U.S. patent application number 14/015605 was filed with the patent office on 2014-03-06 for apparatus and method for measuring biochemical parameters.
This patent application is currently assigned to Proteus Digital Health, Inc.. The applicant listed for this patent is Proteus Digital Health, Inc.. Invention is credited to Mark Zdeblick.
Application Number | 20140066734 14/015605 |
Document ID | / |
Family ID | 43607615 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066734 |
Kind Code |
A1 |
Zdeblick; Mark |
March 6, 2014 |
Apparatus and Method for Measuring Biochemical Parameters
Abstract
In a first embodiment, electrodes are coupled to a surface at
first, second, and third locations, the first location being
further from the third location than from the second location.
Impedance is measured at distinct frequencies between pairs of the
electrodes. As a result, impedance is measured at differing regions
below the surface, one region being deeper below the surface than
the other region. In a second embodiment, a microfluidic device
carries out an analysis. The analysis may be within a flexible
patch adhered to a surface, or may be in a solid device implanted
in a body of liquid surrounded by tissue. The analysis may involve
pumping a fluid or may involve drawing an analyte
electrophoretically through a microfluidic channel.
Inventors: |
Zdeblick; Mark; (Portola
Valley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Proteus Digital Health, Inc. |
Redwood City |
CA |
US |
|
|
Assignee: |
Proteus Digital Health,
Inc.
Redwood City
CA
|
Family ID: |
43607615 |
Appl. No.: |
14/015605 |
Filed: |
August 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13390866 |
Feb 16, 2012 |
8558563 |
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PCT/US2010/046381 |
Aug 23, 2010 |
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14015605 |
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61235979 |
Aug 21, 2009 |
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Current U.S.
Class: |
600/362 ;
600/309 |
Current CPC
Class: |
A61B 5/150877 20130101;
A61B 5/150229 20130101; A61B 5/6846 20130101; A61B 5/0537 20130101;
A61B 5/14503 20130101; A61B 5/6833 20130101; A61B 5/0002 20130101;
A61B 5/150305 20130101; A61B 5/14517 20130101; A61B 5/150969
20130101; A61B 5/14532 20130101; A61B 10/0064 20130101; A61B
2560/0412 20130101; A61B 5/157 20130101 |
Class at
Publication: |
600/362 ;
600/309 |
International
Class: |
A61B 5/15 20060101
A61B005/15; A61B 5/157 20060101 A61B005/157; A61B 5/00 20060101
A61B005/00; A61B 10/00 20060101 A61B010/00; A61B 5/145 20060101
A61B005/145 |
Claims
1. (canceled)
2. Apparatus comprising: an adhesive patch disposed for adhesion to
a surface; the patch being flexible; the patch comprising a
microfluidic channel disposed to receive fluid from the surface;
the patch further comprising a pump connected with the channel, the
pump responsive to a control signal for pumping fluid received from
the surface along the microfluidic channel; the patch further
comprising a sensor positioned along the channel, the sensor
disposed to sense a biochemical parameter of interest and
responsive to the sensing to generate a data signal; the patch
unpowered by any power source external thereto and further
comprising an electrochemical cell; the patch wirelessly
communicatively coupled to electronic equipment external thereto by
means of a wireless communications link; the patch further
comprising a microcontroller controlling the pump by means of the
control signal, the microcontroller receiving the data signal from
the sensor, the microcontroller connected to the electrochemical
cell to be powered thereby, the microcontroller electrically
connected to the wireless communications link; the patch being
sterile; the patch contained within a wrapper preserving said
sterile condition; wherein the channel diameter is in the range of
50 nanometers to 100 micrometers.
3. The apparatus of claim 2 wherein the channel diameter is in the
range of 50 nanometers to 50 micrometers.
4. The apparatus of claim 3 wherein the channel diameter is in the
range of 50 nanometers to 100 nanometers.
