U.S. patent application number 13/034281 was filed with the patent office on 2011-08-25 for capacitance detection in electrochemical assays.
This patent application is currently assigned to LifeScan Scotland Ltd.. Invention is credited to David ELDER, Sven RIPPEL.
Application Number | 20110208435 13/034281 |
Document ID | / |
Family ID | 44645737 |
Filed Date | 2011-08-25 |
United States Patent
Application |
20110208435 |
Kind Code |
A1 |
ELDER; David ; et
al. |
August 25, 2011 |
CAPACITANCE DETECTION IN ELECTROCHEMICAL ASSAYS
Abstract
A method and system are provided to determine fill sufficiency
of a biosensor test chamber by determining capacitance of the test
chamber.
Inventors: |
ELDER; David; (Inverness,
GB) ; RIPPEL; Sven; (Zwingenberg, DE) |
Assignee: |
LifeScan Scotland Ltd.
Inverness-shire
GB
|
Family ID: |
44645737 |
Appl. No.: |
13/034281 |
Filed: |
February 24, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61308167 |
Feb 25, 2010 |
|
|
|
Current U.S.
Class: |
702/19 ;
702/22 |
Current CPC
Class: |
G01N 27/22 20130101;
G01N 27/3274 20130101; G01N 27/307 20130101 |
Class at
Publication: |
702/19 ;
702/22 |
International
Class: |
G06F 19/00 20110101
G06F019/00; G01N 31/00 20060101 G01N031/00; G01N 33/50 20060101
G01N033/50; G01N 27/22 20060101 G01N027/22 |
Claims
1. A method of determining capacitance of a biosensor chamber
having a two electrodes disposed in the chamber and coupled to a
microcontroller, the method comprising: initiating an
electrochemical reaction in the biosensor chamber; applying an
oscillating voltage of a predetermined frequency to the chamber;
determining a phase angle between a current output and the
oscillating voltage from the chamber; and calculating a capacitance
of the chamber based on a product of the current output and a sine
of the phase angle divided by a product of two times pi times the
frequency and the voltage.
2. The method of claim 1, in which the calculating comprises
calculating capacitance with an equation of the form:
C=|(i.sub.Tsin.PHI.)|/2.pi.fV where: C.apprxeq.capacitance;
i.sub.T.apprxeq.total current; .PHI..apprxeq.phase angle between
total current and resistor current; f.apprxeq.frequency; and
V.apprxeq.voltage.
3. The method of claim 2, in which the calculating comprises:
sampling a plurality of current outputs from the chamber over one
cycle of the frequency; obtaining a mean of sampled current output;
subtracting the mean from each sampled current of the plurality of
current outputs; and extracting root-mean-squared value of all
negative values from the subtracting to provide for the total
current output.
4. The method of claim 3, in which the calculating comprises:
determining from the sampling, at least one cross-over point of the
current from negative to positive values; and interpolating
proximate the at least one cross-over point of the current to
determine a first angle at which the current changes from positive
to negative or negative to positive.
5. The method of claim 4, in which the interpolating the at least
one cross-over point of the current comprises: interpolating
another cross-over point from the sampling to determine another
angle at which the current changes from positive to negative or
negative to positive; and subtracting from the another angle
approximately 180 degrees to provide for a second angle.
6. The method of claim 5, in which the subtracting further
comprises calculating an average of the first and second
angles.
7. The method of claim 5, in which the calculating comprises
determining a difference in the angle between the oscillating input
current and the output current as the phase angle.
8. An analyte measurement system comprising: An analyte test strip
including: a substrate having a reagent disposed thereon; at least
two electrodes proximate the reagent in test chamber; an analyte
meter including: a strip port connector disposed to connect to the
two electrodes; a power supply; and a microcontroller electrically
coupled to the strip port connector and the power supply, the
microcontroller being programmed to: (a) initiate an
electrochemical reaction in the biosensor chamber; apply an
oscillating voltage of a predetermined frequency to the chamber;
(b) determine a phase angle between a current output and the
oscillating voltage from the chamber; and (c) calculate a
capacitance of the chamber based on a product of the current output
and a sine of the phase angle divided by a product of two times pi
times the frequency and the voltage.
9. An analyte measurement system comprising: An analyte test strip
including: a substrate having a reagent disposed thereon; at least
two electrodes proximate the reagent in test chamber; an analyte
meter including: a strip port connector disposed to connect to the
two electrodes; a power supply; and a microcontroller electrically
coupled to the strip port connector and the power supply such that
a percent error in capacitance measurement of the test strip across
a range of capacitance as compared to a referential parallel R-C
circuit is less than about 3%.
Description
[0001] This application claims the benefits of priority under 35
USC.sctn.119 and/or .sctn.120 from prior filed U.S. Provisional
Application Ser. No. 61/308,167 filed on Feb. 25, 2010, which
applications are incorporated by reference in their entirety into
this application.
BACKGROUND
[0002] Analyte detection in physiological fluids, e.g. blood or
blood derived products, is of ever increasing importance to today's
society. Analyte detection assays find use in a variety of
applications, including clinical laboratory testing, home testing,
etc., where the results of such testing play a prominent role in
diagnosis and management in a variety of disease conditions.
Analytes of interest include glucose for diabetes management,
cholesterol, and the like. In response to this growing importance
of analyte detection, a variety of analyte detection protocols and
devices for both clinical and home use have been developed.
