U.S. patent application number 10/656997 was filed with the patent office on 2006-01-05 for impedance spectroscopy based systems and methods.
Invention is credited to Andreas Caduff, Etienne Hirt, Thomas W. Schrepfer.
Application Number | 20060004269 10/656997 |
Document ID | / |
Family ID | 32738052 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060004269 |
Kind Code |
A9 |
Caduff; Andreas ; et
al. |
January 5, 2006 |
Impedance spectroscopy based systems and methods
Abstract
One aspect of the invention provides a device that
non-invasively determines the concentration of a substance in a
target. The device includes a first electrode, a measuring circuit,
and a data processor. In one embodiment of the device, the first
electrode can be electrically insulated from the target, e.g., a
cover layer of insulating material covers the first electrode.
Inventors: |
Caduff; Andreas; (Zurich,
CH) ; Hirt; Etienne; (Cham, CH) ; Schrepfer;
Thomas W.; (Oberbozberg, CH) |
Correspondence
Address: |
MINTZ, LEVIN, COHN, FERRIS, GLOVSKY;AND POPEO, P.C.
ONE FINANCIAL CENTER
BOSTON
MA
02111
US
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Prior
Publication: |
|
Document Identifier |
Publication Date |
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US 20040147819 A1 |
July 29, 2004 |
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Family ID: |
32738052 |
Appl. No.: |
10/656997 |
Filed: |
September 5, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09980661 |
Oct 2, 2003 |
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PCT/IB01/00334 |
Mar 6, 2001 |
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10656997 |
Sep 5, 2003 |
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60408377 |
Sep 5, 2002 |
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Current U.S.
Class: |
600/316 |
Current CPC
Class: |
Y10T 436/11 20150115;
Y10T 436/144444 20150115; A61B 5/05 20130101; A61B 5/14532
20130101; G01N 22/00 20130101 |
Class at
Publication: |
600/316 |
International
Class: |
A61B 5/00 20060101
A61B005/00 |
Claims
1. A system for controlling a process involving a specimen, the
system comprising: a first electrode covered by a cover layer of
insulating material and adapted to receive a modulated electrical
voltage for generating an electric field in the specimen; a
measuring circuit for measuring at least one parameter depending on
a response of the specimen to the field; a data processor section
connected to the measuring circuit and operative to determine a
concentration of a substance in the specimen from the parameter and
to out-put data in response to the determined concentration; and a
control circuit connected to the data processor section and
operative to receive data from the data processor section and to
control an aspect of the process based at least in part on the data
from the data processor.
2. The system of claim 1 wherein the control means comprises: a
valve control adapted for controlling a valve based at least in
part on the concentration data.
3. The system of claim 1 wherein the data from the data processor
section is concentration data.
4. The system of claim 1 wherein the system further comprises: an
electrically insulating substrate, wherein the first electrode is
arranged on a first side of the substrate between the substrate and
the cover layer.
5. The system of claim 4 further comprising a second electrode
arranged on the substrate, and wherein the first and second
electrodes are adapted to generate a modulated field between the
electrodes in response to the modulated electric voltage..
6. The system of claim 5, wherein the second electrode comprises a
bottom electrode layer arranged on a second side of the substrate,
the bottom electrode layer having a larger extension than the first
electrode.
7. The system of claim 6 wherein the second electrode comprises a
top electrode layer arranged on the first side of the substrate,
the top electrode layer being arranged around at least part of the
first electrode.
8. The system of claim 7 wherein the system further comprises:
first and second signal paths between the signal source and the
measuring circuit, wherein the first electrode is arranged in the
first signal path and a reference load is arranged in the second
signal path, and wherein the measuring circuit is adapted to
measure at least one of a relative amplitude (A) and a phase (phi)
of signals from the first and second paths.
9. The system of claim 8 wherein the first electrode is part of a
capacitor of a resonant circuit comprising the capacitor and an
inductance, the resonant circuit being connected to the signal
source.
10. The system of claim 9 wherein the capacitor and the inductance
are arranged in series.
11. The system of claim 9 wherein the system further comprises an
antenna electrode arranged in proximity to the first electrode and
wherein the measuring circuit is adapted to measure a signal
transmitted from the first electrode to the antenna electrode.
12. A method for managing a process involving a specimen, the
method comprising: arranging a first electrode at the specimen,
wherein the first electrode is electrically insulated from the
specimen; receiving a modulated electrical voltage signal at the
first electrode to generate a modulated field in the specimen;
measuring at least one parameter depending on a response of the
specimen to the field; determining a concentration of a substance
in the specimen based at least in part on the measured parameter;
and controlling an aspect of the process based at least in part on
the determined concentration.
13. The method of claim 12 wherein controlling an aspect of the
process comprises controlling a valve based at least in part on the
determined concentration.
14. The method of claim 12 wherein the method further comprises
arranging a second electrode at the specimen and wherein the
modulated electrical voltage generates a modulated field between
the first and the second electrode.
15. The method of claim 14 wherein the second electrode is in
electric contact with the specimen.
16. The method of claim 14 wherein the method further comprises
measuring a temperature of the specimen and using the temperature
in the determination of the concentration.
17. The method of claim 12 wherein the modulated electrical voltage
signal is a sine wave.
18. The method of claim 17 wherein the modulated electrical voltage
signal has a frequency between 10 MHz and 2 GHz.
19. The method of claim 12 wherein the method further comprises
arranging an antenna electrode at the specimen in proximity to the
first electrode and wherein the response of the specimen is
measured by measuring a signal transmitted from the first electrode
to the antenna electrode.
