U.S. patent application number 15/512982 was filed with the patent office on 2017-08-31 for sweat sensing with analytical assurance.
The applicant listed for this patent is University of Cincinnati. Invention is credited to Jason C. Heikenfeld.
Application Number | 20170245788 15/512982 |
Document ID | / |
Family ID | 55581899 |
Filed Date | 2017-08-31 |
United States Patent
Application |
20170245788 |
Kind Code |
A1 |
Heikenfeld; Jason C. |
August 31, 2017 |
SWEAT SENSING WITH ANALYTICAL ASSURANCE
Abstract
A sweat sensor device (200) with analytical assurance includes
at least one sensor (220) for detecting a first analyte, and at
least one calibration medium (270) containing at least the first
analyte. When the first analyte in the at least one calibration
medium (270) comes into contact with the at least one sensor (220),
the calibration medium (270) provides a calibration of the at least
one sensor (220). A sweat sensor device (200) may further include a
carrier (240) having at least one aperture (220a) and a reservoir
(254) for storing the at least one calibration medium (270). The at
least one aperture (220a) provides fluidic access to the at least
one sensor (220) from the reservoir (254).
Inventors: |
Heikenfeld; Jason C.;
(Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
University of Cincinnati |
Cincinnati |
OH |
US |
|
|
Family ID: |
55581899 |
Appl. No.: |
15/512982 |
Filed: |
September 22, 2015 |
PCT Filed: |
September 22, 2015 |
PCT NO: |
PCT/US15/51439 |
371 Date: |
March 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62155527 |
May 1, 2015 |
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62053388 |
Sep 22, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/6832 20130101;
A61B 5/14517 20130101; A61B 5/1495 20130101; A61B 5/4266 20130101;
A61B 5/6801 20130101; A61B 2560/0223 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/1495 20060101 A61B005/1495; A61B 5/00 20060101
A61B005/00 |
Claims
1. A sweat sensor device with analytical assurance comprising: at
least one sensor for detecting a first analyte; and at least one
calibration medium containing at least said first analyte, wherein
when said first analyte in said at least one calibration medium
comes into contact with said at least one sensor, said calibration
medium provides a calibration of said at least one sensor.
2. The device of claim 1, further comprising: a carrier having at
least one aperture; and a reservoir for storing said at least one
calibration medium, wherein said at least one aperture provides
fluidic access to said at least one sensor from said reservoir.
3. The device of claim 2, further comprising: a rupturable membrane
in said reservoir that when ruptured allows said calibration medium
to come into contact with said aperture.
4. The device of claim 1, further comprising: a sweat pumping
element; and a flow restricting element between said calibration
medium and said sweat pumping element.
5. The device of claim 1, further comprising: more than one
calibration medium.
6. The device of claim 1, wherein said calibration medium includes
a plurality of solutes.
7. The device of claim 1, further comprising: a microfluidic
component for transporting said calibration medium to said at least
one sensor.
8. The device of claim 7, further comprising: at least one port
providing fluidic access to said microfluidic component.
9. The device of claim 1 further comprising: a material between
said at least one sensor and skin when said device is positioned on
skin, wherein said calibration medium is confined against said
sensor by said material at least initially when said device is
positioned on skin.
10. The device of claim 9 wherein said material is at least
initially impermeable to said first analyte.
11. The device of claim 9 wherein said material is permeable to
water and said calibration medium is dry.
12. The device of claim 9 wherein said material defines a fixed
volume around said at least one sensor.
13. The device of claim 9 wherein said at least one sensor includes
a first sensor for detecting said first analyte and a second sensor
for detecting said first analyte, said material being between said
first sensor and skin and not being between said second sensor and
skin.
14. The device of claim 13 further comprising: a third sensor for
detecting a solute to determine an amount of dilution of said at
least one calibration medium when sweat permeates said material,
wherein said material surrounds said third sensor.
15. The device of claim 9 wherein said material is a membrane.
16. The device of claim 9 wherein said material is a dissolvable
polymer.
17. The device of claim 9 wherein said material is a swellable
polymer.
18. The device of claim 1 further comprising: a membrane
impermeable to said first analyte, said membrane surrounding said
at least one sensor and said at least one calibration medium; and
at least one fluidic gate that controls fluidic access to said
first sensor.
19. The device of claim 18 wherein said membrane is impermeable to
sweat.
20. The device of claim 18 wherein said at least one fluidic gate
includes a water dissolvable polymer.
21. The device of claim 1 wherein said at least one calibration
medium is dissolvable and, during calibration of said device, said
at least one calibration medium has a fixed volume providing for a
fixed concentration of said first analyte in said calibration
medium.
22. The device of claim 21 wherein said at least one calibration
medium includes a first calibration medium and a second calibration
medium, said second calibration medium including a second analyte
different from said first analyte.
23. The device of claim 1 further comprising: at least one binding
medium that reduces a concentration of an analyte in sweat as said
sweat reaches said calibration medium.
24. The device of claim 1 wherein said calibration medium provides
a concentration calibration of said at least one sensor.
25. The device of claim 1 wherein said calibration medium provides
a lag time calibration of said at least one sensor.
