U.S. patent application number 15/770262 was filed with the patent office on 2018-11-08 for devices capable of fluid sample concentration for extended sensing of analytes.
This patent application is currently assigned to Eccrine Systems, Inc.. The applicant listed for this patent is Eccrine Systems, Inc., University of Cincinnati. Invention is credited to Jacob A. Bertrand, Michael Brothers, Jason Heikenfeld, Andrew Jajack.
Application Number | 20180317833 15/770262 |
Document ID | / |
Family ID | 58558219 |
Filed Date | 2018-11-08 |
United States Patent
Application |
20180317833 |
Kind Code |
A1 |
Heikenfeld; Jason ; et
al. |
November 8, 2018 |
DEVICES CAPABLE OF FLUID SAMPLE CONCENTRATION FOR EXTENDED SENSING
OF ANALYTES
Abstract
The disclosed invention provides a fluid sensing device and
method capable of collecting a fluid sample, concentrating the
sample with respect to one or more target analytes, and measuring
the target analyte(s) in the concentrated sample. The invention is
also capable of determining the change in molarity of the fluid
sample with respect to the target analyte(s), as the sample is
concentrated by the device. The invention further includes a method
for using a fluid sensing device to concentrate a fluid sample with
respect to one or more target analytes. The disclosed method
further includes the ability to correlate the measured target
analyte concentration to a physiological condition of a device
wearer, or of a fluid source.
Inventors: |
Heikenfeld; Jason;
(Cincinnati, OH) ; Bertrand; Jacob A.; (Norwood,
OH) ; Brothers; Michael; (Lebanon, OH) ;
Jajack; Andrew; (Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Eccrine Systems, Inc.
University of Cincinnati |
Cincinnati
Cincinnati |
OH
OH |
US
US |
|
|
Assignee: |
Eccrine Systems, Inc.
Cincinnati
OH
University of Cincinnati
Cincinnati
OH
|
Family ID: |
58558219 |
Appl. No.: |
15/770262 |
Filed: |
October 23, 2016 |
PCT Filed: |
October 23, 2016 |
PCT NO: |
PCT/US2016/058356 |
371 Date: |
April 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62245638 |
Oct 23, 2015 |
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62269447 |
Dec 18, 2015 |
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62269244 |
Dec 18, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 13/0246 20130101;
G01N 33/5438 20130101; A61B 5/14521 20130101; A61B 5/14532
20130101; A61B 5/14546 20130101; A61B 2010/0016 20130101; A61B
5/4266 20130101; A61B 10/0064 20130101; G01N 33/66 20130101; A61B
5/6833 20130101; A61B 5/0002 20130101; A61B 10/0012 20130101; G01N
33/5308 20130101; G01N 33/50 20130101; A61B 5/1468 20130101; A61B
5/14517 20130101; A61B 5/0004 20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 10/00 20060101 A61B010/00; A61F 13/02 20060101
A61F013/02; A61B 5/145 20060101 A61B005/145; G01N 33/66 20060101
G01N033/66 |
Claims
1. A sweat sensing device capable of sample concentration and
configured to be placed on a device wearer's skin, comprising: at
least one first analyte-specific sensor for measuring a first
analyte in a concentrated sweat sample; at least one sweat
collector that collects an unconcentrated sweat sample from skin,
where the unconcentrated sweat sample contains the first analyte at
a first molarity; and at least one sample concentrator receiving
the unconcentrated sweat sample from the sweat collector, where the
sample concentrator concentrates the sweat sample, so that the
concentrated sweat sample contains the first analyte at a second
molarity that is at least 2 times higher than the first
molarity.
2. The device of claim 1 including at least one sweat stimulation
component.
3. The device of claim 1 where the sample concentrator includes a
membrane that is permeable to water but impermeable to the first
analyte, and where the membrane has a first side adjacent to a
sweat sample and a second side opposite the sweat sample.
4. The device of claim 1, further comprising: at least one second
analyte-specific sensor for measuring a second analyte in the
concentrated sweat sample; where the unconcentrated sweat sample
contains the second analyte at a third molarity; and where the
sample concentrator concentrates the sweat sample, so that the
concentrated sweat sample contains the second analyte at a fourth
molarity that is at least 2 times higher than the third
molarity.
5. The device of claim 4 where the ratio of the first molarity to
the second molarity is the same as the ratio of the third molarity
to the fourth molarity.
6. The device of claim 1 where a plurality of the first
analyte-specific sensors includes at least one sensor that measures
the first analyte in a concentrated sweat sample; and at least one
sensor that measures the first analyte in an unconcentrated sweat
sample.
7. The device of claim 1 where the sample concentrator includes at
least one gas-filled pathway that is permeable to evaporated water
but impermeable to the first analyte, and where the gap has a first
side adjacent to a sweat sample and a second side opposite the
sweat sample.
8. The device of claim 1, including at least one sensor for
providing a volumetric measurement of a sweat sample.
9. The device of claim 1, including at least one microfluidic
gate.
10. The device of claim 7, including at least one desiccant on the
second side of the gas-filled pathway.
11. The device of claim 7, including at least one heating component
to promote evaporation of water.
12. The device of claim 1, including at least one component capable
of creating a reversible flow of a sweat sample.
13. The device of claim 12, where the reversible-flow component
includes the application of a voltage gradient.
14. The device of claim 1, including at least one component capable
of applying a non-equilibrium pressure to a sweat sample to reverse
the flow of the sweat sample.
15. The device of claim 1, where the first analyte-specific sensor
is surrounded by an immiscible material which has a distribution
coefficient with respect to water or sweat that is greater than 2
for the first analyte.
16. The device of claim 9, where said microfluidic gate controls
the flow of a sweat to the first analyte-specific sensor.
17. The device of claim 1, including at least one flow sensor.
18. The device of claim 1, where the device includes a first
first-analyte specific sensor and a second first analyte-specific
sensor, where the second sensor has a dynamic range of detection
that is centered on a higher concentration than for the first
sensor.
19. The device of claim 3, including at least one draw material on
the second side of the membrane.
20. The device of claim 19, where the draw material contains at
least one solute found in sweat, where the solute has a draw
material molarity that is at least 2 times greater than a sweat
molarity, where the sweat molarity is a concentration of the solute
as it is typically found in sweat.
21. The device of claim 20, including at least one analyte-specific
sensor for said solute.
22. The device of claim 1, including at least one tunable
valve.
23. The device of claim 22, where said tunable valve is in contact
with a fluid that is not sweat.
24. The device of claim 1, including at least one channel for
transporting a sweat sample that reduces the sample's flow
deceleration due to a volume of water that passes into the sample
concentrator.
25. The device of claim 1, including at least one of the following:
a plurality of sweat stimulation components, and a plurality of
reverse iontophoresis components.
26. The device of claim 1, including at least one wicking
component, and where the sample concentrator has an osmotic
pressure that is at least one of more than 2 times greater than a
wicking pressure of the wicking component; and more than 10 times
greater than a wicking pressure of the wicking component.
27. The device of claim 26, where the wicking component and the
sweat collector are at least partially the same component.
28. The device of claim 19, where the draw material includes a
wicking material.
29. The device of claim 19, where the draw material is a
polyelectrolyte.
30. The device of claim 19, where the draw material has a volume
that is greater than the volume of the total sweat sample volume
collected by the device, by at least one of the following: 2 times;
10 times; 100 times; and 1000 times.
31. The device of claim 1, including at least one sensor which
measures the total osmolality of the sweat sample.
32. The device of claim 19, including at least one sensor which
measures the total osmolality of the draw material.
33. The device of claim 1, where concentrated sweat sample contains
the first analyte at a second molarity that is one of the
following: at least 2 times higher than the first molarity; at
least 10 times higher than the first molarity; and at least 100
times higher than the first molarity; and at least 1000 times
higher than the first molarity.
34. The device of claim 1, where the sample concentrator is a
microfluidic concentrator channel of known length, and includes a
plurality of first analyte-specific sensors that are placed at
known intervals within the channel.
35. The device of claim 1, where the sample concentrator is a
concentrator channel, where the concentrator channel includes a
functionalized surface configured to interact with the first
analyte.
36. The device of claim 35, where the sample concentrator is
configured to interact with a plurality of target analytes.
37. The device of claim 35, including a plurality of first
analyte-specific sensors that are placed at known intervals within
the channel
38. The device of claim 35, where the functionalized surface
includes one of the following: a functionalized silica gel, a
plurality of functionalized beads, or a plurality of functionalized
silicon dioxide nanoparticles.
39. The device of claim 35, where the device is configured to cause
the first analyte to release from the functionalized surface.
40. The device of claim 39, where the first analyte is released by
one of the following: introducing a solvent into the sweat sample;
changing the sweat sample pH; changing the sweat sample
temperature; or introducing electromagnetic radiation to the sweat
sample.
41. The device of claim 35, where the concentrator channel includes
a medium having an increasing density gradient oriented in the
direction of sweat sample flow through the channel.
42. The device of claim 35, where the concentrator channel includes
a medium having a plurality of different densities that create a
stepped increasing density gradient oriented in the direction of
sweat sample flow through the channel.
43. The device of claim 35, where the concentrator channel includes
a medium with pores configured to interact with the first analyte
as the sweat sample flows through the channel.
44. The device of claim 35, where the concentrator channel further
includes: a plurality of capture beads; and a heating element.