5-8. (canceled)
9. Apparatus comprising: An adhesive patch disposed for adhesion to
a surface; the patch being flexible; the patch comprising a
microfluidic channel having first and second ends, the microfluidic
channel at its first end disposed to receive fluid from the
surface; the patch further comprising a source of electrical
potential, the source of electrical potential disposed to develop
said electrical potential between the surface and the second end of
the microfluidic channel; the source of electrical potential
responsive to a control signal; the patch further comprising a
sensor positioned along the channel, the sensor disposed to sense a
biochemical parameter of interest and responsive to the sensing to
generate a data signal; the patch unpowered by any power source
external thereto and further comprising an electrochemical cell;
the patch wirelessly communicatively coupled to electronic
equipment external thereto by means of a wireless communications
link; the patch further comprising a microcontroller controlling
the source of electrical potential by means of the control signal,
the microcontroller receiving the data signal from the sensor, the
microcontroller connected to the electrochemical cell to be powered
thereby, the microcontroller electrically connected to the wireless
communications link; the patch being sterile; the patch contained
within a wrapper preserving said sterile condition; wherein the
channel diameter is in the range of 50 nanometers to 100
micrometers.
10. The apparatus of claim 9 wherein the channel diameter is in the
range of 50 nanometers to 50 micrometers.
11. The apparatus of claim 10 wherein the channel diameter is in
the range of 50 nanometers to 100 nanometers.
12-15. (canceled)
16. Apparatus comprising: a solid device disposed for implantation
within a body of liquid surrounded by tissue; the device comprising
a microfluidic channel disposed to receive fluid from the body of
liquid; the device further comprising a pump connected with the
channel, the pump responsive to a control signal for pumping fluid
received from the body of liquid along the microfluidic channel;
the device further comprising a sensor positioned along the
channel, the sensor disposed to sense a biochemical parameter of
interest and responsive to the sensing to generate a data signal;
the device unpowered by any power source external thereto and
further comprising an electrochemical cell; the device wirelessly
communicatively coupled to electronic equipment external thereto by
means of a wireless communications link; the device further
comprising a microcontroller controlling the pump by means of the
control signal, the microcontroller receiving the data signal from
the sensor, the microcontroller connected to the electrochemical
cell to be powered thereby, the microcontroller electrically
connected to the wireless communications link; the device being
sterile; the device contained within a wrapper preserving said
sterile condition; wherein the channel diameter is in the range of
50 nanometers to 100 micrometers.
17. The apparatus of claim 16 wherein the channel diameter is in
the range of 50 nanometers to 50 micrometers.
18. The apparatus of claim 17 wherein the channel diameter is in
the range of 50 nanometers to 100 nanometers.
19-20. (canceled)
21. Apparatus comprising: a solid device disposed for implantation
within a body of liquid surrounded by tissue; the device comprising
a microfluidic channel disposed to receive fluid from the body of
liquid; the device further comprising a pump connected with the
channel, the pump responsive to a control signal for pumping fluid
received from the body of liquid along the microfluidic channel;
the device further comprising a sensor positioned along the
channel, the sensor disposed to sense a biochemical parameter of
interest and responsive to the sensing to generate a data signal;
the device unpowered by any power source external thereto and
further comprising an electrochemical cell; the device wirelessly
communicatively coupled to electronic equipment external thereto by
means of a wireless communications link; the device further
comprising a microcontroller controlling the pump by means of the
control signal, the microcontroller receiving the data signal from
the sensor, the microcontroller connected to the electrochemical
cell to be powered thereby, the microcontroller electrically
connected to the wireless communications link; the device being
sterile; the device contained within a wrapper preserving said
sterile condition; further comprising a reagent disposed to react
with the fluid from the body of liquid, the sensor disposed to
sense a product of said reaction.
22. (canceled)
23. Apparatus comprising: a solid device disposed for implantation
within a body of liquid surrounded by tissue; the device comprising
a microfluidic channel having first and second ends, the
microfluidic channel at its first end disposed to receive fluid
from the body of liquid; the device further comprising a source of
electrical potential, the source of electrical potential disposed
to develop said electrical potential between the body of liquid and
the second end of the microfluidic channel; the source of
electrical potential responsive to a control signal; the device
further comprising a sensor positioned along the channel, the
sensor disposed to sense a biochemical parameter of interest and
responsive to the sensing to generate a data signal; the device
unpowered by any power source external thereto and further
comprising an electrochemical cell; the device wirelessly
communicatively coupled to electronic equipment external thereto by
means of a wireless communications link; the device further
comprising a microcontroller controlling the source of electrical
potential by means of the control signal, the microcontroller
receiving the data signal from the sensor, the microcontroller
connected to the electrochemical cell to be powered thereby, the
microcontroller electrically connected to the wireless
communications link; the device being sterile; the device contained
within a wrapper preserving said sterile condition; wherein the
channel diameter is in the range of 50 nanometers to 100
micrometers.
