Patent Application
20190254641
Wearable biofluid sensing technologies have enormous potential for applications ranging from athletics, to neonatology, to pharmacological monitoring, to personal digital health, to name a few applications. Sweat contains many of the same biomarkers, chemicals, or solutes that are carried in blood and can provide significant information enabling one to diagnose illness, health status, exposure to toxins, performance, and other physiological attributes even in advance of any physical sign. Furthermore, sweat itself, the action of sweating, and other parameters, attributes, solutes, or features on, near, or beneath the skin can be measured to further reveal physiological information.
Of all the other physiological fluids used for bio monitoring (e.g., blood, urine, saliva, tears), sweat has arguably the least predictable sampling rate in the absence of technology. However, with proper application of technology, sweat can be made to outperform other non-invasive or less invasive biofluids in predictable sampling. For example, it is difficult to control saliva or tear rate without negative consequences for the user (e.g., dry eyes, tears, dry mouth, or excessive saliva while talking). Urine is also a difficult fluid for physiological monitoring, because it is inconvenient to take multiple urine samples, it is not always possible to take a urine sample when needed, and control of biomarker dilution in urine imposes further significant inconveniences on the user or test subject.
Known and existing methods of reducing sweat volume and increasing sampling rate predictability include those reported frequently in the clinical literature, such as coating the skin with petroleum jelly or oil through which sweat can push. However, these techniques have been demonstrated only for sweat collection and are not necessarily compatible with a wearable sensor. For example, petroleum jelly would wet against the sensor and effectively seal it from any sweat. Furthermore, other possible sweat pressure-activated methods must somehow be affixed to skin so that sweat is confined horizontally (otherwise sweat pressure activation is not possible). Conventional approaches will not work with wearable sensors, and inventive steps are required for enablement. Clearly, the state of art is lacking in devices to properly reduce the volume between sensors and skin, which is critical for fast sampling times or for sampling during intervals with very low sweat rates. In addition, it also may be critical for prolonged stimulation (i.e., where less stimulation is required over longer periods), and for improving biomarker measurements where a low sweat rate is required to ensure correlation between biomarker concentrations in sweat and those in blood.
One novel method of reducing sweat volume as disclosed in PCT/US2016/043771 involves using pressure-activated sealants to horizontally confine sweat flow and reduce sweat volume. In order to reduce sweat volume, however, sweat pressure-activated methods also require the sensor to be properly aligned with sweat glands, which can prove difficult. Since it would be impractical for sweat sensing device users to reliably place a device in ideal alignment with sweat glands, devices may be designed to optimize sweat gland coverage when the device is randomly placed on skin. However, even with such designs, sweat gland density may vary with between individuals, or even body location on the same individual. Therefore, a sweat sensing device that is self-aligning with sweat glands may improve sensor proximity to sweat glands under a variety of circumstances, thereby reducing sweat volume.
However, self-aligning sweat sensing designs must also be configured to access prolonged sweat stimulation, which is a significant challenge. Further, as with other referenced means of reducing sweat volume, self-aligning sensors must also be protected from abrasion. The disclosed invention, therefore, discloses a means of providing prolonged sweat stimulation for abrasion-protected self-aligning sensors by configuring a sweat-stimulating chemical in close proximity to the sensors, and enabling sudomotor axon reflex sweat response through diffusion of the sweat stimulation compound into the skin.
The disclosed invention provides a biofluid sensing device configured with a membrane-enhanced sensor located in a sweat collector. The disclosed analyte-specific sensor is configured to reduce biofluid sample volume due to its close proximity to the skin and source of sweat biofluid. The sensor is contained within a pH and salinity-stabilized fluid that, in turn, is contained in a selectively permeable membrane to improve sensor performance in variable biofluids, and to protect the sensor from skin contact. In one embodiment, the biofluid sensing device includes means to protect the self-aligning sensors from abrasion against the skin or device components. Other embodiments of the disclosed invention include a track-etched membrane to provide sensor protection.