20. The method of claim 12 wherein the substance is glucose.
21. The method of claim 12 wherein the specimen is a living
body.
22. The method of claim 12 wherein the determining the
concentration comprises using calibration data to convert the
parameter to the concentration.
23. The method of claim 12 wherein the first electrode forms part
of a resonant circuit having a resonance frequency and wherein the
resonant circuit is operated substantially at the resonance
frequency.
24. The method of claim 23 wherein the resonant circuit is at least
part of a tank circuit of an active oscillator and wherein the
parameter is one of an amplitude and a frequency of a signal
generated by the oscillator.
25. The method of claim 12 wherein receiving a modulated voltage
comprises receiving a frequency sweeped modulated voltage wherein
the frequency is swept from a frequency below the resonance
frequency to a frequency above the resonance frequency.
26. The method of claim 12 wherein the substance is an alcohol.
27. The method of claim 12 wherein the specimen is a salt
solution.
28. The method of claim 12 wherein the substance is a salt.
29. A method for obtaining an indication of a condition of a
specimen, the method comprising: arranging a first electrode at the
specimen, wherein the first electrode is electrically insulated
from the specimen; receiving a modulated electrical voltage signal
at the first electrode to generate a modulated field in the
specimen; measuring at least one parameter depending on a response
of the specimen to the field; determining an impedance of the
specimen based at least in part on the measured parameter; and
determining whether an indication of a condition exists based at
least in part on the impedence of the specimen.
30. The method of claim 29 wherein the determining whether an
indication of a condition exists comprises using calibration
data.
31. The method of claim 29 wherein the condition is edema.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to, and benefit of, U.S.
provisional patent application Ser. No. 60/408,377, filed Sep. 5,
2002, entitled "METHODS AND DEVICES FOR DETERMINING THE
CONCENTRATION OF A SUBSTANCE IN A TARGET" and incorporated herein
by reference in its entirety. This application also claims priority
to, and benefit of, U.S. patent application Ser. No. 09/980,661,
filed Nov. 15, 2001 and entitled "Method and Device for Determining
the Concentration of a Substance in Body Liquid" which claims
priority to PCT application No. PCT/IB01/00334 filed Mar. 6, 2001
and entitled "Method and Device for Determining the Concentration
of a Substance in Body Liquid."
TECHNICAL FIELD
[0002] The invention relates to systems, methods and devices for
non-invasively determining the concentration of a substance in a
target. Examples of targets include an in-vitro or an in-vivo
target containing body liquid, a non-body liquid target such as
wastewater or beer, and a non-liquid target such as baby food or
biological tissue. One can apply the invention in fields such as
biotechnology, medicine, industry, environmental monitoring,
agriculture, and manufacturing (such as food manufacturing).
BACKGROUND OF THE INVENTION
[0003] One application of conventional impedance spectroscopy is to
attempt to determine the concentration of glucose and other
substances in body fluids. In particular, this technology is of
substantial interest for the determination of glucose concentration
in blood and/or inter- or intracellular liquid.
[0004] It is well known that glucose and electrolyte concentrations
vary in blood and underlying tissues. Several techniques for
providing glucose analysis are known. These techniques permit
subjects to determine their own glucose levels. Unfortunately many
such techniques require invasive sampling of the subject.
[0005] Impedance spectroscopy practitioners have attempted to
determine glucose concentration noninvasively. Stated another way,
impedance spectroscopy practitioners have attempted to determine
glucose concentration in a body liquid by analyzing the interaction
of electromagnetic waves with the target material. The goal of such
a technique is to provide a non-invasive in-vivo analysis.
[0006] U.S. Pat. No. 5,792,668, incorporated herein by reference in
its entirety, describes one example of a device for measuring blood
level glucose. According to this patent, one brings two electrodes
into direct contact with the human body and attempts to measure the
impedance between the electrodes.
[0007] However, one drawback of conventional impedance spectroscopy
involving the direct contact of two electrodes with the human body
is that the results often depend to some extent on variables
affecting the electrical contact between the body and the
electrodes, such as variables describing the surface condition of
the body at the point of contact. As a consequence, such techniques
have limited resolution in the measurement of the concentration of
blood level glucose. Thus, a need remains for methods and systems
for the accurate, effective, and noninvasive determination of the
concentration of a substance (such as glucose) in a target (such as
a body liquid). Furthermore, a need remains for methods and systems
for non-invasively determining the concentration of a substance in
a target, the methods and systems being applicable in other
contexts such as in environmental monitoring and in food
processing.
SUMMARY OF THE INVENTION
[0008] The invention relates to systems, methods and devices for
accurately and effectively determining the concentration of a
substance in a target. Examples of targets include: an in-vitro or
an in-vivo target containing body liquid; non-body liquids such as
wastewater or beer; and non-liquids such as baby food or biological
tissue. One can apply the invention in fields such as
biotechnology, medicine, industry (such as corrosion testing),
environmental monitoring, agriculture, and manufacturing (such as
food manufacturing).
[0009] In a first aspect of the invention, the invention provides a
device that determines the concentration of a substance in a
target. The device includes a first electrode, a signal source, a
measuring circuit, and a data processor.
[0010] In one embodiment of the device, the first electrode can be
electrically insulated from the target, e.g., a cover layer of
insulating material covers the first electrode. Hence, the measured
parameter(s), e.g., the magnitude of the impedance, does not depend
on the surface conditions of the target to the extent it does when
two electrodes are in direct contact with a target. Rather, the
device capacitively couples a signal to the target and the measured
parameter depends therefore primarily on the conditions within the
target. The parameter measured in this way can then be converted to
the desired concentration, e.g., by using calibration data.