26. A method of detecting a solute in sweat comprising: directing a
calibration medium in a device to at least one sensor for detecting
said solute in said device; calibrating said at least one sensor;
positioning said device on skin; directing sweat to said device;
and measuring said solute in said sweat using said device.
27. The method of claim 26 wherein positioning the device on skin
occurs before calibrating said at least one sensor.
28. The method of claim 26 wherein directing sweat to said device
occurs before calibrating said at least one sensor, the method
further comprising: directing at least a portion of said sweat to
said calibration medium to create a calibration solution, wherein
calibrating said at least one sensor includes using said
calibration solution.
29. A method of detecting a solute in sweat using a device for
detecting said solute in sweat, said device including at least one
sensor, the method comprising: providing fluidic access to said at
least one sensor through an aperture in a first backing element;
directing at least one calibration medium to said at least one
sensor through said aperture; calibrating said at least one sensor;
placing said device on skin; directing sweat to said device; and
measuring said solute in said sweat using said device.
30. The method of claim 29 wherein providing fluidic access
includes removing a second backing element from said device.
31. The method of claim 29 further comprising: before placing said
device on skin, removing said first backing element from said
device.
32. The method of claim 29 wherein directing a calibration medium
to said device includes directing more than one calibration medium
to said device.
33. The method of claim 32 wherein one of said more than one
calibration mediums is different from another of said more than one
calibration mediums.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application relates to U.S. Provisional Application
Nos. 62/053,388, filed on Sep. 22, 2014, and 62/155,527, filed on
May 1, 2015, the disclosures of which are hereby incorporated by
reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] Sweat 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 ailments, health
status, 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.
[0003] If sweat has such significant potential as a sensing
paradigm, then why has it not emerged beyond decades-old usage in
infant chloride assays for Cystic Fibrosis or in illicit drug
monitoring patches? In decades of sweat sensing literature, the
majority of medical literature utilizes the crude, slow, and
inconvenient process of sweat stimulation, collection of a sample,
transport of the sample to a lab, and then analysis of the sample
by a bench-top machine and a trained expert. This process is so
labor intensive, complicated, and costly that in most cases, one
would just as well implement a blood draw since it is the gold
standard for most forms of high performance biomarker sensing.
Hence, sweat sensing has not emerged into its fullest opportunity
and capability for biosensing, especially for continuous or
repeated biosensing or monitoring. Furthermore, attempts at using
sweat to sense "holy grails" such as glucose have not yet succeeded
to produce viable commercial products, reducing the publically
perceived capability and opportunity space for sweat sensing.
[0004] Small, portable, and wearable biosensors are difficult to
make so that they are precise and accurate. Such sensors are often
generally challenged in their ability to make quality analytical
measurements equal to what can be done with a dedicated measurement
machine or large lab. This is especially true for sensors
integrated in a small patch or wearable device because of the need
for miniaturization and lower cost, and because such devices are
placed in less controllable environments than many lab or machine
settings.
[0005] Many of the drawbacks stated above can be resolved by
creating novel and advanced interplays of chemicals, materials,
sensors, electronics, microfluidics, algorithms, computing,
software, systems, and other features or designs, in a manner that
affordably, effectively, conveniently, intelligently, or reliably
brings sweat sensing technology into intimate proximity with sweat
as it is generated. Further, a sweat sensor capable of analytical
assurance is needed. With such a new invention, sweat sensing could
become a compelling new paradigm as a biosensing platform.
SUMMARY OF THE INVENTION
[0006] The present invention provides a wearable sweat sensor
device capable of analytical assurance. In one embodiment, a sweat
sensor device with analytical assurance includes at least one
sensor for detecting a first analyte, and at least one calibration
medium containing at least the first analyte. When the first
analyte in the at least one calibration medium comes into contact
with the at least one sensor, the concentration medium provides a
calibration of the at least one sensor.
[0007] In another embodiment, a method of detecting a solute in
sweat includes directing a calibration medium in a device to at
least one sensor for detecting the solute in the device,
calibrating the at least one sensor, positioning the device on
skin, directing sweat to the device, and measuring the solute in
the sweat using the device.
[0008] In another embodiment, a method of detecting a solute in
sweat using a device for detecting the solute in sweat, the device
including at least one sensor, includes providing fluidic access to
the at least one sensor through an aperture in a first backing
element, directing at least one calibration medium to the at least
one sensor through the aperture, calibrating the at least one
sensor, placing the device on skin, directing sweat to the device,
and measuring the solute in the sweat using the device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The objects and advantages of the present invention will be
further appreciated in light of the following detailed descriptions
and drawings in which:
[0010] FIG. 1A is a cross-sectional view of a device according to
an embodiment of the present invention.
[0011] FIG. 1B is a cross-sectional view of the device of FIG. 1A
during calibration.
[0012] FIG. 1C is a cross-sectional view of the device of FIG. 1A
positioned on skin.
[0013] FIG. 2A is a cross-sectional view of a device and a
calibration module according to an embodiment of the present
invention.
[0014] FIG. 2B is a cross-sectional view of the device and
calibration module of FIG. 2A during calibration.