The objects and advantages of the disclosed invention will be further appreciated in light of the following detailed descriptions and drawings in which:
As used herein, “sweat” means a biofluid that is primarily sweat, such as eccrine or apocrine sweat, and may also include mixtures of biofluids such as sweat and blood, or sweat and interstitial fluid, so long as advective transport of the biofluid mixtures (e.g., flow) is primarily driven by sweat.
As used herein, “biofluid” may mean any human biofluid, including, without limitation, sweat, interstitial fluid, blood, plasma, serum, tears, and saliva.
“Biofluid sensor” means any type of sensor that measures a state, presence, flow rate, solute concentration, solute presence, in absolute, relative, trending, or other ways in a biofluid. Biofluid sensors can include, for example, potentiometric, amperometric, impedance, optical, mechanical, antibody, peptide, aptamer, or other means known by those skilled in the art of sensing or biosensing.
“EAB sensor” means an electrochemical aptamer-based biosensor that is configured with a plurality of aptamer sensing elements that, in the presence of a target analyte in a fluid sample, produce a signal indicating analyte capture, and which signal can be added to the signals of other such sensing elements, so that a signal threshold may be reached that indicates the presence or concentration of the target analyte. Such sensors can be in the forms disclosed in U.S. Pat. Nos. 7,803,542 and 8,003,374 (the “Multi-capture Aptamer Sensor” (MCAS)), or in U.S. Provisional Application No. 62/523,835 (the “Docked Aptamer Sensor” (DAS)).
“Continuous monitoring” means the capability of a device to provide at least one measurement of biofluid determined by a continuous or multiple collection and sensing of that measurement or to provide a plurality of measurements of biofluid over time.
“Chronological assurance” means the sampling rate or sampling interval that assures measurement(s) of analytes in biofluid in terms of the rate at which measurements can be made of new biofluid analytes emerging from the body. Chronological assurance may also include a determination of the effect of sensor function, potential contamination with previously generated analytes, other fluids, or other measurement contamination sources for the measurement(s). Chronological assurance may have an offset for time delays in the body (e.g., a well-known 5- to 30-minute lag time between analytes in blood emerging in interstitial fluid), but the resulting sampling interval is independent of lag time, and furthermore, this lag time is inside the body, and therefore, for chronological assurance as defined above and interpreted herein, this lag time does not apply.
As used herein, “determined” may encompass more specific meanings including but not limited to: something that is predetermined before use of a device; something that is determined during use of a device; something that could be a combination of determinations made before and during use of a device.
As used herein, “sweat sampling rate” is the effective rate at which new sweat, or sweat solutes, originating from the sweat gland or from skin or tissue, reaches a sensor that measures a property of sweat or its solutes. Sweat sampling rate, in some cases, can be far more complex than just sweat generation rate. Sweat sampling rate directly determines, or is a contributing factor in determining the chronological assurance. Times and rates are inversely proportional (rates having at least partial units of 1/seconds), therefore a short or small time required to refill a sweat volume can also be said to have a fast or high sweat sampling rate. The inverse of sweat sampling rate (1/s) could also be interpreted as a “sweat sampling interval(s)”. Sweat sampling rates or intervals are not necessarily regular, discrete, periodic, discontinuous, or subject to other limitations. Like chronological assurance, sweat sampling rate may also include a determination of the effect of potential contamination with previously generated sweat, previously generated solutes, other fluid, or other measurement contamination sources for the measurement(s). Sweat sampling rate can also be in whole or in part determined from solute generation, transport, advective transport of fluid, diffusion transport of solutes, or other factors that will impact the rate at which new sweat or sweat solutes reach a sensor and/or are altered by older sweat or solutes or other contamination sources. Sensor response times may also affect sampling rate.
As used herein, “sweat stimulation” is the direct or indirect causing of sweat generation by any external stimulus, the external stimulus being applied for the purpose of stimulating sweat. One example of sweat stimulation is the administration of a sweat stimulant such as pilocarpine. Going for a jog, which stimulates sweat, is only sweat stimulation if the subject jogging is jogging for the purpose of stimulating sweat.
