Note: Descriptions are shown in the official language in which they were submitted.
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TE. E. .ATI.T. E C FNSAT~ ~ FOR ENZYME
ELECTRODES
CI,AIM ()F I'I2I()IZITY TJNI7I;R 3 5 IJ.S,C. & 119
[0001] "I'he present application claims priority from tJ.S. Provisional
Patent Application Number 60/859,586, filed November 16, 2006,
entitled "'1,EMPE12A"1,U1ZE COMPENSATION FC)1Z. ENZYME
FLECTR(7DES," which is assigned to the assignee hereof and hereby
expressly incorporated by reference herein.
BACKGROUND OF TIIFs INVENTION
1. Field of the Inveiltion.
[0002] The invention relates generally to enzym electrodes. More
particularly, the invention relates to temperature compensation for
enzyme electrodes.
2. Description of Related Art.
[0003] When diabetics control their blood sugar (glueose), they are
more lilcely to live and stay healthy. They may monitor and test for
glucose in the blood using a prior art glucose monitoring systern, such
as an amperometric glucose detector. The glucose monitoring system is
desigf-ted to control arriperon7etric biosensors in a static and stable
environment, such as a medical laboratory. 'The amperometric
biosensors may be coated with chemicals, such as glucose oxidase,
dehydrogenase or hexokinase, which combine with glucose in the blood
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sample. Some sensors measure the amount of current generated by the
sensor in the blood sat-nple, while others measure how much light
reflects from it. These naeasurements are fiirther analyzed and
quantified by the glucose monitoring system to determirre the glucose
level in the blood sanlple.
[00041 Recently, new sensors have been introduced into the marlcet that
can be inserted percutaneously into subeutaneous tissue. These sensors
provide continuous, or near continuous, readings of glucose
concentration, thereby allowing patients to better manage their glucose
levels.
(0005] The biosensors are calibrated to provide actual measurements at
a specific temperature. Figure 1 is a graph illustrating the relationship
between the glucose level in the blood sample and the current measured
from the biosensors at varying teinperatures. The measurements
obtained from the biosensors are dependent on the temperature of the
surroundings. If the temperature of the surroundings changes, an error
occurs in the measurements. An increase in temperature increases the
slope of the curve, while a decrease in temperature decreases the slope
of the curve. If the slope increases, the computed glucose level is lower
than the actual glucose level. in contrast, if the slope decreases the
computed glucose level is higher than the actual glucose level. flence,
a change in temperature of the surroundings provides an error in the
computed g'iucose level.
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[0006] Figure 2 is a graph illustrating current change as a function of
temperature. Data from a prior art glucose monitoring systein was
taken at four different glucose concentrations over a temperature range
of 32 C to 41 C. The current was normalized to 1 at 37 C, As shown
for the different glucose concentrations, an increase in temperature
increases the current measured from the biosensors, thereby providing
an inaccurate measurement of the glucose level in the blood. The
resulting error is illustrated in the Clark Error grid of Figure 3. The grid
shows how the glucose measurements, without temperature compensation, compare
to the true glucose concentration values.
[0007] As is well known in the art, Zone A represents clinically
accurate measurements. Zone 1-3 represents measurements deviating
from the reference glucose level by more than 20% but would lead to
benign or no treatment. Zone C represents measurements deviating
from the reference glucose level by more than 20% and would lead to
unnecessary corrective treatment errors. Zone D represents
measurements that are potentially dangerous by failing to detect and
treat blood glucose levels outside of desired target range. Finally, Zone
E represents measurements resulting in erroneous treatment. As shown
in the Clark Error grid of Figure 3, some of the error measurements
were close to the Zone B, thereby deviating from the reference by more
than 20%. Hence, when no temperature compensation is employed
there are large errors.
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[0008] There are many factors that can affect a change in the
temperature surrounding the sensor. Since sensors are inserted in the
human body, via a catheter, the temperature of the body may affect the
sensor readings. The body temperature may be higher or lower than the
temperature at which the sensors were calibrated. The sensors may also
be affected by the room teinperature prior to insertion in the human
body. Furthermore, the infusion of fluid through a lumen in the
catheter can have an affect on the sensor's measurements. The fluid
may have a different temperature from the human body, and
accordingly, would affect the sensor's readings during fluid infusion.
