CN101541239A

CN101541239A - Temperature compensation for enzyme electrodes

Info

Publication number: CN101541239A
Application number: CNA2007800425419A
Authority: CN
Inventors: T·菲耶尔德; M·J·希金斯; K·库里; P·卡林
Original assignee: Edwards Lifesciences Corp
Current assignee: Edwards Lifesciences Corp
Priority date: 2006-11-16
Filing date: 2007-11-16
Publication date: 2009-09-23
Also published as: WO2008076574A2; WO2008076574A3; CA2667243A1; EP2088927A2

Abstract

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 measurement between the current generated and a reference current at the operating temperature, determining an enzyme concentration corresponding to the measured current, and calibrating the enzyme concentration to compensate for the deviation in measurement.

Description

Temperature compensation of enzyme electrodes

In accordance with 35U.S.C. § 119 priority requirements

【0001】 This application claims priority to U.S. provisional patent application No. 60/859,586 entitled "temperature compensation of enzyme electrodes" filed on 16.11.2006, which is assigned to the assignee hereof and hereby expressly incorporated herein by reference.

Background

1. Field of the invention

【0002】 The present invention relates generally to enzyme electrodes. More particularly, the invention relates to temperature compensation of enzyme electrodes.

2. Description of the related Art

【0003】 When diabetics control their blood sugar (glucose), they are more likely to live and remain healthy. They can monitor and detect glucose in blood using prior art glucose monitoring systems, such as current glucose meters. Glucose monitoring systems are designed to control amperometric biosensors in static and stable environments such as medical laboratories. The amperometric biosensor may be coated with a chemical, such as glucose oxidase, dehydrogenase, or hexokinase, which binds to glucose in the blood sample. Some sensors measure the amount of current in the blood sample produced by the sensor, while others measure the amount of light reflected therefrom. These measurements are further analyzed and quantified by a glucose monitoring system to determine the glucose level in the blood sample.

【0004】 Recently, new sensors capable of being inserted percutaneously into subcutaneous tissue have been introduced into the market. These sensors provide continuous or near continuous glucose concentration readings, thus allowing patients to better control their glucose levels.

【0005】 To provide an actual measurement at a particular temperature, the biosensor is calibrated. FIG. 1 is a graph illustrating the relationship between the glucose level in a blood sample and the current measured by a biosensor at different temperatures. The measurements obtained from the biosensor are dependent on the temperature of the environment. If the ambient temperature changes, errors in the measurements may occur. 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 calculated glucose level is lower than the actual glucose level. Conversely, if the slope decreases, the calculated glucose level is higher than the actual glucose level. Thus, changes in ambient temperature produce errors in the calculated glucose level.

【0006】 Fig. 2 is a graph illustrating the change in current as a function of temperature. Data from prior art glucose monitoring systems were measured at four different glucose concentrations over a temperature range of 32 ℃ to 41 ℃. The current is normalized to 1 at 37 ℃. As shown for different glucose concentrations, an increase in temperature increases the current measured by the biosensor, thus providing an inaccurate measurement of the glucose level in the blood. The resulting Error is illustrated in the Clark Error grid (Clark Error grid) of fig. 3. The grid shows the comparison of the glucose measurement without temperature compensation with the true glucose concentration value.

【0007】 As is well known in the art, zone a represents a clinically accurate measurement. Region B represents measurements that deviate by more than 20% from the reference glucose level, but which result in no or no risk of treatment. Region C represents measurements that deviate by more than 20% from the reference glucose level and which may cause unnecessary corrective treatment errors. Region D represents a potentially dangerous measurement due to the failure to detect a glucose level outside the desired target range and not being treatable. Finally, region E represents measurements that lead to erroneous treatment. As shown in the clark error grid of fig. 3, some of the error measurements are near region B, and thus deviate by more than 20% from the reference. Therefore, when temperature compensation is not applied, there is a large error.

