangement device 144 to transport / migrate sweat droplets 112 can provide relatively rapid migration and precise control over the transport (e.g., velocity) 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 in both cases an energy source is required.

[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. Nevertheless, the choice of migration principle can depend on the application intended for use in device 100. As noted above, the migration of sweat droplets 112 via a chemical gradient does not require an energy source.

[0212] Although Figure 1-10 The illustration shows a single chamber 102 from which sweat droplets 112 are delivered to the sensor, but the device 100 may also include multiple chambers 102, and the fluid delivery assembly may release sweat droplets 112 protruding from the respective outlets 114 of the chamber 102 and deliver the respective sweat droplets 112 to the sensor.

[0213] In this 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 serially, 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 (e.g., trapped) by the outlet 114 of a downstream chamber 102.

[0215] Figure 12 The device 100 is schematically depicted, wherein corresponding sweat droplets 112 from a plurality of chambers 102 are delivered via an arrangement of paths defining branch structures. The plurality of chambers 102 are arranged in groups 154. A subset of the plurality of chambers belongs to each group. The groups 154 can be spatially separated from each other such that each group 154 ​​is supplied with sweat from a region of skin 106, spatially removing that region of skin 106 from the corresponding region 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 interconnect can be provided for every two or more groups. The second interconnect is capable of fluid connection 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 a corresponding third interconnect, wherein the corresponding third interconnect is in Figure 12 The asterisk indicates the location. 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. A migration speed of the sweat droplets 112 that is at least as fast as, and preferably significantly faster than, the formation of sweat droplets 112 in this example allows the necessary discrete queue of sweat droplets 112 to be 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 collision between migrating sweat droplets 112 and sweat droplets 112 formed from the portion protruding from the corresponding outlet 114 is effectively eliminated. Coagulation 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 of each gland.

[0220] This branching structure also prevents fully formed, migrating sweat droplets 112 from being obstructed (e.g., 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 one sensor 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 each chamber 102 having an average of 0.1 sweat glands 108, an average of nine chambers 102 will produce sweat droplets 112 originating from a single sweat gland 108, and an average of approximately 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 sweat gland 108 can be detected relatively directly. This is especially true where most of the sweat droplets 112 delivered to the sensor will not combine with other sweat droplets, thus providing a baseline. The sensor to which the device 100 delivers the sweat droplets 112 can be configured to both 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 via 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 and reaches 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 conceivable. 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 can also be compatible with the use of pressure gradients. In this case, it is possible to... Figure 12 Pressure 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 discrete queue of sweat droplets 112 is that relatively simple sensors can be used to detect each droplet 112, thereby enabling the estimation of 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 the estimation of the time it takes for a sweat droplet 112 to pass through the detector (i.e., between the plates of a capacitor). The time taken for the sweat droplet 112 to pass through the sensor can indicate the volume of the sweat droplet 112, such as when considering... 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. For example... Figure 13 As shown, sensor 166 includes a unit 168 through which sweat droplets 112 pass. Unit 168 can employ one or more principles, for example, those described above regarding the fluid delivery assembly of device 100 for the delivery of sweat droplets 112. In this respect, Figure 13In 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 electrodes 170 may come into direct contact with sweat droplets 112 passing through unit 168. Alternatively, direct contact between one or both 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 also be anticipated, such as with reference to 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. Therefore, this capacitor can be connected to a preamplifier circuit that utilizes an 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. This small current can be converted into a measurable voltage using operational amplifier 174 and resistor 176, which is then fed by subsequent readout electronics (such as...). Figure 13 As shown, (obtained via voltmeter 178) minimizes capacitor leakage. To further reduce noise, the sensor can be shielded, for example, by adding a preamplifier. Many alternative sensor circuit designs will be apparent to those skilled in the art.

[0233] As an alternative 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 would be particularly suitable. Therefore, the conductivity unit can count the sweat droplets 112, measure the time taken for each sweat droplet 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 on the order of 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 taken for sweat droplets 112 to pass through sensor 166. Many alternative electrical schemes will be apparent to those skilled in the art.

[0236] Variations in the conductivity of sweat droplets 112 can originate from changes in the concentration of dissolved salts (particularly sodium chloride). Sodium chloride is the dominant compound determining these variations in sweat conductivity. The concentration of sodium chloride in sweat varies between 0.06 g / 100 mL and 0.76 g / 100 mL, representing 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 usable for clinical interpretation, a reliable estimate of the sweat rate from each gland is required. Therefore, it is 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 14Example 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. Sweat droplets 112 may come into contact with electrodes 170, or may be prevented from contacting electrodes 170 due to, for example, an insulating coating applied to electrodes 170, as previously described.

[0240] Figure 14 Example B is essentially 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 facilitate the migration of sweat droplets 112 from the chamber(s) 102 from which they originate.

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

[0242] Figure 14 Example D illustrates a sensor 166 having 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 a meniscus across the cross-section of the unit 168 (e.g., a square, rectangular, triangular, circular, etc. cross-section) at the head and tail of the sweat droplets 112. 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 from 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 essentially 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 to the electrowetting tile 124.

[0244] Figure 14Example F is essentially the same as Example E, except that a gradient (e.g., a chemical gradient 180 and / or a pressure gradient) is provided in a channel within unit 168. If a pressure gradient is provided along the length of the channel, no chemical gradient or electrowetting tiles are needed to transport sweat droplets 112 through unit 168.

[0245] When capacitive sensing is employed, all examples of AF can be envisioned with or without 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 used, examples A, B, D, E, and F can be envisioned, 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 parts. One part can, for example, take the form where the outer edge is coated with an insulating material and the central portion is not connected to the outer edge. This concentric electrode structure can alternatively include corresponding uncoated electrodes for conductivity measurement.

[0248] The sweat droplets 112 delivered from device 100 to sensor 166 can have different sizes / volumes. This can be due to variations in the size of the sweat droplets 112 formed at outlets 114 of chamber(one or more) of chamber(one or more) 102. Such size / volume variations can also be caused by the 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 may be conveyed through sensor 166 in a form or shape substantially the same as that taken in the fluid delivery assembly upstream of sensor 166 (e.g., a hemispherical shape). Alternatively, sweat droplets 112 may be fed into channel 168 (e.g., cylindrical, cubic, or prismatic channel 168) to reshape sweat droplets 112 as described above. Figure 13As briefly described. Therefore, the hemispherical sweat droplet 112 can be formed, for example, into a cylindrical or bundle shape, 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 prevent transport through the channel 168 from being obstructed because the surface area of ​​the gradient or electrowetting tile 124 is relatively small compared to the surface area of ​​the channel not covered by the gradient or electrowetting tile 124.

[0252] The time it takes for the sweat droplet 112 to pass through the sensor 166, as a function of its volume, can depend on the shape of the cross-section of the channel 168 that the sweat droplet 112 presents as it passes through the sensor 166. Figure 15 The diagram illustrates this situation. Figure 15 A plot is provided showing the time taken for sweat droplets 112 to pass through sensor 166 as a function of the volume of sweat droplets 112 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., the 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: (diameter of sweat droplet 112 + length of sensor) / (migration speed of sweat droplet 112).

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

[0256] like Figure 15As shown, the time it takes 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, the time it takes for a hemispherical sweat droplet 112 to pass through the sensor 166 can be approximately 1.14 times that of a hemispherical sweat droplet 112 of half its volume. However, the time it takes for a cylindrical or bundled sweat droplet 112 to pass through the sensor 166 can be approximately twice that of a similarly shaped sweat droplet 112 of half its volume.

[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 at the head and tail of sweat droplet 112 across the meniscus of the cross section of unit 168.

[0258] For reference, in the case of hemispherical sweat droplets... Figure 15 The volume range spanned by the plot corresponds to a sweat droplet diameter of 70 to 140 μm, and in the case of bundled droplets, Figure 15 The volume range spanned by the plot in the figure corresponds to the length of a sweat droplet 112, which is 40 to 340 μm.