[0009] I)epending on the location of the sensor and the configuration of
the device in which the sensor is located, temperature changes may
cause the current produced by the sensor to change for the same glucose
concentration, thereby invalidating the calibration curves. This may
cause the accuracy of these sensors to be unacceptable for clinical use
and perhaps dangerous for guiding therapy.
[0010] Past solutions include withdrawing a sample of blood and
measuring the glucose level in an isolate static envirom-nent with
constant teniperature. Another prior art method includes withdrawing a
sample of blood across a sensor and recirculating the blood back to the
patient. These solutions do not compensate for the temperature
changes; rather, they seek to avoid the possibility of temperature
changes.
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[00111 With an increasing demand for improved glucose monitoring
systems, there remains a need in the art for temperature compensation
for sensor electrodes to provide reliable measurements despite a change
in surrounding temperature.
SC1MMAIZY C)F'THE INVENTION
[0012] The present invention fills this need by providing a temperature
compensation method for an enzyme electrode by measuring an
operating temperature of the enzyme electrode, measuring the current
generated by the enzyme electrode, determining a deviation in
temperature between the operating temperature and the reference
temperature, determining a glucose concentration corresponding to the
measured current at the operating temperature, and compensating the
glucose concentration measurement for the deviation in temperature.
[00131 In one embodiment, temperature compensation may be achieved
by using a calibration curve that corrects for the variation in the current
produced due to a temperature change. For an enzyme electrode with
linear or nearly linear characteristics, the glucose concentration with
temperature colnpensation = slope = currc-nt = e'0
Absolute" or
"relative" calibration curves may be determined for an electrode with
nonmlinear characteristics.
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BRIF;F DESCRIPTION OF '1,HE DRAWINGS
[0014] The exact nature of this invention, as well as the objects and
advantages thereof, will become readily apparent from consideration of
the following specification in conjunction with the accompanying
drawings in which like reference numerals designate like parts
throughout the figures thereof and wherein:
[0015] Figure 1 is a graph illustrating the relationship between the
glucose level in the blood sample and the current measured from the
biosensors at varying temperatures.
[0016] Figure 2 is a graph illustrating current change as a function of
temperature at several glucose concentrations.
[0017] Figure 3 is a Clark Error Grid illustrating prior art glucose
measurements, without temperature compensation, in relation to true
glucose concentration values.
[0018] Figure 4 illustrates a catheter with a temperature element
ineluded for the purpose of temperature compensation.
[0019) Figure 5 is a crossmsectional view of the catheter of Figure 4
aloiig line 5-5. [0020] Figure 6 is a cross-sectional view of the catheter of
Figure 4
along line 6m6.
[0021] Figure 7 is a graph illustrating the change in temperature as a
function of time.
[0022] Figure 8 is a graph illustrating the glucose concentration
measurement, with and without temperature compensation, relative to
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true glucose levels as a functiori of time, when the sensor is subjected to
the teiiiperature variation as shown in Figure 7.
[0023] Figure 9 is a Clark Error Grid illustrating glucose
measurements, with temperature compensation, in relation to true
glucose concentration values.
[0024] Figure 10 is a cross-sectional view of the sensor with a
temperature compensation element.
DETAILED DESCRIPTION
[0025] A sensor electrode operable in an environment with varying
temperature is provided. The sensor provides glucose measurements
with acceptable accuracy for clinical setting, specifically to guide
therapy. The sensor may be used in an access device, such as a
catheter, for both venous and arterial environments. The catheter may
be configured to allow for the infusion of fluid. The fluid may infuse
into the body at a temperature different from the body temperature.
[0026] F'igure 4 illustrates an example of a catheter I1 (e.g., a glucose
monitoring catheter). Figure 5 is a cross-sectional view oi'the catheter
11 of Figure 4. Figure 10 is a cross-sectional view of a sensor (e.g., an
enzyme electrode or a glucose electrode or seiisor) with a temperature
sensing device or temperature coinpensation element 15. The catheter
11 has at least one opening 12 that exposes one or more sensor
electrodes 13. In an embodiment, underneath the sensor electrodes 13
is a temperature sensing device, such as a thermistor 15, held in place
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by adhesive or filling material 16, as shown in Figure 6. The catheter
11 also has one or more pathways, such as lunlens 17, along its length
for infusion of fluid in the blood. The flow of fluid in pathways 17 of
the catheter 11 can have an affect on the sensor's measurements. Thc
fluid may have a different temperature frorn the human body, and
accordingly, would affect the sensor 13 readings during fluid infusion.