[0011] Depending on the frequency, in one embodiment the first
electrode is part of a sensor, e.g., a microstrip nearfield antenna
or at lower frequencies a fringing capacitor. In one embodiment the
microstrip nearfield antenna includes a microstrip electrode, i.e.,
the first electrode, surrounded by a ground electrode. In this
two-electrode embodiment, a modulated voltage is applied between
the microstrip electrode and the ground electrode. By using two
electrodes, a defined field can be established within the target.
One embodiment of a method according to the present invention
places the second electrode, i.e., the ground electrode, in
electric contact with the target.
[0012] The measured parameter preferably depends on the electrical
impedance of the sensor. It has been found that the concentration
of various substances in the target, for example substances that
can change electrical properties of the target (such as colloids
suspensions, electrolytes, bio molecular solutions, dyes etc.,
affects the impedance because it changes the loss (i.e., loss of
power) properties and/or the dielectric properties of the
target.
[0013] In one embodiment, the sensor forms part of a resonant
circuit, which is operated at or close to its resonance frequency.
Under such conditions, a change of the dielectric properties or
loss properties of the target leads to shifts in the parameters of
the resonant circuit and can therefore be measured.
[0014] The target can be a liquid including body liquids such as
blood, extracellular fluid, intracellular fluid, interstitial
fluid, and transcellular fluid, measured in vivo or in vitro. The
device also can be used to measure tissue flux in a body. Various
diseases can impede tissue flux, i.e., microvascular blood flow,
reducing supply of necessary molecules leading to alterations in
the skin and tissue structure and thus having an im pact on the
impedance pattern produced by the tissue in question.
[0015] Embodiments of the invention also can be used with targets
containing non-body liquids such as water in rivers, lakes,
puddles, streets, waste-treatment systems, liquids present in
foodstuffs, liquids present in growing crops, and liquids used
during manufacturing processes.
[0016] Embodiments of the invention provides systems for measuring
the concentration of a substance in a target, such as the glucose
level in blood or tissue. The systems include a sensor having a
strip electrode and a ring electrode arranged at the target. In one
embodiment, the ring electrode is adapted for direct electrical
contact with the target while the strip electrode is electrically
insulated therefrom (in an alternative embodiment, the strip
electrode can be in electrical contact with the target and the ring
electrode be electrically isolated from the target). The strip
electrode is adapted to provide a large interaction length with the
target. The ring and strip electrodes form a capacitor in a
resonant circuit. A modulated voltage in the MHz range close to or
at the resonance frequency is applied to the electrodes and the
system measures the response of the target. This arrangement
permits a high accuracy measurement.
[0017] In another aspect, the invention provides a method for
determining the concentration of a substance in a target. The
method includes arranging a sensor, e.g., a microstrip nearfield
antenna (having a microstrip electrode) at the target wherein at
least part of the sensor can be electrically insulated from the
target. The method includes applying a modulated electrical voltage
to the sensor for generating a modulated field in the target. The
method further includes measuring at least one parameter (for
example the amplitude or the impedance, the phase shift, and/or the
frequency), the parameter depending on a response of the target to
the field. The method also includes determining the concentration
of the substance in the target based at least in part on the
measured parameter
[0018] In one embodiment, the method can include providing a sensor
(e.g., a microstrip nearfield antenna with both a microstrip
electrode and a second, ground electrode and placing the second,
ground electrode in electrical contact with the target), so that,
in the antenna example, the modulated electrical voltage is applied
between the microstrip and the ground electrodes.
[0019] In another embodiment, the method includes measuring the
temperature of the target and using the measured temperature in the
determination of the concentration. In at least one embodiment, the
response of the target is measured by arranging a near field
microstrip antenna in proximity to the target.
[0020] One can use embodiments of the invention for in-vivo
measurements of the human body. Thus, embodiments of a device
according to the invention include an elongate electrode having a
width much smaller than its length. Embodiments of the invention
also include a holder to mount the elongate electrode to an arm or
a leg with the longitudinal axis of the electrode extending
parallel to the longitudinal axis of the arm or leg.. The methods
and devices of this aspect of the invention have been found to be
especially suited for measuring the glucose concentration in body
fluid.
[0021] One can also use embodiments of the device according to the
invention in other medical and/or biochemical applications. Such
applications include: monitoring the concentrations of substances
such as glucose or sodium chloride during biochemical processes;
detection of changes in tissues of the body, such as those
resulting from inflammatory processes in skin and underlying
tissues, skin or breast cancer, and edemas; measuring tissue flux;
and tracking concentrations of substances in infusions, fermenters,
and cell suspensions.
[0022] In addition, one can use embodiments of the invention in
industrial applications. Industrial applications include: waste
water analysis; measuring salt in bodies of water including street
water; corrosion testing, and environmental monitoring.
[0023] Still other applications of embodiments of a device
according to the invention include monitoring the growth and
harvesting of agricultural products and food and beverage
processing applications. For example, one can use embodiments of
the invention in connection with production of brewed and/or
fermented beverages, production of baby food, production of dairy
products, growing of agricultural products, and production of
ingredients used in food and beverage processing, such as high
fructose corn syrup.
[0024] Still another embodiment of the invention provides a system
for measuring the concentration of a substance, e.g., a polluting
or toxic substance, in a target, such as in product flow or in
wastewater. In one embodiment, the system includes a sensor (e.g.,
a microstrip nearfield antenna, having a microstrip electrode
surrounded by a ground electrode) arranged at the target. In the
antenna example, the ground electrode is adapted for direct
electrical contact with the target while the microstrip electrode
can be electrically insulated there from. The ground and microstrip
electrodes form a capacitor in a resonant circuit. The system is
adapted to apply a modulated voltage in the appropriate range for
the target, e.g., in the MHz range, and close to or at the
resonance frequency of the circuit. The system is adapted to apply
the appropriate range to the electrodes and the system measures the
response of the target.