[0003] One type of method that is employed for analyte detection is
an electrochemical method. In such methods, an aqueous liquid
sample is placed into a sample-receiving chamber in an
electrochemical cell that includes two electrodes, e.g., a counter
and working electrode. The analyte is allowed to react with a redox
reagent to form an oxidizable (or reducible) substance in an amount
corresponding to the analyte concentration. The quantity of the
oxidizable (or reducible) substance present is then estimated
electrochemically and related to the amount of analyte present in
the initial sample.
[0004] Such systems are susceptible to various modes of
inefficiency and/or error. For example, variations in temperatures
can affect the results of the method. This is especially relevant
when the method is carried out in an uncontrolled environment, as
is often the case in home applications or in third world countries.
Errors can also occur when the sample size is insufficient to get
an accurate result. Partially filled test strips can potentially
give an inaccurate result because the measured test currents are
proportional to the area of the working electrode that is wetted
with sample. Thus, partially filled test strips can under certain
conditions provide a glucose concentration that is negatively
biased.
SUMMARY OF THE DISCLOSURE
[0005] Applicants believe that effects of parallel strip resistance
in determining filled biosensor test strips have been ignored,
leading to inaccurate high measurement of capacitance in a test
strip, especially when lower parallel resistance is encountered.
Exemplary embodiments of applicants' invention take into
consideration this effect and at the same time obviate the need to
determine the resistance in a biosensor test chamber.
[0006] In one aspect, a method of determining capacitance of a
biosensor is provided. The biosensor includes a chamber having two
electrodes disposed in the chamber and coupled to a
microcontroller. The method can be achieved by: initiating an
electrochemical reaction in the biosensor chamber; applying an
oscillating voltage of a predetermined frequency to the chamber;
determining a phase angle between a current output and the
oscillating voltage from the chamber; and calculating a capacitance
of the chamber based on a product of the current output and a sine
of the phase angle divided by a product of two times pi times the
frequency and the voltage.
[0007] In a further aspect, an analyte measurement system is
provided that includes an analyte test strip and analyte test
meter. The analyte test strip includes a substrate having a reagent
disposed thereon, and at least two electrodes proximate the reagent
in test chamber. The analyte meter includes a strip port connector
disposed to connect to the two electrodes, a power supply, and a
microcontroller electrically coupled to the strip port connector
and the power supply. The microcontroller is programmed to:
initiate an electrochemical reaction in the biosensor chamber;
apply an oscillating voltage of a predetermined frequency to the
chamber; determine a phase angle between a current output and the
oscillating voltage from the chamber; and calculate a capacitance
of the chamber based on a product of the current output and a sine
of the phase angle divided by a product of two times pi times the
frequency and the voltage.
[0008] In yet another aspect, analyte measurement system is
provided that includes an analyte test strip and analyte test
meter. The test strip includes a substrate having a reagent
disposed thereon, and at least two electrodes proximate the reagent
in test chamber. The analyte meter includes a strip port connector
disposed to connect to the two electrodes, a power supply, and a
microcontroller electrically coupled to the strip port connector
and the power supply such that a percent error in capacitance
measurement of the test strip across a range of capacitance as
compared to a referential parallel R-C circuit is less than about
3%.
[0009] These and other embodiments, features and advantages will
become apparent to those skilled in the art when taken with
reference to the following more detailed description of various
exemplary embodiments of the invention in conjunction with the
accompanying drawings that are first briefly described.
BRIEF DESCRIPTION OF THE FIGURES
[0010] The accompanying drawings, which are incorporated herein and
constitute part of this specification, illustrate presently
preferred embodiments of the invention, and, together with the
general description given above and the detailed description given
below, serve to explain features of the invention (wherein like
numerals represent like elements).
[0011] FIG. 1 illustrates an exemplary analyte measurement system
including an analyte test meter and test strip.
[0012] FIG. 2 illustrates in simplified schematic view of an
exemplary circuit board for the meter of FIG. 1.
[0013] FIG. 3 illustrates an exploded perspective view of the test
strip of FIG. 1.
[0014] FIG. 4 illustrates a simplified schematic of the components
to determine capacitance of a filled test strip.
[0015] FIG. 5A illustrates the application of voltage over time
applied to the test strip.
[0016] FIG. 5B illustrates the measured current response from the
test strip over time.
[0017] FIG. 6A illustrates a sampling of the current output
indicated at area 602.
[0018] FIG. 6B illustrates the alternating current output once the
direct-current component has been removed from the sampled data of
FIG. 6A.
[0019] FIGS. 6C and 6D illustrate the phase angle between the
alternating voltage applied to the test strip and the alternating
current output from the test strip.
[0020] FIG. 6E illustrates an interpolation of the sampled data to
determine the cross-over point of FIG. 6D for comparison with the
cross-over point of the applied current of FIG. 6C.
[0021] FIG. 7 illustrates an exemplary flow chart of the method to
determine capacitance in the exemplary test strip.
[0022] FIG. 8A illustrates the percent error of the exemplary
embodiments versus a known system and other related techniques of
the applicants.
[0023] FIG. 8B illustrates the distribution of capacitance of
respective capacitance measurement techniques over the range of
resistance in the exemplary test strip.