[0015] FIG. 2C is a cross-sectional view of a portion of the device
of FIG. 2A.
[0016] FIG. 3 is a cross-sectional view of a device and a
calibration module according to an embodiment of the present
invention.
[0017] FIG. 4 is a cross-sectional view of a device according to an
embodiment of the present invention.
[0018] FIG. 5 is a cross-sectional view of a device according to an
embodiment of the present invention positioned on skin.
[0019] FIG. 6A is a cross-sectional view of a device according to
an embodiment of the present invention positioned on skin.
[0020] FIG. 6B is a cross-sectional view of the device of FIG. 6A
during calibration.
[0021] FIG. 6C is a cross-sectional view of a device according to
an embodiment of the present invention positioned on skin.
[0022] FIG. 7A is a cross-sectional view of a device according to
an embodiment of the present invention positioned on skin.
[0023] FIG. 7B is a cross-sectional view of the device of FIG. 7A
during calibration.
[0024] FIG. 7C is a cross-sectional view of the device of FIG. 7A
after calibration.
[0025] FIG. 8 is a cross-sectional view of a device according to an
embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present application has specification that builds upon
International Application Nos. PCT/US13/35092, filed Apr. 2, 2013,
PCT/US14/61083, filed Oct. 17, 2014, PCT/US14/61098, filed Oct. 17,
2014, PCT/US15/32830, filed May 28, 2015, PCT/US15/32843, filed May
28, 2015, PCT/US15/32866, filed May 28, 2015, PCT/US15/32893, filed
May 28, 2015, and PCT/US15/40113, filed Jul. 13, 2015, the
disclosures of which are hereby incorporated herein by reference in
their entirety.
[0027] Embodiments of the present invention apply at least to any
type of sweat sensor device that measures sweat, sweat generation
rate, sweat chronological assurance, sweat solutes, solutes that
transfer into sweat from skin, properties of or items on the
surface of skin, or properties or items beneath the skin.
Embodiments of the present invention further apply to sweat sensing
devices that have differing 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 by the body. While certain embodiments of the present
invention utilize adhesives to hold the device near the skin, other
embodiments include devices held by other mechanisms that hold the
device secure against the skin, such as a strap or embedding in a
helmet.
[0028] Sweat stimulation, or sweat activation, can be achieved by
known methods. For example, sweat stimulation can be achieved by
simple thermal stimulation, by orally administering a drug, by
intradermal injection of drugs such as methylcholine or
pilocarpine, and by dermal introduction of such drugs using
iontophoresis. Sweat can also be controlled or created by asking
the subject using the patch to enact or increase activities or
conditions which cause them to sweat. These techniques may be
referred to as active control of sweat generation rate.
[0029] Certain embodiments of the present 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 which 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.
[0030] In an aspect of the present invention, a sweat sensor device
is capable of providing analytical assurance as described below.
Analytical assurance means (but is not limited to) an assurance of
the precision, accuracy, or quality of measurements provided by the
sweat sensor device. In other words, analytical assurance could
further refer to improved confidence in the precision, accuracy, or
quality of measurements made.
[0031] With reference to FIGS. 1A-1C, a sweat sensor device is
designed to be calibrated before use. The sweat sensor device 100
has an adhesive side supported by carrier 150 and carrier 152.
Carriers 150, 152 could be a variety of materials. By way of
example, carriers 150, 152 could be wax or siliconized paper, such
as that used in bandage backings. Carrier 150 is sufficiently
sealed against the underside of the device 100 such that it covers
and seals the adhesive side of the device 100 with exception to
aperture 120a. Aperture 120a allows access to one or more sensors
(not shown) via direct access or through microfluidic connections.
Carriers 150, 152 are removable from device 100. In the
illustrative embodiment, the carrier 152 may be removed without
removing the carrier 150.
[0032] With reference to FIG. 1B, the carrier 152 of the device 100
may be removed to expose the aperture 120a. A sponge 160, which is
permeated with a calibrating solution or medium, is pressed against
the device 100 to bring the solution in contact with the sensors of
the device 100. Importantly, the carrier 150 shields the rest of
the device 100 from the application of the calibrating solution but
allows the calibration solution or medium to contact at least one
sensor though the aperture 120a. The calibrating solution is
provided with pre-determined concentration of solutes or other
properties of sweat (e.g., pH). The sponge 160 is held against the
device 100 for a period of time adequate to allow the sensors to be
calibrated based on measurements of analytes in the solution. The
time required for a sensor to be calibrated may vary depending on
the sensor stabilization time. The time required for a sensor to
stabilize can be, for example, as short as several minutes, to as
long as 30 minutes for a nM or pM sensor, or as long as multiple
hours for ion-selective electrodes that require wetting periods.
Once the sweat sensor device 100 has completed calibration, it is
now capable of providing sweat measurements with analytical
assurance. Carrier 150 may be subsequently removed, and the device
100 may be applied to skin 12 to be used, as shown in FIG. 1C. The
calibration techniques disclosed herein significantly improve the
ease with which sensors in patches or wearable devices may be
calibrated. Conventional sensor calibration techniques require the
sensor to be dipped into a beaker or vial containing a calibration
solution. For a sensor in a patch or wearable device, as taught
herein, such techniques are generally impractical for commercial
usage (e.g. a non-laboratory setting such as a home, or may damage
or degrade the sweat sensor device.