Sudomotor axon reflex (SAR) is a biological response in which innervation of sweat glands occurs as a result of peripheral functionality of sudomotor units (i.e., the body will stimulate a group of sweat glands near the direct stimulation region).
As used herein, “sweat generation rate” is the rate at which sweat is generated by the sweat glands themselves. Sweat generation rate is typically measured by the flow rate from each gland in nL/min/gland. In some cases, the measurement is then multiplied by the number of sweat glands from which the sweat is being sampled.
As used herein, “measured” can imply an exact or precise quantitative measurement and can include broader meanings such as, for example, measuring a relative amount of change of something. Measured can also imply a binary measurement, such as ‘yes’ or ‘no’ type measurements.
As used herein, “sweat volume” is the fluidic volume in a space that can be defined multiple ways. Sweat volume may be the volume that exists between a sensor and the point of generation of sweat or a solute moving into or out of sweat from the body or from other sources. Sweat volume can include the volume that can be occupied by sweat between: the sampling site on the skin and a sensor on the skin where the sensor has no intervening layers, materials, or components between it and the skin; or the sampling site on the skin and a sensor on the skin where there are one or more layers, materials, or components between the sensor and the sampling site on the skin.
As used herein, “solute generation rate” is simply the rate at which solutes move from the body or other sources into sweat. “Solute sampling rate” includes the rate at which these solutes reach one or more sensors.
As used herein, “microfluidic components” are channels in polymer, textiles, paper, or other components known in the art of microfluidics for guiding movement of a fluid or at least partial containment of a fluid.
As used herein, “state void of sweat” is where a space or material or surface that can be wetted, filled, or partially filled by sweat is in a state where it is entirely or substantially (e.g., >50%) dry or void of sweat.
As used herein, “advective transport” is a transport mechanism of a substance or conserved property by a fluid due to the fluid's bulk motion.
As used herein, “diffusion” is the net movement of a substance from a region of high concentration to a region of low concentration. This is also referred to as the movement of a substance down a concentration gradient.
As used herein, “convection” is the concerted, collective movement of groups or aggregates of molecules within fluids and rheids, either through advection or through diffusion or a combination of both.
As used herein, a “volume-reduced pathway” is a sweat volume that has been reduced by addition of a material, device, layer, or other body-foreign substance, which therefore decreases the chronologically assured sweat sampling interval for a given sweat generation rate. This term can also be used interchangeably in some cases with a “reduced sweat pathway”, which is a pathway between eccrine sweat glands and sensors that is reduced in terms of volume or in terms of surfaces wetted by sweat along the pathway. Volume reduced pathways or reduced sweat pathways include those created by sealing the surface of skin, because skin can exchange water and solutes with sweat.
As used herein, “volume reducing component” means any component that reduces the sweat volume. In some cases, the volume reducing component is more than just a volume reducing material, because a volume reducing material by itself may not allow proper device function (e.g., the volume reducing material would need to be isolated from a sensor for which the volume reducing material could damage or degrade, and therefore the volume reducing component may comprise the volume reducing material and at least one additional material or layer to isolate volume reducing material from said sensors).
As used herein “pressure-permeated component” is a component that requires pressure to be permeated by sweat. Pressure-permeated components may also include all known one-way valves, which are opened by pressure, including those known by those skilled in the art of microfluidics. Sweat can be occluded using pressure. In one example, antiperspirants use pressure to stop sweat. Therefore, a pressure-permeated component can be designed to allow sweat flow at the low pressures that correlate with low sweat rates.
As used herein, a “horizontally-confining component” is a component that substantially prevents fluid from spreading horizontally along the skin surface.
As used herein, a “curable fluid or gel” is a fluid or gel that either dries or chemically cures into a solid.
