DE9422378U1 - Biosensor measuring device with a procedure and a system for estimating the ambient temperature - Google Patents

Description

EP94 916 757.1

PCT/US 94/05321 = WO 94/29704

German translation = Gbm-Anmeldung (branch)

RD 4243/OG/DE

Biosensor measuring device with a procedure and a system &iacgr;&ogr; for estimating the ambient temperature

Field of application of the invention

The invention relates to a biosensor measuring device for determining the presence of an analyte in a biological sample, the determination being dependent on the ambient temperature, in particular to a procedure and a system for estimating the ambient temperature.

Background of the invention

Biosensor measuring devices are widely used to determine the concentration of various analytes (e.g. glucose and cholesterol) in the blood. Disposable test strips are used which have a receiving area or a reaction zone for receiving a blood sample. The analysis results obtained with such instruments depend on the ambient temperature in the area around the sample receiving area or the reaction zone. Various devices known from the prior art use external temperature sensors or attempt to regulate the temperature in the reaction zone. External temperature sensors react quickly to changes

the temperature. However, in certain circumstances this is more of a disadvantage than an advantage. For example, in a biosensor meter small enough to be held in the user's hand, a rapid change in temperature occurs when the device is placed on a table surface. This renders subsequent biochemical measurements useless until the ambient temperature is stabilized. In battery-operated biosensor meters, controlling (regulating) the temperature of the reaction zone is not practical because it requires an unacceptable consumption of electrical energy from the battery.

A number of descriptions of biosensor measuring devices are known in the art in which temperature correction is used. US Patent 5,108,564 (Szuminsky et al.) describes a biosensor measuring device which is used to measure glucose concentrations in the blood. The device is based on a reaction in which glucose in the presence of an enzyme catalyzes a reaction of potassium ferricyanide to potassium ferrocyanide. After the reaction has been completed, a voltage is applied to a reaction zone which leads to a reversal of the reaction, generating a small but measurable current flow. This current is called the Cottrell current. Depending on the concentration of glucose in the reaction zone, it follows a predetermined curve during the reverse reaction. By determining the position of the curve, a measure of the glucose concentration can be determined.

European patent application 0471986 by Tsutsumi et al. describes a blood glucose measuring system using disposable test strips. The presence of a blood sample is determined by

·· t

Resistance is measured between a pair of electrodes. In addition, a plurality of sample-like strips are used, each of which has a specified resistance value that distinguishes it from other strips. Each of these strips has a specific application purpose, i.e. it is used for adjusting the device, compensating for a measurement error, for calibration, etc.

&iacgr;&ogr; In U.S. Patent Application 07/451,309, filed December 15, 1989 (White), entitled "Biosensing Instrument and Method" , which is assigned to the assignee of the present application, a biosensing meter is described which uses the Cottrell curve to determine glucose concentration. In this patent application, a relationship between current measurements and times at which the current measurements are taken is used to determine whether the current flow through the reaction zone of a test strip actually conforms to the Cottrell relationship.

US Patent 4,420,564 (Tsuji et al.) describes a blood glucose analyzer that uses a reaction cell that includes a sensor with a fixed enzyme membrane and a measuring electrode. The Tsuji et al. system uses a number of error protection routines. One of these is determining whether the reaction is taking place within specific defined temperature limits. A second procedure determines whether a reaction current is within a predetermined range.

As far as the necessity of temperature determination is mentioned in the above-mentioned literature, temperature measurements are taken using temperature sensors.

en and these measurements are used immediately. Fluctuations in the measured temperature can cause significant variations in the biochemical measurements and lead to erroneous analysis results. However, it is of central importance that erroneous analysis results are avoided because the analysis results are of vital importance to the user and, in the event of errors, can lead to incorrect medication. Therefore, biosensor measuring devices should have facilities to avoid erroneous results caused by incorrectly determined ambient temperature measurements.

Therefore, an object of the invention is to provide a biosensor device in which a procedure and means are realized by which temperature values are determined with sufficient accuracy to ensure the determination of correct analysis results.

Another object of the invention is to provide a biosensor measuring device with a temperature sensor that is resistant to rapid temperature fluctuations due to changes in environmental conditions and yet enables the determination of accurate temperature values for determining analysis results.