【0008】 There are many factors that can affect the change in temperature around the sensor. As the sensor is inserted into the body through a catheter, the temperature of the body can affect the sensor readings. The body temperature may be higher or lower than the temperature at which the sensor is calibrated. The sensor may also be affected by room temperature prior to insertion into the body. Also, the injection of fluid through a lumen in the catheter may have an effect on the measurements of the sensor. The fluid may have a different temperature than the human body and therefore may affect the sensor readings during fluid infusion.

【0009】 Depending on the location of the sensor and the configuration of the device in which the sensor is located, a temperature change may cause the sensor to produce a changing current for the same glucose concentration, thereby invalidating the calibration curve. This can result in the accuracy of these sensors being unacceptable for clinical use and potentially dangerous for guiding therapy.

【0010】 Previous solutions include drawing a blood sample and measuring glucose levels in an isolated static environment with a constant temperature. Another prior art method involves drawing a sample of blood past the sensor and recirculating the blood back to the patient. These solutions do not compensate for temperature changes; they would rather seek the possibility of avoiding temperature changes.

【0011】 As the need for improved glucose monitoring systems increases, there is a need in the art for temperature compensation of sensor electrodes to provide reliable measurements despite any change in ambient temperature.

Summary of The Invention

【0012】 The present invention meets this need by providing an enzyme electrode temperature compensation method by measuring an operating temperature of an enzyme electrode, measuring a current generated by the enzyme electrode, determining a temperature deviation between the operating temperature and a reference temperature, determining a glucose concentration corresponding to the measured current at the operating temperature, and compensating for the glucose concentration measurement caused by the temperature deviation.

【0013】 In one embodiment, temperature compensation may be achieved by using a calibration curve that corrects for current changes due to temperature changes. With temperature compensation for enzyme electrodes having linear or near-linear characteristics

For electrodes with non-linear characteristics, either an "absolute" or "relative" calibration curve may be determined.

Brief Description of Drawings

【0014】 The exact nature of this invention, as well as its objects and advantages, will become readily apparent from consideration of the following specification in conjunction with the accompanying drawings; in the drawings, wherein like reference numerals refer to like parts throughout the several views:

【0015】 FIG. 1 is a graph illustrating the relationship between the glucose level in a blood sample and the current measured by a biosensor at different temperatures.

【0016】 FIG. 2 is a graph illustrating the change in current as a function of temperature at different glucose concentrations.

【0017】 FIG. 3 is a Clark error grid illustrating prior art glucose measurements compared to true glucose concentration values without temperature compensation.

【0018】 FIG. 4 is a diagram illustrating a catheter having a temperature element included for temperature compensation purposes.

【0019】 Fig. 5 is a cross-sectional view of the catheter of fig. 4 along line 5-5.

【0020】 Fig. 6 is a cross-sectional view of the catheter of fig. 4 along line 6-6.

【0021】 Fig. 7 is a graph illustrating temperature change as a function of time.

【0022】 FIG. 8 is a graph illustrating glucose concentration measurements with and without temperature compensation as a function of time with respect to true glucose level when the sensor experiences a change in temperature as shown in FIG. 7.

【0023】 FIG. 9 is a Clark error grid illustrating a comparison of glucose measurements with temperature compensation to true glucose concentration values.

【0024】 FIG. 10 is a cross-sectional view of a sensor having a temperature compensation element.

Detailed Description

【0025】 Sensor electrodes operable in environments with varying temperatures are provided. The sensor provides glucose measurements with acceptable accuracy for the clinical setting (clinical setting), particularly to guide treatment. Such sensors may be used in access devices, such as catheters, for venous and arterial environments. The conduit may be arranged to allow injection of fluid. The fluid may be injected into the body at a temperature different from body temperature.

【0026】 Fig. 4 illustrates an example of a catheter 11, such as a glucose monitoring catheter. Fig. 5 is a cross-sectional view of the catheter 11 of fig. 4. Fig. 10 is a cross-sectional view of a sensor (e.g., an enzyme electrode or a glucose electrode or sensor) with a temperature sensing device or temperature compensation element 15. The catheter 11 has at least one opening 12 exposing one or more sensor electrodes 13. In one embodiment, located below the sensor electrodes 13 is a temperature sensing device, such as a thermistor 15, which is held in place by an adhesive or filler material 16, as shown in fig. 6. Catheter 11 also has one or more channels, such as lumen 17, along its length for infusing fluid into the blood. The flow of fluid in the channel 17 of the conduit 11 can have an effect on the measurement of the sensor. The fluid may have a different temperature than the human body and therefore may affect the reading of the sensor 13 during fluid infusion.