DETAILED DESCRIPTION OF THE EXEMPLARY FIGURES
[0024] The following detailed description should be read with
reference to the drawings, in which like elements in different
drawings are identically numbered. The drawings, which are not
necessarily to scale, depict selected embodiments and are not
intended to limit the scope of the invention. The detailed
description illustrates by way of example, not by way of
limitation, the principles of the invention. This description will
clearly enable one skilled in the art to make and use the
invention, and describes several embodiments, adaptations,
variations, alternatives and uses of the invention, including what
is presently believed to be the best mode of carrying out the
invention.
[0025] As used herein, the terms "about" or "approximately" for any
numerical values or ranges indicate a suitable dimensional
tolerance that allows the part or collection of components to
function for its intended purpose as described herein. In addition,
as used herein, the terms "patient," "host," "user," and "subject"
refer to any human or animal subject and are not intended to limit
the systems or methods to human use, although use of the subject
invention in a human patient represents a preferred embodiment.
[0026] The subject systems and methods are suitable for use in the
determination of a wide variety of analytes in a wide variety of
samples, and are particularly suited for use in the determination
of analytes in whole blood, plasma, serum, interstitial fluid, or
derivatives thereof. In an exemplary embodiment, a glucose test
system based on a thin-layer cell design with opposing electrodes
and tri-pulse electrochemical detection that is fast (e.g., about 5
second analysis time), requires a small sample (e.g., about 0.4
.mu.L(microliter)), and can provide improved reliability and
accuracy of blood glucose measurements. In the reaction cell,
glucose in the sample can be oxidized to gluconolactone using
glucose dehydrogenase and an electrochemically active mediator can
be used to shuttle electrons from the enzyme to a working
electrode. A potentiostat can be utilized to apply a tri-pulse
potential waveform to the working and counter electrodes, resulting
in test current transients used to calculate the glucose
concentration. Further, additional information gained from the test
current transients may be used to discriminate between sample
matrices and correct for variability in blood samples due to
hematocrit, temperature variation, electrochemically active
components, and identify possible system errors.
[0027] The subject methods can be used, in principle, with any type
of electrochemical cell having spaced apart first and second
electrodes and a reagent layer. For example, an electrochemical
cell can be in the form of a test strip. In one aspect, the test
strip may include two opposing electrodes separated by a thin
spacer for defining a sample-receiving chamber or zone in which a
reagent layer is located. One skilled in the art will appreciate
that other types of test strips, including, for example, test
strips with co-planar electrodes may also be used with the methods
described herein.
[0028] FIG. 1 illustrates a diabetes management system that
includes a diabetes data management unit 10 and a biosensor in the
form of a glucose test strip 80. Note that the diabetes data
management unit (DMU) may be referred to as an analyte measurement
and management unit, a glucose meter, a meter, and an analyte
measurement device. In an embodiment, the DMU may be combined with
an insulin delivery device, an additional analyte testing device,
and a drug delivery device. The DMU may be connected to the
computer 26 or server 70 via a cable or a suitable wireless
technology such as, for example, GSM, CDMA, BlueTooth, WiFi and the
like.
[0029] Referring back to FIG. 1, glucose meter 10 can include a
housing 11, user interface buttons (16, 18, and 20), a display 14,
and a strip port opening 22. User interface buttons (16, 18, and
20) can be configured to allow the entry of data, navigation of
menus, and execution of commands. User interface button 18 can be
in the form of a two way toggle switch. Data can include values
representative of analyte concentration, and/or information, which
are related to the everyday lifestyle of an individual.
Information, which is related to the everyday lifestyle, can
include food intake, medication use, occurrence of health
check-ups, and general health condition and exercise levels of an
individual.
[0030] The electronic components of meter 10 can be disposed on a
circuit board 34 that is within housing 11. FIG. 2 illustrates (in
simplified schematic form) the electronic components disposed on a
top surface of circuit board 34. On the top surface, the electronic
components may include a strip port opening 308, a microcontroller
38, a non-volatile flash memory 306, a data port 13, a real time
clock 42, and a plurality of operational amplifiers (46-49). On the
bottom surface, the electronic components may include a plurality
of analog switches, a backlight driver, and an electrically
erasable programmable read-only memory (EEPROM, not shown).
Microcontroller 38 can be electrically connected to strip port
opening 308, non-volatile flash memory 306, data port 13, real time
clock 42, the plurality of operational amplifiers (46-49), the
plurality of analog switches, the backlight driver, and the
EEPROM.
[0031] Referring back to FIG. 2, the plurality of operational
amplifiers can include gain stage operational amplifiers (46 and
47), a trans-impedance operational amplifier 48, and a bias driver
operational amplifier 49. The plurality of operational amplifiers
can be configured to provide a portion of the potentiostat function
and the current measurement function. The potentiostat function can
refer to the application of a test voltage between at least two
electrodes of a test strip. The current function can refer to the
measurement of a test current resulting from the applied test
voltage. The current measurement may be performed with a
current-to-voltage converter. Microcontroller 38 can be in the form
of a mixed signal microprocessor (MSP) such as, for example, the
Texas Instrument MSP 430. The MSP 430 can be configured to also
perform a portion of the potentiostat function and the current
measurement function. In addition, the MSP 430 can also include
volatile and non-volatile memory. In another embodiment, many of
the electronic components can be integrated with the
microcontroller in the form of an application specific integrated
circuit (ASIC).