100271 The current produced by the sensor electrode 13 for a given
analyte concentration is based on a number of factors. For example, it
depends on the concentration of enzyines and the diffusion rates
through the inembrane containing or encapsulating the electrodes, such
as a polyurethane, hydro polymer or gel membrane. The turnover rate
of the enzyines and the diffusion rates through the membrane are
typically temperature dependent. While the purpose of the sensor
electrode 13 is to produce a laiown magnitude of current for a lalown
concentration of an analyte, a small temperature variation can introduce
an error in the irieasurement. Typically, errors resulting from
teinperature variation range from 2 to 7 %.
[0028] One way to mitigate the error introduced by temperature
variation is to control the temperature of the sensor 13 and/or solution
containing the analyte of interest, such that the temperature remains
constant. However, when the sensor is integrated into a catheter 11,
controlling the temperature of the sensor 13 and/or solution is not
feasible. For exan-tple, body tcs-npcrature changes or a tempcrature
and/or rate of an infusion fluid would affect the serrsor reading.
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Accordingly, temperature compensation is necessary to obtain accurate
measurements. The catheter 11 may be ari intravascular catheter.
[0029] The temperature compensation or sensing element 15 (e.g., a
thermistor or a silver trace or any device whose resistance changes with
changing temperature) may be attached to the sensor 13, located
adjacent to the sensor 13, co-located on the same plane or membrane as
the sensor 13, integrated into the sensor 13 itself, attached to a device in
which the sensor 13 is located, placed in the vicinity of the sensor 13,
placed at a location that is representative of the temperature around the
sensor 13, or placed in a location that tracks the temperature variation
around the sensor 13. `I'he temperature sensing element 15 and/or the
sensor 13 may be positioned within the catheter 11. The temperature
sensing element 15 measures temperature at the sensor 13 to
compensate for blood or infusates traveling through the catheter 11. In
one embodiment, the temperature sensing element 15 may be
configured or positioned so that it can measure the temperature of the
sensor 13 or a change in temperature due to an external condition (e.g.,
body temperature) or an internal condition (e.g., infusates). 'The
infusate rate may also need to be calculated during the internal
condition. In one enlbodiment, the temperature sensing element 15
directly measure the temperature of the sensor 13 that is in contact with
the blood stream. 10030] Preferably, the ten, perature sensing elenient 115
may be insulated
from the infusion fluid using insulatirig structures, as disclosed in U.S.
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I'ub. No. 2002/0128568, and incorporated herein by reference. Various
insulating lumens 17 and insulating members may be used to insulate
the temperature seflising element 15 from the infusion fluid, which
might otherwise degrade the accuracy of the temperature measurement.
[0031] 7'emperature compensation may be achieved by using a
temperature compensation element that corrects/calibrates for the error
in the current measurcment due to a temperature change. Under
predetermined operating conditions, the effect of temperature on the
calibration curve of the temperature compensation element may be an
increase in the first order term at higher temperatures and a change in
the offset. For electrodes 13 with linear or nearly linear characteristics,
the first order term is the slope. Hence, the temperature compensation
for electrodes 13 with linear or nearly linear characteristics may be
expressed in the following form:
Correction ~'actof = 4T = T 0e~ -slope
(1)
where,
4I' is the change in temperature from the temperature at which
the electrode 13 was calibrated;
T,O,t~ is the temperature coefficient (change in slope per degree);
and
slope is the change in analyte conceiitration divided by the
change in current.
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[00321 Equation (1) holds true for glucose electrodes 13 with linear or
nearly linear characteristics where there is no infusion of fluid through
the catheter over the temperature range in which the correction factor
remains linear or nearly linear with temperature. llowever, a
calibration curve may also be used for a sensor 13 with non-linear
characteristics, where fluid is infi.lsed into the body through lumen 17 in
the catheter 11.