45. A method of using a sweat sensing device configured to be
placed on a device wearer's skin, and capable of sweat sample
concentration, comprising: placing the device on a wearer;
receiving an unconcentrated sweat sample from the wearer's skin;
concentrating the sweat sample with respect to at least one target
analyte; measuring the target analyte in the sweat sample with an
analyte-specific sensor; and correlating the measurement with a
physiological condition of the wearer.
46. The method of claim 45, further including using a sweat
stimulation component to stimulate sweat from the wearer's
skin.
47. The method of claim 45, where the analyte-specific sensor does
not receive the sweat sample until one of the following events
occurs: at least one secondary sensor provides an input; a
scheduled time; and a device user provides an input.
48. The method of claim 45, further including using at least one
flow sensor to determine the degree of concentration of the sweat
sample with respect to the target analyte.
49. The method of claim 45, further including: using at least one
analyte-specific sensor to measure a reference analyte in the sweat
sample; concentrating the sweat sample with respect to the
reference analyte, where the reference analyte is concentrated to a
similar degree as the target analyte; and comparing the target
analyte measurement to the reference analyte measurement.
50. The method of claim 45, further including: using a tunable
valve to control the degree of sweat sample concentration with
respect to the target analyte.
51. The method of claim 45, further including: using at least one
analyte-specific sensor to measure a target analyte in a sweat
sample that is unconcentrated with respect to the target analyte;
using at least one analyte-specific sensor to measure the target
analyte in a sweat sample that is concentrated with respect to the
target analyte; comparing the unconcentrated target analyte
measurement to the concentrated target analyte measurement; and
determining a flow rate for the sweat sample.
52. The method of claim 45, where the sweat sample is concentrated
at least 2 times with respect to at least one target analyte; at
least 10 times with respect to at least one target analyte; at
least 100 times with respect to at least one target analyte; or at
least 1000 times with respect to at least one target analyte;
53. The method of claim 45, where the device includes a
microfluidic channel of known length, and a plurality of
analyte-specific sensors for measuring a target analyte that are
placed at known intervals within the channel, further comprising:
measuring the difference in target analyte concentration between
successive sensors; determining the target analyte concentration
increase per unit length of channel; and determining the total
amount of target analyte concentration at each sensor.
54. The method of claim 45, where the device includes a
concentrator channel configured to interact with at least one
target analyte, further comprising: flowing a sweat sample through
the channel; concentrating the at least one target analyte in the
sweat sample; and measuring the concentration of the at least one
target analyte.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application relates to PCT/US2015/032893; U.S.
Provisional No. 62/245,638, filed Oct. 23, 2015; U.S. Provisional
No. 62/269,244, filed Dec. 18, 2015, and U.S. Provisional No.
62/269,447, filed Dec. 18, 2015, the disclosures of which are
hereby incorporated by reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] Non-invasive biosensing technologies have enormous potential
for several medical, fitness, and personal well-being applications.
The sweat ducts can provide a route of access to 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. Sweat has many of
the same analytes and analyte concentrations found in blood and
interstitial fluid. Interstitial fluid has even more analytes
nearer to blood concentrations than sweat does, especially for
larger sized and more hydrophilic analytes (such as proteins).
[0003] While bio-monitoring fluids offer their greatest potential
when used a source of continuous information about the body, the
technological challenges of accomplishing such continuous
monitoring are considerable. For example, many techniques that work
well in a laboratory are difficult to implement in a wearable
device. This is especially true for laboratory techniques used to
measure analytes that typically emerge in sweat, interstitial
fluid, or other fluid below the detection limit for available
sensors. To overcome this challenge, devices and methods for
concentrating fluid samples inside a wearable device are needed,
and disclosed herein.
[0004] Many of the drawbacks and limitations 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 biofluid sensing technology into proximity with
a fluid as it is generated.
SUMMARY OF THE INVENTION
[0005] The disclosed invention provides a fluid sensing device
capable of collecting a fluid sample, concentrating the sample with
respect to a target analyte, and measuring the target analyte in
the concentrated sample. The invention is also capable of
determining the change in molarity of the fluid sample with respect
to the target analyte, as the sample is concentrated by the
device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The objects and advantages of the present disclosure will be
further appreciated in light of the following detailed descriptions
and drawings in which:
[0007] FIG. 1 is a depiction of at least a portion of a wearable
device for sweat biosensing.
[0008] FIG. 2 is an example embodiment of at least a portion of a
device capable of fluid sample concentration.
[0009] FIGS. 3A and 3B is an example embodiment of at least a
portion of a device capable of fluid sample concentration.
[0010] FIG. 4 is an example embodiment of at least a portion of a
device capable of fluid sample concentration.
[0011] FIG. 5 is an example embodiment of at least a portion of a
device capable of fluid sample concentration.
[0012] FIG. 6 is an example embodiment of at least a portion of a
device capable of fluid sample concentration.
[0013] FIG. 7 is an illustrated data plot of how the disclosed
invention could be utilized.
[0014] FIG. 8 depicts an example embodiment of at least a portion
of a device capable of fluid sample concentration.
[0015] FIG. 9 depicts an example embodiment of at least a portion
of a device capable of fluid sample concentration.
[0016] FIG. 10 depicts an example embodiment of at least a portion
of a device capable of fluid sample concentration.
[0017] FIG. 11 depicts an example embodiment of at least a portion
of a device capable of fluid sample concentration.
[0018] FIGS. 12A to 12C depict an example embodiment of at least a
portion of a device capable of fluid sample concentration.
[0019] FIGS. 13A to 13D depict an example embodiment of at least a
portion of a device capable of sweat sample concentration and which
is additionally capable of sweat stimulation and/or reverse
iontophoresis.
[0020] FIGS. 14A and 14B depict an example embodiment of at least a
portion of a device capable of fluid sample concentration.
[0021] FIGS. 15A and 15B depict an example embodiment of at least a
portion of a device capable of fluid sample concentration.
DEFINITIONS
[0022] As used herein, "sweat" or "sweat biofluid" 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.
[0023] As used herein, "biofluid" may mean any human biofluid,
including, without limitation, sweat, interstitial fluid, blood,
plasma, serum, tears, and saliva. A biofluid may be diluted with
water or other solvents inside a device because the term biofluid
refers to the state of the fluid as it emerges from the body.
[0024] As used herein, "fluid" may mean any human biofluid, or
other fluid, such as water, including without limitation,
groundwater, sea water, freshwater, etc., or other fluids.
[0025] As used herein, "continuous monitoring" means the capability
of a device to provide at least one sensing and measurement of
fluid collected continuously or on multiple occasions, or to
provide a plurality of fluid measurements over time.
[0026] As used herein, "chronological assurance" is an assurance of
the sampling rate for measurement(s) of sweat (or other biofluid or
fluid), or solutes in sweat, being the rate at which measurements
can be made of new sweat or its new solutes as they originate from
the body. Chronological assurance may also include a determination
of the effect of sensor function, or potential contamination with
previously generated sweat, previously generated solutes, other
fluid, or other measurement contamination sources for the
measurement(s).
[0027] 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.
[0028] 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.
[0029] 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. 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 carbachol, 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 device wearer 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.
[0030] As used herein, "sweat generation rate" is the rate at which
sweat is generated by eccrine sweat glands. 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 sweat is being sampled to
calculate the sweat volume sampled per unit time.
[0031] As used herein, "fluid sampling rate" is the effective rate
at which new fluid, or fluid solutes, originating from the fluid
source, reaches a sensor that measures a property of the fluid or
its solutes. Fluid 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 fluidic volume can also be said to have a fast
or high fluid sampling rate. The inverse of fluid sampling rate
(1/s) could also be interpreted as a "fluid sampling interval(s)".
Fluid sampling rates or intervals are not necessarily regular,
discrete, periodic, discontinuous, or subject to other limitations.
Like chronological assurance, fluid sampling rate may also include
a determination of the effect of potential contamination with
previously generated fluid, previously generated solutes, other
fluid, or other measurement contamination sources for the
measurement(s). Fluid 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 fluid or fluid solutes reach a
sensor and/or are altered by older fluid or solutes or other
contamination sources. Sensor response times may also affect
sampling rate.
[0032] 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`, present/not present type measurements.
[0033] As used herein, "fluidic volume" is the fluidic volume in a
space that can be defined multiple ways. Fluidic volume may be the
volume that exists between a sensor and the point of generation of
a fluid or a solute moving into or out of the fluid from the body
or from other sources. Fluidic volume can include the volume that
can be occupied by fluid 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.
[0034] As used herein, "solute generation rate" is simply the rate
at which solutes move from the body or other sources into a fluid.
"Solute sampling rate" includes the rate at which these solutes
reach one or more sensors.
[0035] 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.
[0036] As used herein, "state void of fluid" means a fluid sensing
device component, such as a space, material or surface, that can be
wetted, filled, or partially filled by fluid, when the component is
entirely or substantially (e.g., >50%) dry or void of fluid.
[0037] As used herein, "advective transport" is a transport
mechanism of a substance, or conserved property by a fluid, that is
due to the fluid's bulk motion.
[0038] 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.
[0039] As used herein, a "sample concentrator" is any portion of a
device, material, subsystem, or other component that can be
utilized to increase the molarity of at least one fluid analyte, at
least in part by removing a portion of the water that was
originally with the at least one analyte when it exited the
body.
[0040] "EAB sensor" means an electrochemical aptamer-based
biosensor that is configured with multiple 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)).