[0032] Strip port connector 308 can be located proximate the strip
port opening 22 and configured to form an electrical connection to
the test strip. Display 14 can be in the form of a liquid crystal
display for reporting measured glucose levels, and for facilitating
entry of lifestyle related information. Display 14 can optionally
include a backlight. Data port 13 can accept a suitable connector
attached to a connecting lead, thereby allowing glucose meter 10 to
be linked to an external device such as a personal computer. Data
port 13 can be any port that allows for transmission of data such
as, for example, a serial, USB, or a parallel port.
[0033] Real time clock 42 can be configured to keep current time
related to the geographic region in which the user is located and
also for measuring time. Real time clock 42 may include a clock
circuit 45, a crystal 44, and a super capacitor 43. The DMU can be
configured to be electrically connected to a power supply such as,
for example, a battery. The super capacitor 43 can be configured to
provide power for a prolonged period of time to power real time
clock 42 in case there is an interruption in the power supply.
Thus, when a battery discharges or is replaced, real time clock
does not have to be re-set by the user to a proper time. The use of
real time clock 42 with super capacitor 43 can mitigate the risk
that a user may re-set real time clock 42 incorrectly.
[0034] FIG. 3 illustrates an exemplary test strip 80, which
includes an elongate body extending from a distal end 80 to a
proximal end 82, and having lateral edges. As shown here, the test
strip 80 also includes a first electrode layer 66a, insulation
layer 66b, a second electrode layer 64a, insulation layer 64b, and
a spacer 60 sandwiched in between the two electrode layers 64a and
66a. The first electrode layer 66a can include a first electrode
67a, a first connection track 76, and a first contact pad 47, where
the first connection track 76 electrically connects the first
electrode layer 66a to the first contact pad 67, as shown in FIGS.
3 and 4. Note that the first electrode 67a is a portion of the
first electrode layer 66a that is immediately underneath the
reagent layer 72. Similarly, the second electrode layer 64a can
include a second electrode 67b, a second connection track 78, and a
second contact pad 78, where the second connection track 78
electrically connects the second electrode 67b with the second
contact pad 78, as shown in FIGS. 3 and 4. Note that the second
electrode includes a portion of the second electrode layer 64a that
is above the reagent layer 72.
[0035] As shown in FIG. 3, the sample-receiving chamber 61 is
defined by the first electrode, the second electrode, and the
spacer 60 near the distal end 80 of the test strip 80. The first
electrode 67a and the second electrode 67b can define the bottom
and the top of sample-receiving chamber 61, respectively. A cutout
area 68 of the spacer 60 can define the sidewalls of the
sample-receiving chamber 61. In one aspect, the sample-receiving
chamber 61 can include ports 70 that provide a sample inlet and/or
a vent. For example, one of the ports can allow a fluid sample to
ingress and the other port can allow air to egress. In one
exemplary embodiment, the first electrode layer 66a and the second
electrode layer 64a can be made from sputtered palladium and
sputtered gold, respectively. Suitable materials that can be
employed as spacer 60 include a variety of insulating materials,
such as, for example, plastics (e.g., PET, PETG, polyimide,
polycarbonate, polystyrene), silicon, ceramic, glass, adhesives,
and combinations thereof. In one embodiment, the spacer 60 may be
in the form of a double sided adhesive coated on opposing sides of
a polyester sheet where the adhesive may be pressure sensitive or
heat activated.
[0036] Referring back to FIG. 3, the area of first electrode and
second electrode can be defined by the two lateral edges and cutout
area 68. Note that the area can be defined as the surface of the
electrode layer that is wetted by liquid sample. In an embodiment,
the adhesive portion of spacer 60 can intermingle and/or partially
dissolve the reagent layer so that the adhesive forms a bond to the
first electrode layer 66A. Such an adhesive bond helps define the
portion of the electrode layer that can be wetted by liquid sample
and also electrooxidize or electroreduce mediator.
[0037] Either the first electrode or the second electrode can
perform the function of a working electrode depending on the
magnitude and/or polarity of the applied test voltage. The working
electrode may measure a limiting test current that is proportional
to the reduced mediator concentration. For example, if the current
limiting species is a reduced mediator (e.g., ferrocyanide), then
it can be oxidized at the first electrode as long as the test
voltage is sufficiently less than the redox mediator potential with
respect to the second electrode. In such a situation, the first
electrode performs the function of the working electrode and the
second electrode performs the function of a counter/reference
electrode. Note that one skilled in the art may refer to a
counter/reference electrode simply as a reference electrode or a
counter electrode. A limiting oxidation occurs when all reduced
mediator has been depleted at the working electrode surface such
that the measured oxidation current is proportional to the flux of
reduced mediator diffusing from the bulk solution towards the
working electrode surface. The term bulk solution refers to a
portion of the solution sufficiently far away from the working
electrode where the reduced mediator is not located within a
depletion zone. It should be noted that unless otherwise stated for
test strip 80, all potentials applied by test meter 10 will
hereinafter be stated with respect to second electrode. Similarly,
if the test voltage is sufficiently greater than the redox mediator
potential, then the reduced mediator can be oxidized at the second
electrode as a limiting current. In such a situation, the second
electrode performs the function of the working electrode and the
first electrode performs the function of the counter/reference
electrode. Details regarding the exemplary test strip, operation of
the strip and the test meter are found in U.S. Patent Application
Publication No. 20090301899, which is incorporated by reference in
its entirety herein, with a copy attached to the Appendix.