[0259] When the bundle of sweat droplets 112 passes through the sensor 166 and a gradient (e.g., a chemical gradient) is used to transport the sweat droplets 112 through the sensor 166, 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 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 16A sensor 166 is shown, including a channel 168 as described above for shaping sweat droplets 112. Multiple electrowetting paths 188 are provided in the channel 168, spatially separated from each other in a direction perpendicular to the direction of flow through the sensor 166, such that, depending on the volume of the sweat droplets 112, one or more of the electrowetting paths 188 transport the sweat droplets 112 through the sensor 166. Each of these electrowetting paths 188 includes multiple electrowetting tiles 124 for transporting the sweat droplets 112 from the fluid delivery assembly to and through the sensor 166.

[0262] The corresponding electrowetting waves can be provided to the electrowetting path 188 substantially simultaneously, so that sweat droplets 112 crossing 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 can initially enter channel 168. As previously described, 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. 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, this electrowetting wave is generated by the following operation: First, simultaneously applying the four electrowetting tiles 124 that the sweat droplet 112 first encounters after entering channel 168. Figure 16Each of the four electrowetting tiles 124 on the left (which have an increasing width in the transport direction) is charged; then, for example, these four electrowetting tiles 124 are discharged after 0.1 seconds, and immediately the four center electrowetting tiles 124 adjacent to the initially charged and discharged electrowetting tiles 124 are simultaneously charged for, for example, 0.1 seconds. After the four center electrowetting tiles 124 are discharged, the next group of electrowetting tiles 124 is simultaneously charged, and so on.

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

[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 taken for the sweat droplets 112 to pass through sensor module 190. Therefore, sensor 166 can accommodate the migration of both relatively small and relatively large sweat droplets 112. Because a corresponding sensor module 190 is provided for each electrowetting path 188, the sweat droplets 112 transported to sensor 166 via device 100 can be better distinguished by their size / volume, while enabling electrowetting to transport the sweat droplets 112 through channel 168.

[0268] For example, multiple parallel sensor modules 190 can be considered to provide a linear difference from the diameter of the sweat droplet 112. For example, if the sweat droplet 112 is split on two sensor modules 190, then a sweat droplet 112 with twice the diameter will be split on four sensor modules 190 and thus will be detected by twice the number of sensor modules 190.

[0269] exist Figure 16 In the non-limiting example shown, each sensing module in 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. Alternative sensing principles for sensing module 190 may be contemplated, for example, optical detection techniques and / or biomarker detection techniques.

[0270] The electrowetting arrangement 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 shaped to interlock with each other (e.g., via pairs of electrowetting tiles 124 with corresponding adjacent surfaces having complementary zigzag profiles). For example, the overlap of each electrowetting tile with sweat droplets 112 in such an interlocked pair of electrowetting tiles 124 can be increased relative to a pair of electrowetting tiles 124 with corresponding adjacent flat profiles. Thus, the interlocked electrowetting tiles 124 can facilitate the delivery of 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 achieved, for example, via the reference above. Figure 12 The branching structure described is used to achieve this. In this example, a step-by-step approach can be used to break the relatively large sweat droplet 112 into smaller sweat droplets 112 before the sweat droplet 112 reaches the interconnect. The branching structure, which fluidly connects the chamber 102 in parallel to the sensor 166, can help reduce or eliminate the possibility that the smaller sweat droplet 112 is 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 capacitive and conductivity sensors, or may be additionally included in the previously described capacitive and conductivity sensors.

[0274] An optical sensor can sense the sweat droplets 112 in any suitable manner. For example, the optical sensor may include a light source for emitting 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 is redirected as the meniscus of the sweat droplets 112 passes through it. The sweat droplets 112 can be detected by the change in emitted light sensed by the accompanying optical detector.

[0275] Alternatively or additionally, an optical sensor can be configured to detect the absorption of light by components in sweat. Sweat may have a specific spectral fingerprint derived from the spectral properties of each component in 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 that can simplify a system including device 100 and the biomarker sensor, particularly because no additional sensor type is required in the system.

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

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

[0279] If the response time of a biomarker sensor is limited by the diffusion of the relevant biomarker from the sweat droplet 112 to the detection surface of the biomarker sensor, 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 diffused biomarker needs to travel. 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 to half, the time required for diffusion can be reduced to a quarter, thus enabling the biomarker sensor to respond more quickly (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. During a sweat burst, sweat gland 108 typically excretes for about 30 seconds, followed by a rest period of about 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, Vol. 174, pp. 803-812).

[0282] During the sweat burst phase, at a sweat rate of 1.2 nanoliters / minute / gland, approximately 0.24 nanoliters of sweat droplets 112 can be formed approximately 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 nanoliters / minute / gland. In this case, the volume of the hemispherical sweat droplets 112 will be approximately 6 nanoliters, 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 alarm and / or a 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 arrangement 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 spacing of 10 μm between adjacent electrowetting tiles 124 (in the delivery direction).

[0285] The aforementioned electrowetting tile 124 is sized to accommodate sweat droplets 112 with a diameter of 100 μm, but is not suitable for larger sweat droplets 112 that would cover more of the electrowetting tile 124. In this case, the region 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 the relatively large sweat droplets 112 can be solved by adjusting the time intervals of the separate, successive electrowetting waves.

[0287] For example, instead of a 12-second interval between successive electrowetting waves, an electrowetting wave can be initiated every second. In this case, at a sweat rate of 0.2 nanoliters / minute / 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, thus failing to induce the migration of the sweat droplet 112. 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 enabling the release of the sweat droplet 112 from the outlet 114 and the migration of the sweat droplet 112.

[0288] At a sweat rate of 5 nanoliters / minute / 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. Thus, a dynamic range from 0.2 nanoliters / minute / gland to 5 nanoliters / minute / gland can be accommodated when an electrowetting wave is generated per second. The sweat rate during the sweat burst period of the sweat gland 108 can then be calculated using 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.

[0289] exist Figure 17In the case of the illustrated device 100, where an electrowetting tile 124 is provided on the upper surface of the plate 110, different sweat rates 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 to the sensor 166 and determine the time taken for each sweat droplet 112 to pass through the sensor 166. The latter is proportional to the volume of the sweat droplet 112. Therefore, the sweat rate of each sweat gland 108 can be precisely assessed.

[0290] More generally, when the electrowetting arrangement 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 frequency at which the electric field generator charges / discharges the corresponding electrowetting tiles 124 in the series. This switching frequency can be, for example, approximately 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 velocity at which the sweat droplet 112 is delivered can be 700 μm / s.

[0291] Figure 18 The diagram shows a graph (top pane) depicting two sweat bursts 192A, 192B and two rest periods 194A, 194B, an enlarged view of the first sweat burst 192A and the first rest period 194A (middle pane), and a graph of the sensor signal as a function of time (bottom pane).

[0292] In the top pane, the sweat rate is shown as a function of time. This example shows two bursts of 30 seconds 192A, 192B and two rest periods of 150 seconds 194A, 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 nanoliters / minute / gland. In the bottom pane, the sweat rate sensor signal for the first sweat burst 192A as a function of time is depicted.

[0293] There is a noticeable delay 196 between the start of the first sweat burst 192A and the first sweat droplet 112 recorded by sensor 166. This delay 196 can be attributed to the time required for the first sweat droplet 112 of the burst to form (i.e., 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 18In 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, the sweat droplet 112 takes 6 seconds to grow to a sufficiently large diameter to overlap with the electrowetting tile 124 defining the outlet 114 of the chamber 102, such that the electrowetting wave causes the sweat droplet 112 to detach from the outlet 114, as previously described. In this respect, Figure 18 It depicts a scenario where the rate of sweating 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 / s, it takes approximately 7 seconds to deliver 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 recorded five sweat droplets 112, which lasted for 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 / s, the time taken for the sweat droplet 112 to pass through the sensor 166 is 0.196 seconds.