24. The apparatus of claim 23 wherein the channel diameter is in
the range of 50 nanometers to 50 micrometers.
25. The apparatus of claim 24 wherein the channel diameter is in
the range of 50 nanometers to 100 nanometers.
26. (canceled)
27. Apparatus comprising: a solid device disposed for implantation
within a body of liquid surrounded by tissue; the device comprising
a microfluidic channel having first and second ends, the
microfluidic channel at its first end disposed to receive fluid
from the body of liquid; the device further comprising a source of
electrical potential, the source of electrical potential disposed
to develop said electrical potential between the body of liquid and
the second end of the microfluidic channel; the source of
electrical potential responsive to a control signal; the device
further comprising a sensor positioned along the channel, the
sensor disposed to sense a biochemical parameter of interest and
responsive to the sensing to generate a data signal; the device
unpowered by any power source external thereto and further
comprising an electrochemical cell; the device wirelessly
communicatively coupled to electronic equipment external thereto by
means of a wireless communications link; the device further
comprising a microcontroller controlling the source of electrical
potential by means of the control signal, the microcontroller
receiving the data signal from the sensor, the microcontroller
connected to the electrochemical cell to be powered thereby, the
microcontroller electrically connected to the wireless
communications link; the device being sterile; the device contained
within a wrapper preserving said sterile condition; further
comprising a reagent disposed to react with the fluid from the body
of liquid, the sensor disposed to sense a product of said
reaction.
28-64. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. application No.
61/235,979 filed Aug. 21, 2009, which application is incorporated
herein by reference for all purposes.
BACKGROUND
[0002] Microfluidic technology and other techniques may be employed
to measure various types of physiologic parameters that might be
important to diagnose or manage a disease.
[0003] Generally, the term "microfluidics" refers to the art making
very small channels using microlithographic and microfabrication
techniques. For example, a substrate such as glass with polymers
may be used to make channels. Other substances used in formulating
substrates include, for example, silicon and aluminum. Various
other types of substrates are possible. The channels may be
fabricated using various techniques, e.g., by etching silicon using
a deep reactive ion etch with a mask that provides precise control
of geometry. Various patterns may be employed, e.g., curved lines,
straight lines, etc.
[0004] Microfluidics may be used, inter alia, to perform a function
such as ion chromatography or liquid chromatography to look for and
measure an ion or molecule. A typical application in an ion
chromatograph is introduction of a small sample liquid in a column
of fluid that is otherwise neutral. Introduction, for example, may
be achieved via various fluid introduction components, e.g., a
pump, a microsuction component, etc.
[0005] The sample moves through the column. In some examples, a
field, e.g., an electric field, is applied across the column which
affects the diffusion times of the ions of the sample as the ions
move through the column. The ions are detected, e.g., at the end of
the column. A time of injection of the ions of the sample can be
calculated based on detection, diffusion rates, and the dimensions
of the column.
[0006] Information may be obtained in various ways, e.g., based on
measuring electroconnectivity. In various aspects, channels are
filled with different materials that modify the motion rates of
different ions.
[0007] Such diagnosis or disease management by means of a
microfluidic approach would be helpful if it could be done
conveniently and in conjunction with other processes that might
already be taking place for other reasons.
SUMMARY OF THE INVENTION
[0008] In a first embodiment, electrodes are coupled to a surface
at first, second, and third locations, the first location being
further from the third location than from the second location.
Impedance is measured at distinct frequencies between pairs of the
electrodes. As a result, impedance is measured at differing regions
below the surface, one region being deeper below the surface than
the other region. In a second embodiment, a microfluidic device
carries out an analysis. The analysis may be within a flexible
patch adhered to a surface, or may be in a solid device implanted
in a body of liquid surrounded by tissue. The analysis may involve
pumping a fluid or may involve drawing an analyte
electrophoretically through a microfluidic channel.