[0041] As used herein, the term "analyte-specific sensor" is a
sensor specific to an analyte and performs specific chemical
recognition of the analyte's presence or concentration (e.g.,
ion-selective electrodes, enzymatic sensors, electrochemical
aptamer-based sensors, etc.). For example, sensors that sense
impedance or conductance of a fluid, such as sweat, are excluded
from the definition of analyte-specific sensor because sensing
impedance or conductance merges measurements of all ions in sweat
(i.e., the sensor is not chemically selective; it provides an
indirect measurement). Sensors could also be optical, mechanical,
or use other physical/chemical methods which are specific to a
single analyte. Further, multiple sensors can each be specific to
one of multiple analytes.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The disclosed invention applies at least to any type of
fluid sensor device that measures fluid, fluid generation rate,
fluid chronological assurance, its solutes, solutes that transfer
into fluid from skin, tissue, or other source, a property of or
things on the surface of skin, or properties or things beneath the
skin. The invention applies to fluid sensing devices which can take
on forms including patches, bands, straps, portions of clothing,
wearables, or any suitable mechanism that reliably brings sweat
stimulating, fluid collecting, and/or fluid sensing technology into
intimate proximity with fluid as it is generated. Some embodiments
of the 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.
[0043] Certain embodiments of the invention show sensors as simple
individual components. 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 fluid 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 fluid 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 invention. As a further
example, many embodiments of the 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
present application has specification that builds upon
PCT/US13/35092, the disclosure of which is hereby incorporated
herein by reference in its entirety.
[0044] With reference to FIG. 1, a sweat sensing device 100 is
placed on or near skin 12. In an alternate embodiment, the sweat
sensing device may be fluidically connected to skin or regions near
skin through microfluidics or other suitable techniques. Device 100
is in wired communication 152 or wireless communication 154 with a
reader device 150. In one embodiment of the invention, the reader
device 150 would be a smart phone or portable electronic device. In
alternate embodiments, device 100 and reader device 150 can be
combined. In further alternate embodiments, communication 152 or
154 is not constant and could be a simple one-time data download
from device 100 once it has completed its measurements of
sweat.
[0045] With reference to FIG. 2, a device 200 provides a reduced
fluidic volume 280 between a wearer's skin 12 and at least one
analyte-specific sensor 220, as disclosed in PCT/US2015/032893. The
fluidic volume 280 is bounded by a fluid impermeable substrate 270
such as PET, and an adhesive layer 210, which also functions to
secure the device to the skin. Material 270 has an opening in the
center 255, to allow fluid to access the sensor 220. Adhesives can
be pressure sensitive, liquid, tacky hydrogels, which promote
robust electrical, fluidic, and iontophoretic contact with skin.
The device 200 further includes fluid impermeable materials 215 and
272, where 215 may also serve as a substrate for fabrication (e.g.,
one or more layers shown in FIG. 2 could be fabricated on the
substrate, for example a Kapton substrate for flexible
electronics). The locations of sweat ducts 14 are also noted.
[0046] The device 200 is also configured to provide a reduced
wicking volume, as disclosed in PCT US2016/43771. Accordingly, the
device includes a sweat collector 234, which draws sweat through
opening 255, and creates volume reduced pathway(s) 290 between the
ducts and the opening 255. The sweat collector 234 is in fluidic
communication with a fluid sample coupler 232, which carries sweat
past the sensor 220. Sensor 220 could be any sensor specific to an
analyte in sweat, such as an ion-selective electrode, enzymatic
sensor, electrochemical aptamer sensor, etc. The fluid sample
coupler 232 is in fluid communication with a fluid sample pump 230,
which is comprised of a textile, paper, or hydrogel, and that
serves to maintain fluid flow through the device. The sweat
collector 234 must be adequately thin so that its fluidic volume is
less than the fluidic volume of the wicking space 280. As an
example of a proper implementation of the sweat collector 234, the
wicking space 280 could have an average height of 50 .mu.m due to
skin roughness, or more if hair or debris is present. The wicking
material could be a 5 .mu.m thick layer of screen-printed
nanocellulose with a weak binder and or a thin hydrogel material to
hold the cellulose together. Importantly, in terms of strength of
capillary force, material 232 should have greater capillary force
than material 230, which in turn should have greater capillary
force than wicking space 280. In a preferred embodiment, fluid
sample coupler 232 would have the greatest wicking force relative
to the other wicking materials, such as 234 and 230, so that sensor
220 remains wetted with sweat.
[0047] With further reference to FIG. 2, the device 200 also
includes a sample concentrator 295. In one embodiment of the
invention, the sample concentrator 295 is a dialysis membrane that
is permeable to inorganic ions but impermeable to small molecules
and proteins. In other embodiments, the sample concentrator may be
any membrane or material that is at least porous to water, but that
is not substantially porous to the analyte that is to be
concentrated. As sweat flows onto fluid sample pump 230 by wicking
through the concentrator membrane 295, solutes are concentrated in
fluid sample coupler 232. The device may be configured to
concentrate a target analyte in the fluid sample by at least
2.times. higher than the unconcentrated molarity. Depending on the
application, the target analyte may be concentrated at least
10.times., 100.times., or 1000.times. higher than the
unconcentrated molarity. The fluid sample coupler 232 could be
hydrogel, textile, or other suitable wicking material.
Analyte-specific sensor 220 may be, for example, two or more
electrochemical sensors for cortisol and didehydroepiandrosterone
(DHEA) to measure the ratio of these two biomarkers in sweat. This
ratio is a well-known marker of many conditions, see, e.g.,
http://metabolichealing.com/cortisol-dhea-the-major-hormone-balance/,
and furthermore allows meaningful sensing without having to
determine the molarity of the fluid sample concentrated by the
sample concentrator 295.
[0048] In an alternate embodiment, an osmosis membrane can be used
as the sample concentrator 295, where the membrane is
water-permeable, but is impermeable to electrolytes, such as
K.sup.+. Because sweat K.sup.+ concentration does not vary
significantly with sweat rate, the sensor 220 could measure K.sup.+
and another analyte, such as cortisol, to determine the molarity of
the fluid sample, and therefore allow accurate back-calculation of
the original cortisol concentration. Embodiments of the disclosed
invention may accordingly be configured with a first sensor
specific to a first fluid analyte and a second sensor specific to a
second fluid analyte, wherein both the first and second analytes
are concentrated. Similarly, additional sensors may be added to
measure additional concentrated analytes. In other embodiments,
sweat conductivity could be measured and used to determine the
molarity, although this method would be less reliable, since sweat
conductivity is more variable with sweat generation rate.
[0049] With reference to FIG. 3A, where like numerals refer to like
features of previous figures, a microchannel 380 is created and
filled with a fluid sample 16 between sample concentrator membrane
395 and fluid impermeable material or film 370. The microchannel
380 includes at least one pair of sensors 320a and 320b, that form
a sensor pair 320. For example, a first sensor 320a may be for
K.sup.+, and a second sensor 320b may be for cortisol. Sensor pair
320 measures the unconcentrated sweat concentrations of K.sup.+ and
cortisol as they emerge from the skin 12. As fluid 16 flows
leftward through the microchannel 380 in the direction of the arrow
301, water 18 from the fluid diffuses into the fluid sample pump
330, which may be a hydrogel, a desiccant, salt, or microfluidic
wicking material, by osmosis or capillary wicking force. By this
mechanism, the fluid sample 16 becomes more concentrated as it
moves through the microchannel 380. Sensor pairs 322, 324, 326
likewise measure K.sup.+ and cortisol, but at increasing
concentrations as the fluid sample 16 becomes more concentrated
(i.e., loses more water through sample concentrator 395). The
K.sup.+ sensor is used to predict the molarity of the sweat sample
16 and therefore correct the cortisol reading for the increasing
molarity. One will recognize that the channel flow volume will
decrease as the sample 16 moves through the microchannel 380 along
the arrow 301, and in some cases the flow velocity or pressure will
become too low to allow reliable measurement (e.g., diffusion or
backflow will contaminate the sample). Therefore, in one example,
the channel 380 may be tapered in at least one dimension along the
channel length moving right to left. With such a configuration, as
the fluid sample 16 flows from right to left, the sample's
deceleration from fluid loss may be reduced, fluid velocity may
remain steady, or fluid velocity may actually increase, as the
volume of the microchannel decreases (as will be illustrated in a
later figure). The sample concentrator membrane 395 could also have
a surface charge in water, which would tend to reject permeation by
ions such as K.sup.+. The invention may include a plurality of
analyte-specific sensors for detecting at least one target analyte,
wherein at least two of said plurality of sensors comprise a first
sensor group, and at least two of said plurality of sensors
comprise a second sensor group, and wherein the first sensor group
measures the target analyte in a less concentrated fluid sample,
and the second sensor group measures the target analyte in a more
concentrated fluid sample.
[0050] With reference to FIG. 3B, the device 300b is similar to
device 300a of FIG. 3A with several exceptions. As an initial
matter, the sensors 320, 322, 324, 326 could be similar to those
described previously, or may detect the presence of a fluid sample
16 by potential or conductance, where the fluid 16 is in its
original, unconcentrated form, or in a concentrated form. A
channel, tube, or other capillary component 380 is created between
concentrator membrane 395 and water-impermeable film 370.
Alternately, the channel could be formed entirely out of a tube of
membrane material, such as used for the membrane 395 (e.g., a small
dialysis tube). Multiple arrangements are possible, so long as they
satisfy the general inventive aspects described herein. As shown,
the advancing edge 14 of fluid 16 is concave and moving toward
fluid sample pump 330. The fluid sample pump 330 could be a gel, a
desiccant, and the membrane 395 could be membranes like previously
taught for FIG. 2 or porous Teflon membrane filled with air, or
other material which provides at least one gas filled pathway.