[0298] In Figure 17 and Figure 18 In the corresponding examples, the rise and fall of the sweat rate at the beginning and end of sweat bursts 192A and 192B are faster than the (1 second) period of the electrowetting wave. However, the size of the sweat droplets 112 can vary during the rise and fall of sweat bursts 192A and 192B, 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 / s represents the average velocity of the sweat droplets 112 when they are transported via electrowetting waves. However, since subsequent electrowetting tiles 124 in this series are charged by an electric field generator every 0.1 seconds, the sweat droplets 112 can be considered to move in a stepwise manner. 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 from the sensor 166, and the time of constant output from 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 can alternatively be arranged on the lower surface of an additional plate 128 positioned opposite the outlet 114. In this example, the size / volume of the sweat droplets 112 can depend on the distance 130 between the outlet 114 and the additional plate 128, and therefore the size / volume of the sweat droplets 112 can be independent of the time interval between the 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 droplets 112 protrude from the outlet 114 to the extent that they contact the lower surface of the other plate 128, an electrowetting wave can be used to deliver the sweat droplets 112 along the series of electrowetting tiles 124 toward the sensor 166. Furthermore, since the size / volume of the hemispherical sweat droplets 112 is determined solely by the distance 130 between the outlet 114 and the other plate 128, the frequency at which the electrowetting wave can be applied (e.g., 0.1 droplets / second) can be faster than the frequency at which the sweat droplets 112 form. This ensures that successive sweat droplets 112 remain separated from each other. This example may be suitable, for instance, when the sweat rate is relatively high (e.g., when the system is used to monitor the sweating of athletes participating in high-intensity exercise). During the rise and fall of sweat bursts 192A, 192B, the formation of sweat droplets 112 will be higher than, for example... Figure 17 The example shown takes longer. Therefore, the sweat droplets 112 formed during this rise and fall phases take longer to reach the sensor 166 than when 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., a chemical gradient and / or a topological gradient) is used to release sweat droplets 112 from outlet 114, all sweat droplets 112 may have similar size / volume, as previously referenced. Figure 5 As described.

[0304] A key objective is the ability to determine the sweat rate of each gland without relying on data from volunteer tests, as such data ignores individual differences that can be significant. To this end, a system for determining the sweat rate of each gland is provided. The system includes a sensor 166 for sensing sweat droplets 112, and 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 can be, for example, a means 100 of the type described above. The sensor 166 can be, for example, a sensor 166 of the type previously described (capacitance, conductivity, 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 period of time and to determine the time interval between the sweat droplets 112 sensed successively during that 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 a time interval and a measure of the volume of each sweat droplet in 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 simultaneously 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 active and rest periods, and subsequently determines the sweat rate of each sweat gland based on the number of sweat droplets 112, a measure of the volume of each sweat droplet in the counted sweat droplets 112, and the determined number of sweat glands 108.

[0308] Therefore, this system, based on the intermittent sweat excretion behavior of sweat glands 108, determines the sweat rate of each gland by distributing sweat droplets 112 to specific sweat glands 108. This 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 may employ a thermal sweat rate sensor that includes a pair of temperature probes and a heater, which consumes relatively high amounts of energy. 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 the electrodes.

[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 that deliver sweat as a continuous flow can be relatively 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 (e.g., sensing cumulative changes in dielectric properties) may also have relatively low accuracy and may require additional sensors (e.g., sodium sensors) to determine the sweat rate per gland.

[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 generated 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 a capacitive sensor, impedance sensor, and / or conductivity sensor, 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 the sensor 166 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 is easily determined a priori. The processor can, for example via a lookup table, apply an appropriate correction factor to account for any size dependence of the sweat droplet 112 on the velocity at which it is 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 sensor 166 can be approximately twice that taken for, for example, sweat droplets 112 that have not yet merged to pass through sensor 166, depending on the shape of the sweat droplets 112 within sensor 166, as previously discussed. Figure 15 As described. This means that such a large volume of sweat droplet 112 can be directly and clearly attributed to the coalescence of two fully formed sweat droplets 112.

[0315] Figure 17 The illustrated device 100 has a chamber 102 with a truncated conical shape. 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 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 and 1 sweat gland, respectively.

[0317] The probability of multiple sweat 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 will 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 zones on skin 106. For this purpose, device 100 includes 25 [unclear - possibly referring to a specific type of device] in each collection zone. 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), such that the area of ​​each inlet 104 is 0.1 mm². 2 .

[0322] Of these 25 chambers 102 (each collection area), there will typically be 22 or 23 chambers 102 that do not receive sweat from any sweat glands 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 these 25 chambers 102 (each collection area), approximately two to three chambers of chamber 102 will receive sweat from a sweat gland 108. Sensor 166 can sense the sweat droplets 112 collected by each of these two to three chambers 102. However, the problem of determining the number of sweat glands 108 that contribute to the formation of sweat droplets 112 remains.

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

[0325] The aforementioned system addresses these issues based on the understanding that the periodic behavior of sweat glands 108 can be used 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 rates among sweat glands 108, as will be explained below.

[0326] In a scenario where chamber 102 does not receive sweat from any sweat glands 108, no sweat droplets 112 will be correspondingly delivered to sensor 166.

[0327] In a scenario where chamber 102 receives sweat from a single sweat gland 108, the sweat gland 108 can exhibit an average sweat rate of 0.2 nanoliters per minute, wherein the sweat rate during sweat bursts 192A and 192B is approximately 1.2 nanoliters per minute (assuming a typical burst phase 192A, 192B lasts approximately 30 seconds and a rest phase 194A, 194B lasts approximately 150 seconds). After chamber 102 is filled with sweat excreted by the corresponding sweat gland 108 (e.g., this may take approximately 1 to 10 minutes), sweat droplets 112 can protrude from outlet 114, such as... Figure 17 It is depicted illustratively.

[0328] Sweat glands 108 that are relatively close to each other can simultaneously receive nerve impulses that activate them. However, the time required for metabolism to produce the pumping effect on the sweat gland cells may vary between different sweat glands 108, thus potentially resulting in partially overlapping cycles.

[0329] In at least some examples (e.g., Figure 12In the example shown, the distance between each chamber 102 and the sensor 166 can be the same. Since sweat glands 108 excrete into their respective chambers 102 simultaneously, this could cause a synchronized sweat burst to be detected. One way to address this problem 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 experience 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 happen to overlap. Recognition performed by the processor allows for the explicit determination of the sweat rate of each gland, regardless of whether there is overlap between sensor signals corresponding to different sweat glands 108. Therefore, a typical cycle of 30 seconds of excretion followed by a 150-second rest period is considered.

[0330] Figure 19 The graphs showing the relationship between sweat rate and time (top pane) and sensor signal and time (bottom pane) are shown when the corresponding sweat glands 108 have sweat bursts 192A, 192B, 198A, and 198B relative to each other at different times.

[0331] exist Figure 19 In the illustrated scenario, 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 the time periods indicated 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 will still be correct. Furthermore, in the unlikely scenario where the sweat burst 198A of the second sweat gland 108 happens to follow the sweat burst 192A of the first sweat gland 108, causing the resulting sensor data 166 to be interpreted as a single long sweat burst from a single sweat gland 108, such an erroneous assignment can be insignificant since the determined sweat rate does not change during the sweat burst period.

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

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

[0335] exist Figure 6 In the example shown (where a series of electrowetting tiles 124 are provided on the lower surface of an additional plate 128 opposite to outlet 114), all sweat droplets 112 are formed to be of the same size / volume, as previously described, determined by the distance 130 between outlet 114 and the additional plate 128. Since the sweat droplets 112 are formed to a priori known size / volume, the size of the coalesced sweat droplets 112, determined by the time it takes for these droplets 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 the alternative scenario illustrated (where a series of electrowetting tiles 124 are provided on the upper surface of plate 110, and no additional plate is used to allow sweat droplets 112 to detach 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 scenario of two sweat glands 108 excreting at the same rate. However, such an interpretation of a single sweat gland 108 can be ruled out because the time between detected successive sweat droplets 112 should be correspondingly shorter, which is not... Figure 20 The situation in the middle.