As used herein, “hydrophobic” refers to materials through which non-charged non-hydrophilic solutes (hydrophobic solutes) will diffuse, but through which charged or hydrophilic solutes will not diffuse. For example, silicone-based oils or polymers can allow a hydrophobic analyte such as ethanol or such as cortisol or other steroid hormones to diffuse through them, but can block ions such Ca+, K+, Na+ and Cl− and OH− or H+ (e.g., block pH altering solutes). Quantitatively, we will use a testable definition for hydrophobic as being a material that has diffusive flux and/or solubility for solute ions such as Nat, Cl−, OH− or H+ that is at least 100× lower than for solutes such as ethanol or cortisol. Simply, the hydrophobic solutes, even though larger in size, diffuse more rapidly through hydrophobic material. This same analogy can be applied in the present invention to gas molecules as well.
This specification builds upon on PCT/US15/32893, filed May 28, 2015, the disclosure of which is incorporated by reference herein in its entirety. The disclosed invention applies at least to any type of biofluid sensing device that measures sweat, sweat generation rate, sweat chronological assurance, its solutes, solutes that transfer into sweat from skin, a property of or things on the surface of skin, or properties or things beneath the skin. The disclosed invention applies to biofluid sensing devices which can take on forms including patches, bands, straps, portions of clothing, wearables, or any suitable mechanism that reliably brings sweat stimulating, sweat collecting, and/or sweat sensing technology into intimate proximity with sweat as it is generated. Some embodiments of the disclosed invention utilize adhesives to hold the device near the skin, but devices could also be held by other mechanisms that hold the device secure against the skin, such as a strap or embedding in a helmet.
One skilled in the art will recognize that the various embodiments may be practiced without one or more of the specific details described herein, or with other replacement and/or additional methods, materials, or components. In other instances, well-known structures, materials, or operations are not shown or described in detail herein to avoid obscuring aspects of various embodiments of the invention. Similarly, for purposes of explanation, specific numbers, materials, and configurations are set forth herein in order to provide a thorough understanding of the invention. Furthermore, it is understood that the various embodiments shown in the figures are illustrative representations and are not necessarily drawn to scale.
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention, but does not denote that they are present in every embodiment. Thus, the appearances of the phrases “in an embodiment” or “in another embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Further, “a component” may be representative of one or more components and, thus, may be used herein to mean “at least one.”
Certain embodiments of the disclosed invention show sensors as simple individual elements. It is understood that many sensors require two or more electrodes, reference electrodes, or additional supporting technology or features that are not captured in the description herein. Sensors are preferably electrical in nature, but may also include optical, chemical, mechanical, or other known biosensing mechanisms. Sensors can be in duplicate, triplicate, or more, to provide improved data and readings. Sensors may be referred to by what the sensor is sensing, for example: a sweat sensor; an impedance sensor; a sweat volume sensor; a sweat generation rate sensor; and a solute generation rate sensor. Certain embodiments of the disclosed invention show sub-components of what would be biofluid sensing devices with more sub-components needed for use of the device in various applications, which are obvious (such as a battery), and for purpose of brevity and focus on inventive aspects are not explicitly shown in the diagrams or described in the embodiments of the disclosed invention. As a further example, many embodiments of the disclosed invention could benefit from mechanical or other means known to those skilled in wearable devices, patches, bandages, and other technologies or materials affixed to skin, to keep the devices or sub-components of the skin firmly affixed to skin or with pressure favoring constant contact with skin or conformal contact with even ridges or grooves in skin, and are included within the spirit of the disclosed invention.
The invention includes reference to the article in press for publication in the journal IEEE Transactions on Biomedical Engineering, titled “Adhesive RFID Sensor Patch for Monitoring of Sweat Electrolytes”; the article published in the journal AIP Biomicrofluidics, 9 031301 (2015), titled “The Microfluidics of the Eccrine Sweat Gland, Including Biomarker Partitioning, Transport, and Biosensing Implications”; as well as PCT/US16/36038, which are incorporated herein by reference in their entirety. Techniques for concentrating a biofluid sample are disclosed in PCT/US16/58356, and U.S. Provisional Application No. 62/457,604, which are also hereby incorporated herein by reference in their entirety.