Membrane 395 could therefore allow water to pass into the air as
water vapor (evaporation). If evaporation is relied upon, then
concentrator 395 may not need to be permi-selective to solutes in
fluid, but rather would help define the microfluidic channel 380. A
fluid sample 16 could be collected, fill the channel, and water or
solutes that are not of interest for sensing may be extracted
through concentrator membrane 395. As water is lost, the fluid
sample 16 reduces in volume, and the sensors 320, 322, 324, 326 can
use a volume measurement to predict how much fluid sample 16 was
collected initially and how much sample 16 has been concentrated.
Therefore, the disclosed invention may include at least one sensor
for volumetric measurement. Other sensor arrangements to determine
the molarity of the sample 16 may also be possible, and the use of
sensors 320, 322, 324, 326 are one non-limiting example.
[0051] In another example embodiment, sensor 328 may sense a target
analyte, and the analyte's actual molarity can be calculated based
on successive sensor 320, 322, 324, 326 measurements that estimate
the volume of water extracted through the membrane 395 into the
fluid sample pump 330. For the most reliable and repeatable
results, at least one microfluidic gate (not shown) may be added to
allow a fluid sample 16 to enter the device, then the gate could
close to prevent, or adequately slow, introduction of new fluid
into the microchannel 380. Integration of microfluidic gates will
be further taught in later figures and embodiments. The aspect
ratios of the microchannel 380 shown in FIG. 3 are for diagrammatic
purposes only, and the channel 380 could be very long with a small
cross section, e.g., a coiled tube.
[0052] With reference to FIG. 4, where like numerals refer to like
features of previous figures, a fluid sample coupler 432 wicks and
holds a fluid sample 16. Alternately, fluid sample coupler 432
could be a channel, capillary, or wetted surface with fluid 16 at
least partially exposed and unconfined (allowing evaporation).
Outside the fluid sample coupler 432 is an air or gas gap 411,
followed by a water vapor porous concentrator or membrane material
495, followed by a fluid sample pump 430 comprised of, e.g., a
desiccant. The air gap 411 is used, because in some cases, small
ions or other target analytes will penetrate through an osmosis
membrane as described in previous embodiments. Therefore, the air
gap 411 will only allow exit of volatile compounds such as water,
and retain more solutes than a membrane could, in some cases. An
external film 472 that is not water vapor permeable is also
provided, to prevent desiccant from becoming saturated due to
moisture or water vapor from outside the device 400. In an
alternate embodiment, the device may omit the pump and film, and
will therefore operate by evaporation of the fluid sample into
ambient air (not shown). Other beneficial features may be included
(not shown) such as a heater to promote evaporation, for example.
The heater could be integrated onto substrate 470 between fluid
sample coupler 432 and substrate 470, and could be, for example, a
simple heater based on electrical resistance. To prevent the device
wearer from feeling heat on their skin, low thermal conductivity or
thermal isolation materials may also be added between the heater
and skin (not shown). The disclosed invention may include at least
one air gap as a pathway for evaporation concentration of fluid,
and may include at least one desiccant that receives water
evaporated from the fluid, and may include at least one heater that
promotes evaporation of water from the fluid. Similarly, vacuum
pressure could also be applied to promote evaporation.
[0053] With reference to FIG. 5, where like numerals refer to like
features of previous figures, a microfluidic channel 580 is formed
between film or material 570 and film or material 572. Like
previous embodiments, the concentrator membrane 595 is
permi-selective in terms of which analytes may pass through it, or
concentrator 595 could pass primarily only water. In such
embodiments, sample concentration is achieved by one of several
active microfluidic mechanisms, such as electrophoresis,
iontophoresis, electro-osmosis, dielectrophoresis, electro-wetting,
pressure-driven advective flow, etc. For example, as shown in FIG.
5, if the driving force were electrical, electrodes 560 and 562
could provide voltage or current, and therefore drive a flow of
fluid sample 16 containing a target analyte leftward in the
direction of arrow 501. Concentrator membrane 595 would block the
target analyte, (e.g., glucose), causing an increased molar
concentration of the target analyte. In some embodiments, the
membrane may also be configured to block a second target analyte
for calibration purposes, (e.g., testosterone). The molarities of
the two target analytes would be measured through use of sensors
520a and 520b, respectively. Such a device 500 could be used to
take multiple measurements of the target analytes, the performance
improved by removing the fluid sample after sensing by reversing
the voltage, or by using other flow driving means, so that the
fluid sample 16 moves away in the direction of arrow 502. In some
embodiments, the present disclosure may include at least one
component capable of creating a reversible flow of fluid. In other
embodiments, the invention may include at least one component for
applying a non-equilibrium pressure (e.g., electrical, mechanical,
etc.) to reverse the fluid sample 16 flow.
[0054] With reference to FIG. 6, where like numerals refer to like
features of previous figures, a microfluidic channel 680 is formed
between film or material 670 and film or material 672. A sensor 620
is coated or surrounded by an immiscible material 655. Immiscible
material 655 is non-dissolvable in the fluid sample 16. The
immiscible material could be an ionic liquid, a hydrocarbon, a
liquid crystal, a porous polymer, or any material which has a
distribution coefficient with respect to water or other fluid which
is greater than 2. For example, if immiscible material 655 were a
fluid or gel that is more hydrophobic than water, then hydrophobic
solutes in sweat or interstitial fluid, such as cortisol, lipids,
or other solutes, would passively concentrate into immiscible
material 655. The distribution coefficient is k and can be
predetermined or measured, and the target analyte molarity that
occurs will equal k, and therefore the target analyte sweat
concentration can be easily predicted. Distribution coefficients
can be in the 1's to 10's even 100's or more. An example would be
electrochemical sensing of hemoglobin using glassy carbon
surrounded by an ionic liquid. The analytes which have the greatest
distribution coefficients with respect to sweat generally make
electrochemical sensing more challenging, and therefore other
methods of sensing, such as optical techniques may be
preferred.
[0055] With reference to FIG. 7, a graph is provided to illustrate
one example of how the invention could be utilized. At low
concentrations of an analyte, there is no signal change (the
concentration is below the limits of detection) and at high
concentrations, sensor signals can become saturated. The fluid
sensing device may measure continuously or repeatedly to determine
whether a proper sensing window had been achieved. For example,
because K.sup.+ maintains a fairly consistent sweat concentration
relative to changes in sweat rate, K.sup.+ could be used to
determine the molarity of a concentrated sweat sample. This
molarity measurement would indicate when an adequate concentration
of another analyte, for example the peptide BNP, had been reached
to enable an accurate measurement of its concentration. The K.sup.+
measurement could then be used to back-calculate the BNP molarity
in unconcentrated sweat. This is represented by window 1 in FIG. 7.
Similarly, window 2 represents the range for which sweat
concentrations of albumin would be used to determine the molarity
increase of the sweat sample (because albumin concentration is
fairly constant in blood). In one embodiment, an analyte-specific
sensor may be continually operating to measure K.sup.+, albumin, or
another marker with fairly consistent sweat concentration, and
other analyte-specific sensors would be activated only when a
target analyte reached an appropriate concentration window. As will
be taught in later embodiments, devices can also adapt the amount
of sample concentration to maintain the sweat sample in the sensing
windows as exemplified in FIG. 7.
[0056] With reference to FIG. 8, where like numerals refer to like
features of previous figures, an amperometric sensor 820 and
enzymatic material 857 is provided, along with a secondary sensor
822 which can measure fluid collection rate or fluid generation
rate. For example, sensor 822 could be a thermal flow sensor
operable in the range of 0.1 to 100 nL/min. Amperometric sensors
are a type of analyte-consuming sensor, which reduce the amount of
target analyte present in the fluid sample by performing an
enzymatic conversion of the analyte, allowing measurement to occur.
Other sensor technologies that consume or irreversibly alter the
target analyte may also be used, especially those where sample
volume can limit proper sensor function. Such sensor modalities are
useful for measuring analytes like ethanol, glucose, or lactate.
Assume, for example, that sensor 820 and material 857 are
configured to facilitate the amperometric sensing of ethanol.
During the measurement process, the analyte undergoes a two or more
step process of enzymatic conversion, followed by a charge transfer
to or from sensor 820. Since analyte-consuming sensors deplete the
available analyte, if they are continuously operated, the
steady-state detection signal may remain below the sensor's lower
limit of detection, or below the level of background electrical
noise.
[0057] An embodiment of the disclosed invention allows continuous
sensing with analyte-consuming sensors by periodically sampling
only when a chronologically assured new (or unmeasured) fluid
sample is introduced to the sensor 820, and after a sufficient
amount of analyte is enzymatically converted. The flow sensor 822
measures the rate at which new fluid enters the device 800, which
allows the device to determine when the fluid sample is fully
refreshed. Once the chronologically assured new fluid sample is
introduced to sensor 820, and after at least some of the target
analyte is enzymatically converted, the device activates sensor 820
to sense amperometric charge. As a result, instead of continuous
measurement, the sensor 820 only operates periodically, which
allows the analyte concentration to build during intervals between
measurements, which increases the signal relative to the lower
limit of detection, or relative to the noise level. In another
embodiment, flow sensor 822 is absent, and sensor 820 may be
activated periodically, or according to a predetermined schedule.