[0337] exist Figure 21In the scenario shown, 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 these 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, the following possibilities exist to consider: (a) two sweat bursts, each producing five sweat droplets 112 that are time-displaced during sensing; and (b) one sweat burst from the first gland producing seven sweat droplets 112 and one shorter sweat burst from the second gland producing 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) can 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 the 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 sweat gland 108 with relatively slow rise and fall. 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 scenario shown, sweat droplets 112 originate from two sweat glands 108 that excrete sweat into corresponding 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 corresponding sensor signal sets, but the corresponding sweat droplets 112 do not coalesce with each other. This sensor signal pattern can be attributed to each sweat gland 108 producing a set of five sweat droplets 112 that are time-shifted. An alternative explanation would require highly unstable behavior of one sweat gland 108, which is physiologically unlikely; that is, an oscillating sweat rate during a sweat burst is unlikely. 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 nanoliters / minute / 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 for two sweat glands 108 do not overlap, the processor can directly identify the corresponding patterns and directly derive the sweat rate of each sweat gland based on the data patterns, 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 therefore be distinguished by considering the periodic behavior of the sweat gland 108 (sweating bursts and resting periods). Even if sweat bursts are improperly distributed, it may have no effect on 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 of each gland.

[0345] Figure 23 A flowchart of a method 224 for determining the sweat rate of each 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, a sensor is used to sense sweat droplets over a period of time. For example, the sensor 166 described above can be used to implement step 230. In step 232, the sweat droplets are counted over a period of time. At 234, the time interval between the sweat droplets sensed successively during this time period is determined. This time interval may correspond to the period between the sensor signal returning to the baseline and the subsequent increase of 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] At 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 a time interval and a measure of the volume of each sweat droplet in the counted sweat droplets, as previously referenced. Figure 19-22 As described.

[0348] At step 240, the number of sweat glands assigned to active and resting periods is determined. Then, at step 242, the sweat rate of each gland is determined. This determination of the sweat rate of each gland uses the number of sweat droplets, a measure of the volume of each sweat droplet among 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 to 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 within 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 following factors: 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 reasonable sweat bursts and rest periods.

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

[0353] In a specific example, the algorithm begins with a template for the following: (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, 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. A goodness-of-fit criterion 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 through this subtraction, the remaining pulses are retained in the dataset. These 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 repetition 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 evaluated, and if, for example, it is greater than 5% to 20% of the original dataset, a new iteration begins with new fitting parameter values. In this way, 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 (compared to when the volume of the (unaggregated) sweat droplets 112 is not prior known).

[0358] For example, when Figure 17 When the illustrated device 100 is used to deliver sweat droplets 112 to sensor 166, the sweat droplets 112 can have different sizes / volumes, particularly during the rising and falling phases of a sweat burst. This may require a more complex implementation of step 238, for example, using a more complex model where the pulse time is variable. 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. This is because the size of each inlet 104 and the number of chambers 102 in each sensor 166 are limited (e.g., limited to 25), 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, wherein each device 100 has 25 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 would result in a smaller variation in the average sweat rate of each identified gland.

[0361] Figure 20 A highly improbable scenario is illustrated 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 glands 108, as previously described.

[0362] However, in Figure 17 In the case of the device shown, the larger sweat droplets 112 may be caused by the aggregation of sweat droplets 112 or by a higher sweat rate (recall that in this example, the diameter of the hemispherical sweat droplets could vary between 77 μm and 124 μm, depending on the sweat rate of each 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 nanoliters / minute / 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 nanoliters / minute / gland. However, since aggregated sweat droplets 112 at the low sweat rate (0.2 nanoliters / minute / gland) can be detected every 6 seconds, while single droplets 112 at the higher sweat rate (2.5 nanoliters / minute / 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 excretory 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 this sweat gland 108 activation into account. In this respect, for example, it can be calculated per cm... 2 The system was configured under the assumption of one hundred active sweat glands. This relatively high estimate can be explained by the activation of additional sweat glands 108 at an increased rate of sweat production.

[0366] Even when the sweat rate is relatively high (e.g., 5 nanoliters / minute / gland), Figure 6 The exemplary device 100 shown can also provide a 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 during a 30-second sweat burst. During subsequent rest periods (e.g., 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 as when the sweat rate is relatively low. Figure 25 The graph shows the sweat rate sensor signal as a function of time when the sweat rate is relatively high.

[0367] exist Figure 25In the example shown, the average sweat rate is 5 nanoliters / minute / 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 / s 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 / s).

[0368] As indicated 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 unlikely to receive sweat from a single sweat gland 108, the unlikely scenario 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 contemplated for determining whether two (or more) sweat glands 108 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 25 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 by using probability theory, the risk of violating this requirement is approximately 3 / 10000. 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 / 1000. Therefore, this boundary requirement helps ensure a sufficient number of single sweat gland 108 events are provided to establish a baseline sensor signal pattern, i.e., corresponding to a single sweat gland 108 excreting into a single chamber 102. With this baseline established, it is then possible to identify the sensor signal pattern resulting from two sweat glands 108 excreting into one chamber 102.

[0371] In principle, the requirement that four chambers 102 receive sweat from a single sweat gland 108 can, for example, be relaxed to allow two chambers 102 to receive sweat from a single sweat gland 108. In this case, the probability of violating this requirement would be 9 / 10000.

[0372] Figure 26 The diagram shows a graph (top pane) of the sweat rate sensor signal as a function of time when each sweat droplet 112 in chamber 102 originates from one sweat gland 108, and a graph (bottom pane) of the sweat rate sensor signal as a function of time when each sweat droplet 112 in chamber 102 originates from two sweat glands 108. It should be noted that the latter scenario is similar to... Figure 19-21 The scenes depicted in the text are clearly different, in 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 scene 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 under the assumption that sweat glands 108 in local areas of 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 nanoliters / minute / gland. However, the single gland baseline described above has been established, ruling 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 to be simultaneously bursting with sweat. This is reasonable because the corresponding 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 cause, for example, a 6-second interval between the start and end of the sweat burst, and a 3-second interval between the sensor signals during the sweat burst (see, for example...). Figure 22 This will immediately point to two asynchronous sweat glands and allow for direct identification of the situation.

[0375] It can be done Figure 24 The algorithm shown analyzes droplet pattern events where two sweat glands 108 excrete into a common chamber 102. The exception is that, 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 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 droplet 112 count”).

[0376] Sweat droplets 112 can be sensed, and the contact time between the sweat droplets 112 and the sensor 166 can be determined using, for example, a capacitive sensor and / or a conductivity sensor, as previously described. In particular, the conductivity sensor can help determine the sweat rate of each 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 from 0.06 g / 100 mL to 0.76 g / 100 mL depending on the sweat flow rate. 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 chamber 102 at a rate of 5 nanoliters / minute / gland; two sweat glands 108 excrete sweat into chamber 102, for example, simultaneously, with each sweat gland 108 excreting at a rate of 2.5 nanoliters / minute / gland; and three sweat glands 108 excrete sweat into chamber 102, for example, simultaneously, with each sweat gland 108 excreting at a rate of 1.67 nanoliters / minute / 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 situations because the sensor signal pattern will be the same in each of these scenarios. To determine the sweat rate of each 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 whose concentration 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 scenario to the second and third scenarios due to the sweat rate dependence of ion concentration (and sodium ion concentration). This difference in ion concentration between the corresponding scenarios can be directly detected. Due to the aforementioned advantages of scenarios 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 advantage can be used to determine the baseline ion concentration for a single sweat gland 108, allowing the various scenarios 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 concentration of the analyte measured (e.g., via conductivity measurement).

[0382] Alternatively, consider the following pair of additional scenarios: one sweat gland 108 excretes sweat into chamber 102 at a rate of 5 nanoliters / minute / gland; and two sweat glands 108 excrete sweat into chamber 102, for example, synchronously, wherein each sweat gland 108 excretes at a rate of 5 nanoliters / minute / gland.

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

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

[0385] While the second scenario seems unlikely, since localized sweat glands 108 physiologically do not tend to exhibit such significantly different sweat rates, a definitive interpretation can be obtained by detecting parameters related to the concentration of the analyte, which varies with the sweat rate (e.g., conductivity). In this particular illustrative example, the first interpretation would result in equal ion concentrations measured in the corresponding scenario, while the second interpretation would result in different ion concentrations measured; therefore, only one of these interpretations will be consistent with the measured parameters.

[0386] Another possible scenario is that one sweat gland 108 excretes sweat into chamber 102 at a rate of 5 nanoliters per minute per 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 nanoliters per minute per gland.