[0033] A variety of techniques and compositions may be used to
calibrate sensors according to methods of the present invention.
For instance, a calibration solution may be used where the solution
composition is based on properties of skin, contaminants on skin,
or other solutes or properties that would affect analytical
assurance for a sensor placed on skin. A collected human sweat
sample or an artificial sweat sample (e.g., such as one available
from Pickering Laboratories) may also be used to calibrate a
sensor. Further, the solution could be concentrated, diluted, or
spiked with a solute or property of interest. The selected
concentration of solutes could be, for example: low enough to
confirm the lower limit of detection for the sensor, or could be
near or below physiological levels to confirm the accuracy of the
sensor. Where a device includes more than one sensor, the
concentration of solutes in the applied sponge 160 could be
designed to calibrate all of the sensors, one of the sensors, or a
subset of the sensors. In an alternate embodiment, sponge 160 can
be replaced by any other technique to apply a calibrating solution,
including for example using a spray bottle (not shown).
[0034] In one embodiment, more than one calibration solution may be
applied with similar or different concentrations or properties of
sweat to calibrate a sensor. In the embodiment illustrated in FIG.
1B, more than one sponge 160 may be applied in sequence (not shown)
to the device 100. When multiple sponges 160 are applied in
sequence, the different sponges 160 may have calibration solutions,
for example, that increase in concentration, or properties to
calibrate sensor response or linearity with change in
concentration. Alternatively, the different sponges 160 may have
solution concentrations that increase or decrease to determine the
rate of response or adaptation of sensors. Determining the sensor
response rate improves analytical assurance because some sensors
experience a lag between the change in analyte concentration in
solution and the change in measured analyte concentration that is
caused by the analytes' tendency to adhere to the sensor.
[0035] The application of a calibration solution (e.g., using the
sponge 160) also allows one to determine other properties such as
drift of sensors over time. In one embodiment, a sponge 160 may be
applied for a sufficient time such that sensor drift can be
determined to improve the analytical assurance for the sensor. For
high quality sensors, drift typically is observable only after a
period of hours or more.
[0036] With reference to FIGS. 2A and 2B, a sweat sensor device 200
is coupled to a calibration module 240. The calibration module 240
includes a housing 250 that defines a reservoir 254. The
calibration module 240 acts as a carrier for the device 200 similar
to the carrier 150 of FIG. 1A. Housing 250 includes aperture 220a
that provides fluidic access from the reservoir 254 to at least one
sensor 220 (shown in FIG. 2C) within the device 200. A calibration
solution 270 is sealed inside the housing 250 by a membrane 260. On
the other side of the membrane 260 (i.e., the side of the reservoir
254 adjacent the aperture 220a) is a gas, inert gas, or fluid 278.
The application of pressure (as indicated by arrow 280) to the
housing 250 causes the membrane to rupture, as shown in FIG. 2B. In
this regard, the calibration module 240 has been activated by the
pressure applied in the direction of arrow 280 and the calibration
solution 270 comes into contact with one or more sensors of the
device 200 near aperture 220a. The pressure may be applied, for
example, by a user pressing against the housing 250. In one
embodiment, to ensure the sensors are wetted, the calibration
module 240 may include a sponge material (not shown) on the side of
the membrane 260 adjacent to the aperture 220a. Alternatively, the
housing 250 may be designed such that gravity is not a factor in
the movement of the calibration solution 270 past the sensor and/or
that a shaking motion could be applied to ensure calibration
solution 270 comes into contact with one or more sensors of the
device 200.
[0037] In one embodiment, the device 200 may include a flow
restricting element. As illustrated in FIG. 2C, the flow
restricting element 290 may be positioned adjacent the aperture
220a between the device 200 and the housing 250. A wicking material
230 surrounds a sensor 220 and the flow restricting element 290.
The flow restricting element 290 may be, for example, a flow
limiting element (e.g., reduced porosity in a textile), a flow
constriction element (e.g., small pore or aperture), or a flow
stopping element. In the illustrated embodiment, the restricting
element 290 is a polymer film with a flow restriction component,
such as a small gap. In this configuration, the gap restricts the
flow of sweat from the skin to wicking material 230. The flow
restricting element may prevent a sweat pumping element, such as
wicking material 230, within the device 200 from being saturated
with the calibration solution 270. In other words, the flow
restricting element 290 prevents the calibration solution 270 from
saturating the sweat pumping capacity of device 200. While the
restricting element 290 in FIG. 2C is shown as being part of device
200, other configurations and techniques are capable of being used
to restrict the flow of sweat to the device 200. In one embodiment,
the flow restricting element 290 could be a component of element
250 shown in FIGS. 2A and 2B. In another embodiment, pumping or
wicking elements could be removed or not fluidically connected to
sensors during calibration and added or connected after calibration
is complete.