[0025] The system can include or can be adapted to interface with a
process control device such that the process being observed is
managed at least under certain circumstances (e.g., when a
specified concentration of a pollutant is exceeded during the
process) based on impedance spectroscopy data.
[0026] Details relating to these and other embodiments and aspects
of the invention are described more fully in the detailed
description and with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWING
[0027] The invention will be better understood and objects other
than those set forth above will become apparent when consideration
is given to the following detailed description thereof. Such
description makes reference to the annexed drawings, wherein:
[0028] FIG. 1 is a block circuit diagram of a one embodiment for
carrying out the invention,
[0029] FIG. 2 is a view onto a possible embodiment of the
device,
[0030] FIG. 3 is a section along line III-III of FIG. 2,
[0031] FIG. 4 is the device of FIG. 3 with a wristband,
[0032] FIG. 5 shows the behavior of the relative amplitude A as a
function of frequency,
[0033] FIG. 6 is a second embodiment of the circuit,
[0034] FIG. 7 is an alternative electrode geometry,
[0035] FIG. 8 a third embodiment of the circuit,
[0036] FIG. 9 is a schematic of a system using the circuit of FIG.
1, in accordance with an embodiment of the invention,
[0037] FIGS. 10A-F illustrate alternative embodiments of systems or
portions of systems for monitoring processes such as the process
illustrated in FIG. 9, and
[0038] FIG. 11 is a block circuit diagram of an alternative
embodiment to the embodiment of FIG. 1 for carrying out the
invention.
[0039] The drawings are not necessarily to scale, emphasis instead
generally being placed upon illustrating the principles of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0040] FIG. 1 shows a block circuit diagram of one embodiment of a
device according to the invention. The device includes a voltage
controlled oscillator (VCO) 1 as a signal source for generating a
waveform, e.g., a sine wave signal, the frequency of which depends
on an input control voltage. This signal is fed to two amplifiers
2, 3 (In the alternative embodiment of FIG. 11, the signal is fed
to a single amplifier 2). The output of first amplifier 2 is
connected via a resistor R1 to a first signal path 4. A resonant
circuit 5 comprising an inductance L and a capacitor C in series is
connected between first signal path 4 and ground. The output of
second amplifier 3 is connected via a resistor R2 to a second
signal path 6. Second signal path 6 is substantially identical to
first signal path 4 but comprises a resistor R3 as a reference load
instead of resonant circuit 5.
[0041] Both signal paths 4, 6 are fed to a measuring circuit 7,
which determines the relative amplitude A of both signals as well
as, optionally, their mutual phase shift, phi. Relative amplitude A
can be, e.g. the amplitude of first signal path 4 in units of the
amplitude of second signal path 6 (wherein the amplitudes are the
peak values of the sine waves). In one embodiment, circuit 7 is a
conventional circuit for measuring the relative amplitude of both
signals.
[0042] The output signal of measuring circuit 7 is fed to a
microprocessor 8, which also controls the operation of VCO 1.
[0043] As can be seen from FIG. 1, the device in the present
embodiment further includes a temperature sensor 10, a display 11
and an input device 12 with user operable controls, all of which
are coupled to microprocessor 8.
[0044] Inductance L of the device of FIG. 1 can be generated by a
coil and/or by the leads and electrodes of capacitor C. The
inductance values can range depending on various factors including
the substance and target of interest. In the case of determining
the concentration of glucose in a body liquid, the inductance value
ranges between about 220 nH and about 470 nH. One embodiment uses a
value of about 330 nH.
[0045] A sensor (e.g., a near field microstrip an tenna, making up
part of the capacitor C of the device of FIG. 1) probes a target.
In other words, the device of FIG. 1 includes a capacitor C having
electrodes adapted for placement near the target. In one
embodiment, the near field microstrip antenna is located close to
the target but remote from the rest of the device of FIG. 1. This
arrangement can be useful in situations where the target itself may
present an environment that could be damaging to all or part of the
device (e.g., applications where the target comprises running
water, such as waste water monitoring and/or environmental
monitoring). With reference to FIGS. 6 and 7, in one embodiment,
the device of FIG. 1 includes an extra antenna electrode 33 that is
in electrical communication with the device but is located remote
from the device.
[0046] The geometry of the electrodes is such that the electric
field generated by them extends into the target. Representative
examples of suitable geometries are discussed below. As mentioned
above, at least one of the electrodes of the capacitor is
electrically insulated from the target such that capacitor C is
primarily a capacitive load, the capacitance and loss of which
depends on the electrical properties (i.e. the response) of the
target at the frequency of VCO 1.
[0047] The depth of the electromagnetic fields produced is strongly
dependent on the electrode/antenna geometry (defined by the
distance of the microstrip and the ground electrodes as well as by
the shape of the microstrip antenna/electrode itself). Decreasing
the distance between the microstrip electrode and the ground
electrode increases the density of the electromagnetic field lines
produced by the electrodes. The shape of the microstrip antenna
itself has an impact as well. More generally, the configuration
(e.g., frequency used) and dimensions of a sensor for use with the
invention depend on the application (e.g., water content and
dimensions of the object).