[0038] Referring to FIG. 3, test strip 80 can include one or more
working electrodes and a counter electrode. Test strip 80 can also
include a plurality of electrical contact pads, where each
electrode can be in electrical communication with at least one
electrical contact pad. Strip port connector 308 can be configured
to electrically interface to the electrical contact pads and form
electrical communication with the electrodes. Test strip 80 can
include a reagent layer that is disposed over at least one
electrode. The reagent layer can include an enzyme and a mediator.
Exemplary enzymes suitable for use in the reagent layer include
glucose oxidase, glucose dehydrogenase (with pyrroloquinoline
quinone co-factor, "PQQ"), and glucose dehydrogenase (with flavin
adenine dinucleotide co-factor, "FAD"). An exemplary mediator
suitable for use in the reagent layer includes ferricyanide, which
in this case is in the oxidized form. The reagent layer can be
configured to physically transform glucose into an enzymatic
by-product and in the process generate an amount of reduced
mediator (e.g., ferrocyanide) that is proportional to the glucose
concentration. The working electrode can then measure a
concentration of the reduced mediator in the form of a current. In
turn, glucose meter 10 can convert the current magnitude into a
glucose concentration. Details of the preferred test strip are
provided in U.S. Pat. Nos. 6,179,979; 6,193,873; 6,284,125;
6,413,410; 6,475,372; 6,716,577; 6,749,887; 6,863,801; 6,890,421;
7,045,046; 7,291,256; 7,498,132, all of which are incorporated by
reference in their entireties herein.
[0039] FIG. 4 illustrates, in simplified schematic form, of various
functional components utilized for capacitance determination. In
particular, the components include a microcontroller 300. A
preferred embodiment of the microcontroller 300 is available from
Texas Instrument as ultra-low power microcontroller model MSP430.
Microcontroller ("MC") 300 may be provided with DAC output and
built-in A-D conversion. MC 300 is suitably connected to a LCD
screen 304 to provide a display of the test results or other
information related to the test results. Memory 306 is electrically
connected to the MC 300 for storage of test results, sensed current
and other necessary information or data. The test strip may be
coupled for a test measurement via a strip port connector ("SPC")
308. SPC 308 allows the test strip to interface with MC 300 via a
first contact pad 47a, 47b and a second contact pad 43. The second
contact pad 43 can be used to establish an electrical connection to
the test meter through a U-shaped notch 45, as illustrated in FIG.
4. SPC 308 may also be provided with electrode connectors 308a and
308c. The first contact pad 47 can include two prongs denoted as
47a and 47b. In one exemplary embodiment, the first electrode
connectors 308a and 308c separately connect to prongs 47a and 47b,
respectively. The second electrode connector 308b can connect to
second contact pad 43. The test meter 10 can measure the resistance
or electrical continuity between the prongs 47a and 47b to
determine whether the test strip 80 is electrically connected to
the test meter 10.
[0040] Referring to FIG. 4, SPC 308 is connected to switch 310.
Switch 310 is connected to the bias driver 312. Bias driver 312 is
provided with the DAC signal 312a; current drive 312b and switch
signal 312c. The MC 300 provides the DAC signal 312a, which
includes analogue voltages in the range 0 to Vref (e.g., about
2.048V). The bias driver 312 can operate in two modes--constant
voltage, or constant current. The current-driver line 312b controls
the mode of the bias driver 312. Setting the line 312b low converts
an op-amp in the bias driver 312 to a voltage follower amplifier.
DAC signal 312a output is scaled to Vref/2+/-400 mV full scale. The
op-amp in the bias driver outputs this voltage directly to the MC
300 as line driver-line 312d. The voltage of line 312d is generated
with respect to the Vref/2 virtual ground. So to drive a suitable
bias (e.g., about 20 mV bias), the DAC must drive (through a
suitable scaler) about 1.044V. To drive a bias of about +300 mV,
the DAC must generally provide about 1.324V, and for the -300 mV
bias, the DAC must generally provide about 0.724V. The bias driver
circuit 312 also generates the 109 Hz sine wave, which is used for
fill detection via capacitance measurement.
[0041] On the other hand, if current-drive signal 312a to bias
driver 312 is held high, the DAC output is scaled to approximately
0 to approximately 60 mV full scale. Switch signal 312c may also be
energized, causing the current path through the test strip to be
diverted through a resistor in bias driver 312. The op-amp in bias
driver 312 attempts to control the voltage drop across the resistor
to be the same as the scaled DAC drive--producing in this case a
current of approximately 600 nA. This current is used for sample
detection in order to initiate a test measurement.
[0042] Bias driver 312 is also connected to a trans-impedance
amplifier circuit ("TIA circuit") 314. TIA circuit 314 converts the
current flowing though the strip's electrode layer 66a (e.g.,
palladium) to electrode layer 64a (e.g., gold) contacts into a
voltage. The overall gain is controlled by a resistor in TIA
circuit 314. Because the strip 80 is a highly capacitive load,
normal low-offset amplifiers tend to oscillate. For this reason a
low-cost op-amp is provided in the TIA circuit 314 as a unity gain
buffer and incorporated within the overall feedback loop. As a
functional block, circuit 314 acts as dual op-amp system with both
high drive capability and low voltage offset. The TIA circuit 314
also utilizes a virtual ground (or virtual earth) to generate the
1.024V bias on the electrode layer 64a (e.g., gold) contact of the
SPC 308. Circuit 314 is also connected to a Vref amplifier circuit
316. This circuit, when in current measuring mode, uses a virtual
ground rail set at Vref/2 (approximately 1.024V), allowing both
positive and negative currents to be measured. This voltage feeds
all of the gain amplifier stage 318. To prevent any circuit loads
from `pulling` this voltage, a unity gain buffer amplifier may be
utilized within the Vref amplifier circuit 316.