[0038] With further reference to FIGS. 2A and 2B, in one
embodiment, the calibration solution 270 could be a gel and
component 278 may be a gel (rather than the gas 278 discussed
above). As membrane 260 ruptures, the calibration gel 270 comes in
contact with the gel 278. The solutes in the calibration gel 270
will diffuse, rather than flow by advection, through the gel 278 to
come into contact with one or more sensors of the device 200 near
aperture 220a. The materials for gels 270, 278 could be similar or
different gel materials, so long as the diffusion of solutes in gel
270 can occur through the gel 278. This configuration allows for
calibration of the sensors over a varying concentration level as
the calibration solution diffuses into gel 278. For example, a
sensor could be calibrated between a zero concentration
level--which is the starting concentration for gel 270--and the
maximum concentration of the solutes which results from slow
diffusion-based mixing of concentrations between gel 270 and gel
278 where gel 270 contains a concentration of at least one solute
to be used for calibration. Although a calibration involving a
concentration gradient could be achieved where components 270, 278
are liquids, such a calibration would be less predictable, because
fluid mixing is often more chaotic than the diffusion of solutes
where components 270, 278 are gels, which are more homogeneous.
[0039] With further reference to FIG. 2B, in one embodiment, the
rupture of membrane 260 could be caused by removing the housing 250
from the device 200. This may be convenient for use, since the
device 200 cannot be adhered onto skin until housing 250 is
removed. During the removal of the housing 250, the calibration
solution 270 could be quickly (as little as seconds) brought into
contact with sensors of the device 200, and the device may be
applied to the skin. The calibration of the sensors may continue
until sweat from the skin replaces the calibration solution, which
is a process that may take at least several minutes, if not much
longer. This approach ensures that the user always calibrates the
device before use, without any extra steps beyond the expected
minimum (i.e., removal of the housing 250) for applying an adhesive
patch to the skin. This may be more broadly referred to as
calibration which occurs as backing element or material, or housing
material, is removed from the adhesive side of a device.
[0040] In one aspect of the invention, a calibration module may
include more than one calibration solution or medium. With
reference to FIG. 3, a device and a calibration module according to
another embodiment of the invention are shown. The device 300 and
calibration module 340 are similar in construction to those shown
in FIGS. 2A and 2B, and similar reference numerals refer to similar
features shown and described in connection with FIGS. 2A and 2B,
except as otherwise described below. The calibration module 340
includes multiple solutions 370, 372, 374 within the reservoir 354.
The solutions 370, 372, 374 could sequentially flow over aperture
320a past the sensors (as indicated by arrow 380) inside
calibration module 340. The solutions 370, 372, 374 displace gas
378 as they flow past aperture 320a. The calibration module 340 may
include a mechanism for pumping, gating, or introducing fluids as
known by those skilled in the art. For example, component 378 could
be a sponge material (not shown) that wicks the solutions 370, 372,
374 against the sensor. Further, the device 300 may include an
electrowetting gate (not shown) to form a capillary between the
solutions 370, 372, 374 and the sponge. It will be recognized that
more complex arrangements with mechanical pumps and valves could be
also used in other embodiments of the present invention. The
solutions 370, 372, 374 may have the same or varying
concentrations. In one embodiment, the solutions 370, 372, 374
contain a lowest concentration, a middle concentration, and a
highest concentration, respectively, for calibration.
[0041] In another aspect of the present invention, a calibration
module may include one or more calibration solutions containing
more than one solute. Such a configuration allows sensor
calibration, while also allowing a determination of any
cross-interference between various solutes in, or properties of,
sweat. For example, potassium (K.sup.+) and ammonium
(NH.sub.4.sup.+) are known to interfere with each other in
ion-selective electrode sensors. In one embodiment, a calibration
module (e.g., module 340) may include a first solution containing a
high concentration of K.sup.+ and a low concentration of
NH.sub.4.sup.+. A second solution in the calibration module may
contain a low concentration of K.sup.+ and a high concentration of
NH.sub.4.sup.+. Further solutions may contain equal concentrations
of K.sup.+ and NH.sub.4.sup.+, which could be high, moderate, or
low. In this manner, any cross-interference between K.sup.+ and
NH.sub.4.sup.+ for a device (e.g., device 300) may be
determined.
[0042] With reference to FIG. 4, device 400 includes an external
introduction port 490, a microfluidic component 480 that moves
fluid to or past sensors, and an optional outlet port 492 with
absorbing sponge 460. Microfluidic component 480 may be, for
example, a 50 micron polymer channel that is 500 microns wide. One
or more calibration solutions could be introduced at port 490 while
the device 400 is on the skin 12. The calibration solution may be
introduced at port 490 using a variety of methods. For example, the
calibration solution could be introduced at port 490 by the
application of droplets, by using a cartridge, by using a carrier,
such as those discussed above, or using another approach. In
addition to a calibration solution, a fluid that refreshes the
usability of sensors may also be introduced to the device 400
though port 490 and be wicked through the microfluidic component
480 across sensors by sponge 460. In various embodiments, the fluid
may change the pH level or cause a sensor probe to release an
analyte. In one embodiment, such a refreshing fluid could be
introduced to the device 400, followed by the introduction of the
calibration fluid. The introduction of a fluid (e.g., a calibration
solution) may be followed by a removal of the fluid. For example,
in one embodiment, the sponge 460 could be removed after collection
of the refreshing fluid and disposed of. The sponge 460 could be a
wicking sponge material, a textile, hydrogel, or other material
capable of wicking and collecting a fluid.