[0048] To measure the concentration of a substance in the fluid of
the target, one embodiment of microprocessor 8 can initiate a
measurement cycle consisting of a frequency sweep of VCO 1. The
sweep can start at a frequency fmin below the expected resonance
frequency f0 of the resonant circuit 5 and extend to a frequency
fmax above resonance frequency f0. The sweep from fmin to fmax can
occur as a single sweep or as a sequence of discrete sweeps. Each
sweep provides a set of data points useful in calculating the
concentration of the substance in the liquid. In one embodiment,
the VCO is a symmetrical VCO to provide low harmonics and is a FET
implementation providing a relatively wide frequency range. A
symmetrical VCO cancels out most of the first harmonic because a
differential signal is used. A FET implementation provides a higher
frequency range as less parasitic capacitance exists in the
resonating circuit because the FET Gate can be controlled directly
avoiding a capacitive coupled feedback.
[0049] Note also that the range of the frequency sweep may be
influenced by the application and/or the equipment used. For
example, sweeps performed on a living body may use a lower fmax
than sweeps performed on a target other than a living body. During
the sweep or series of sweeps, the electrical properties of signal
path 4 will change substantially, while those of signal path 6 will
vary only slightly. The amplitude determined by measuring circuit A
will therefore fall to a minimum A0 at f0, as shown in FIG. 5. At
the same time, phase shift phi crosses zero.
FIRST EXAMPLE APPLICATION
Measurement, e.g., In Vivo Measurement, of a Substance, e.g.,
Glucose, in a Body Liquid, e.g., Blood
[0050] The specific conductivity .rho.(f) and the dielectric
constant .di-elect cons.(f) for a given fluid vary depending on the
type of fluid. For example, it is presently believed that the
specific impedance of at least some body fluids (i.e. the specific
conductivity .rho.(f) and the di-electric constant .di-elect
cons.(f)) in a frequency range between 10 MHz and 2000 MHz, more
particularly between 20 MHz and 70 MHz and most particularly
between 38 MHz and 58 MHz, is a function of the properties and
concentration of the salty (ionic) components of the human body,
related to variations in blood glucose. These salty components
primarily include solvated sodium, potassium, calcium and other
minor ions and their counter ions, the primary counter ion being
chloride.
[0051] In one embodiment of the invention, only amplitude A0 is
measured as a parameter for the determination of the concentration
of the substance. Suitable calibration data stored in
microprocessor 8 is used to convert amplitude A0 into the desired
concentration level. In this example, the calibration data stored
in microprocessor 8 is calibration data that is appropriate for the
measurement of glucose in blood. In one embodiment, the calibration
data includes an offset .alpha.0, a factor .alpha.1 for the
relative amplitude and a factor .alpha.2 for the temperature
correction. Thus, the resulting concentration equals .alpha.0
+.alpha.1*(measured impedance) +.alpha.2*temperature. Measurements
of other types of targets, as described herein, may have their own
respective types of calibration data.
[0052] In the example of measuring glucose levels in blood, the
effects exploited for the measurement are temperature dependent.
Temperature has an effect on permittivity and conductivity.
Temperature appears to have a nonlinear effect on the measurement
of impedance conducted in vivo with the current glucose monitoring
device, that originates from nonlinear physiologic responses of the
human body to temperatures conditions and changes. Changes in
temperature have a more or less linear effect on ac conductivity
per se. However, the human body reacts physiologically in a
nonlinear way to changes in temperature. Thus, other embodiments of
the invention take into account an appropriate temperature
correction in applications where the target shows temperature
dependence, e.g., nonlinear temperature dependence.
[0053] In order to obtain high accuracy over a wide temperature
range, one brings temperature sensor 10 into thermal contact with
the target. In the present example, the temperature sensor 10 does
not need to be in physical contact with the target (i.e., blood or
other liquid) being measured. Rather, the temperature sensor 10 can
contact the skin to obtain temperature. The signals from
temperature sensor 10 are used to correct the obtained result,
again using calibration data obtained from calibration
measurements.
[0054] A proper design of the electrodes of capacitor C permits
optimization of the accuracy and sensitivity of the present device
in a given application. Example geometry of a device suitable for
taking in-vivo measurements in a living body is shown in FIGS. 2
and 3.
[0055] The device comprises a housing 13 closed on one side by an
electrode plate 14. The display 11 is arranged opposite electrode
plate 14. The electronic circuits 16 are arranged between electrode
plate 14 and display 11.
[0056] Electrode plate 14 can include an electrically insulating
substrate 17 with a sensor, e.g., a microstrip nearfield antenna
having a microstrip electrode 18 and a top or ring/ground electrode
19 arranged on an outer side 20 thereof. A bottom electrode 22
covers an inner side 21 of insulating substrate 17. A plurality of
through-contacts 23 is provided to connect ring/ground electrode 19
to bottom electrode 22. A further through-contact 24 connects one
end of microstrip electrode 18 to a small bond pad 25 arranged in
an opening 26 of bottom electrode 22 on inner side 21.
[0057] Temperature sensor 10 is mounted to bottom electrode 22. The
large number of through-contacts 23 ensure that bottom electrode 22
follows the temperature of ring/ground electrode 18 and therefore
the temperature of the target closely.
[0058] A typical size of electrode plate 14 is 32 mm .times.21 mm.
Bottom electrode 22 covers all of inner side 21 except for the
small opening 26 and is therefore much larger than strip electrode
18.
[0059] Leads 28 are provided to connect bottom electrode 22,
contact pad 26 and temperature sensor 10 to the electronic circuits
16.
[0060] While bottom electrode 22 and ring/ground electrode 19 are
connected to ground, strip electrode 18 is connected to inductance
L of resonant circuit 5. Therefore, the capacitor C is formed
between strip electrode 18 as a first electrode and ring electrode
19 and bottom electrode 22 as a second electrode. In other words,
the second electrode consists of two electrode layers: a top
electrode layer formed by ring electrode 19 and a bottom electrode
layer formed by bottom electrode 22.