FIGURES
[0009] FIG. 1 illustrates various components associated with a
first measuring device;
[0010] FIG. 2a illustrates various components associated with a
second measuring device;
[0011] FIG. 2b illustrates various components associated with
multiple measuring devices; and
[0012] FIG. 3 illustrates an electrophoretic approach in a
measuring device.
DETAILED DESCRIPTION
[0013] A medical device and method for measuring physiologic
parameters is provided. The medical device and method may be
practiced independently and/or associated with other device(s),
components, and method(s). One example of integration with a device
is integration with a receiver, e.g., a receiver of RFID signals
and/or conduction signals. One example of a receiver of conduction
signals is an ingestible event marker receiver device, as disclosed
in U.S. patent application No. 61/160,289 entitled "Body-Associated
Signal Receiver" filed Mar. 13, 2009. The foregoing is hereby
incorporated by reference in its entirety.
[0014] One example of such a device is a microfluidic device such
as a bandage-type patch designed to be temporarily or permanently
attachable to the skin or implanted into the body. Another such
example is one or more removably attachable or implantable devices
having electrodes for measurement of various physiologic
parameters. In certain aspects, the medical device may be an
independently configure device or associated, e.g., wholly or
partially integrated with other device(s).
[0015] In various aspects, a version of the aforementioned
technique is created on the skin where the effluent is so small it
simply evaporates. A reservoir liquid that represents a control
liquid such as pure water may be stored on the patch and, using a
microfluidic pump, the ions are pumped through the column. A sample
of a patient's bodily fluid, such as sweat, is injected into the
column. Other techniques such as microsuction, electrophoresis,
etc., may be used as well.
[0016] Electrophoresis generally involves putting a voltage between
the skin and the column to pull ions and other types of biological
materials through the skin using electrophoresion and into the
sampling column to be introduced into the chromatography column.
The column may be flushed at a certain rate with a background fluid
or carrier fluid, for example water, and as different ions diffuse
through the fluid at a different rate, the ions are separated from
one another and are collected at the distal end of the column by
using electrical or optical means.
[0017] Another aspect includes application of electrophoretic
voltage across the column, e.g., the length of the column, the end
of the column, switched in and out, etc. For example, one segment
of the column can be used to view simple diffusion to separate
molecules and a valve may be used to control and or regulate the
samples or a cross-channel may be activated which takes a certain
amount of material which may be further separated using, for
example, electrophoresis.
[0018] Aspects may be used to perform chemical analyses,
physiologic analysis, and other pursuits. Examples include analysis
of sweat, urine, blood etc. In some aspects, a device utilizing
microfluidic principles such as the aforedescribed may be
implanted, e.g., inside a bladder. Various aspects include
miniaturized devices, components, subcomponents, etc., as deemed
suitable for such pursuits.
[0019] In some aspects, reagent(s) may be used. Generally, such
reagents react chemically with the ions in some way to change the
rate of diffusion or change their rate of electro-phoretic
advancement.
[0020] To illustrate, and as depicted in FIG. 1, a first measuring
device 100 such as a patch device is associated with a patient. The
patch device has a column 102 and may have a reservoir which may
include one or more fluids and a valve for regulating intake of the
sample. The reservoir may be an independent component or integrated
with one or more other components, e.g., the column. As the fluids
leave a column 102 at outlet 108, they creep off the patient's skin
or are released into the air and essentially evaporate because the
quantities, e.g., amounts of fluids, are so low that they would be
virtually non-noticeable. The sample intake is facilitated by a
pump 104. The reservoir, e.g., a serpentine column, with a valve,
and other components such as the pump 104 may be micro-fabricated.
The liquid goes through the reservoir and through a detector
device, e.g., an array of sensors, such as detector array 106 and
is discharged through an outlet 108 as described in the art of ion
chromatography. Coming out the detector array 106 is the column
102, which may empty the fluid. Typically, such a small quantity of
fluid would be emptied that the fluid may be absorbed, e.g., by a
material such as cotton that may be associated with the patch,
and/or may evaporate over time.