Summary of the invention

A biosensor measuring device is proposed which is used to determine an analysis value in a biological sample. An algorithm for determining the analysis result is implemented in the measuring device, whereby the analysis result depends on the ambient temperature of the biological sample located in a reaction zone. The bio-

sensor meter includes a processor and a temperature sensor. The temperature sensor is positioned within the device structure. This results in a delayed response of the temperature sensor to changes in ambient temperature. The meter performs an ambient temperature estimation procedure to compensate for the delayed temperature response. It begins with the meter periodically taking temperature readings from the temperature sensor both when the meter is on and when the meter is off. When the meter is on, the ambient temperature estimation algorithm uses at least two of the most recent temperature readings and extrapolates from them to determine an estimate of the ambient temperature. When the meter is off, temperature readings are determined by the meter at first intervals, while when the meter is on, they are determined at second, shorter intervals and the temperature extrapolations only occur when the meter is on.

Description of the drawings

Figure 1 shows a perspective view of a

biosensor measuring device according to the invention; Figure 2 shows a block diagram of the electrical circuit contained in the biosensor measuring device according to Figure 1;

Figure 3 shows a curve diagram of both a

an excitation electrode of a disposable test strip used for the measuring device according to Figure 1 as well as the resulting measuring current which is applied to a measuring electrode

electrode of the disposable test strip;

Figure 4 shows a representation of a change in the ambient temperature and a resulting change in the temperature measured by a temperature sensor of the measuring device.

device according to Figure 1;

Figure 5 shows a flow chart at a high level of abstraction to illustrate the procedure used in the invention.

Detailed description of the invention

The biosensor meter 10 shown in Figure 1 has an LCD display 12, control buttons 14 and a slot 16 for receiving a disposable test strip 18. The test strip 18 has a receiving zone 20 (i.e., a reaction zone) which includes a pair of conductive electrodes 24 and 26. A layer of enzymatic reagents (not shown) overlies the electrodes 24 and 26 in the receiving zone 20 and forms a substrate for receiving a liquid containing the analyte.

The disposable test strip 18 has an opening 28 through which the distal ends of the electrodes 24 and 26 are accessible to enable electrical connection to connection contacts (not shown in Figure 1) of the biosensor measuring device 10.

A temperature sensor 30 (shown in dashed lines) is positioned in the housing of the biosensor measuring device 10. It continuously supplies temperature input signals to a microprocessor contained in the biosensor measuring device 10. The arrangement of the temperature sensor 30 within the biosensor measuring device 10 means that it is directly

ible temperature changes that occur in the environment outside the measuring device. Therefore, the temperature sensor 3 0 reacts to changes in the ambient temperature, but does so with a delay that corresponds to a multiple of a thermal time constant, the length of the time constant depending on the degree of isolation of the temperature sensor 3 0 from the environment.

 Figure 2 shows a schematic representation of the circuit in a biosensor measuring device 10, wherein a disposable test strip 18 is inserted into the slot 16. An excitation voltage source 32 supplies a variable voltage to a connection contact 34, which establishes a connection with the electrode 24 when the disposable test strip 18 is inserted into the measuring device 10. Via a connection contact 36, a current can be passed from the electrode 26 to a measuring amplifier 38, the output signal of which (a voltage) is in turn applied to an analog/digital converter (A/D converter) 40. The temperature sensor 30 also transmits its output signal to an A/D converter 42. The output signals of the A/D converters 40 and 42 are applied to a bus 44, which enables communication between the modules contained in the biosensor measuring device 10. A microprocessor 46 with an associated display unit 12 serves to control the operation of the biosensor measuring device 10. The microprocessor 46 also fulfills various timing functions with the aid of a timer 50, the use of which is explained in the following description.

The excitation voltage source 32 receives its commands from the microprocessor 46 via the bus 44 and, based on these commands, applies different values of an excitation potential to the electrode 24. In the biosensor

A ROM memory device 52 can be plugged into the meter 10. It contains non-volatile memory which stores constants and other data necessary to enable the meter 10 to perform the procedures required to determine an analyte. The ROM memory device 52 is pluggable into the top of the meter 10 as shown in Figure 1. Generally, each lot of disposable test strips 18 is supplied with a ROM memory device 52 which contains various constants which adjust the measurement parameters of the meter 10 to match the specific characteristics of the particular lot of disposable test strip 18.