[0061] An electrically insulating cover layer 29 covers all of
strip electrode 18 but not ring electrode 19. In other words, strip
electrode 18 is arranged between substrate 17 and cover layer 29.
Cover layer 29 is preferably made of a hard, moisture- and
salt-impervious material such as glass, ceramics, a polycarbonate
or diamond-like carbon (DLC) of a thickness preferably between 50
and 100 .mu.m.
[0062] FIGS. 2 and 3 illustrate a device that may be especially
useful in applications where the device is to be disposed against a
substantially flat surface, such as an area of skin on a living
body. The geometry and orientation shown in FIGS. 2 and 3 are not
limiting, however. Many different orientations, shapes, and sizes
are usable in accordance with the invention. For example, the
display 11 may be disposed along a side of the housing 13, or may
be entirely separate from the housing 13 (e.g., in operable
communication with the electronic circuits 16 but disposed at a
location remote from the housing.)
[0063] In another embodiment, the display 11 and electronic
circuits 16 are disposed within a first housing while the electrode
plate 14 (or other configuration of electrodes) is disposed within
a second housing, the electrodes being in operable communication
with the electronic circuits 16. This configuration may be
advantageous in embodiments of the invention that are used for
applications and/or in environments that could cause damage and/or
stress to the electronic circuits 16 and/or the display 11.
[0064] As can be seen in FIG. 4, a holder or wristband 31 is
attached to housing 13 for fixing the device to an arm or a leg of
a human body with cover layer 29 facing the body and a longitudinal
axis of strip electrode 18 parallel to the arm or leg. In this way,
ring electrode 19 comes into contact with the user's skin and the
ring electrode and the area of the user's body in contact with the
ring electrode come to a common reference potential.
[0065] As described above, a pure sine voltage has been found to be
sufficient for the measurements. However, other types of modulated
voltages, such as square-wave voltages or pulses can be used as
well. In this case, measuring circuit 7 is preferably provided with
suitable filters for selectively sampling one or more frequency
components. At least one measured frequency component is preferably
close to the resonance frequency of resonant circuit 5 for
exploiting the circuit's high sensitivity to the target's
properties at that frequency.
[0066] The electrode geometry can be varied for adapting it to a
given application. While the design of FIG. 2 is optimized for a
measurement on an arm or leg, a circular design can be used for
measurement on a flatter body part or an in-vitro sample. Further,
in embodiments of the invention that are used in the manufacturing,
environmental, and/or agricultural industries, the electrode may
have a geometry adapted for the given application, such as a
partially-curved shape, a ring-like shape, a triangular shape, and
a cylindrical shape. These other applications are described further
herein.
[0067] Ring electrode 19 does not necessarily have to form a closed
ring as long as it provides sufficient grounding of the site (e.g.,
in this example, the body part) to be measured. The ring electrode
19 can, e.g., also have a U-shape or consist of two stripes
parallel to and laterally enclosing strip electrode 18. Ring
electrode 19 can also be omitted completely or be covered by cover
layer 29, especially for measurements (such as in-vitro
measurements) where noise is low.
[0068] Part of one embodiment of an alternative embodiment of a
circuit according to the invention is shown in FIG. 6. In FIG. 6,
there is no direct wired connection between resonant circuit 5 and
measuring circuit 7. Rather, an antenna electrode 33 is located in
proximity to the electrodes of capacitor C, and measuring circuit 7
measures the signal returned by antenna electrode 33.
[0069] A possible arrangement of the electrodes for the circuit of
FIG. 6 is shown in FIG. 7. As can be seen, antenna electrode 33 is
strip shaped and arranged in parallel to strip electrode 18. Both,
antenna electrode 33 and strip electrode 18 are covered by cover
layer 29 and therefore electrically insulated from the target.
[0070] The device of FIGS. 6 and 7 is again sweeping VCO 1 between
a frequency fmin below the resonance frequency f0 of resonant
circuit 5 and a frequency fmax above it. In contrast to FIG. 5,
measuring circuit 7 now detects a maximum amplitude A0 at f0,
wherein the value of A0 depends on the response, i.e. the
electrical properties of the target at the resonance frequency f0.
Changing the resonant circuit to a tank circuit also changes the
resonance curve in a way that a maximum rather then minimum
amplitude results. The parameter AO can now again be processed
using calibration data as described above.
[0071] A second embodiment of a circuit is shown in FIG. 8. Here,
the capacitor C formed by the electrodes is part of the resonant
tank circuit of an active, self-oscillating oscillator 40. The
amplitude A and frequency fO of the output signal of oscillator 40
depend on the capacitance and losses in capacitor C. The
corresponding signal is fed to measuring circuit 7, which evaluates
the parameters A and f0. Measuring the corresponding parameters A
and f0 again allows a sensitive measurement of the desired
concentration using calibration data.
[0072] In the examples shown so far, the invention was used in a
device for qualitatively or quantitatively displaying the
concentration a substance (such as glucose) in body liquid. The
invention can, however, also be used in devices that automatically
administer medication to a body, such as an insulin pump, where the
amount and/or time for administering the medication depends on the
measured concentration of the substance in question. The invention
can also be used in any other type of device that requires the
measurement of the concentration of a substance in a target.