[0043] With reference to FIG. 5, a device 500 includes a first
reservoir 530 and a second reservoir 532 that are fluidically
coupled by microfluidic component 580. The first reservoir 530
includes a calibrating solution 570, and the second reservoir 532
includes a displaceable gas 578. Microfluidic component 580 is
designed to provide access to a sensor (not shown). Calibration of
the device 500 using aspects of the present invention could occur
before device 500 operation begins, before sweat from skin 12 is
sampled, or at times during the use of the device 500 using one
more methods of timed microfluidic operation known by those skilled
in the art. By way of example, the device 500 may include gates
that swell (close) or dissolve (open) after prolonged exposure to a
fluid. The gates (not shown) may be formed by a swellable polymer
or a soluble salt or sugar, for example. The calibration solution
570 could stay in contact with the sensors for a determined period
of time before it is removed. The calibration solution 570 may be
removed, for example, by wicking or by pumping. Pumping may be
accomplished through gas pressure (not shown) using the release of
an internal pressurized gas source or generated gas source (e.g.,
electrolysis of water). Alternatively, the calibration solution 570
could remain in contact with sensors until it is replaced by
sweat.
[0044] With reference to FIGS. 6A and 6B, a device 600 is shown
which includes a substrate 610 carrying two similar sensors 620,
622 and a membrane 615 that covers the sensor 620. The sensors 620,
622 are similar in that, if one is calibrated, they are similar
enough that calibration for one can be used for the others. In one
embodiment, the sensors are of the same generation type (e.g.
amperometric) but have different analyte targets (e.g. glucose and
lactate). In another embodiment, the sensors target the same
analyte, and calibration for one sensor will typically best predict
the calibration for the second. Device 600 further includes a dry
dissolvable calibration medium 670 for one or more analytes between
the membrane 615 and the sensor 620. The calibration medium 670
could also be a liquid or a gel. FIG. 6B shows a flow of sweat 690
generated by the skin 12 as indicated by arrows 690a. The water in
the sweat 690 penetrates through membrane 615 and dissolves
calibration medium 670 to create a calibration solution 670a.
Membrane 615 allows water transport through the membrane 615, while
delaying or preventing transport of analytes to be sensed from the
sweat 690 at least during a calibration between sensors. By way of
example, the membrane 615 could be made of a dialysis membrane,
Nafion membrane, track-etch membrane, reverse-osmosis membrane, or
sealed reference electrodes. In this configuration, sensors 620,
622 can be compared in their readings of an analyte. If the
concentration of an analyte in solution 670a is known, then the
concentration of the analyte in sweat 690 can be better determined
through comparison of the measured signal from sensors 620, 622. In
an exemplary embodiment, membrane 615 creates a defined volume
around sensor 620 such that the concentration of analytes is
predictable (i.e., known amount of dilution as the calibration
medium 670 dissolves). For example, a porous polymer or polymer
textile could be used which has a finite porous volume in it to fix
the volume of calibration solution 670a around the sensor 620. In
one embodiment, calibration solution 670a may include a
concentration of the analyte that is greater than the concentration
of that analyte present in sweat. For example, the calibration
solution 670a may include an analyte at a concentration roughly 10
times or more than that found in the sweat that wets the
calibration medium 670.
[0045] With reference to FIG. 6C, in one embodiment, element 620 of
the device 600 represents two or more different sensors 620a and
620b requiring calibration. For example, the first sensor 620a in
element 620 could be for detecting cortisol, and often these types
of sensors require calibration. Sensor 622 shown in FIG. 6A would,
in this example, also be for detecting cortisol and would measure
cortisol found in sweat directly. The second sensor 620b in element
620 could be for detecting Na.sup.+ (such as an ion-selective
electrode or through simple electrical conductance of solution).
The dry dissolvable calibration medium 670 includes a known
starting concentration of cortisol 672a and Na.sup.+ 672b. As water
moves through the membrane 615, it dissolves or dilutes the
calibration medium 670 to create the calibration solution 270a, in
which concentrations of both Na.sup.+ and cortisol could be
measured. The Na.sup.+ sensor 620b may be configured so that it
would not need calibration using the calibration solution 270a. For
example, sensor 620b may be an ion-selective electrode having a
sealed reference electrode (not shown) to allow it to accurately
quantify Na.sup.+ concentrations. As the Na.sup.+ dilutes as the
water moves in, the amount of water is also indirectly measured (by
measuring Na.sup.+), and therefore the amount of dilution of
cortisol would be known from the time when the water began moving
through the membrane 615 until the water fills the space between
the membrane 615 and the sensors 620a, 620b. In summary, the
measurement of Na.sup.+ would be used to determine the total
dilution that has occurred as water moves into the calibrating
solution 670a, and therefore the amount of dilution of cortisol in
calibrating solution 670a is also known. Therefore a dilution
calibration curve could be provided for the first sensor 620a,
which would then provide a dilution calibration for sensor 622 as
well.