In the example described here, it is assumed that the sample containing the analyte is a drop of blood in which the glucose content is to be determined. A disposable test strip for determining glucose contains the following reactants in the absorption zone 2 0: an enzyme, an electrolyte, a mediator, a film former and a buffer. The enzyme can be, for example, glucose oxidase or glucose dehydrogenase; the buffer can be organic or inorganic; the electrolyte can be potassium chloride or sodium chloride; the mediator is preferably potassium ferricyanide and gelatin and propiofin can be used as film formers. (If the test strip is intended to be used for the determination of cholesterol, the enzyme is preferably cholesterol oxidase with or without the addition of cholesterol esterase. The buffer is preferably inorganic and contains an electrolyte such as potassium chloride or sodium chloride. In this case, two mediators are used, i.e. ferricyanide and quinones, which are incorporated into a gelatin film as mentioned above.)

•♦

·

Since the chemistry for such analytical determinations is well known in the professional world, it will not be described in detail here. Suffice it to say that a glucose determination is carried out by first placing a blood sample in the sample holder 20. The glucose contained in the sample causes a forward reaction from potassium ferricyanide to potassium ferrocyanide. The forward reaction is completed within an incubation time. The subsequent application of an excitation voltage to

γ one electrode of the disposable test strip 18 causes a small current to flow through the opposite electrode, resulting from the reverse reaction of potassium ferrocyanide to potassium ferricyanide. The electron current during the reverse reaction is detected and measured at several points in order to establish that the reaction follows the Cottrell curve and also to determine the value of the Cottrell curve. This value is a measure of the glucose concentration. The resulting glucose value must, however, be corrected to take the ambient temperature into account.

In Figure 3, the excitation potentials applied by the excitation voltage source 32 to the electrode 24 are shown as curve 60. The resulting measuring current, which is determined by the measuring amplifier 38, is shown as curve 62. Initially, the excitation voltage source 32 supplies a potential value 64 to the electrode 24. When a blood sample is placed in the sample receptacle 20, this results in a current pulse 66 which indicates to the microprocessor 46 that an incubation period should begin. At this time, the excitation potential 64 is removed from the electrode 24 (potential value 68) to enable a reaction between the blood drop and the reactants. At the end of the incubation period, the voltage source 32 supplies a voltage

voltage value 70 to the electrode 24. As a result, the measuring amplifier 3 8 detects and measures a number of measured values of the current flowing through the electrode 2 6 (shown as curve 72).
5

If one assumes that the current flowing through the recording zone 2 0 follows the Cottrell relationship, the current values of the curve 72 will increase or decrease depending on the glucose concentration contained in the blood sample.

β is shifted downwards. The microprocessor 46, in conjunction with the ROM memory module 52, uses the measured values obtained on the curve 72 to determine the position of the curve 72 and derives the glucose value from this. In order to correct the glucose value determined in this way, the ambient temperature must be determined and a correction carried out. Only after this correction is the glucose value shown to the user on the display 12.

Referring to Figures 4 and 5, the temperature estimation procedure performed in the biosensor meter 10 will be described. Since it is desirable to isolate the temperature sensor 30 from rapid temperature changes, it is mounted within the biosensor meter so that it is isolated from the ambient temperature to some extent. Consequently, when the ambient temperature changes, the temperature sensor 30 begins to change its output signal accordingly, but it does not reach the actual ambient temperature until a period of time corresponding to several thermal time constants has elapsed. A thermal time constant of the biosensor meter 10 is the time required for the temperature sensor 30 to change its signal corresponding to about 60% of the temperature difference between the initial temperature . of the temperature sensor 30 and the actual ambient temperature.

In one embodiment of a measuring device constructed according to the invention, the thermal time constant is approximately ten minutes. In order for the temperature sensor 30 to make a signal change corresponding to 98% of the temperature difference between the initial temperature of the temperature sensor 30 and the ambient temperature, it is necessary to wait a period of time corresponding to four times the time constant or forty minutes - if the biosensor measuring device 10 is to wait for this condition to occur.