This example embodiment merely illustrates one device configuration
that improves the function of enzymatic and other analyte-consuming
sensors when used with sample concentration.
[0058] With reference to FIG. 9, where like numerals refer to like
features of previous figures, a device 900 includes a plurality of
different sensor types that may be used at different times. The
device depicted in FIG. 9 is an illustrative example, but the
invention is not so limited (multiple analytes may be sensed using
various device, material, and sensor configurations). Sensor 920 is
for estrogen, and sensor 922 is for progesterone, both of which
have electrochemical aptamer-based sensors configured to operate at
the analytes' natural concentration ranges found in sweat. In the
appropriate concentrations, these analytes can indicate the
likelihood of impending female ovulation. Concentrator membrane 995
is permeable to solutes with size <1000 Da, and relatively
impermeable to solutes with size >1000 Da, such that estrogen or
progesterone are able to pass through the membrane 995 (generally,
size selective). Sensor 924 is any sensor type that measures one of
an analyte, flow, or property of sweat, which can be used to
indicate the fluid sample's increase in molarity for analytes
>1000 Da. Note, the microchannel 980 near substrate or material
970 and membrane 995 could be larger than shown, and therefore,
this, like other embodiments, should not be strictly interpreted by
the apparent dimensions in the figures. The device 900 is applied,
for example, at 8 PM, and the next day, the user has selected 8 PM
as a moment to determine the likelihood of ovulation within the
next several hours. During device operation, sensors 920 and 922
measure the likelihood of ovulation by measuring estrogen and
progesterone concentrations. Sensors 920 and 922 are able to
measure estrogen and progesterone molarities in an unconcentrated
sweat sample, because these analytes are .about.300 Da in size, and
will pass through membrane 995 into fluid sample pump 930. As sweat
continues to enter the channel 980, larger solutes unable to pass
through the concentrator 995 will become concentrated in the sweat
sample. At a size of .about.30,000 Da luteinizing hormone will be
unable to pass through the membrane 995, and with therefore be one
of the solutes concentrated. At around 8 PM, a microfluidic gate
988, which could be any gate type known to those skilled in the art
of microfluidics, allows the concentrated sweat sample to flow onto
sensor 926, which could be any type of sensor for luteinizing
hormone, for example a lateral flow assay such as are commonly used
in commercial urinary test strips for ovulation. If sensor 926 is a
lateral flow assay, larger sample volumes may be required.
Luteinizing hormone, like other proteins, is likely dilute in sweat
compared to blood, but a device that collected sweat for 24 hours
could collect and concentrate a sweat sample with a sufficient
number of luteinizing hormone molecules to be detected by sensor
926. Sensor 924 may be used to inform the amount of concentration
that has occurred, but would not be necessary if a simple
qualitative measurement of the analyte is required. After
stabilization, sensor 926 would then inform the user of the
likelihood of ovulation.
[0059] This is an example of a device of the present disclosure
that may be configured a number of different ways, and may include
at least one microfluidic gate between a first sensor and the fluid
sample that is being concentrated, an electrochemical sensor or a
non-electrochemical sensor, a sensor for concentrated samples or a
sensor for non-concentrated samples, or a sensor that does not
receive a sample of fluid until one of the following occurs: 1)
another sensor provides an input; 2) a scheduled time; or 3) a user
provides an input or request. For example, if concentration of
estrogen or progesterone were to change significantly in sweat then
signals from those sensors could go to electronics (not shown)
which would then further trigger gate 988 to open or close as
needed.
[0060] With reference to FIG. 10, where like numerals refer to like
features of previous figures, a device 1000 includes a concentrator
membrane 1095, such as a forward osmosis membrane, and a
concentrator pump 1097. The concentrator pump 1097 could be
comprised of a draw solution or material, like sucrose dissolved in
water, or a dry draw material, e.g., a wicking material, hydrogel,
dissolvable polymer, a large-molecule salt, dry sucrose, or other
suitable materials capable of exerting a wicking or osmotic force
or pressure. The device further includes a sweat collector 1032,
which could be a cellulose film or a network of hydrophilic
microchannels; fluid impermeable material or films 1070, 1072; a
fluid sample pump 1030; fluid flow rate sensors 1026, 1028; and
fluid analyte sensors 1020, 1022, 1024. As sweat is moved 16 along
sweat collector 1032, water and certain sweat-abundant solutes will
pass through the concentrator membrane 1095 and into the
concentrator pump 1097, while the remaining sweat sample flows
toward the fluid sample pump 1030. The sweat sample will
accordingly become more concentrated with respect to the target
analyte as it moves in the direction of the arrow 16 along the
sweat collector toward the fluid sample pump 1030. The flow rate
sensors 1026, 1028 could be mass thermal flow sensors, or other
suitable sensor type. As the sweat sample is concentrated by the
concentrator membrane 1095, the geometry of the sweat collector
1032 and the ratio of fluid flow at flow sensors 1026 and 1028
could be used to determine the total amount of fluid concentration
achieved by the device. The disclosed invention may include at
least one flow sensor or a plurality of flow sensors for
determining the degree of concentration. The sensors 1020, 1022,
and 1024 could be for the same analytes, or different analytes, or
could be different sensor modalities, for example, they could all
be configured to sense for cortisol. Sweat cortisol concentration
would be sufficient to allow measurement as long as at least one of
the sensors 1020, 1022, 1024 experienced the necessary
concentration range for an accurate cortisol reading. Therefore,
the disclosed invention may include a plurality of sensors for the
same analyte, wherein at least one of said sensors measures a fluid
sample that is more concentrated with respect to a target analyte
than the fluid sample measured by at least one other of said
sensors.
[0061] With further reference to FIG. 10, in an alternate
embodiment of the disclosed invention, each of sensors 1020, 1022,
1024 could further contain two subsensors, one subsensor may be an
electrochemical aptamer-based sensor for albumin, and the other
subsensor may be an electrochemical aptamer-based sensor for
luteinizing hormone. Because an individual's blood albumin
concentration is usually constant, albumin could serve as a
reference analyte for a target analyte that does show significant
blood concentration variation (e.g., luteinizing hormone). Such an
arrangement and use of two sensors can help increase the analytical
accuracy of the device, especially since albumin and luteinizing
hormone are large, and most types of filtration membranes that can
be used in the disclosed invention would be impervious to their
passage. Therefore, the invention may include at least one sensor
specific to a reference analyte, where said reference analyte is
concentrated to a similar degree as a target analyte, at least one
sensor specific to the target analyte, and where concentrations of
the reference and target analytes can be compared.
[0062] In another alternate embodiment, a first sensor can measure
the fluid concentration of a reference analyte (e.g., albumin)
before sample concentration, and a second sensor can measure the
reference analyte concentration after or during sample
concentration. Sample concentration as disclosed complicates
analyte sensing, because most sensing modalities have a limited
dynamic range (e.g., EAB sensors typically have a dynamic range of
between -40.times. to +40.times. the aptamer's linear range
K.sub.D), which means that sample concentration (e.g., 10.times. or
more) and biological concentration variances (e.g., 10.times. or
more) can put analyte concentrations outside the dynamic range of
the sensors. Therefore, sensors may be arranged along the sweat
collector 1032 so that their dynamic ranges increase as sweat moves
in the direction of the arrow 16. For example, sensor 1020 and its
subsensors for albumin and luteinizing hormone could have a dynamic
range centered at lower concentrations than the dynamic range for
sensor 1022 and its subsensors for albumin and luteinizing hormone,
and 1024 could have dynamic ranges centered at the highest
concentrations. Embodiments of the disclosed invention may,
therefore, include a first sensor for measuring a fluid analyte
concentration, and a second sensor for the fluid analyte
concentration, where the second sensor has a dynamic range of
detection that is centered on a higher concentration (K.sub.D) than
that of the first sensor.
[0063] With further reference to FIG. 10, some materials comprising
the concentrator membrane 1095 need to be stored in a primarily wet
condition, and some membrane materials need to be stored in a
primarily dry condition. For dry storage materials, concentrator
pump material 1097, such as a draw solution, can be introduced near
or at the time of first use by numerous methods, including
injection by a syringe, or use of foil burst valves, like those
used in other types of point-of-care diagnostic cartridges.
[0064] With further reference to FIG. 10, in an alternate
embodiment, the degree to which a target analyte will be
concentrated by the device while in use is easily predictable.
Generally, achieving analytical accuracy becomes more challenging
as fluid generation rates or fluid sampling intervals change,
because the amount of concentration produced by the concentrator
pump disclosed herein varies with variations in fluid flow rates
through the device. The flow rate of, e.g., sweat through the
device depends on the inlet flow from skin, the outlet to the fluid
sample pump 1030, and a flow of at least water into the
concentrator pump 1097. To reduce this variability, in some
embodiments, the device is configured so that the degree of sample
concentration for a target analyte is predetermined or predictable
based on the specific ion concentrations or the total ionic
strength/osmolarity in the sample fluid or in the concentrator pump
1097. For example, the concentrator membrane 1095 could be a
membrane that allows mainly water transport, but is impervious to
the target analyte, lactate. Sensor 1026 could measure a fluid
lactate concentration before the sample is concentrated. Next,
assume that the incoming sweat flows into the device at a sweat
generation rate that produces .about.20 mM concentration of lactate
in the concentrated sample. Concentrator pump 1097 would be
configured with a draw solution containing 400 mM in lactate
concentration and have other solutes that match natural sweat
concentrations or that match the general (total equivalent)
osmolality of sweat, except for the additional osmolality
contribution of the 400 mM lactate concentration. The concentrator
membrane would be long enough or large enough (e.g. mm's or cm's
long) so that the fluid sample in sweat collector 1032 loses water
until it also reaches 400 mM lactate concentration by water loss,
resulting in .about.20.times. concentration. Importantly, this
degree of concentration could be accurately determined prior to
device use because a sensor 1020 measures the unconcentrated fluid
lactate concentration and the concentrator pump 1027 has a draw
solution with a known lactate concentration (purposely configured).