[0043] The strip current signal 314a from the TIA circuit 314 and
the virtual ground rail 316a (.about.Vref/2) from the voltage
reference amplifier 316 are scaled up as needed for various stages
of the test measurement cycle. In the exemplary embodiment, MC 300
is provided with four channels of amplified signal sensed from the
test strip with varying amplifications of the sensed current as
need for different stages of the measurement cycle of the test
strip during an analyte assay.
[0044] In one embodiment, the test meter 10 can apply a test
voltage and/or a current between the first contact pad 47 and the
second contact pad 43 of the test strip 80. Once the test meter 10
recognizes that the strip 80 has been inserted, the test meter 10
turns on and initiates a fluid detection mode. In one embodiment,
the meter attempts to drive a small current (e.g. 0.2 to 1 .mu.A)
through the strip 80. When there is no sample present the
resistance is greater than several Mega Ohms, so the driving
voltage on the op-amp trying to apply the current goes to the rail.
When a sample is introduced the resistance drops precipitously and
the driving voltage follows. When the driving voltage drops below a
pre-determined threshold the test sequence is initiated.
[0045] FIG. 5A shows the voltage to be applied between the
electrodes. Time zero is taken to be when the sample detection
method has detected that a sample first begins to fill the strip.
Note that the sine wave component shown at approximately 1.3
seconds in FIG. 5A is not drawn on the correct timescale for
illustration purposes.
[0046] After a sample has been detected in the test strip chamber
61, the voltage between the strip electrodes is stepped to a
suitable voltage in millivolts of magnitude and maintained for a
set amount of time, e.g., about 1 second, then stepped to a higher
voltage and held for a fixed amount of time, then a sine wave
voltage is applied on top of the DC voltage for a set amount of
time, then the DC voltage is applied for a further amount of time,
then reversed to a negative voltage and held for a set amount of
time. The voltage is then disconnected from the strip. This series
of applied voltages generates a current transient such as the one
shown in FIG. 5B.
[0047] In FIG. 5B, the current signal from about 0 to about 1
second (as well as later current samples) may be used for error
checking and to distinguish a control solution sample from a blood
sample. The signal from about 1 to about 5 seconds is analyzed to
obtain a glucose result. The signal during this period is also
analyzed for various errors. The signal from about 1.3 to 1.4
seconds is used to detect whether or not the sensor is completely
filled with sample. The current from 1.3 to 1.32 seconds, denoted
here as trace 500, is sampled at approximately 150 microsecond
intervals to determine whether sufficient volume of physiological
fluid has filled chamber 61 of the test strip.
[0048] In one embodiment for performing a sufficient volume check,
a capacitance measurement is used to infer sufficient analyte fill
of the chamber 61 of the test strip 80. A magnitude of the
capacitance can be proportional to the area of an electrode that
has been coated with sample fluid. Once the magnitude of the
capacitance is measured, if the value is greater than a threshold
and thus the test strip has a sufficient volume of liquid for an
accurate measurement, a glucose concentration can be outputted. But
if the value is not greater than a threshold, indicating that the
test strip has insufficient volume of liquid for an accurate
measurement, and then an error message can be outputted.
[0049] In one method for measuring capacitance, a test voltage
having a constant component and an oscillating component is applied
to the test strip. In such an instance, the resulting test current
can be mathematically processed, as described in further detail
below, to determine a capacitance value.
[0050] Applicants believe that the biosensor test chamber 61 with
the electrode layers can be modeled in the form of a circuit having
a parallel resistor and capacitor as shown in Table 1.
[0051] In this model in Table 1, R represents the resistance
encountered by the current and C represents a capacitance resulting
from the combination of the physiological fluid and reagent
electrically coupled to the electrodes. To initiate a determination
of capacitance of the chamber, an alternating bias voltage may be
applied across the respective electrodes disposed in the chamber,
and a current from the chamber is measured. The filling of the
chamber 61 is believed to be generally a measure of capacitance
only and thus any parasitic resistance, such as, for example, R,
must not be included in any determination or calculation of
capacitance. Hence, in measuring or sensing the current, any
parasitic resistance is believed to affect the measured current.
Applicants, however, have discovered a technique to derive
capacitance without requiring utilization or knowledge of the
resistance through the chamber as modeled above. In order to
further explain this technique, a short discussion of the
mathematical foundation underlying the technique is warranted.
[0052] According to Kirchhoff's Law, total current (i.sub.T)
through the circuit of Table 1 is approximately the sum of the
current flowing through the resistor (i.sub.R) and through the
capacitor (i.sub.C). When an alternating voltage V (as measured as
RMS) is applied, the resistor current (i.sub.R) may be expressed
as:
i.sub.R=V/R Eq. 1
[0053] Capacitor current (i.sub.C) can be expressed as:
i.sub.C=j.omega.CV Eq. 2 [0054] Where: [0055] j is an imaginary
number operator indicating that current leads voltage by about 90
degrees in a capacitor; and [0056] .omega. is the angular frequency
2.pi.f where f is frequency in Hertz.