Of course, it is not advantageous if the user has to wait for forty minutes to obtain an accurate glucose measurement. The invention has found that accurate glucose measurements can be obtained by estimating the ambient temperature on the basis of a few temperature measurements from the temperature sensor 30. These measurements are obtained in a short period of time, typically less than one minute. In order to enable such an estimation of the temperature, at least two temperature measurements must be available for calculation by the microprocessor 46. Such a temperature measurement is referred to below as T _old and a later temperature measurement as T _new .

To avoid the user having to wait until two temperature readings have been obtained, the biosensor meter 10 is operated to take temperature readings at periodic intervals even when it is turned off. In such a turned off state, the microprocessor 46 is supplied with sufficient electrical power to obtain a temperature reading from the temperature sensor 30 every three minutes.

This temperature measurement is stored as T _new , with the previous T _new value replacing the previous T _old value stored in the RAM of the microprocessor 46. It is of course common knowledge for those skilled in the art that the time of three minutes is not critical and can be varied depending on the requirements of the measuring instrument.

When the meter 10 is subsequently turned on, the microprocessor 46 takes readings from the temperature sensor 30 every thirty seconds to obtain T _new values. The first such T _new reading after power-on is combined with the T _old reading already stored in the RAM of the microprocessor 46. On the basis of these two readings, a first extrapolation is carried out to determine T _ambient . Thereafter, further temperature measurements T _new are taken, each time replacing a T _old reading with the previous T _new reading, which becomes the T _old reading. In this way, the meter 10 can obtain T _ambient readings very quickly after power-on, on the basis of which appropriate corrections to the glucose readings can be carried out.

The illustration in Figure 4 assumes that T _ambient changes from the value 80 to the value 82. It is also assumed that the measuring device is switched off for ten minutes and then switched on. Up to the time t = 10, a temperature measurement is obtained and stored every three minutes (in the switched off state). From the time the measuring device is switched on, a temperature measurement is determined every thirty seconds and a temperature extrapolation is carried out after each time. When T _ambient changes from the value 80 to the value 82, the output signal 84 of the temperature sensor 30 begins to adapt to the new ambient.

•&iacgr; I The ** «!*«

ambient temperature (value 82) exponentially. The temperature measurements taken by the temperature sensor 30 during this time enable the microprocessor 46 to estimate T _ambient according to the following equation:

T —Ta- *· »eu ~ old ) (&Aacgr;)

i-environment ~ ^A new "·" _e mA(_j ^ '

where: m = inverse thermal time constant

of the measuring instrument (in seconds); At = time in seconds between the determination of T _new and T _old .

Referring to Figure 5, the procedure for estimating the ambient temperature carried out by the microprocessor 46 is described. When the measuring device 10 is switched off, it is determined, as represented by the decision symbol 100, whether three minutes have passed since the last temperature measurement (decision symbol 102). If the three minutes have not yet elapsed, the routine is repeated. After three minutes have elapsed, a _new measurement value T is determined (field 104).

The old temperature reading T _old is replaced by the previous T _new reading (field 106). The routine is then repeated to again determine whether the meter 10 is on or off.

As soon as the measuring device 10 is switched on, the time At that has passed since the last temperature measurement is determined and compared with a limit value that has been called up from the memory. If At is greater than the limit value (eg thirty seconds), a _new measured value T is determined and stored with the T _old measured value (field 110).

If the time difference At is smaller than the limit, the routine is repeated until a corresponding time interval has elapsed.

The comparison limit At explained above serves to prevent the microprocessor 46 from carrying out extrapolations based on temperature measurements that were determined too close together in time. Such measurements could lead to significant errors and thus

Î can spoil the temperature estimate. As can be seen from equation A, the value of e ^At approaches unity as the value of At decreases. Consequently, for very small At the factor l/(e ^mAt -l) becomes large. Small errors in the measured values of T _new and T _ale are multiplied by this factor. This leads to an erroneous deviation in the finally determined value of T _Uragebung .

After a _new temperature measurement T has been determined, part of equation A is calculated as follows (field 112):

(B)

-l

Once equation B has been calculated, it is determined whether the difference between the newly measured temperature T _new and the old temperature T _old is less than a temperature limit value aT (decision symbol 114). The limit value aT is taken from the ROM memory chip 52. If the values of T _new and T _old are very close to each other, the estimation algorithm could detect a significant temperature change, although in reality the difference may only be due to noise. Therefore, the difference between T _new and T _old is compared with a temperature limit value aT taken from the ROM memory chip 52. If

·

·

the temperature difference is greater than the Δ�T limit, it is appropriate to perform the full temperature estimation. On the other hand, if the difference between the temperature readings is less than the Δ�T value taken from the ROM memory device 52, it is assumed that the temperature readings are substantially the same and that no temperature change has occurred during the entire period Δt (indicating that the measuring device 10 is probably in equilibrium). Therefore, it is not necessary to perform an estimation and the T _new reading can be used as the new value for the ambient temperature.