[0033] An "absolute" or "relative" calibration curve may be deterinined
for glucose electrodes 13 with nonmlinear characteristics. For an
"absolute" calibration curve, a correction factor or calibration curve is
ascertained at specific measured temperatures, whereas for a "relative"
calibration curve, a correction factor is determined based on a
temperature change from the temperature at which the electrode 13 was
calibrated and/or another reference temperature.
[0034] According to a temperature compensation method for glucose
electrodes with linear or nonalulear eharacteristies, the temperature of
the area or solution surrounding the sensor 13 or the temperature of a
device to which the sensor is attached is measured by the temperature
sensing element 15. Based on previous measurements, an individual
calibration curve at the measured temperature is predetermined. As the
teinperature changes, due to an in9'usion of fluid, for example, various
calibration curves may be substituted, such that each calibration curve
reflects the curi ent produced as a functiori of analyte concentration at
the measured temperature.
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[0035] According to another ternperature compensation method for
glucose with linear or non-linear characteristics, the temperature
deviation from the temperature at which the electrodes 13 was
calibrated is measured by a temperature sensing element 15. Based on
this deviation, calibration curves may be substituted, such that each
calibration curve reflects the current produced as a function of analyte
concentration at the measured temperature deviation.
[0036] To better demonstrate the effect of calibration curves on glucose
measurements, an exemplary in vitro test is described with and without
temperature compensation. The temperature of the area or solution
surrounding the sensor 13 or the temperature of a device to which the
sensor 13 is attached was varied from 30 C to 42 C over time, as
shown in Figure 7. After a predetermined period, the glucose
concentration was increased by about 100 mg/dL for about every 40
minutes.
[0037] Figure 8 is a graph illustrating the change in glucose
concentration over a period of time. As shown in Figure 8, the solid
line illustrates the true glucose concentration at a specific time, the
dotted line represents the measured glucose concentration without
tenlperature compensation, and the dashed line represents the measured
glucose concentration with temperature compensation. The
ternperature compensation used in Figure 8 was in the forin;
glucose concentration = slope = current = e'~'~ (7o"
(2)
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where, slope is the change in glucose concentration divided by the
change in current;
current is the current generated by the electrode 13;
7CO,ff is the temperature coefficient of the sensor(s);
1Gal is the temperature at which the electrode 13 was calibrated;
and
T is the temperature of the electrode 13 measured by the
temperature sensing element 15.
[0035] Without temperature compensation, there are large errors in the
measured glucose values. 14owever, with temperature compensation
using equation (2), the measured glucose values line up relatively close
to the true glucose values. A Clark Error grid, illustrated in Figure 9,
shows how the glucose measurements, with temperature compensation,
compare to the true glucose concentration values. The Clark Error grid
of Figure 9 shows significantly less error in measured glucose
concentration, when compared to the Clark Error grid of Figure 3. The
measured glucose concentration with temperature compensation is
clinically accurate (Zone A) with measurements close to the reference
glucose level.
[00391 While certain exemplary embodiments have been described and
shown in the accompanying drawings, it is to be understood that such
ernbodiments are merely illustrative of and not restrictive on the broad
invention, and that this inventiori not be liinited to the specifitc
constructions and arrangements shown and described, since various
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other changes, combinations, omissions, modifications and
substitutions, in addition to those set forth in the above paragraphs, are
possible. Those skilled in the art will appreciate that various
adaptations and modifications of the just described preferred
embodiment can be contigured without departing fronl the scope and
spirit of the invention. 7'herefore, it is to be understood that, within the
scope of the appended claii-ns, the invention may be practiced other than
as specifically described herein.
[0040] For example, the temperature compensation was described in
the context of sensor 13. A person skilled in the art would understand
that the temperature conipensation of the invention may be applied to
other enzyme electrodes and/or other biosensors affected by
temperature change.
[0041] While certain embodiments were described in the context of
using one temperature sensing element 15 to measure the teniperature
of the sensor, those skilled in the art would appreciate the use of a
plurality of temperature sensing elements 15 that would aid in obtaining
a calibration curve for different operating conditions. For example, two
temperature sensing elements may be used to measure temperature: one
temperature sensing element measures the body teinperature (T1) while
the second temperature sensing element measures the temperature (T2)
of the infusion fluid. 'The temperature results may be calibrated and
correlated to obtain an analyte calibration curve that is compensated by
a. function of temperature ('r 1) and temperature ('I'2).