[0046] With further reference to FIGS. 6A-6C, in one aspect of the
present invention, membrane 615 may act as a binding medium that
binds solutes in sweat such that sweat is diluted of one or more
analytes before it reaches the calibrating medium. Such a binding
medium would be in the sweat flow path between sweat glands and at
least one sensor. The binding medium may provide specific binding
(e.g., a layer of beads doped with ionophores) or non-specific
binding (e.g., cellulose). As a result, the calibration medium 670
would not need to provide a concentration of analyte or analytes
greater than that found in real sweat, as the initial sweat which
reaches the calibration sensor would be diluted of the analyte to
be calibrated. Specific binding materials include beads or other
materials those known by those skilled in the art that promote
specific absorption.
[0047] In another aspect of the present invention, conditions can
be provided that denature or alter an analyte in sweat such that
its concentration is effectively lowered before reaching a
calibration medium. In one embodiment, a binding solute in solution
that binds to the analyte in a way similar to how the analyte binds
to a probe on the sensor is provided at a location between the
sensor and skin. In one embodiment, the binding solute may be
present in a wicking textile (not shown) that brings sweat from
skin to the sensors. Because the analyte will bind with the binding
solute, the sensor probes are prevented from binding with such
analytes. For example, the sensor could be an electrochemical
aptamer or antibody sensor, and the binding solute could be an
aptamer or antibody that is suspended in solution. Those skilled in
the art will recognize other techniques that are useful for
lowering concentrations of analytes in sweat such that a more pure
fluid is provided for the purposes of calibration.
[0048] With reference to FIGS. 7A-7C, a device 700 includes a
sensor 720 for sensing a first analyte and a sensor 722 for sensing
a second analyte, and the device 700 further includes a polymer
substrate 710, and calibration mediums 770, 772 for calibrating the
first and second sensors 720, 722, respectively. The calibration
mediums 770, 772 may be positioned adjacent to the sensors 720, 722
using a variety of techniques. For example, the calibration mediums
770, 772 could be a dry powder placed adjacent to a sensor, held in
place by a glue or a dissolvable medium, or held in place by
another technique until wetted by sweat. The calibration mediums
770, 772 generally: (1) can rapidly take up sweat and allow wetting
of sweat against sensors 720, 722; (2) release a concentration of
calibrating analytes into sweat near sensors 720, 722 quickly
enough to alter the concentration of said analytes in sweat; (3)
maintain calibration concentrations of analytes in sweat long
enough for sensor 720, 722 calibration to be performed; and (4)
promote a generally fixed fluid volume initially as they uptake
sweat such that calibration analyte concentrations are repeatable.
In one embodiment, calibration mediums 770, 722 may be made of a
material that would rapidly swell to a known volume as it wets but
would more slowly dissolve and wash away, therefore allowing
adequate time for calibration (discussed further below). With
reference to FIG. 7B, once calibration mediums 770, 772 are wetted
with sweat 790 generated as shown by arrows 790a, calibration
solutions 770a, 772a are formed. Over time, the calibration
analytes within calibration solutions 770a, 772a are transported
away from sensors 720, 722 by the sweat 790 such that sensing can
be performed on new sweat, as shown in FIG. 7C.
[0049] Calibration mediums, useful in embodiments of the present
invention can be constructed using a variety of methods. With
further reference to FIGS. 7A-7C, calibration mediums 770, 772 may
release the analytes contained therein initially upon contact with
sweat, or at some time thereafter, through time-release techniques.
In various embodiments, a calibration medium could be formed from a
dissolvable polymer, such as a water soluble polymer or a hydrogel.
Exemplary polymers include polyvinylpyrolidone (PVP),
polyvinylachohol (PVA), and poly-ethylene oxide. PVP can be used as
a dissolvable polymer that can swell with up to 40% water in a
humid environment or can be used as a hydrogel if cross-linked
using, for example, UV light exposure. Like PVP, PVA can be used as
a water dissolvable material or as a hydrogel. Also, such polymers
can have a wide range of molecular weights that can affect the rate
at which such polymers dissolve. Consider several exemplary
embodiments. In one embodiment, a calibration medium of PVP with a
known concentration of at least one analyte is coated onto a sensor
or is positioned adjacent to a sensor. When wetted or hydrated, the
PVP will act as a calibration solution. Such a calibration medium
could also contain one or more preservatives. If PVP, or another
suitable material, were used as a water dissolvable polymer, its
surface would wet quickly with sweat before the PVP appreciably
dissolves. Then, before the PVP fully dissolves, the sweat would
hydrate the polymer and allow for sensor calibration. Therefore,
the polymer itself could provide a predictable volume and dilution
of calibrating analytes confined inside the polymer for a period of
time (seconds, or minutes) before it fully dissolves. In one
embodiment where the device includes a protein-based sensor, such
as an electrically active beacon aptamer sensor, the calibrating
analyte confined in the polymer could be a protein, such as a
cytokine. Initially, as water and ions from sweat permeate the
polymer to wet it, the calibrating protein solution would remain at
least partially immobilized inside the polymer, and outside
proteins in sweat would be at least partially excluded. The
calibration medium may be adapted to prevent outside proteins from
being absorbed based on the size of the proteins, based on
properties such as the solubility or lipophilicity of the proteins.