Alternately, the target analyte need not be measured in
unconcentrated fluid if the analyte concentration varies little in
the fluid, or if an application does not require a high degree of
analytical accuracy.
[0065] In an alternate embodiment, a device's target analyte
concentration can be predetermined or predicted where the device
measures the ionic strength or conductivity in the sample fluid and
uses a draw solution with a near constant osmotic pressure greater
than that of the fluid (at least 2.times.). Maximum analytical
accuracy will therefore be achieved if sensors 1022, 1024 for
target analytes are near the end of the concentrator membrane 1095
(near the fluid sample pump 1030), where lactate (or ionic
strength) in the fluid sample would be near or equal to the
concentration of lactate (or other draw solution) in the
concentrator pump 1097. Lactate is not the only possible example,
since Na.sup.+ and Cl.sup.- are also possible targets, especially
if draw materials utilize materials such as MgCl.sub.2 or
CeCl.sub.3 which will have greater difficulty leaking back into the
fluid sample from the concentrator pump 1097 (divalent cations,
etc.). Alternatively, uncharged solutes can be used, including
sugars. Finally, polyelectrolytes, both positively and negatively
charged, can be used as additional draw solutions including but not
limited to polyacrylic acids, polysulfonic acids, polyimidazoles,
polyethylenimines, etc. The disclosed invention may therefore
provide a determined amount of sample concentration, where at least
one first solute in the concentrator pump is also a solute in the
fluid, and the concentration of the first solute in the
concentrator pump is greater than that in the fluid by at least
2.times. to enable sample concentration by osmosis. The invention
may also include at least one sensor to measure the first solute's
concentration in an unconcentrated fluid sample.
[0066] With reference to FIG. 11, where like numerals refer to like
features of previous figures, a device 1100 includes an incoming
flow path 1101 and two exit flow paths 1102, and 1103. A
microfluidic or other type of controllable valve 1155, such as a
PDMS pneumatic control valve, is provided to control fluid flow to
concentrator pump 1197. In one example embodiment, the draw rate of
concentrator pump 1197 would be sufficient to reduce fluid flow
through path 1103 to zero if valve 1155 were fully opened. The
device therefore works as follows: sensors 1126 and 1128 detect the
presence of fluid, and are used to provide feedback control for
valve 1155. Valve 1155 would be configured to control fluid flow so
that sensor 1126 is wetted by fluid, but sensor 1128 remains
unwetted. As a result, the device would ensure that at least one
analyte-specific sensor 1120 is wetted by the fluid sample being
concentrated. Using one or more techniques described herein, once
the target analyte is sufficiently concentrated to allow the sensor
1120 to take an accurate reading, the valve 1155 may be partially
or completely closed, restricting flow path 1102. Restricting flow
path 1102 activates flow path 1103, and the (old) fluid sample
moves away from sensor 1120 and onto fluid sample pump 1130. In
this configuration, the device could repeatedly concentrate a fluid
sample, sense the analyte, and then eliminate the fluid sample in
preparation for another sensing event. Therefore, embodiments of
the invention may include at least one tunable valve that controls
the amount of sample concentration that occurs.
[0067] With reference to alternate embodiments, components taught
for FIG. 11 may be extended to more general embodiments such as
that illustrated in FIG. 11B. Component 1101 introduces the fluid
to be measured, component 1105 introduces an unconcentrated fluid
such as water, saline, buffer, or other fluid, component 1100 is
where sample concentration may occur and where the amount of water
loss due to concentration is regulated by component 1102, and
component 1103 is a pump like that taught for previous figures.
Therefore, the invention may include a plurality of valves, or an
inlet valve for at least one unconcentrated fluid. In some
embodiments, the sample concentration component could become
clogged as a high concentration of solutes in the tested fluid
build up. Therefore, component 1105 could introduce an
unconcentrated fluid such as water, which could be used to flush
the device and clear the highly concentrated solutes. FIG. 11B also
generally teaches that valves and inlets could be placed at
multiple locations. For example, component 1101 could have a valve
that regulates the introduction of fluid sample into the device.
Therefore, the disclosed invention may include at least one valve
that controls the flow rate of a fluid that is unconcentrated.
[0068] An example embodiment of the device described in FIG. 11
requires several controls and sensors that may be unnecessarily
complex or sophisticated for some applications. With reference to
FIGS. 12A and 12B, where like numerals refer to like features of
previous figures, a simpler device 1200 includes a top view diagram
1200A and a side view diagram 1200B, which depicts a cross section
of 1200A along axis 1200Y. A fluid sample 16 enters the device at
opening 1201 and flows inside a channel that is constrained on its
upper surface by a concentrator membrane 1295 or fluid impermeable
material 1272, and ends in opening 1202. A plurality of sensors
1220, 1222, 1224, 1226, 1228 are provided within the channel. As
the fluid sample 16 moves along the channel, a concentrator pump
1297 causes water (and in some embodiments certain small
fluid-abundant solutes) to pass through the concentrator 1295. If
the fluid flow rates are very low, then only sensors nearer to
opening 1201, such as sensors 1220 and 1222, may experience analyte
concentrations sufficient to allow accurate measurements. Sensors
farther along the channel, such as 1226 and 1228, will remain
unused if the fluid 16 does not reach them, or their data discarded
if the analyte concentration remains inadequate. Conversely, at
very high fluid flow rates, sensor 1228 may be the only sensor to
receive sufficiently concentrated analytes. In some embodiments,
opening 1202 could be configured adjacent to a fluid sample pump
(not shown). Or concentrator membrane 1295 and concentrator pump
1297 could both concentrate the fluid sample and supply wicking
pressure to move fluid 16 through the channel. A specific example
may be taught through FIGS. 12A and 12B. Assume 2 nL/min/gland
sweat generation rate, 10 eccrine sweat glands under the device,
and sweat collected from 0.1 cm.sup.2 area. This would provide a
sweat flow rate of 20 nL/min, or 100 nL every 5 minutes. Assume
10,000.times. concentration of the fluid sample by the end of the
channel (0.01 nL) and by the end of 5 minutes. Assume the draw rate
of the forward osmosis concentrator membrane is 200 nL/min/mm.sup.2
or 1000 nL/mm.sup.2 every 5 minutes. Assume a channel that is 500
.mu.m wide by 50 .mu.m high, with additional spacers added to the
middle of the channel if needed for support of the channel height.
If the channel is 2 cm long, then it has a volume of
2(500E-4)(50E-4)=5E-4 mL or 500 nL. This channel would tolerate a
fluid flow rate up to a maximum of 10 nL/min/gland, which is
unlikely to be encountered, meaning the channel as disclosed would
be able to accommodate all typical sweat generation rates.
[0069] With further reference to FIG. 12, consider a case where the
sensors are electrochemical aptamer-based sensors with an attached
redox couple. Such sensors typically have a linear range of
80.times. the K.sub.D value for the target analyte. If 100.times.
sample concentration were needed, as little as 2 to 3 sensors could
achieve a proper reading within range. The distance between the
sensors is known, and therefore the amount of concentration
measured from sensor to sensor could be used to determine the flow
rate through the channel (the concentrator membrane flow rate out
of the channel would also be known). This could then be used to
back-calculate the original analyte concentration in the fluid
sample. Furthermore, flow rate could be determined by simply
knowing which sensors are wet with a sample of fluid, which would
then allow calculation of the flow rate of fluid coming into the
concentration portion of the device. Therefore, the disclosed
invention may include a plurality of sensors that determine a fluid
flow rate into the device by measuring an unconcentrated analyte
concentration and comparing it to a concentrated analyte
concentration. Furthermore, if the length of the channel is known,
and the concentration difference between successive sensors
measured (e.g., between 1222 and 1224), then the device may
determine the concentration increase per unit length of channel,
and thereby determine the total amount of concentration increase at
each sensor.
[0070] With reference to FIG. 12C, in an alternate embodiment, the
channel containing fluid 16 can be tapered or geometrically reduced
in any manner that minimizes the reduction in fluid flow velocity
caused by volume loss as the fluid moves through the sample
concentration component of the device and water is extracted by the
concentrator membrane 1295. If a device achieved a high degree of
fluid sample concentration, there could be very little fluid sample
volume (and hence little fluid flow) left by the time fluid exits
the concentration component. Therefore, to ensure an adequate flow
of fluid through the device, the channel dimensions reduce along
the channel in the direction of fluid flow.
[0071] With reference to FIG. 13A, which is a variant of the
previously taught FIG. 10, a device 1300 may include sweat
stimulation and/or reverse iontophoresis or iontophoresis
capabilities. For example, component 1350 could be an electrode,
and component 1340 is an agar gel with pilocarpine or carbachol,
and component 1380 is a track-etch membrane or other suitable
membrane to reduce passive diffusion between the wicking component
1332 and the gel 1340. As a result, the device 1300 is capable of
integrated sweat stimulation. Alternately, component 1340 could be
a gel containing a buffer against pH changes, and electrode 1380
used to extract analytes in part from the body by reverse
iontophoresis in order to increase their concentrations in
sweat.