If, however, the temperature difference between T _new and T _old is equal to or greater than the Δ�T limit, equation (C) is calculated as shown in box 118:

^T Uir,um ~ ^T new + [ ( ^T new ~ ^T old) ^X1 1 ( ^C )

Equation (C) enables a new estimate of T _ambient to be determined. The previously stored value of ^T ambient is then replaced by the new value (field 120). The new T _ambient value is then compared with an operating range limit value taken from the ROM memory device 52 (decision symbol 122). If T _ambient is not within suitable operating range limits, the analysis is aborted (field 124). If T _ambient is within suitable operating range limits, the T _ambient value is used to temperature compensate the glucose measurement (field 126). The operating range limits are the limits of the temperature correction algorithm (eg between 18 ⁰ C and 32°C).

It should be understood that the foregoing description is only an example of the invention. Numerous alternatives and modifications will be apparent to those skilled in the art without departing from the invention. For example, while two A/D converters 40 and 42 are shown in Figure 2, a single A/D converter for both inputs will work just as well. Accordingly, the invention is directed to all alternatives, modifications and variations that come within the scope of the appended claims.

Claims (9)

1. Biosensor measuring device for determining an analysis value of an analyte in a biological sample, wherein the determined analysis value depends on the ambient temperature in the vicinity of the biological sample, the biosensor measuring device has a processor and a temperature sensor, the temperature sensor is positioned in the measuring device and thereby reacts with a delay to changes in the ambient temperature and the measuring device carries out a temperature estimation procedure under the control of the processor with the aim of compensating for the delayed reaction, and wherein the procedure includes the following steps: a) periodic determination of temperature measurement values of the temperature sensor both when the biosensor measuring device is switched on and when it is switched off and b) Estimating the ambient temperature using at least two of the most recent temperature readings when the biosensor meter is in the powered-on state. 2. The procedure of claim 1, wherein in step b) the ambient temperature is estimated using the two most recent temperature measurements and extrapolating therefrom to determine the ambient temperature estimate. 3. The procedure of claim 2, wherein the temperature measurements are determined at first intervals when the biosensor meter is turned off and at second, shorter intervals when the meter is turned on, and the biosensor meter uses a temperature measurement obtained when the meter is turned off and a temperature measurement obtained when the device is turned on in determining at least one temperature estimate. 4. A procedure according to claim 1, wherein the estimating step is performed only when a difference between the two most recent temperature readings exceeds a threshold, wherein a most recent temperature reading is used as the ambient temperature if the threshold is not exceeded. 5. A procedure according to claim 1, wherein the estimation step includes an extrapolation based on the two most recent temperature measurements T _old and T _new to determine T _ambient using the following formula:


where: m = inverse thermal time constant of the measuring device (in seconds);
Δt = time in seconds between the determination of T _new and T _old . 6. A procedure according to claim 5, wherein T _old is determined when the measuring device is in the off state and a T _new value is determined after the measuring device has been brought into the on state, comprising the following additional steps:
Determination of the time interval between the determination of the values of T _old and T _new ;
Comparing the time interval with a time limit; and
Neglect the T _new measurement value if the time interval is not at least as large as the time limit. 7. Procedure according to claim 5, comprising the following additional steps:
Determination of a temperature difference value between T _new and T _old ;
Comparing the temperature difference value with a temperature difference limit value; and
Use the Tnew measurement value as the new _Tambient value if the temperature difference value is less than the temperature difference limit, assuming that the biosensor meter is at a stable temperature. 8. The procedure of claim 7, wherein the biosensor meter has a pluggable ROM chip and wherein the temperature difference limit is taken from the pluggable ROM chip. 9. A procedure according to claim 5, wherein the biosensor measuring device is arranged to operate only when T _ambient is within predetermined operating temperature limits.