[0387] When two sweat glands 108 excrete into their respective chambers 102, the accidental coalescence of sweat droplets 112 from both chambers 102 will cause the time taken for the coalesced sweat droplets 112 to pass through the sensor 166 to increase (approximately 1.14 times longer in the case of hemispherical sweat droplets 112; and 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 in the case of 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. In scenarios where the corresponding sensor signal patterns do not overlap, the excretion of individual sweat glands 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 sweat glands 108 excreted into the same chamber 102 overlap, the sensor signal pattern can 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, and the situation can be directly identified. As additional evidence that two sweat glands 108, rather than one, are excreting into chamber 102, parametric measurements, such as measurements of ion concentration, as previously described, can 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 in that an electrowetting tile 124 is provided on the upper surface of a plate 110 defining a chamber 102. Sweat droplets 112 with different sizes / volumes 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 generated every second. A sweat burst can begin at some point during this second, such that the size / volume of the first sweat droplet 112 delivered to the sensor 166 can be smaller than the size / volume of subsequent sweat droplets 112 formed during the entire second between successive electrowetting waves. The latter can be considered "fully formed" sweat droplets 112, while the smaller sweat droplets 112 generated during the rising or falling phase of the sweat burst can be considered "partially formed."

[0391] It needs to be reiterated that, in Figure 17 In the example shown, at a low sweat rate, sweat droplet 112 may be too small to overlap with the two electrowetting tiles 124 that partially define outlet 114. Therefore, the sweat droplet 112 may not be delivered to sensor 166. However, after six electrowetting waves, and assuming an average sweat rate of 0.2 nanoliters / minute / gland, the sweat droplet 112 may have grown large enough to partially overlap with the two electrowetting tiles 124.

[0392] However, if only 0.5 seconds are available for sweat droplet 112 formation during the first electrowetting cycle, the total time for sweat droplet 112 growth 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 nanoliters / minute / 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 by the portion that migrates to the sensor can be much smaller than the fully developed sweat droplets 112.

[0394] Figure 27A graph (top pane) schematically depicting the sweat rate as a function of time, representing the frequency of the electrowetting wave 260 as a function of time, and the associated sweat rate sensor signal as a function of time, is shown when the electrowetting wave 260 and the sweat droplet 112 are asynchronous. In the depicted example, the average sweat rate is 5 nanoliters / minute / gland, and the sweat burst 192A begins 0.2 seconds before the electrowetting wave 260, such that the first sweat droplet 112 has only 0.2 seconds to form before being delivered to the sensor 166. This reflects that the time (0.19 seconds) taken for the first sweat droplet 112 to pass through the sensor 166 is shorter than the time (0.26 seconds) for the sweat droplet 112 to form during the entire one-second interval between successive electrowetting waves 260.

[0395] The final sweat droplet 112 has a formation time of 0.8 seconds, which reflects that the time (0.25 seconds) that the sweat droplet 112 takes to pass the sensor 166 is shorter than the time (0.26 seconds) that the sweat droplet 112 takes to form during the entire one-second period between the electrowetting waves 260.

[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 ramp is fast relative to the 1-second cycle of the electrowetting arrangement device 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 lower than the sweat rate in the middle of the sweat burst.

[0397] Based on the above regarding Figure 27 For reasons similar to those discussed, sweat droplets 112 formed during ascent / descent are smaller in size than those formed in the middle of an upslope. However, this results in the generation of unique sensor signal patterns, such as Figure 28 The lower pane is shown. The algorithm discussed above can either recognize this pattern or ignore this triggering effect. 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 sweat burst, as indicated by the arrows. At these extreme start and end points during 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 sensed sweat droplet 112 and the second sensed sweat droplet 112 take the same amount of time to pass through sensor 166 (0.2 seconds). The increasing time it takes for sweat droplets 112 to pass through sensor 166 clearly shows that subsequent sweat droplets 112 sensed by sensor 166 become increasingly larger during the rise. In the middle of the burst, the time it takes 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, while 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. Some sweat droplets 112 formed during descent are too small to be delivered to 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 there is no missing sensor signal during ascent in those subsequent sweat bursts.

[0402] The above considerations can be combined with Figure 6 In contrast to the case of the device 100 shown, in Figure 6 In the case of the illustrated device 100, the initiation of sweat droplet 112 delivery is not determined by the applied frequency of the electrowetting wave, 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 successive sweat droplets 112 generated in the middle of the burst. If larger sweat droplets 112 are sensed, these larger sweat droplets will be caused by the aggregation of sweat droplets 112 originating from different sweat glands 108 excreted into the corresponding chambers 102.

[0403] As a second example, the system includes three devices 100, each having three chambers 102. A sweat rate sensor 166 is provided for each of the three devices 100. Therefore, 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 incidence of two or more sweat glands 108 excreting sweat into the same chamber 102 may be higher 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 can lead to particularly complex overlapping data patterns, but with the aid of appropriate criteria in the algorithm, the results can be declared valid, 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, for example, in 0.75mm 2 Up to 1.5mm 2 Within a certain range. This ensures that (one or more) chambers 102 receive sweat from sweat glands 108, but prevents each chamber 102 from receiving sweat from so many sweat glands 108 (which 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 sensor 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 one or more sweat glands 108 that have been excreted into a particular chamber 102.

[0411] Those skilled in the art will recognize that more chambers 102 can be employed to handle variations in the sensed data. In this example, each cm... 2 The density of 100 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 adjusted to optimize the results. For example, when the device 100 is applied to a skin location with relatively few active sweat glands 108, the skin surface area used for sampling can be increased accordingly to obtain sufficiently meaningful data.

[0412] Lactic acid is an important biomarker because cells produce lactic acid when hypoxia occurs. 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, it is highly desirable to measure the concentration of lactic acid in sweat discreetly. However, there are two complicating factors when correlating the concentration of lactic acid in sweat with that in the 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 in the human body can take up to approximately 10 minutes, which is an acceptable delay from a clinical point of view.

[0414] To date, this disclosure provides 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 through sweat likely originates from the sweat glands themselves, while the remainder (5-10%) originates from the blood. It is necessary to distinguish in some way between lactic acid originating from the sweat gland cells themselves and lactic acid originating from the blood.

[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 nerve activity is relatively high, the rate of sweat production increases and requires a larger amount of oxygen. It is conceivable that oxygen consumption would cause the sweat gland to switch to an alternative (anaerobic) pathway, thereby producing lactic acid.

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

[0417] Furthermore, clinically relevant increases in blood lactate concentrations can have significantly different timescales on the order of several hours (e.g., 1–3 hours). These different timescales associated with sweat gland-related changes and blood-related changes in lactate concentration in sweat secreted onto the skin can be used to distinguish between previous and subsequent lactate sources. Therefore, measuring sweat lactate concentration as a function of time allows for a proper differentiation between changes in lactate concentration originating from sweat glands and those 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 as a function of time. In a brief summary of the above embodiments, sweat produced by sweat glands 108 is converted into individual sweat droplets 112 via chamber 102 (defined by plate 110). These sweat droplets 112 are then migrated toward sensor 166 via fluid transport components, such as using interfacial tension methods (employing topological gradients 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 as a function of time, sensor 166 may include a biomarker sensor specifically designed for such a particular biomarker). The concentration of lactate in each sweat droplet 112 can be detected when it comes into contact with (e.g., passes through) the detection surface of the lactate sensor.

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

[0421] In the various examples described in detail above, the fluid delivery assembly is arranged to deliver sweat droplets at a speed of 700 μm / s. When the length of the lactic acid sensor in the delivery direction of the sweat droplet 112 is, for example, approximately 60 μm, the time taken for each sweat droplet 112 to pass through the lactic acid sensor can be approximately 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 approximately 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 and 90 seconds, measures can be taken to reduce the migration rate of sweat droplets 112 on the detection surface of sensor 166. Nevertheless, care should be taken not to reduce the transport rate of sweat droplets 112 to the point that sweat droplets 112 originating from the same chamber 102 coalesce.