【0027】 The current generated by the sensor electrode 13 for a particular analyte concentration is based on a number of factors. For example, it depends on the enzyme concentration and the diffusion rate through the membrane, e.g. polyurethane, hydrogenated polymer or gel membrane, housing or encapsulating the electrode. The turnover rate of the enzyme and the diffusion rate through the membrane are typically temperature dependent. Although the purpose of the sensor electrodes 13 is to generate a known amount of current for a known concentration of analyte, small temperature variations can introduce measurement errors. Typically, the error range resulting from temperature variation is from 2% to 7%.

【0028】 One way to mitigate the error introduced by temperature variations is to control the temperature of the sensor 13 and/or the solution containing the analyte of interest such that the temperature remains constant. However, when a sensor is incorporated into the catheter 11, it is not feasible to control the temperature of the sensor 13 and/or the solution. For example, changes in body temperature or the temperature and/or rate of infusion fluid can affect sensor readings. Therefore, temperature compensation is necessary in order to obtain accurate measurements. The catheter 11 may be an intravascular catheter.

【0029】 A temperature compensation or sensing element 15 (e.g., a thermistor or trace silver or any device whose resistance changes with temperature) may be attached to the sensor 13, disposed adjacent to the sensor 13, co-disposed on the same plane or film as the sensor 13, integral with the sensor 13 itself, attached to a device in which the sensor 13 is located, placed adjacent to the sensor 13, placed in a location that is representative of the temperature surrounding the sensor 13, or placed in a location that tracks changes in the temperature surrounding the sensor 13. The temperature sensing element 15 and/or the sensor 13 may be placed inside the catheter 11. Temperature sensing element 15 measures the temperature at sensor 13 to compensate for blood or infusate (infusion) traveling through 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., infusate). In internal conditions, it may also be necessary to calculate the infusion rate. In one embodiment, the temperature sensing element 15 directly measures the temperature of the sensor 13 in contact with the blood stream.

【0030】 Preferably, the temperature sensing element 15 may be isolated from the injection fluid using an insulating structure, as disclosed in U.S. patent publication No. 2002/0128568, which is incorporated herein by reference. Various insulating cavities 17 and insulating films may be used to isolate the temperature sensor element 15 from the injection fluid that might otherwise degrade the accuracy of the temperature measurement.

【0031】 Temperature compensation can be achieved by using a temperature compensation element that corrects/calibrates for errors in the current measurement due to temperature changes. Under predetermined operating conditions, the effect of temperature on the calibration curve of the temperature compensation element may be an increase in first order terms (first order term) at higher temperatures and a change in offset. For electrodes 13 having linear or near linear characteristics, the first order term is the slope. Thus, the temperature compensation for an electrode 13 having a linear or near linear characteristic can be expressed by the following equation:

correction factor Δ T · T_coeffSlope of

(1)

Wherein,

Δ T is a temperature change compared to the temperature at which the electrode 13 is calibrated;

T_coeffis the temperature coefficient (change in slope per degree); and

the slope is the change in analyte concentration divided by the change in current.

【0032】 Equation (1) applies to a glucose electrode 13 having a linear or near linear characteristic, in which case no fluid is injected through the catheter in the temperature range where the correction factor remains linear or near linear with temperature. However, the calibration curve may also be used for sensors 13 having non-linear characteristics, in which case fluid is injected into the body through a lumen 17 in the catheter 11.

【0033】 An "absolute" or "relative" calibration curve may be determined for a glucose electrode 13 having a non-linear characteristic. For an "absolute" calibration curve, a correction factor or calibration curve is determined at a particular measured temperature, while for a "relative" calibration curve, a calibration factor is determined based on a temperature change compared to the temperature at which the electrode 13 is calibrated and/or another reference temperature.