SECOND EXAMPLE APPLICATION
Monitoring Concentrations of Substances During Biochemical
Processes
[0073] Another aspect of the invention is directed to using the
above-described device in other medical and/or biochemical
applications, such as monitoring the concentrations of substances
that can change electrical properties of the target such as sodium
during biochemical processes. Biochemical processing is essential
to many food, chemical, and pharmaceutical industries. At least one
embodiment of the invention is directed to an application of the
above-described device that is suitable for serving as a measuring
device for defined levels of a substance in a liquid during a
biochemical process in a bioreactor.
[0074] One example of a biochemical process for which the invention
may be used is in connection with a fermenter. Fermentation is one
typical biochemical process that may be used in the production of
products such as organic acids or dairy products. The fermenter is
an important part of an ethanol production process. Ethanol may be
produced in a fermenter during the biodegradation of glucose by
yeast. After sterilizing, the glucose solution is fed to a
fermenter. Nutrients to support cell growth may also be
provided.
[0075] The production of a chemical such as ethanol may be
monitored to improve the efficiency of the process. One way this
can be accomplished using the present invention is by providing a
fermenter with an online sensor or a plurality of online sensors
constructed and arranged to track a concentration of product(s)
during the fermenting process. Impedance spectroscopy techniques
according to embodiments of the invention can use data provided by
these sensors to provide a non-invasive and online way to monitor
alcohol production.
[0076] More generally, with reference to FIG. 9, an initial process
50 can produce product that is then transported 52 to a new
location. The product is then pumped into fermenter 54. A valve 56
controls flow of the product. A sensor 58 monitors the
concentration of a substance of interest in the product. Elements
60 and 62 perform a second process on the product. Sensor 64
monitors the concentration of a substance of interest during the
second process and sensor 66 monitors the concentration of a
substance of interest in the waste flow from the second process. In
one embodiment, one or more of the sensors can provide data to a
control on the valve to allow the control to manage the valve based
at least in part on the sensor data. For example, if the
concentration of a substance of interest goes too high, the valve
control may shut the valve.
[0077] In addition, the devices and methods as applied to the
monitoring of fermentation may also be applicable to monitoring the
manufacture and processing of brewed and/or fermented beverages,
such as beer, in a substantially similar manner to that described
above.
[0078] FIGS. 10A-F show various configurations of systems for
monitoring processes as described above. With reference to FIG.
10A, a pipe 70 is transporting product, e.g., wastewater, and a
sensor 72 is mounted to the pipe 70. With reference to FIG. 10B,
the sensor 72 is shown in greater detail mounted onto/into a pipe.
In one embodiment, the configuration of the sensor 72 is a shown in
FIGS. 2 and 3. With reference to FIG. 10C, an interior section of
the pipe shows the microstrip 18 and the ring electrode 19, the
ground is actually in touch with the target, i.e., the product. Yet
the microstrip can be electrically insulated from the target. FIGS.
10D and E show the same configuration with the sensor providing
data to a valve control 76 associated with a valve 74 in the pipe
70. Thus, the sensor 72 provides data, e.g., concentration
measurements of a substance of interest, to a control element 76 ,
e.g., a valve controller other process controller. In the valve
control embodiment, the valve control manages, e.g., closes, the
valve based at least in part on the sensor data.
[0079] Finally, with reference to FIG. 10F, a fermentor 78 having
an input pipe 80 can have a sensor 72 mounted on it. The sensor can
monitor the progress of a reaction. The fermenter can brew a
product where electrolyte concentration is changing, or the
fermenter can brew beer where the concentration of a substance of
interest is monitored.
THIRD EXAMPLE APPLICATION
Detecting changes in Body Tissue
[0080] Inflammatory processes in the body have a characteristic
impact on the impedance pattern of living tissue (in both humans
and animals). Thus, in at least one embodiment, the devices and
methods of the invention may be applied to diagnose changes in
tissue, such as those resulting from inflammatory processes in the
body, cancer, and edemas.
[0081] Edemas are accumulations of water in tissues (although water
in cells and serous cavities also may be considered to be edemas as
well). These accumulations of water show a significantly different
impedance pattern compared to that of healthy tissue. Using devices
and methods such as those described herein, at least superficial
edemas could be discriminated from normal tissue, in a
non-invasive, quick, inexpensive, and relatively pain-free
manner.
[0082] Thus, one can use an embodiment of a device according to the
invention to detect edemas by sizing the housing and the electrodes
to fit over the area of the body being measured.
[0083] Furthermore, certain electrical properties of tumor cells
differ from those of the normal tissues that surround them. Tumor
cells demonstrate greater permittivity (ability to resist the
formation of an electrical field) and conductivity of electrical
current. These findings are thought to occur because (a) cancer
cells tend to have higher sodium and water content than normal
cells, and (b) their cell membranes have different electrochemical
properties. Thus, the devices and methods of the invention could be
applied to detect other types of changes in the tissue of a body,
especially changes detectable near the surface of the skin, such as
skin cancer, breast cancer, and some types of tumors.
FOURTH EXAMPLE APPLICATION
Determining Conditions of Cells During Processing
[0084] During various types of processes (such as biochemical
processes, and growth of cell cultures), batches of cells sometimes
produce low yields because of partly damaged cells, e.g., damaged
cell walls or membranes. It can be difficult to evaluate the
presence or extent of this type of damage prior to the start of a
process. However, impedance spectroscopy techniques, such as those
techniques used in the devices and methods of the invention, may be
used to assess the quality of a given cell before a process moves
to the next production step.