Sweat stimulation, or sweat activation, can be achieved by known methods. For example, sweat stimulation can be achieved by simple thermal stimulation, chemical heating pad, infrared light, by orally administering a drug, by intradermal injection of drugs such as methylcholine or pilocarpine, and by dermal introduction of such drugs using iontophoresis. A device for iontophoresis may, for example, provide direct current and use large lead electrodes lined with porous material, where the positive pole is dampened with 2% pilocarpine hydrochloride and the negative one with 0.9% NaCl solution. Sweat can also be controlled or created by asking the subject using the patch to enact or increase activities or conditions that cause them to sweat. These techniques may be referred to as active control of sweat generation rate.
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Many biofluid sensing device applications place delicate sensors in dynamic environments for extended periods of time, which can expose the sensors to shear, abrasion, compression, or other forces through single or repeated contact with skin, or device components, such as wicking materials. Ionophore sensors and sensors that rely on a monolayer of a probe, such as impedance-based antibody or EAB sensors, are especially vulnerable to damage, which can introduce significant error into measurements of analytes that are present in sweat at very low concentrations (μM to pM and lower). Therefore, some sort of protection for the sensor may be required, and is provided by embodiments of the present disclosure.
Having provided solutions to the problem of sensor abrasion, embodiments of the disclosed invention also have reduced sweat volumes through the use of sensor-centered sweat flow, as disclosed in PCT/US15/32893. Sensor-centered flow involves directing new sweat from sweat glands toward the center of device sensors. To illustrate the advantage of having sensor-centered sweat flow, consider the case where the sweat sample flow is not centered on the sensor. When such a flow of sweat, e.g., one primarily centered to one side or adjacent to the sensor, reaches the sensor, the sensor will see non-uniform sweat flow, with relatively faster flow near where the sweat flow is targeted, and relatively slower flow elsewhere. Having slower sweat flow on part of the sensor will cause older sweat to be measured along with newer sweat, which increases the chronological sampling interval.
For embodiments using circular sensors, having the sweat flow centered on the sensor optimizes sweat sampling rate for a given sweat generation rate, providing sampling rates as much as ˜6× faster than a non-centered flow, as taught by Sonner, et al., in Biomicrofluidics. 2015 May 15; 9(3):031301. Doi: 10.1063/1.4921039. For embodiments using non-circular sensors, a centered flow would similarly improve sweat sampling rates.
While the theoretical benefits of configuring a biofluid sensing device with sensor-centered flow seem apparent, in practice, easily and reliably achieving alignment between device sensors and sweat glands poses a difficulty. Sweat glands are not uniformly distributed in skin, having variations in density between different body parts, and having random distribution in any one area of the body. Therefore, some embodiments of the disclosed invention are configured to allow sensors or other device components to self-align with sweat glands when placed on a device wearer's skin.
Other embodiments are configured to stimulate sweat while minimizing chemical contamination of the resulting sweat sample through use of sudomotor axon reflex (SAR) sweat stimulation, as disclosed in PCT/US2016/17726, which is incorporated herein by reference in its entirety. By using SAR sweat stimulation, the device can stimulate sweat glands within close proximity of a sensor array or sweat sample collector to generate sweat directly underneath the sensors or sweat collector. In combination, SAR sweat stimulation and sensor centered flow can greatly improve sweat sampling rates and reduce necessary sweat volumes, while decreasing contamination of the sweat sample.
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Within a plurality of blocking areas 662 of the wicking material 634, some embodiments can be configured with a sweat stimulating compound 640, such as carbachol, acetylcholine, or methylcholine. The compound 640 may be arranged in different patterns to optimize sweat stimulation and minimize contamination of the sweat sample for various applications. Within the blocking areas, the compound would be separated from the skin by a sweat-dissolvable barrier, such as a material that dissolves in the presence of low pH solutions. In some embodiments, the compound may be co-formulated or mixed with an agent facilitating time release of the compound. Such time-release agents and techniques could be, for example, slow-release binders such as biocompatible polymers and copolymers, carrier agents that slow release, or agents that delay absorption of the stimulating compound, all as known in the art of sustained release chemistry. When activated, the sweat stimulating compound would diffuse into skin 12 slowly over time, for example over a 24-hour period. As with other embodiments, glycol, iontophoresis, or other means may be required to facilitate sweat stimulation. In this manner, the disclosed invention can supply low levels of prolonged sweat stimulation to facilitate continuous measurement of sweat analytes with minimal irritation to the device wearer, and with controlled sweat generation rates.