[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 "lower power" chemical gradient than that used by the 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 example, sweat droplets 112 can be delivered through the detection surface of the lactic acid sensor by using an electrowetting arrangement device 144. Figure 29 A portion of an exemplary electrowetting arrangement device 144 is shown. The migration of electrowetting-driven sweat droplets 112 can be achieved by a series of charging and discharging of the electrowetting tiles 124, as previously described. Figure 29 In the example shown, electrowetting waves are created on electrowetting tiles 124 numbered 1 to 8. Figure 29 The connection scheme shown in the upper pane allows for the generation of a new electrowetting wave every eight tiles.

[0425] Therefore, the following connection scheme can be used to deliver sweat droplets 112 through a series of electrowetting tiles 124, designated 1 to 32, at a constant speed. For example... Figure 29As 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 created by, for example, implementing a generator in the following sequence: 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 created for 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, corresponding to a sweat droplet 112 velocity of 700 μm / s. Since the 1-second time intervals are successively cycled, the frequency of the electrowetting wave in this particular example is 1 Hz.

[0428] exist Figure 29 In the case of the connection scheme shown in the upper pane, the corresponding electrowetting waves created for every eight tiles are effectively combined to form an electrowetting wave over the entire length of the 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 device 144 shown in Figure 11.

[0429] exist Figure 29The lower pane shows different connection schemes (connection scheme B) 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 arrangement device 144. This is to accommodate the relatively slow response of the lactic acid sensor (e.g., an electrochemical lactic acid sensor), as explained above.

[0430] Figure 29 Connection 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 top pane has been reduced to one-quarter.

[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 / s. 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. Additionally, 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 (e.g., by means of the detection surface of the lactic acid sensor being opposite the electrowetting tile AC).

[0433] As described above, when the migration velocity is 700 μm / s, 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 approximately 0.15 to 0.57 seconds when the sweat droplet 112 is bundled. However, when using an electrowetting wave that delivers the sweat droplet 112 at a speed as slow as one-quarter (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 stepping duration of a local area of ​​sensor 166 to be neither equal to nor greater than one second, as this may lead to the following risk: the sweat droplets 112 in that area may be caught up by the sweat droplets 112 transported by the electrowetting wave with a period of 1 second, resulting in uncontrolled collisions of the sweat droplets 112.

[0435] Repeating the three local tiles (A, B, and C) can further extend the time it takes for sweat droplets 112 to pass through sensor 166. For example, connecting four successive sets (ABCABCABCABC) of these three tiles in configuration B 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, thus requiring the use of larger tiles, which would offset the increase in contact time.

[0436] It has been determined that 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, and the system can be used accordingly to measure the lactic acid concentration of each sweat droplet 112. Depending on the sweat rate, typically 5 to 30 sweat droplets from each sweat burst of the sweat gland 108 can be delivered to the lactic acid sensor. Therefore, the lactic acid concentration as a function of time can be determined.

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

[0438] The apparatus, systems, and methods of this disclosure enable close monitoring of lactic acid concentration in sweat as a function of 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 time scale can be determined, and the lactate concentration in sweat derived from blood can be determined. In this way, a reliable correlation can be established between blood lactate levels and lactate levels in sweat. It can be shown that it is not necessary to find an exact correlation, 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 inquire into lactate kinetics, which is a prerequisite for verifying the time-scale-based distinction between changes in lactate concentration derived from sweat glands and changes in lactate concentration derived from blood.

[0440] Figure 30 The top pane provides a plot of the sweat rate sensor signal as a function of time during a 30-second sweat burst. In this example, there is one sweat gland excreting at an average sweat rate of 0.4 nanoliters / minute / gland. Figure 30 The lower left and lower right panes provide two seemingly reasonable models for lactic acid concentration, which varies according to sweat gland metabolism. Both the lower left and lower right panes indicate a baseline level of blood-derived lactic acid concentration of 278 in sweat. This baseline level is virtually constant during a 30-second time period, but may rise when, for example, an impending infection is present.

[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, up to a certain maximum, and then the concentration decreases again.

[0442] Figure 30The model shown in the lower right pane illustrates 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 peak after multiple sweat bursts, and the sweat glands become inactive for an extended period despite further neural stimulation.

[0443] It is worth noting that baseline lactate concentrations change slowly only over several hours, and this baseline level can be considered almost constant within 10 sweat bursts (equivalent to a 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, this observation 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 referenced 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 sensor, impedance sensor, conductivity sensor, 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 the two may be in parallel, independent microfluidic loops.

[0445] It needs to be reiterated that 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 because the biomarker sensor has relatively high sensitivity, as such a biomarker sensor is often needed to sense relatively low (e.g., sub-millimolar) concentrations of biomarkers (e.g., glucose). Therefore, the biomarker sensor can be sensitive enough to be used to count the sweat droplets 112 and measure the contact time of each sweat droplet 112 with the sensor 166. Thus, in some examples, the system can be implemented using only the biomarker sensor, as described above. Omitting the additional sweat flow rate sensor can advantageously reduce the complexity of the system and can also save energy, thereby extending the working 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 sensor. Typically, electrochemical sensors for semi-continuous monitoring are based on enzymatic conversion steps that may involve more than one hundred conversions per second for each 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 (e.g., 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 (e.g., when the biomarker sensor is dropped or bumped against a hard surface or immersed in a liquid), and manufacturing variations between sensors.

[0448] When this system is used to monitor objects, offline calibration of biomarker sensors can negatively impact the workflow. 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 arrangement device for supplying the calibration fluid dropwise to the biomarker sensor.

[0450] Various methods are conceivable for implementing the dropwise supply of calibration fluid to biomarker sensors (e.g., electrochemical biomarker sensors). The calibration fluid contains dissolved calibration components at known concentrations required for calibrating the biomarker. 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, such as those used to stabilize 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 the calibration fluid at a constant and relatively high concentration. This can cause the additional components to saturate the absorption and interaction of the biomarker sensor, thereby creating 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 arrangement device 278 can be configured to inject calibration fluid droplets into a conduit 280, which delivers the calibration fluid droplets 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 calibration fluid droplets to the biomarker sensor.

[0453] The dosing arrangement device 278 may, for example, include a valve for controlling the injection of calibration fluid droplets from the reservoir 282 into the conduit 280. This 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 31 As shown, conduit 280 meets passage 284, which delivers sweat droplet 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 droplet 112, calibration fluid droplets may be delivered downwards to the biomarker sensor along the chemical gradient and / or topological gradient 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 device 144. In this example, the dosing arrangement 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 arrangement 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 additional electrowetting waves provided by the 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. This pressure gradient can be provided by storing the calibration fluid in reservoir 282 at a pressure above atmospheric pressure (e.g., approximately 3-4 bar). Therefore, the pressure on the sensor 166 side of the valve of the dosing arrangement device 278 can be lower than the pressure in reservoir 282 (e.g., approximately atmospheric pressure). This pressurization can be achieved, for example, using pressurized air.

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

[0460] Figure 32 A non-limiting example of a sweat sensing system 300 is schematically depicted. Individual chambers 102 collect sweat, but only a single chamber 102 is shown for clarity. In this example, sweat enters chamber 102 via inlet 104 and forms hemispherical sweat droplets 112, which protrude from outlet 114. The sweat droplets 112 may contact an additional plate 128 opposite outlet 114 when they grow to a certain size / volume, and detach onto the additional plate 128. In this example, the additional 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 As 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 device 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 an additional plate 128 and sidewalls, which at least partially define a closed pathway 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 the additional plate 128 is typically 150 μm. This distance 130 defines the size / volume of the sweat droplets 112, as previously described. After the electrowetting wave is initiated at tile 1, the sweat droplets 112 are transported in the direction of sensor 166.

[0464] Sensor 166 includes a channel 168 sized such that each sweat droplet in sweat droplet 112 forms a meniscus across the cross-section of channel 168 at the head and tail of sweat droplet 112, 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 sensor module in sensor module 190 is arranged to sense sweat delivered by the corresponding one or more electrowetting paths 188.

[0466] Each sensor module in the corresponding sensor module 190 may include, for example, 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 include, for example, 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] Within the area defined by tiles A1-A4, B1-B4, and C1-C4, it is possible to proceed via the above-mentioned... Figure 28 The described electrical connection scheme aims to slow down the migration speed of sweat droplets.