[0085] It is believed that a cell and its surrounding environment
can act like a simple circuit having characteristic impedance. The
cell cytoplasm and the extracellular space (which has a
conductivity) comprise resistive components of the impedance. The
cell membrane itself contributes capacitive effects to the
impedance, especially as the frequency to which the cell is
subjected is increased. By characterizing "high quality cells" at a
given frequency range, it is possible to use the systems and
methods of the invention to monitor cells to determine their
condition relative to the. "high quality cells". For example,
changes in impedance may reflect deviations from normal in the cell
membrane. This may also be done with cells in suspension.
FIFTH EXAMPLE APPLICATION
Monitoring Concentrations of Substances in Infusions
[0086] At least one aspect of the invention is directed to an
application of the above-described device that is suitable for
tracking concentrations of substances in infusions. For example,
the devices and methods of the invention can be applied for
monitoring solutions in medical use, such as sodium, potassium, or
other salt solutions, to ensure constant flux and concentration. A
standard Sodium Chloride infusion given to a patient basically
involves three risks: [0087] a) is it really NaCl and not KCl
[0088] b) is it the correct concentration [0089] c) is it still
running (drift of the rate of infusion)
[0090] The above issues are particularly interesting for prenatal
care units. Thus, embodiments of the present invention can be
utilized to verify concentrations and operation at the point of
delivery.
SIXTH EXAMPLE APPLICATION
Monitoring the Production of Foodstuffs
[0091] Use of the invention in the growth and/or production of food
and/or beverages can help to ensure the quality and safety of the
resulting products and can also save time in the growth and/or
production process. Examples of use of embodiments of the invention
in such processes are shown in FIGS. 9-10F.
[0092] For example, at least one aspect of the invention is
directed to an application of the above-described device that is
suitable for testing foods and beverages, both during growth and
during processing. In this aspect, the invention is used to monitor
the concentration of a substance (e.g., water and sodium chloride)
in a food and/or beverage product being produced, such as baby
food, dairy products, beer, or wine. During growth or preparation
of the food product, the pair of electrodes of the device could be
disposed on the surface of the food product, to detect the
concentration of a given substance (e.g., sodium) in the food
product.
[0093] In one embodiment, the devices and methods of the invention
are applied to monitor wine processing. The quality of wine is said
to depend on a few parameters, one of which is the electrolyte
balance and alcohol content. As with the fermentation process
described previously, the invention is used to monitor the
transformation of glucose into alcohol, so that the process can be
stopped when glucose concentration reaches a predetermined
level.
[0094] In another example, at least one aspect of the invention is
directed to an application of the above-described device that is
suitable for monitoring water concentration in food and/or beverage
products. Monitoring water concentration may be especially useful
in improving the timing and efficiency of dairy processes such as
the making of butter or cheese, where the water content may have
significant impact on the quality of the resulting product.
[0095] In another example, at least one aspect of the invention is
directed to an application of the above-described device that is
suitable for measuring the concentration of water and/or
electrolytes in an agricultural product.
SEVENTH EXAMPLE APPLICATION
Wastewater Analysis
[0096] Because the devices and methods of the invention can be used
to detect changes in water composition, in at least one embodiment
the devices and methods of the invention have use in applications
such as analysis of wastewater. For example, an accident or error
occurring during production at a chemical plant could result in
harmful compounds contaminating drainage water exiting the chemical
plant. The devices and methods of the invention provide an
inexpensive, sensitive method to monitor the exiting wastewater for
this kind of occurrence. The device according to the invention may
be coupled to trigger an alarm when certain predetermined changes
in water composition occur.
[0097] Further, the devices and methods of the invention may be
used throughout the chemical process (e.g., monitoring the status
and progress of chemical processes, as described previously for the
"biochemical processes" application). Examples of use of
embodiments of the invention in such processes are shown in FIGS.
10-11F.
EIGHTH EXAMPLE APPLICATION
Corrosion Testing
[0098] The methods and devices of the invention, which use RF
impedance spectroscopy, are usable to characterize and measure
corrosion. One example of a technique for characterizing corrosion
is described in U.S. Pat. No. 4,238,298, incorporated herein by
reference in its entirety. Passing an alternating current (A.C.) at
a high frequency between two electrodes disposed in a corrosion
medium will give the ohmic resistance of the corrosion medium.
Passing an AC current at a low frequency between the electrodes
gives an impedance that is equal to the sum of the ohmic resistance
and the corrosion reaction resistance. The corrosion reaction
resistance is inversely proportional to the corrosion rate of the
metal in the medium.
[0099] The devices and methods of the invention can be adapted to
measure the ohmic impedance and the corrosion reaction impedances,
as described above, at both low and high frequencies. It is then
possible to compute the reciprocal of the difference between the
ohmic impedance and the corrosion reaction impedance, to give the
corrosion rate.
NINTH EXAMPLE APPLICATION
Measuring Salt in Street Water
[0100] Because the methods and devices of the present invention
detect the concentration of solutes such as salts in an aqueous
solution, one application of the invention is for determining
whether a surface (such as a street) coated with water has been
treated with a substance such as road salt.
[0101] For example, the invention can be used in an automobile, to
detect whether a road or street has been salted (such as when it
snows). The invention is used in connection with a sensor head
located to measure the salt content of the water splashing up from
the wheels.
TENTH EXAMPLE APPLICATION
Environmental Monitoring
[0102] Waters around industries and ecologically sensitive areas
needs to be closely monitored to ensure purity and water quality.
The devices and methods of the invention provide a simple,
inexpensive way to monitor the quality of the water by monitoring
the concentration of water and/or concentration of one or more
substances in the water.
[0103] While there are shown and described presently preferred
embodiments of the invention, it is to be distinctly understood
that the invention is not limited thereto but may be otherwise
variously embodied and practiced within the scope this
disclosure.
* * * * *