[0072] With reference to FIG. 13B, the components taught for FIG.
13A could be arranged such that plurality components for sweat
stimulation or reverse iontophoresis (such as 1340a, 1350a, 1380a
being one of such components) may feed into a common device 1300
that is capable of sample concentration. Such a design could prove
useful, for example, where only a certain sweat flow rate into a
device 1300 is needed and the number of sweat stimulation
components utilized could be chosen to provide the most suitable
total flow rate of sweat into the device 1300.
[0073] With further reference to FIG. 13B, multiple such components
could also be used individually where sweat stimulation or reverse
iontophoresis components could feed into sub-devices with their own
sensors (e.g., a 1300a). Such an embodiment would be particularly
useful where sub-devices such as 1300a, 1300b, 1300c, etc., are
lateral flow assays or other sensor modalities that can be utilized
only once.
[0074] With reference to FIG. 13C, in yet another alternate
embodiment, multiple valve components (1355a, 1355b, 1355c etc.)
could be used to control, initiate, or stop flow of sweat to one or
more sub-devices 1300a, 1300b, 1300c, etc. In this example, sweat
comes from a single common component 1340, 1350, 1380, but could
also use multiple sources as taught for FIGS. 13B and 13C.
[0075] In one embodiment, a functionalized silica gel, silicon
dioxide nanoparticles, or other suitable substrate, can be added to
a concentrator channel surface so that the surface has a high
affinity for a target analyte through physi-sorption or
chemi-sorption. Such a functionalized surface becomes the
stationary phase of the concentrator channel. When fluid, as the
mobile phase, is introduced into the device and flows past the
surface, the target analyte is retained on the surface while the
fluid continues to flow. The surface may be forced to release the
target analyte by changing the fluid composition, e.g., by adding a
solvent, changing the pH, changing solute concentrations, changing
temperature, introducing electromagnetic radiation, or other system
parameter. If the substrate is in the proper form, such as a bead
or nanoparticle, multiple configurations may be present within the
same concentrator/retarder system. This will allow the system to
simultaneously concentrate multiple analytes using a single channel
or using at least fewer channels than target analytes. The device
as disclosed can be used to increase the concentration of analytes
of interest, functioning similarly to the way a chromatography
column is used for purification.
[0076] With reference to FIG. 14A, another embodiment of the
disclosed invention would use a microfluidic channel 1480 that
includes a gel (or other medium) that possesses a gradient in
density or pore size in the direction of the fluid flow 1401. The
pore size may be tuned to correlate with the size of one or more
target analyte(s). As the fluid flows through the gel, the analytes
that are larger than the pores will move slower than the flow rate.
As the pore size decreases, the analyte flow rate will therefore
decrease proportionally. As the analyte flow rate slows relative to
the fluid flow rate, the analyte will gradually become concentrated
in the direction of flow 1401. A similar embodiment depicted in
FIG. 14B would configure two or more gels (or other media) with
different densities in the microchannel 1480. As depicted, a first
section 1432 has a first density, and a second section 1434 has a
second, greater density. Step edges of increasing densities are
thereby created at the boundary 1433 between the sections. These
step edges will cause the analyte to concentrate at the boundaries
and move at a slower rate in the next section. The result is a
"wave front" in the microchannel in which the target analyte exists
at a higher concentration than it occurs in unconcentrated fluid.
Sensors could be placed within these sections to characterize the
analyte concentration factor to facilitate converting the
concentrated value back to the unconcentrated value.
[0077] With reference to FIG. 15A, another embodiment illustrating
fluid sample concentration includes a microfluidic channel 1580
with a plurality of microfluidic capture beads 1585. As a fluid
sample 16 flows through the channel 1580, molecules of the target
analyte 18 are trapped by the capture beads 1585. The embodiment
further includes an analyte-specific sensor 1520 for measuring the
target analyte, well as a heating element 1550. With reference to
FIG. 15B, the fluid sensing device activates the heating element
1550, causing the target analyte molecules 18 to dislodge from the
beads 1585 and flow with the fluid sample across the sensor
1520.
[0078] There are many applications where samples must be
concentrated before analysis, including, without limitation,
biofluids, waste water, municipal water, environmental sources, as
well as food safety and/or quality applications. The embodiments of
the disclosed invention apply broadly to these other fluid and
analyte systems, and other point-of-use scenarios, so long as they
rely on similar mechanisms for integrated sample concentration and
analyte sensing. Not all embodiments will be taught in this way,
rather it will be obvious from the additional specification below
how all embodiments may cover more broadly other fluids, analytes,
and point-of-use scenarios with minimal modification.
[0079] With further reference to FIG. 3B, for example, the fluid
sample 16 may be a liquid food sample of a variety of viscosities,
including without limitation, condiments, juices, and sodas.
Sensors 320, 322, 324, 326 may be configured to measure one or more
analytes relevant to food safety and/or quality.
[0080] With further reference to FIG. 7, an embodiment of the
disclosed invention is configured to collect and measure analytes
in non-sweat biofluids, such as saliva or interstitial fluid. At
low concentrations of an analyte, there may be no signal change
(the concentration is below the limits of detection) and at high
concentrations, sensor signals can become saturated. The fluid
sensing device may measure continuously or repeatedly to determine
whether relatively linear windows (Windows 1 and 2) are achieved as
shown in FIG. 7. As for the example of K.sup.+ in sweat, a similar
strategy of evaluating the degree of biofluid concentration by
examining the concentration of a reference analyte that remains
stable under most physiological conditions may be employed. For
example, albumin concentration in blood remains relatively constant
under most physiological conditions, and consequently, albumin
concentration in most biofluids remains stable. Therefore, the
increase in albumin concentration may be used as a measure of the
extent of concentration for most biofluids. Similar reference
analytes exist for other fluids that will allow quantitative
assessments of the degree of fluid concentration relevant to target
analytes.
[0081] With reference to FIG. 16, where like numerals refer to like
features and functions for FIG. 2, a device 1600 provides a wicking
material such as a sponge 1634 configured to collect a sample
fluid, such as river water, by placing the sponge into the river
water (not shown). The river water would flow into the fluid sample
coupler 1632 and across the sensor 1620. Water in the sample is
drawn into pump 1630 through sample concentrator 1695 and is
concentrated with respect to one or more target analytes, such as
Cryptosporidium or one of that organism's products or toxins, and
sensor 1620 then measures the analyte's concentration, or detects
the analyte's presence, as the river water sample concentrates.
[0082] With further reference to FIG. 6, the device 600 is
configured to detect microbes in a fuel sample. For example, modern
biodiesel is especially hygroscopic. The presence of water
encourages microbial growth, which either occurs at the interface
between the oil and water or on the tank walls, depending on
whether the microbes need oxygen. In this case, the device 600 is
placed in contact with the fuel within the tank, or a stream of
fuel (e.g., a hose transporting the fuel). Microfluidic channel 680
would contain the fuel brought into the device, and the immiscible
material 655 would be non-dissolvable in the fuel. In contrast to
the disclosed device's use in sweat, the immiscible material 655
may be hydrophilic (e.g., a hydrogel with water), which would
passively concentrate the target analyte by distribution
coefficient compared to the fuel. The sensor 620 could then detect
the target analyte. The analyte could be bacteria, fungi, their
toxins, or their other products.
[0083] With further reference to FIG. 10, the device 1000 is
configured to detect a target analyte associated with a sexually
transmitted disease, such as chlamydia or gonorrhea. The user would
urinate onto wicking material 1032, and the device would
concentrate and sense antigens or other target analytes. Sensors
1026 and 1028 could be chloride sensors (bare Ag/AgCl electrodes)
whose ratios of potential determine the degree of concentration
occurring. Sensors 1020, 1222, 1024 are configured to detect the
disease analyte, and further, each sensor 1020, 1022, 1024 may be
configured to detect the disease analyte at different
concentrations. Such an arrangement would be useful for the
described example, because the user would be able to have dilute
urine or concentrated urine, and the device can accommodate this by
operating over a wider range of these conditions for analyte
concentration.
[0084] The following examples are provided to help illustrate the
disclosed invention, and are not comprehensive or limiting in any
manner. These examples serve to illustrate that although the
specification herein does not list all possible device features or
arrangements or methods for all possible applications, the
invention is broad and may incorporate other useful methods or
aspects of materials, devices, or other embodiments that are
readily understood and obvious for the broad applications of the
disclosed invention.
Example 1
[0085] This example provides additional examples of membranes
suitable for the disclosed invention, including calculations of
criteria related to membrane operation in the invention. Membranes
of this and previous embodiments may utilize any material or
filtration technique known by those skilled in the art of sample
concentration or microfiltration. Solutes or analytes may be small
ions, ions, small molecules, proteins, DNA, RNA, micro RNA or DNA,
peptides, lipids, or any other solute or analyte of interest in
sweat. Commercially available ultrafiltration and filtration
membranes are most effective for larger solutes found in sweat,
like proteins or peptides. Smaller molecules, including hormones
and nucleotides, however, present a challenge, as they will
typically pass through such membranes. Furthermore, if a membrane
is used to block small molecules, but pass only water, then the
concentration of salts, lactic acid, and other sweat-abundant
analytes could fall out of solution or hinder proper device or
sensor performance. Other options, such as aquaporin and other
lipid membranes, perform no better with small molecules that are
lipophilic, and further tend to have limited shelf-lives caused by
a tendency to dry out unless stored wet, among other things.