[0057] The summation of these components is shown in the phasor
diagram of Table 1. In the phasor diagram, .PHI. represents the
phase angle of the input as compared to the output. Phase angle
.PHI. is determined by the following trigonometric function:
tan.PHI.=I.sub.c/I.sub.R Eq. 3
[0058] By Pythagoras theorem, the square of the total current
i.sub.T can be calculated as:
i.sub.T.sup.2=i.sub.C.sup.2+i.sub.R.sup.2 Eq. 4
[0059] By rearranging Eq. 4 and substituting Eq. 3, the following
equation is arrived at:
i.sub.C.sup.2=i.sub.T.sup.2-.sup.i.sup.C.sup.2/.sub.(tan.PHI.).sup.2
Eq. 5
[0060] Resolving for capacitor current i.sub.C and combining with
Eq. 2:
i.sub.C= {square root over (()}i.sub.T.sup.2*(tan.PHI.).sup.2/((tan
.PHI.)).sup.2+1))=.omega.CV Eq. 6
[0061] Rearranging for C and expanding .omega., the capacitance
becomes:
C=( {square root over (()}i.sub.T.sup.2*(tan .PHI.).sup.2/((tan
.PHI.).sup.2+1))/2.pi.fV Eq. 7
[0062] Simplification of Eq. 7 leads to:
C=|(i.sub.Tsin.PHI.)|/2.pi.fV Eq. 8
[0063] It can be seen that Eq. 8 does not reference to the resistor
current. Consequently, if the system can drive an alternating
voltage with frequency f and root-mean-squared ("RMS") amplitude V,
and measure total current i.sub.T as RMS value and phase angle
.PHI., capacitance C of the test chamber 61 can be accurately
calculated without having to determine resistance in the biosensor
test chamber. This is believed to be of substantial benefit because
the resistance of the biosensor strip is difficult to measure, and
varies over the 5 second assay time. Resistance is believed to
arise from how many charge carriers can flow through the strip for
a given electrical bias (voltage), and is therefore reaction
dependent. At the 1.3 second point in the assay, the resistance is
expected to be anything from 10 k.OMEGA. to perhaps 100 k.OMEGA..
Hence, by not having to determine the resistance in the biosensor
chamber or even the resistance in the measuring circuit, such as a
sensor resistor, applicants' invention have advanced the state of
the art in improving of the entire test strip.
[0064] Implementation of an exemplary technique to determine
capacitance C based on Eq. 8 can be understood in relation FIGS.
6A, 6B, 6C, 6D, 6E, and 7. As illustrated in FIG. 5A and step 702
of FIG. 7, an AC test voltage (..+-.0.50 mV peak-to-peak) of
approximately 109 Hz can be applied for 2 cycles during
approximately 1-1.3 seconds or at least one cycle indicated in step
704. In the preferred embodiments, the first cycle can be used as a
conditioning pulse and the second cycle can be used to determine
the capacitance. The alternating test voltage can be of a suitable
waveform, such as, for example, a sine wave of approximately 109
Hertz with approximately 50 millivolts peak (FIG. 6C). The sampling
can be of any suitable sampling size per cycle, such as, for
example approximately 64-65 samples per cycle, shown here in FIG.
6A. Hence, each sample represents approximately 5.6 degrees of the
exemplary sine wave.
[0065] In FIG. 6A, the system adds a direct-current voltage offset
to the alternating current bias and therefore the measured samples
in FIG. 6A will also have a direct-current offset, which must be
removed via steps 706 and 708 in order to determine the total
current i.sub.T according to one example of applicant's
technique.
[0066] In this technique, a mean of all the 65 samples, referenced
here as 602, in FIG. 6A is derived in step 706, which will provide
a threshold for the zero current of the a.c. component of the
samples. A benefit of this derivation is that the noise across the
samples is averaged out. For each sample point, the mean value is
subtracted out of each sampled point in step 708, which results in
isolating the alternating current component, shown here in FIG. 6B.
Thereafter, a RMS value of all the negative values is taken in step
710, to provide for a substantially accurate magnitude of the total
current i.sub.T. It is noted that the RMS value of the positive
values could also be taken, but applicants believe that the
positive values are disjointed due to being split across the first
and fourth quadrants of the overall cycle, and therefore the
negative values are preferred. Once the samples 602 have been
manipulated to remove the DC offset, the samples can be plotted to
show the output of the current over time, as referenced here at 604
in FIG. 6B.
[0067] To determine the phase angle, the system or MC, as
appropriately programmed can compare the oscillating input voltage,
shown here in FIG. 6C to the oscillating output current to
determine the phase angle for step 714. In the preferred
embodiments, the sampled data 604 is analyzed to determine a
cross-over point from positive to negative current. Because the
sampling is based on a discrete number of samples, interpolation
can be used to determine substantially when the output current
crosses over the zero current line in FIG. 6E, the interpolated
cross-over point being referenced here as 608. In the embodiment
described here, the phase angle .PHI. is less than 90 degrees and
approximately 87 degrees. For increased accuracy, interpolation can
be performed at another cross-over point 610 with approximately 180
degrees subtracted from this second interpolated point 610. The two
interpolated values should be within a few degrees and may be
averaged out to increase accuracy.