[0469] Electrowetting tiles 124, marked 1 to 1V, 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 (e.g., 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 incompletely developed 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 sits for long periods, filling a chamber 102 with a height of, for example, 25 μm could take several hours. However, by providing a device 100 with more chambers 102 of smaller volume, the time required to fill the chambers 102 can be reduced. For this purpose, Figure 33 A portion of the device 100 with increased chamber 102 density is shown.

[0472] Device 100 includes at least one first track; one of the at least one first track, track 406A, is in Figure 33 The at least one first track is visible. Each of the at least one first track includes a plurality of chambers 102 that receive sweat from the surface of the skin 106. Each of the 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 plates 110. After one or more chambers in the 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 track) may extend perpendicularly to the second track 408. Figure 33In 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, for example, alternative designs using the aforementioned carrier fluid.

[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 also contemplated, such as two, three, four, five, seven, eight or more chambers.

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

[0479] Plate 110 is positioned against skin 106, and inlet 104 of cylindrical chamber 102 is located at the sampling site on skin 106. As shown, outlet 114 of each cylindrical chamber 102 exits and reaches 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) an additional 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 additional plate 128.

[0481] The device 100 may include a conductive layer 402 (e.g., 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] The additional 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 (e.g., 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, with the exception of the electrode of the outlet 114 furthest from the second track 408 that is not aligned.

[0484] In the second track 408, chamber 102 may be absent, and therefore outlet 114 may be absent. Thus, in this example, the second track 408 may be used solely for delivering 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, with particular attention to the electrode 124B of the electrowetting assembly.

[0486] Figure 36 It shows Figure 34 and Figure 35 An overlay of the plan view provided in the image. Figure 38 It shows Figure 36 The superimposed image shows two sweat droplets 112 being transported along the first tracks 406A and 406C.

[0487] Figure 37A Showing the target Figures 34-36 The 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 being trapped in the outlets 114 of other collection chambers 102 can be reduced.

[0488] Alternatively or additionally, this can be achieved by utilizing an outlet 114 (e.g., eccentrically positioned relative to the corresponding relative electrode 124B) Figure 37B (as shown) to achieve this situation.

[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 indeterminate volume of sweat droplets 112.

[0490] As previously described, electrode 124B can be used to create 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 to continuously move the electrowetting wave on the first track 406A-406D and the second track 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 independently.

[0491] Multiple VIA 412s (e.g., conductive vias) can be used to provide Figure 39 The relatively simple assembly shown contains five electrical connections 410 to 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, it is possible to sequentially activate electrodes 124B using five different AC frequencies on a single power line to create an electrowetting wave.

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

[0493] exist Figure 40 and Figure 41 In the example shown, an electrowetting wave is induced by charging / discharging electrodes 124B numbered 1 to 5 in the first tracks 406A-406J. 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 Figure 41 The device 100 shown delivers sweat droplets 112. Figure 43 It shows Figure 41 and Figure 42 The electrical connection of electrode 124B is shown. Similar to the reference above. Figure 39 The example described can be connected using VIA 412. Figure 43 The example shown is electrode 124B (e.g., most of the electrodes in electrode 124B).

[0495] Figure 43 A portion of the device 100 shown may be referred to as a “collection unit”. The collection unit in this example comprises ten first tracks 406A-406J 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 originate from subsequent collection units) are located in the first track 408.

[0496] Figure 44An exemplary device 100 is depicted, which can be considered as a "serpentine route and collection unit" and includes three collection units, for example, Figure 43 The three collection units shown are shown in the collection unit diagram. 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 envisioned, 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 very simple and straightforward to implement in practice, for example, using a relatively small number of VIA 412, as previously described.

[0499] Figure 45 A device 100 with an alternative electrical connection design is shown. By connecting the electrode 124B to the conductive path diagonally relative to tracks 406A-406L, 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 , Figure 43 and Figure 44 In the example shown, 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 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, sweat glands 108 may or may not be associated with a given outlet 114. Assuming a cylindrical chamber 102 with a diameter of 30 μm, and assuming that the sweat gland 108 exits and reaches a skin 106 with a diameter of 40 μm (which can be precisely aligned with the chamber 102 or can barely contact the chamber 102), the chamber 102 may approach 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 track with six chambers 102, this corresponds to approximately 5.7 × 10⁻⁶. 4 μm 2 The total accessible skin surface for collecting sweat. When a person (e.g., a patient) is in a sedentary state, per 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 per 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 100 active glands / cm². 2 The more active the sweat glands 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 / cm² are used for further interpretation.

[0502] This is why it might take 1754 first orbitals to approach 1 cm. 2 The sweat glands are placed on the skin surface for sweat collection. The number of active glands can vary between body locations and can even differ from person to person. These numbers will be used for further explanation below; however, those skilled in the art will understand that, for example, other numbers can also be used depending on body location, and therefore the device 100 and method can be adjusted accordingly.

[0503] 100 active glands / cm 2 And a 5.7 × 10⁻⁶ accessible skin surface for collecting sweat through 6 chambers 102 / first track. 4 μm 2 In this case, there are an average of 0.057 active glands in the represented accessible skin surface area. Using the Poisson distribution equation:

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

[0505] Where PX is the probability that x active sweat glands exist within the accessible skin surface area for the first orbit. <x>Let x be the average number of active sweat glands in a given skin surface area, and let x! be the factorial of x, which can determine the following probabilities:

[0506] P0 = 0.9446

[0507] P1 = 0.0538

[0508] P2 = 0.0015

[0509] These represent the probabilities of no active sweat glands, one active sweat gland, and two active sweat glands spraying sweat onto the first track, 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 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 collision between a fully developed sweat droplet and 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 on each of the first tracks. 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 an uncertain size, varying between one and two fully formed sweat droplets. This equates to 2.9% of the measurements yielding an uncertain droplet size. Using the subtraction algorithm described above, a 2.9% residual is acceptable. Furthermore, larger sweat droplets (a combination of fully formed sweat droplets plus partially formed ones) can still be identified as a single fully formed sweat droplet plus some unidentified droplets, thus reducing the already acceptable residual.

[0517] In the first consideration, a given sweat droplet of a fully developed droplet size can be attributed to: two incompletely developed sweat droplets merging into the size of a fully developed sweat droplet; or three incompletely developed sweat droplets merging into 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 two fully developed sweat droplets can be attributed to: two merged fully developed sweat droplets; or one fully developed sweat droplet merged with two droplets of a total size equal to one fully developed sweat droplet. The latter configuration requires three active sweat glands to spray sweat onto a first track. The ratio between the probability of one active sweat gland and the probability of two or more active sweat glands is:

[0519] P1 / (1–(P0+P1+P2)=1820

[0520] This can result in even smaller residuals.

[0521] Note that there may be some size variation between fully developed sweat droplets, as droplets can 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 is related to the size of the sweat droplets), the precise sweat volume of each droplet remains determinable. Based on the above analysis, one measurement out of 35 might incorrectly identify the sweat droplet size. Nevertheless, most signals can represent the correct size of the sweat droplets, and the algorithm described above achieves acceptable residuals.

[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 a coalesced droplet with twice the volume, which can be easily identified by a sweat rate sensor, as previously described. This can be achieved, for example, by examining the pulse width, which can be pre-defined a priori for a sweat droplet of twice the size. In fact, since most sweat droplets can be single / non-coalescing, a baseline size for such sweat droplets can be established.

[0523] Calculation of chamber surface area

[0524] A typical surface area can comprise approximately 0.1 to 1 active gland. This allows for the use of devices to 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 / mm 2 > 0.05 0.1 6 Number of glands / 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 attributed to a chamber.

[0531] The chamber filling time may, for example, have an additional maximum value in the order of minutes 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 can be in the order of seconds to minutes.

[0532] For a single gland, the rate of sweat production at rest is on the order of 0.2 nanoliters per minute, which is equal to 3.3 × 10⁻⁶. 3 μm 3 / s. For an individual exercising, this can reach 5 nanoliters per minute for a single gland. In exceptional circumstances, the sweat rate may be even higher, for example, 5 nanoliters per minute, which equals 8.25 × 10⁻⁶. 4 μm 3 / s.