The calibration medium may also include ionophores to allow certain
solutes and the water from sweat to electronically activate the
sensor while excluding other solutes. Therefore, a predictable
dilution or concentration of the calibration medium could be
provided long enough to allow sensor calibration (e.g., on the
order of seconds or minutes) before the polymer dissolves. In one
embodiment, the calibrating analytes may be absorbed by the sensor
underneath the polymer, and the sensor will be calibrated when
water and salt (i.e., sweat) reaches the sensor, which enables the
proper electrical connection needed for a complete sensing circuit.
Similarly, hydrogels could be used as calibration mediums as long
as a suitable time period for calibration is provided. For example,
in one embodiment, the thickness of the hydrogel provides adequate
time for the calibrating analyte inside the hydrogel to calibrate
the sensor before external analytes in sweat enter the hydrogel and
dominate the signal provided from the sensor. It should be
recognized that calibration mediums may have alternative
configurations. For example, in various embodiments, the
calibration medium may be constructed of may be a textile that is
coated with analytes or may include multiple layers of polymers or
gels having different properties. Additionally, various techniques,
such as altering the pH, may be used to remove the calibrating
analytes from sensors to prevent interference with measurements of
new sweat.
[0050] With reference to FIG. 8, a device 800 contains two sensors
820, 822 for example, and two identical calibration mediums 870.
Sensors 820, 822 and calibration mediums 870 are enclosed by
substrate 810 and seal 817. Seal 817 includes fluidic gates 880,
882. Fluidic gates 880, 882 only allow sweat to reach sensors 820,
822 as determined by the design of the fluidic gates 880, 882
(e.g., based on a dissolution rate of the gate). In one embodiment,
when gates 880, 882 allow the passage of fluid, sweat would first
enter the space between the membrane 810 and seal 817 and dissolve
calibration mediums 870. In this manner, sensors 820, 822 may be
calibrated similarly to the calibration methods discussed above.
After a period of time (e.g., 30 minutes), the calibration medium
870 would diffuse out through the microfluidic gates 880, 882 as
new sweat enters. As the medium 870 diffuses, the analyte
concentrations near the sensors 820, 822 would be increasingly
dominated by those in new sweat. The device 800 of FIG. 8 is useful
when a sensor is to be calibrated and used only when needed. In one
embodiment, sensors 820, 822 are one-time use, and the device 800
is configured to perform multiple readings. Where more than one
microfluidic gate is used, the gates may be designed to open and
close at the same time or at different times. Multiple fluidic gate
configurations are possible as known by those skilled in the art,
including thermo-capillary, electrowetting, melting of wax
barriers, or other known techniques. In one embodiment, a wicking
element could also be included (not shown) to bring a continuous
flow of sweat to the sensor 820 or 822, and mitigate the need for a
calibration medium to diffuse out, thereby decreasing the time
required to calibrate the device.
[0051] With further reference to FIG. 8, in one embodiment, one or
both of gates 880, 882 could be a dissolvable polymer (e.g., PVP or
PVA) and seal 817 could be a membrane (e.g., a dialysis membrane)
that is permeable to water but highly impermeable to at least one
analyte to be calibrated. Therefore, as sweat wets the membrane
817, water moves though the membrane 817 and dissolves calibration
medium 870 and creates a calibrating solution for calibrating at
least one of the sensors 820, 822. Later, as at least one of the
gates 880, 882 dissolves away, sweat including the analytes that
were previously excluded by membrane 817 enters through the
dissolved gate 880, 882 and begins to be sensed by the
now-calibrated sensor 820 or sensor 822. The exact dimensions shown
in FIG. 8 are non-limiting and are provided as an example only. For
example, in one embodiment, gates 880, 882 could have larger area
than membrane 817.
[0052] For purpose of clarity, layers and materials in the
above-described embodiments of the present invention are
illustrated and described as being positioned `between` sweat and
sensors and, in some cases, `between` one or more of each layer or
material. However, terms such as `between` should not be so
narrowly interpreted. The term `between` may also be interpreted to
mean `in the fluidic pathway of interest`. For example, in one
embodiment, a microfluidic channel that is 3 mm long and 300
.mu.m.times.100 .mu.m in area could be positioned in the pathway
(or `between`) of flow of sweat from the skin to the sensors and
may include any one or more of the features illustrated and
discussed for the present invention. Therefore, `between` or other
terms should be interpreted within the spirit of the present
invention, and alternate embodiments, although not specifically
illustrated or described, are included with the present invention
so long as they would obviously capture similar purpose or function
of the illustrated embodiments.
[0053] This has been a description of the present invention along
with a preferred method of practicing the present invention,
however the invention itself should only be defined by the appended
claims.
* * * * *