[0068] Once the phase angle has been derived, capacitance can be
calculated using Eq. 8. In practice, however, it has been
determined that the implementation of the trans-impedance amplifier
314 and the gain amplifier introduces additional phase shift into
the system. This additional phase shift can be offset by
introduction of a compensation value .PHI..sub.COMP by measuring
the capacitance of the system without a strip in use.
C=|i.sub.Tsin(.PHI.+.PHI..sub.COMP)|/2.pi.fV Eq. 9
[0069] In the preferred embodiments, the compensation phase angle
.PHI..sub.COMP ranges from about 5 to about 7 degrees.
[0070] Once capacitance of the test strip 80 has been determined, a
two-point calibration can be performed to normalize the capacitance
value to a value that is independent of any tolerances of the
analog components (e.g., resistors, capacitors, op-amps, switches
and the like). Briefly, the two-point calibration is performed by:
placing a 550 nF capacitor with 30 k parallel resistance across the
measurement input; command the meter to measure the capacitance,
and note the value produced; place a 800 nF capacitor with 30 k
parallel resistance across the measurement input; command the meter
to measure the capacitance, and note the value produced. These two
points will give an indication of the gain and offset of the
measurement capability of that particular hardware instance (not
the design). A slope and offset are then calculated from the
measurement errors, and stored in the meter's memory. The meter is
now calibrated. [0071] When a strip is inserted and a sample
applied, the capacitance is measured and the stored slope and
offset are applied to correct the measurement.
[0072] After completion of the device calibration, an evaluation is
made to determine whether the test chamber 61 has been sufficiently
filled with test fluid. The evaluation can be based on a
capacitance magnitude of at least 65% to 85% of an average
capacitance value derived from a large sample of good filled test
strips.
[0073] To test the robustness of this exemplary technique,
applicants intentionally introduced noise into the system to
determine the percent error as compared to referential parallel R-C
circuit. In Table 2 below, despite the number of
Analog-to-Digital-Converter ("ADC") noise counts were introduced,
error relating to current, phase angle and capacitance were less
than 1%.
TABLE-US-00001 TABLE 2 ADC Noise Current Phase Angle Capacitance
Counts Error (%) Error (%) Error (%) .+-.1 -0.05 -0.1 -0.09 .+-.2
-0.08 -0.19 -0.21 .+-.3 0.2 -0.34 -0.34 .+-.4 0.21 0.39 0.37
[0074] Comparison of the exemplary techniques with other techniques
confirms the increased accuracy of applicants' technique. For
example, in FIG. 8A, capacitance is measured from a sample of
strips in the range of about 350 to about 800 nanoFarad. A fully
filled strip has capacitance ranging between 600 and 700 nF
depending on whether control solution or blood is used. Partially
filled strips exhibit lower capacitance of course. The capacitance
is measured with the subject embodiment to determine percent
deviation from a referential parallel R-C circuit. The percentage
error is calculated by having several "golden" R-C combinations
that have been calibrated using a commercially available LCR meter.
These R-C combinations (which have been found as generally
error-free exemplars and therefore are "golden") are presented to
the strip connector in turn, and the system is commanded to read
the capacitance. This test is repeated using several other samples
of the system to determine the precision and reliability of the
measurement technique. Reference curve 800 represents the exemplary
technique with error rate from the referential datum of less than
3% through the capacitance range of about 350 nanoFarad to about
850 nanoFarads. In contrast, capacitance measurement in an existing
meter system available from LifeScan Inc., in the Netherlands shows
error curve 806 ranging from less than 2 percent to greater than 10
percent through this range of capacitance. Applicants' related
capacitance measurement techniques 802 and 804 fall in between the
upper boundary 806 sets by the existing analyte measurement system
and the lower boundary 800 sets by the exemplary technique.
[0075] Although the exemplary embodiments, methods, and system have
been described in relation to a blood glucose strip, the principles
described herein are also applicable to any analyte measurement
strips that utilize a physiological fluid on a reagent disposed
between at least two electrodes.
[0076] As noted earlier, the microcontroller can be programmed to
generally carry out the steps of various processes described
herein. The microcontroller can be part of a particular device,
such as, for example, a glucose meter, an insulin pen, an insulin
pump, a server, a mobile phone, personal computer, or mobile hand
held device. Furthermore, the various methods described herein can
be used to generate software codes using off-the-shelf software
development tools such as, for example, C or variants of C such as,
for example, C+, C++, or C-Sharp. The methods, however, may be
transformed into other software languages depending on the
requirements and the availability of new software languages for
coding the methods. Additionally, the various methods described,
once transformed into suitable software codes, may be embodied in
any computer-readable storage medium that, when executed by a
suitable microcontroller or computer, are operable to carry out the
steps described in these methods along with any other necessary
steps.
[0077] While the invention has been described in terms of
particular variations and illustrative figures, those of ordinary
skill in the art will recognize that the invention is not limited
to the variations or figures described. In addition, where methods
and steps described above indicate certain events occurring in
certain order, those of ordinary skill in the art will recognize
that the ordering of certain steps may be modified and that such
modifications are in accordance with the variations of the
invention. Additionally, certain of the steps may be performed
concurrently in a parallel process when possible, as well as
performed sequentially as described above. Therefore, to the extent
there are variations of the invention, which are within the spirit
of the disclosure or equivalent to the inventions found in the
claims, it is the intent that this patent will cover those
variations as well.
* * * * *