[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 chambers in a sedentary environment may not meet the maximum filling time requirements for all sweat gland surface area densities. Therefore, the chamber volume should be smaller, and the range is defined in the table below.

[0537]

[0538] Table 4 Filling time of small chambers

[0539] In this case, the maximum fill time is on the order of 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 / mm 2 The surface area density of active glands, and (ii) the average number of active glands to be measured needs to be measured at 100 mm. 2 (1cm 2 The skin surface area was sampled. The calculations for various sweat gland densities are shown in the table below.

[0542] <![CDATA[Active glands / mm 2 > 0.05 0.1 6 The average total skin area associated with 5 active glands <![CDATA[1cm 2 ]]> <![CDATA[0.5cm 2 ]]> <![CDATA[0.00835cm 2 ]]> The average total skin area associated with 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 a small amount of active glands, it may be necessary to measure at least 1 cm. 2 The skin area.

[0545] A suitable surface area for a relatively small chamber could be 0.0078 mm². 2 The size is on the order of magnitude, resulting 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 12800 (100mm). 2 / 0.0078mm 2 The magnitude is on the order of 3200 to 51200. A suitable range is between 3200 and 51200.

[0547] The device is designed to have individual small chambers that all enter the electrowetting path, for example, as in Figures 33 to 45 As shown in the example.

[0548] Alternatively, the device can be designed to have multiple individual small chambers, with sweat droplets converging along 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 designs shown, each design constitutes one chamber. In this case, only the two smallest chambers (see Table 3) can meet the criterion for maximum filling time, resulting in times between 0.0167 and 0.167 mm. 2 The surface area between them.

[0550] For those exercising only at a rate of at least 5 nanoliters / minute / gland, with a 1mm... 2 Up to 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 nanoliters / minute / gland.

[0551] The apparatus, systems, and methods of this disclosure can be applied to non-invasive, semi-continuous, and long-term monitoring of biomarkers indicating health status 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 also 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 taken only on a sampling basis when patients visit a physician; however, it should be noted that this disclosure can also be usefully applied to perform 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 sweat monitoring system, comprising: Sensor (166), which is used to sense sweat droplets; as well as Device (100) for delivering sweat droplets to the sensor, the device comprising: A plurality of chambers (102), each of the chambers having an inlet (104) and an outlet (114), the inlet for receiving sweat from the skin, the outlet being arranged such that sweat droplets form after the chamber is filled with sweat and the sweat droplets protrude from the outlet; and 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 respective outlet can be used to form subsequent sweat droplets as the respective chamber is further filled and the subsequent sweat droplets protrude from the respective outlet, wherein the fluid delivery assembly is arranged to deliver the released sweat droplets at least as fast as the subsequent sweat droplets protruding from the respective outlet, such that sweat droplets from the same chamber do not contact each other, and wherein the sensor (166) includes a channel (168) sized such that each sweat droplet passing through the channel forms a meniscus across the cross-section of the channel at its head and tail.

2. The system according to claim 1, wherein, The fluid delivery assembly is arranged to deliver the released sweat droplets faster than the subsequent sweat droplets protruding from the corresponding outlet (114).

3. The system according to claim 1 or claim 2, wherein, The fluid delivery assembly includes a surface for delivering the sweat droplets thereon; optionally, the surface is provided with alternating hydrophobic and hydrophilic water areas for delivering the sweat droplets.

4. The system according to claim 3, wherein, The fluid delivery assembly is configured to provide a carrier fluid flow for releasing sweat droplets protruding from the outlet (114) of the respective chamber (102) and / or delivering the released sweat droplets to the sensor; optionally, wherein the surface is a contoured surface, wherein each outlet (114) is provided at the apex of the contoured surface, and the fluid delivery assembly is arranged to direct the carrier fluid flow to the sweat droplets protruding from the respective outlet at the apex.

5. The system according to any one of the preceding claims, wherein, The fluid delivery assembly includes: A series of tiles (124) disposed between the outlet (114) and the sensor; and An electric field generator is used to sequentially charge and discharge each of the tiles in the series to release each of the sweat droplets from the corresponding outlet and / or to convey each of the sweat droplets toward the sensor.

6. The system according to any one of the preceding claims, wherein, Each chamber in the chamber (102) tapers from the inlet (104) toward the outlet (114).

7. The system according to any one of the preceding claims, wherein, Each of the chambers (102) is divided into compartments, at least some of which are fluidly connected to each other to allow the respective chamber to be filled with sweat; optionally, each of the chambers is separated by a plurality of pillars (120) and / or by a porous material (122) having pores defining the compartments.

8. The system according to any one of the preceding claims, wherein, The fluid delivery assembly includes an additional surface opposite at least some of the outlets (114), the additional surface being spaced apart from the at least some of the outlets such that each protruding sweat droplet is released from the at least some of the outlets upon contact with the additional surface; optionally, the fluid delivery assembly is configured to control the spacing (130) between the additional surface and the at least some of the outlets based on a measure of sweat rate.

9. The system according to any one of the preceding claims, wherein, The fluid delivery assembly is arranged to fluidly connect the respective outlets of each chamber in the chambers to the sensor in parallel.

10. The system according to any one of the preceding claims, wherein, The plurality of chambers (102) are arranged in groups (154), a subset of the plurality of chambers belonging to each group, wherein the fluid delivery assembly includes: The first interconnection of each group (158); A first branch (156) is used to fluidly connect each chamber (102) of the corresponding group to the first interconnect; The second interconnecting element (162) in every two or more groups; and A second branch (160) is used to fluidly connect the first interconnect to a corresponding second interconnect, wherein each of the second interconnects is fluidly connected to the sensor; Optionally, the fluid delivery assembly further includes: A third interconnect for every two or more of the second interconnects; and A third branch (164) is used to fluidly connect the two or more second interconnects to a corresponding third interconnect, wherein the third interconnect is fluidly connected to the sensor.

11. The system according to claim 5, comprising: At least one first track (406A, 406B, 406C, 406D), the chamber (102) being defined in the at least one first track; as well as A second track (408) is provided, wherein each of the at least one first track is 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; optionally, wherein the at least one first track is a plurality of first tracks.

12. The system according to claim 11, wherein, The tile (124) is provided along the at least one first track (406A, 406B, 406C, 406D) and along the second track (408); optionally, an electrical connection is provided between one or more pairs of tiles, each pair comprising one tile provided along the at least one first track and one tile provided along the second track.

13. The system according to any one of the preceding claims, wherein, 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 (108), and each inlet has a diameter of 0.005 mm. 2 Up to 20 mm 2 The area.

14. The system according to any one of the preceding claims, wherein, The sensor (166) includes at least one of the following: a capacitive sensor, a conductivity sensor, an impedance sensor, an optical sensor, an electrochemical sensor, and a sweat biomarker sensor.

15. The system according to any one of the preceding claims, wherein, The sensor (166) also includes: Multiple series of tiles (124) are arranged in the channel (168), each series of which extends in the direction in which the sweat droplets are transported through the channel; An electric field generator is used to sequentially charge and discharge each tile in each series of the tiles to convey the sweat droplets through the channel, wherein the respective series of tiles are sufficiently close to each other in a direction perpendicular to the direction in which the sweat droplets are conveyed through the channel, such that, depending on the volume of the sweat droplets, one or more series of the tiles convey the sweat droplets through the sensor; and Multiple sensor modules (190), each of which is arranged to sense sweat delivered by a corresponding series of the multiple series.

16. A method for delivering sweat droplets to a sensor, the method comprising: Multiple chambers are filled with sweat received from the skin, each chamber having an outlet, and the filling continues until one or more sweat droplets protrude from one or more outlets of the chamber, respectively. Release one or more protruding sweat droplets; and The one or more released sweat droplets are delivered to the sensor such that each outlet is configured to form a subsequent sweat droplet as the corresponding chamber is further filled and the subsequent sweat droplet protrudes from the outlet, wherein the released sweat droplets are delivered at least as quickly as the subsequent sweat droplets protruding from the outlet of the corresponding chamber, such that sweat droplets from the same chamber do not contact each other, wherein the sensor includes a channel sized such that each sweat droplet passing through the channel forms a meniscus across the cross-section of the channel at its head and tail.

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