[0021] The device 100 is controlled by a microcontroller 112
powered for example by electrochemical cell 110. A wireless
communications link 114 may be employed to permit the
microcontroller 112 to communicate sensed information to equipment
external to the device 100. The microcontroller 112 controls the
pump 104 and receives signals from the sensor 106. Importantly, the
device 100 is not powered by any equipment external to the device
100 but is self-powered. The cell 110 may be self-contained, or may
get its electrolyte from surrounding liquid or moisture.
[0022] A variant is shown in FIG. 3. In FIG. 3, instead of a pump
104, we see a power supply 118. The power supply 118 develops an
electrical potential between a region 120 of nearby tissue or
liquid 116 and the far end of the column at 122. The electrical
potential draws an analyte (typically ions of interest) through the
column 102 for analysis in the sensor 106.
[0023] The chief application described herein is a patch applied to
the skin. The patch receives for example perspiration from the skin
and detects for example glucose. But the alternative application is
to implant the device in a body of liquid surrounded by, for
example, an organ wall. In such an application, the device draws
fluid from the body of liquid by means of a pump and passes it by a
sensor. Alternatively the device draws an analyte (such as ions of
interest) electrophoretically from the body of liquid.
[0024] In various aspects, devices may be configured to make such
measurements at predetermined intervals, e.g., once a day or twice
a day, and at different points in time when samples are required to
be taken. In various aspects, the amounts of fluid, e.g., water,
may be determined by the geometry of the column. One such example
is a column having a very, very small diameter. Some examples
include channel diameters of 50 nanometers, 100 nanometers, 50
micrometers, 100 micrometers, etc. Other diameters are possible as
well.
[0025] Other applications include identification of various
substances, e.g., glucose. For example, a sample may be
electrophoretically pulled from the skin into the column and then
glucose may be separated from the other constituents by passing it
through the diffusion column.
[0026] It also may be possible to add a reagent to the sample and
look for the change, e.g., look for the products, that would be a
measure of the glucose concentration, glucose oxidation, etc. For
example, hydrogen peroxide may be produced that can be measured
with an electrometer. In another example, a reagent may be added to
a sample to look for indications of pregnancy, etc.
[0027] Various aspects include a variety of different types of
chemical analysis equipment, some or all of which may be
miniaturized.
[0028] In various aspects, fluids may be sampled from various
locations of the body. In one example, the fluid is sampled from
within the body, e.g., using an implantable device. The implantable
device may be implanted into various locations, e.g., a bladder,
kidney, stomach, etc. To illustrate, the implantable device may be
implanted into the bladder and sample urine to measure or identify
glucose. Because glucose tends to reduce the conductivity as
compared to salt, salt makes a fluid more conductive and glucose
makes it less conductive. A measurement of glucose going into the
bladder and the volume of the bladder may be determined by sampling
of fluid associate, e.g., insert or implant a device inside the
bladder. Measuring the concentration of glucose in the bladder
might be a way of measuring glucose in the blood, i.e., may be a
proxy for measuring glucose in the blood.
[0029] Another aspect includes a device that measures fluid
content, e.g., water content of patient's skin. This approach may
be similar to an approach described in U.S. patent application No.
61/160,265, entitled "Volume Sensing Device, System, and Method"
and filed Mar. 13, 2009, herein incorporated by reference in its
entirety. In this application, the approach may be used for
measuring the amount of blood in the heart where the
blood-to-tissue ratio is determined by measuring the impedance at
two points at two different frequencies. A comparison of a ratio of
the first impedance measurement at a point in time to the second
impedance measurement at a corresponding point in time may be made
to determine the blood volume-related value associated with an area
located between the first tissue location and the second tissue
location.
[0030] Various aspects facilitate measurement of various fluids and
determinations inferred from those measurements, e.g., the moisture
in skin, the level of dehydration, the amount of blood volume of
the patient, etc. For example heart-failure patients may be
susceptible to volume overload, insufficient hydration, and other
serious issues. Measurement of various fluids and determinations
inferred from those measurements may provide notice of such pending
or actual condition.
[0031] Continuing with this approach, comparison of these to pure
saline would result in no difference and comparison to pure tissue
would result in a maximum difference. Thus, the amount of fluid in
the tissue is a function of what is produced, so the ratio of those
two frequencies is function of the amount of fluid in the tissue.
In a typical case the tissue being studied is tissue perfused with
blood.