【0034】 The temperature of the area or solution around the sensor 13 or the temperature of the device to which the sensor is attached is measured by the temperature sensing element 15 in accordance with a temperature compensation method for glucose electrodes having linear or non-linear characteristics. Based on previous measurements, a single calibration curve at the time of measuring the temperature is predetermined. As the temperature changes-due to the injection of fluid, for example, some of the calibration curves may be replaced so that each reflects the current generated as a function of analyte concentration at the measurement temperature.

【0035】 According to another temperature compensation method for glucose having linear or non-linear characteristics, the temperature deviation from the temperature at which the electrode 13 is calibrated is measured by the temperature sensing element 15. Based on the deviation, the calibration curves may be replaced such that each reflects the current generated as a function of the analyte concentration at the measurement temperature.

【0036】 To better illustrate the effect of the calibration curve on glucose measurements, exemplary in vitro experiments are described with and without temperature compensation. The temperature of the area or solution surrounding the sensor 13 or the temperature of the device to which the sensor is attached varies over time from 30 ℃ to 42 ℃, as shown in fig. 7. After a predetermined period, the glucose concentration is increased by about 100 mg/dl about every 40 minutes.

【0037】 Fig. 8 is a graph illustrating the change in glucose concentration over time. As shown in fig. 8, the solid line illustrates the true glucose concentration at a specific time, the dotted line represents the glucose concentration measured without temperature compensation, and the dotted line represents the glucose concentration measured with temperature compensation. The form of temperature compensation used in fig. 8 is:

(2)

wherein the slope is the change in glucose concentration divided by the change in current;

the current is the current generated by the sensor 13;

T_coeffis the temperature coefficient of the sensor(s);

T_calis the temperature at which the sensor 13 is calibrated; and

t is the temperature of the electrode 13 measured with the temperature sensing element 15.

【0038】 Without temperature compensation, there is a large error in the measured glucose value. However, using equation (2) with temperature compensation, the measured glucose values form a straight line, quite close to the true glucose values. The clark error grid illustrated in fig. 9 shows the comparison of the glucose measurement with temperature compensation to the true glucose concentration value. The clark error grid of fig. 9 shows a significantly smaller error in measured glucose concentration when compared to the clark error grid of fig. 3. The measured glucose concentration with temperature compensation is clinically accurate (region a), the measurement is close to the reference glucose level.

【0039】 Although a few exemplary embodiments have been described and shown in the accompanying drawings, it is to be understood that such embodiments are merely illustrative of and not restrictive on the broad invention, and that this invention not be limited to the specific constructions and arrangements shown and described, since various other changes, combinations, omissions, modifications and substitutions, in addition to those enumerated in the foregoing paragraphs, are possible. Those skilled in the art will appreciate that various modifications and changes to the just described preferred embodiments can be made without departing from the scope and spirit of the invention. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

【0040】 For example, temperature compensation is described in the context of sensor 13. It will be appreciated by those skilled in the art that the temperature compensation of the present invention can be applied to other enzyme electrodes and/or other biosensors that are affected by temperature changes.

【0041】 Although some embodiments are described in the context of measuring sensor temperature using one temperature sensing element 15, it will be appreciated by those skilled in the art that the use of multiple temperature sensing elements 15 may facilitate obtaining calibration curves for different operating conditions. For example, two temperature sensing elements may be used to measure temperature: one type of temperature sensing element measures body temperature (T1), while a second type of temperature sensing element measures the temperature of the injected fluid (T2). The temperature results may be calibrated and correlated to obtain an analyte calibration curve compensated by a function of temperature (T1) and temperature (T2).

【0042】 Additionally, while the examples included herein illustrate temperature correction factors that depend only on the constant temperature coefficient and temperature, one skilled in the art will recognize that temperature coefficients and/or correction factors that depend, for example, on estimated or measured glucose concentration, oxygen tension, and/or pH are also part of the same invention.