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Sensor 820 can be, for example, an impedance sensor for a cytokine biomarker, an ion-selective electrode to measure sodium, or an EAB sensor to measure cortisol, a drug, or another biomarker. Sensor solution 828 can be a neutral solution that is able to support diffusion of the one or more target analytes from at least the protective component 836 to the sensor 820, and support the reliable operation of the sensor. The salinity, pH, and other aspects of the solution 828 can be regulated to obtain ideal performance of the sensor 820. In some examples, the solution 828 includes a solvent as well as, optionally, one or more solutes. The solvent may be water, a glycol, an alcohol, an ionic liquid, an oil, or any other suitable liquid or fluid. The solvent may contain solutes. In an exemplary embodiment, an electrochemical aptamer-based sensor is stabilized in a pH 7, 50 μM NaCl solution. The thickness of the sensor solution 828, i.e., the distance from the protective component to the sensor, will influence operation of the device. The greater the thickness of the sensor solution 828, the longer the diffusive pathway from the protective component 836 to the sensor 820, and the larger the volume that must be equilibrated with the analyte concentration in the sweat sample. Generally, the thickness of the sensor solution 828 should be at least one of <3 mm, <1 mm, <300 μm, <100μ, <30 μm, <10 μm.
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Second membrane 834 substantially surrounds the first membrane 832 and can facilitate transport of a sweat sample to the first membrane. Second membrane 834 can also provide a reverse barrier between the first membrane 832 and the skin 12. In particular, second membrane 834 can be a hydrophilic track-etched membrane having a plurality of blocking areas 862 that largely prevent the flow of sweat, and a plurality of flow areas 872 that facilitate sweat flow. The flow areas 872 may include a hydrophilic solvent, a hydrogel, or other similar type of material which allows a sweat sample to move through the membrane. Alternatively, the flow areas 872 could comprise areas void of material located between each of the blocking areas, with the void forming a physical barrier between the skin and the first membrane 832. When the first membrane layer 832 comprises an oil membrane, the blocking and flow areas 862, 872 form a reverse barrier to prevent oil from permeating the second membrane and contacting the skin 12. In addition to the first and second membrane layers 832, 834, supplementary membranes could be provided that are comprised of materials with differing properties. For example, membranes could all be permeable to the target analyte but one is impermeable to salt and another is impermeable to pH, so that in combination they better block pH and salt but pass more easily the target analyte.
The thickness of protective component 836 will influence operation of the biofluid sensing device. If the thickness of the protective component is too great, the component can behave as a large sink or storage vessel for an analyte, and increase the diffusive pathway that the analyte must traverse to reach the sensor 820. Therefore, the thickness of the protective component may be at least one of <1 mm, <100 μm, <10 μm, <1 μm, or <0.1 μm.
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This has been a description of the disclosed invention along with a preferred method of practicing the disclosed invention, however the invention itself should only be defined by the appended claims.
This application is a continuation-in-part of U.S. application Ser. No. 15/382,703, filed Dec. 18, 2016, and claims priority to U.S. Provisional Application No. 62/269,254, filed Dec. 18, 2015 and U.S. Provisional Application No. 62/666,921, filed May 4, 2018, and has specification that relates to PCT/US16/43771, filed Jul. 23, 2016, the disclosures of which are hereby incorporated by reference herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62666921 | May 2018 | US | |
| 62269254 | Dec 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15382703 | Dec 2016 | US |
| Child | 16403094 | US |