[0032] To illustrate and with reference to FIG. 2a, a second
medical device 200 includes at least two electrodes 202, e.g., an
array of electrodes. Alternatively, and with respect to FIG. 2b,
each of the at least two electrodes may be associated with a
multiple (respective) devices 206, 208. The devices may be
configured variously and exhibit various form factors, e.g., two
adhesive patches, each adhesive patch having one or more electrodes
202. The amount of tissue sampled is determined by the relative
position of the electrodes 202. The bulk of the current 204 will
flow between the two electrodes 202. There may be some current that
goes at a farther distance and at a greater distance into the
tissue, and the depth will be related to the distance apart of the
two electrodes 202.
[0033] For example, if just the area of tissue near the surface of
the skin is to be sampled, the electrodes may be positioned
relatively close to each other. If sampling is directed to deeper
within the tissue, then the electrodes may be positioned relatively
far apart from each other. To illustrate, if sampling is directed
to the blood tissue ratio of a person's leg, one electrode may be
positioned in the heel region and the other electrode may be
positioned in the groin region.
[0034] A patch that attaches to the skin on the torso thus might
have an array of electrodes at different spacings and, in so doing,
might be able to characterize the relative amount of liquid at
various depths in the skin. The two closest ones would be sampling
the nearest tissues, the ones closest to the surface, and the ones
spaced farthest apart would be sampling more of the in-depth tissue
and looking at the tissue right there. So one could construct a
simple mathematical model of the amount of fluid as a function of
distance into the tissue.
[0035] One may have a two-dimensional array which may be used,
among other things, to construct maps of blood-tissue ratios and
start imaging or looking for various tissue types and
configurations, including cysts and tumors.
[0036] Additional uses include athletic-related uses. For example,
an athlete engaging in exercising, riding a bicycle, or running
across a soccer field or football field may tend to dehydrate at a
faster rate than an individual at rest. To monitor and guard
against this condition, the fluid amount may be measured and the
athlete's fluid intake may be adjusted accordingly. In addition,
hydration may be monitored to ensure that the athlete does not
drink too much fluid during the exercise period. In various
aspects, the device may provide or trigger alert(s), e.g., audible
alert to the wearer, electronic trigger to a designated device,
etc. The alert may be conditioned on various predetermined
parameters such as fluid level too low, too high, etc.
[0037] Further uses include monitoring multiple patients, e.g.,
residents in a nursing home or hospital where are a large number
patients and relatively low number of nurses. Alerts may be sent,
for example, to the nursing station, etc.
[0038] Another use includes monitoring an accident victim, e.g., an
accident victim with a head injury, the goal being to monitor
swelling, lack of fluids leading to shock, etc. Combinations of
parameters can also be monitored, e.g., heart rate, heart rate
variability, and fluid levels through a variable connection, dual
frequency measurement. In one aspect, the medical device is
configured as an implantable lead. Alternatively, the device may be
configured as an external device, e.g., an adhesive patch applied
over the heart region of the body to determine cardiac volume,
heart rate, etc.
[0039] For dehydration applications, various aspects may be
employed by desert travelers, sports players, military personnel,
athletes, acupuncturists, and in agricultural pursuits, e.g.,
determining if steers or other animals are hydrated to a level
necessary for optimum market consideration.
[0040] For various applications, e.g., application to the thorax
region, multiple electrodes may be variously located on the thorax
to observe changes in the region's impedance and to indicate how
much blood is in the thorax as when sampled, for example, at three
or four electrode contact points. A matrix may be derived from such
a sampling.
[0041] Another application includes an implantable device
comprising at least two electrodes for implantation into various
locations, e.g., a bladder, is provided. In one example, the
implantable device may measure or identify glucose. Because glucose
tends to reduce the conductivity as compared to salt, salt makes a
fluid more conductive and glucose makes it less conductive. A
measurement of glucose going into the bladder and the volume of the
bladder may be determined by putting a device inside the bladder.
Measuring the concentration of glucose in the bladder might be a
way of measuring glucose in the blood, i.e., may be a proxy for
measuring glucose in the blood.
[0042] The foregoing examples are illustrative in nature and not
determinative of scope. One skilled in the art will recognize that
various alternatives, components, configurations, and steps may be
used to carry out the invention described herein.
* * * * *