Claims

1. An apparatus for compensating for temperature, comprising:

a catheter having a generally tubular body defining an opening, and a lumen disposed adjacent the opening;

a sensor disposed in the opening for generating an electrical current; and

a temperature sensing device disposed in the cavity for determining a temperature of an area adjacent the sensor and for compensating an output of the sensor.

2. The device of claim 1, wherein the catheter is selected from the group consisting of a glucose monitoring catheter and an intravascular catheter.

3. The device of claim 1, wherein the sensor is selected from the group consisting of an enzyme electrode and a glucose electrode.

4. The apparatus of claim 1, further comprising a material for housing the temperature sensing device in the cavity.

5. The apparatus of claim 1, wherein the temperature sensing device is a thermistor.

6. The device of claim 1, further comprising a passageway disposed adjacent the cavity for passing a fluid.

7. The device of claim 1, further comprising a membrane for housing the sensor.

8. The device of claim 7, wherein the film is selected from the group consisting of polyurethane films, hydrogenated polymer films, and gel films.

9. A catheter for insertion into a body, the catheter comprising:

a sensor for generating a signal responsive to a concentration of an analyte in a body; and

a temperature compensation element for determining the temperature of an area adjacent the sensor and for compensating the output of the sensor.

10. The catheter of claim 9, wherein the sensor is selected from the group consisting of an enzyme electrode and a glucose electrode.

11. The catheter of claim 9, wherein the temperature compensation element is a thermistor.

12. The catheter of claim 9, further comprising a membrane for housing the sensor.

13. The catheter of claim 12, wherein the membrane is selected from the group consisting of a polyurethane membrane, a hydrogenated polymer membrane, and a gel membrane.

14. An apparatus for compensating for temperature, comprising:

a catheter body, generally tubular, defining an opening;

a sensor disposed in the opening for generating a current responsive to an analyte concentration; and

a temperature sensing device positioned adjacent to the sensor for determining a temperature of an area adjacent to the sensor and for compensating an output of the sensor.

15. The device of claim 14, wherein the sensor is selected from the group consisting of an enzyme electrode and a glucose electrode.

16. The apparatus of claim 14, further comprising a material for housing the temperature sensing device in the opening.

17. The apparatus of claim 14, wherein the temperature sensing device is a thermistor.

18. The apparatus of claim 14, further comprising a passageway disposed adjacent the temperature sensing device for communicating a fluid.

19. The device of claim 14, further comprising a passageway disposed adjacent the sensor for passing fluid.

20. The device of claim 14, further comprising a film for coating the sensor.

21. The device of claim 20, wherein the film is selected from the group consisting of a polyurethane film, a hydrogenated polymer film, and a gel film.

22. A method of temperature compensation of an electrode, comprising:

measuring a reference current;

measuring an electrode current received from the electrode;

determining a difference between the reference current and the electrode current;

determining an enzyme concentration corresponding to the electrode current; and

adjusting the enzyme concentration based on a difference between the reference current and the electrode current.

23. The method of claim 22, further comprising measuring an operating temperature of the electrode.

24. The method of claim 22, wherein the enzyme concentration is determined using the following formula:

wherein,

the slope is a predetermined characteristic of the electrode;

the current is the current generated by the electrode;

T_coeffis the temperature coefficient of the electrode;

T_calis the temperature at which the electrode is calibrated; and

t is the operating temperature of the electrode.

25. A method of temperature compensation of an enzyme electrode comprising:

measuring the working temperature of the enzyme electrode;

measuring the current produced by the enzyme electrode;

determining a measured deviation between the measured current and a reference current at the operating temperature;

determining the enzyme concentration corresponding to the measured current; and

the enzyme concentration was calibrated to compensate for the deviation in the measurement using the following relationship:

wherein,

the slope is a predetermined characteristic of the electrode;

the current is the current produced by the enzyme electrode;

T_coeffis the temperature coefficient of the enzyme electrode;

T_calis the temperature at which the enzyme electrode is calibrated; and

t is the working temperature of the enzyme electrode.