Embodiments capable of sampling smaller sweat analytes may
therefore employ a membrane capable of forward osmosis (FO).
Examples include a cellulose triacetate filter, like those produced
by Hydration Technology Innovations; or the Dow Filmtec.TM.
NF90-4040, a composite membrane made up of a polyamide active layer
and a polysulfonic supporting layer, which works at low operating
pressures. See A. Alturki, et al., "Removal of trace organic
contaminants by the forward osmosis process" Separation and
Purification Technology, 103 (2013) 258-266.
[0086] Such membranes can pass lactic acid (lactate), which is
electrically charged and only 90 g/mole, or urea at 60 g/mole, as
well as numerous salts in sweat. These solutes are found at higher
sweat concentrations, so that if a sweat sample were concentrated
100.times., their concentrations would correspondingly increase to
the 1 M range, which could hinder device performance in one or more
ways. Therefore, having a membrane that can concentrate the sweat
sample while allowing these solutes to pass through is
advantageous. Further, the membrane must have high rejection rates
for solutes of interest. For example, a small molecule like
cortisol is uncharged, hydrophobic, and .about.362 g/mole, and
therefore would be substantially rejected by the membrane and
concentrated in the sweat sample to be analyzed. In addition, this
would allow for a second reference sensor next to each analyte
sensor (as taught in previous figures). An example would be sensing
changes in cortisol, and using cholesterol as a reference, because
cholesterol is lipophilic and nearly identical to cortisol in
molecular weight, and suitable sensors exist for cholesterol.
[0087] When operated in FO mode, i.e., with the membrane's dense
side facing the sweat sample to be concentrated, or feeder
solution, and the membrane's porous side facing the concentrated
draw solution, these materials are capable of processing a .about.1
M NaCl solution with a flux near 200 nL/min/mm.sup.2. If the sweat
sensor device's microfluidic channel were 20 .mu.m wide, each 1
mm.sup.2 of that channel would have a sweat volume of 20E-4 cm0.1
cm0.1 cm=2E-5 mL or 20 nL. Therefore, to achieve a sample
concentration of 10.times., the device would require, at most, a
sweat generation rate of approximately 20 nL/min/mm.sup.2. If,
through the use of lower sweat volumes, the device was capable of
fast sweat sampling rates, e.g., every 5 minutes, then only 4
nL/min/mm.sup.2 of sweat would be required. Sweat generation rates
in this range would allow concentration to occur at very low
osmotic draw pressures, eliminating or reducing the need to augment
draw pressures through the addition of a sugar (sucrose or
glucose), or a salt, such as MgSO.sub.4, to the draw solution.
[0088] While having a low osmotic pressure is desirable from a
sweat generation rate standpoint, osmotic pressure across the
membrane still must be greater than the wicking pressure provided
by sweat collecting components, otherwise, the water in sweat would
not pass through the membrane. From A. Alturki, et al., osmotic
pressure for a 0.5 M NaCl solution (with van't Hoff factor of 2)
would be as follows: .PI.=iMRT=2(0.5 mol/L)(0.0821 L atm/mol/K)(298
K)=24.5 atm. Similarly, osmotic pressure for 0.5 M sucrose solution
(with van't Hoff factor of 1) would be: .PI.=MRT=1(0.5
mol/L)(0.0821 L atm/mol/K)(298 K)=12.2 atm. To calculate the
osmotic pressure achieved by adding saturated sucrose to drive
sweat across the membrane, the sucrose solubility limit in water is
2000 g/L/(342.30 g/mol)=5.8 mol/L or 5.8 M. Therefore, adding
sucrose would provide osmotic pressures of around 141 atm or
101,000 N/m.sup.2. Typical wicking pressures would be an order of
magnitude lower. For example, pressure for a 20 .mu.m high wicking
channel (r=10 .mu.M) would be (73E-3 N/m)/(10E-6 m)=7300 N/m.sup.2
(14.times. less). Likewise, if using a 10.times.10 .mu.m sweat
collector groove, the wicking pressures would be comparable to the
20 .mu.m channel. Therefore, osmotic pressures for this embodiment
of the invention would be sufficiently higher than wicking
pressures to allow the FO membranes to function. Therefore, the
invention may include a sample concentration component and at least
one sweat wicking component, where said concentration component has
an osmotic pressure that is at least 2.times. greater and
preferably 10.times. greater than wicking pressure of said wicking
component.
[0089] If needed, draw pressures may also be augmented by adding
capillary wicking pressure to the draw side of the membrane through
use of microfluidics. Some embodiments may use osmotic pressure,
wicking pressure, or a combination, to drive sweat across the
membrane, depending on the application. Therefore, the invention
may also include a draw material that contains a wicking material
that operates by capillary wicking pressure. Considerations
determining the choice of method would include the need to drive
sweat abundant solutes, i.e., Na.sup.+, Cl.sup.- and K.sup.+,
across the membrane to avoid fouling the concentrated sweat sample.
Also, sweat sensor devices with larger sweat volumes may require
additional draw pressures to sense a given analyte. And certain
sweat applications may require or otherwise be limited to lower
sweat generation rates, which would also require higher draw
pressures.
[0090] The above example can provide sample concentration for even
challenging analytes such as cortisol (362 Da), especially if a
similar analyte, i.e., cholesterol (387 Da) is also measured as a
reference analyte, because it has a very low diurnal change (e.g.,
compare ratios of the two analytes). For example, if the membrane
is cellulose acetate (which is very hydrophilic) lipophilic
analytes such as cortisol could achieve 70 to 95% rejection or even
greater. The above example will remove water, and the above example
can also remove Na.sup.+, Cl.sup.-, K.sup.+, lactate (90 Da), urea
(60 Da), and other high-concentration analytes that might be
undesirable if they were also concentrated in the sweat sample. The
above examples could work well with draw solutions that are
monosaccharides or disaccharides (100's of Da). Amino acids are
also found in sweat up mM levels. Many amino acids are small, and
will readily pass through a membrane. Assume average of 0.1 g/mL
solubility limit, and average 100 g/mol. The molar concentration is
0.1.times.1000 g/L/(100 g/mol)=1 mol/L or 1M. Therefore, sweat
could be concentrated by nearly 1000.times. before amino acids
would fall out of sweat due to their solubility limits.
Example 2
[0091] This example provides additional examples of membranes
suitable for the disclosed invention, including in some cases
calculations of criteria related to their operation in the
invention. More specifically, this example teaches an exemplary
case for a determined amount of concentration as taught for FIG.
10. Assume a hydrophilic channel that is 7 .mu.m tall, and 500
.mu.m wide and which has a wicking pressure of .about.20,000
N/m.sup.2. Assume a membrane that as biologically inert and
ultra-pure, such as Biotech Cellulose Ester (CE) membranes, which
offer a large range of concise molecular weight cut-offs (100 to
1,000,000 Da) and that tolerates weak or dilute acids & bases,
as well as mild alcohols. For example, choose a molecular weight
cut-off of .about.500 Da. Assume a concentrator pump with a draw
material that is 7 mM of polyethylenimine in water and/or other
suitable solvent with a molecular weight of .about.10,000 Da, and
the draw solution may also contain other solutes found in natural
sweat (pH, salts, etc.) that may be desirable for proper sensor
function or for other purposes. If each monomer of
polyethylenimine, which is a polyelectrolyte at pH<10, has a
molecular weight of .about.50 Da, then there are .about.200
positive charges, and thus 200 counter-ions, likely chloride at pH
values relevant to sweat (assume pH 6.5). Assuming full
disassociation at the pH's observed in sweat, this draw solution
would yield an osmotic pressure against natural sweat equivalent to
about 10.times. greater the osmotic pressure that sweat can
generate. Therefore, the sweat will be concentrated about 10.times.
for solutes that are >500 Da in size, and for the numerous
solutes <500 Da they will largely be absorbed into the draw
material through the membrane. However, this would generally
require, that for continuous operation, the volume of the draw
material should be very large compared to the total sweat sample
collected (else the osmotic pressure difference will degrade over
time). For example, the volume of the draw material could be
2.times. or 10.times. greater than the total sweat sample volume
collected, and more preferably >100.times. or even
>1000.times.. Polyethylenimine is not a natural solute in sweat.
The disclosed invention may also therefore provide a determined
amount of sample concentration, where the total osmolality of the
concentrator pump is at least 2.times. greater than the total
osmolality of sweat. Still, a question remains as to how the
osmolality differences between polyethylenimine draw solution and
natural sweat can be determined, because if the osmolality
difference is not determined, then the amount of concentration
occurring is more difficult to directly predict unless some other
prediction method (including those taught herein) is utilized. One
example method which would work with multiple figures and
embodiments of the invention, would be to have at least one sensor
which measures the total osmolality of the natural sweat coming
into the device, using methods such as measuring total electrical
conductance of sweat, or by having a common pressure sensor which
is surrounded (covered) by a membrane which passes mainly water and
with an internal draw solution or material which therefore causes
pressure sensor to directly measure osmotic pressure and therefore
osmolality of sweat. For even greater precision, especially if the
osmolality of the draw material/solution changes over time, such
types of osmolality sensors may also be placed in the concentrator
pump.
[0092] This has been a description of the disclosed invention along
with a preferred method of practicing the disclosure, however the
invention itself should only be defined by the appended claims.
* * * * *
References