CN1497256A

CN1497256A - Non-invasive method for monitoring blood sugar and its device

Info

Publication number: CN1497256A
Application number: CNA031581420A
Authority: CN
Inventors: 王湘生
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-09-19
Filing date: 2003-09-12
Publication date: 2004-05-19

Abstract

A gegenionic electromosis equipment with a single-chip microprocessor for continuously monitoring blood sugar at intervals of 20 min for 12 hr without incision is disclosed. Its monitoring method includes such steps as penetrating a very-low current through skin to sample the glucose on a gel tray containing the glucose oxidase, inverting the glucose to hydrogen peroxide by said glucose, oxidase, detecting the hydrogen peroxide by a biosensor to generate an electric signal, and determining the concentration of blood sugar according to the signal intensity which is proportional with the concentration of blood sugar. Its advantages are high correctness and automation level, no pain and simple operation.

Description

Method and device for non-invasive blood sugar monitoring

Technical Field

The invention relates to a blood sugar monitoring method and a device thereof for meta-trauma, in particular to a non-invasive blood sugar monitoring method and a device thereof adopting a reverse iontophoresis technology

Background

In recent years, "diabetes control and complications test" (DCCT) conducted in the united states and canada and prospective diabetes research (UKPDS) in the united kingdom showed that good blood glucose control, whether of type one or type two, could reduce the occurrence of diabetic retinopathy, kidney and neuropathy; there is also a trend towards a reduction in macrovascular diseases such as myocardial infarction, angina pectoris, stroke or peripheral vascular disease. Complications arising from poor glycemic control in the United states cost approximately one billion medical expenses per year, and thus the American Diabetes Association (ADA) recommends glycemic control at 80-120mg/dl before meals, 100 mg/dl before bedtime, and<7.0% glycated hemoglobin (HbA1 c). However, strict glycemic control increases the chance of hypoglycemia by 3 times, and it is important to track and assess diabetes control through self-blood glucose monitoring (SMBG). In the prior art, the way of detecting blood sugar is mainly invasive, so that the willingness and frequency of detection of patients are often reduced due to pain, and people are always researching and developing noninvasive blood sugar monitoring devices. The current noninvasive blood glucose monitoring device is actually a spectrum analyzer: the blood sugar is measured by near infrared rays without taking blood. However, it is susceptible to physical factors such as moisture, fat, skin, muscle, bone, drugs, hemoglobin concentration, body temperature, nutritional status, etc., and is subject to frequent calibration and poor repetition.

Disclosure of Invention

It is therefore a first object of the present invention to provide a method and apparatus for non-invasive measurement of blood glucose, which method and apparatus have a good stability.

The second purpose of the invention is to provide a full-automatic blood sugar monitoring method and device.

The third purpose of the invention is to develop a high-precision digital blood sugar monitoring method and device.

To achieve the above object, the present invention provides a blood glucose monitoring method and apparatus. The device passes a very small current through the intact skin and the glucose sample is collected on a gel tray for measurement. The gel tray contains glucose oxidase which can convert glucose into hydrogen peroxide; the biosensor measures the hydrogen peroxide produced and produces an electrical signal whose intensity is proportional to the patient's blood glucose concentration.

In order to achieve the purpose, the invention provides a micro-electronic device of a single chip microcomputer, blood sugar is monitored once every 20 minutes, the continuous monitoring can be carried out for 12 hours, the blood sugar value can be set to be alert, and if the blood sugar value is too high or too low, an alarm can be automatically sent out. The blood glucose measurement value drops too quickly and the meter will automatically sound an alarm. The patient may also use his or her settings for insulin injection, meals, exercise, sleep and wake-up times.

Compared with the prior device for self-monitoring blood sugar, the invention has the advantages that: has no wound, blood and pain, and can be used repeatedly. The method is automatic, accurate, simple to operate and self-service.

Drawings

FIG. 1 is a schematic diagram of a non-invasive blood glucose monitor of the present invention;

FIG. 2 is a block diagram of a non-invasive blood glucose monitor according to an embodiment of the present invention;

FIG. 3 is a diagram of a reverse iontophoretic gel disk for a non-invasive blood glucose monitor according to an embodiment of the present invention; and

fig. 4 is a block diagram of a microelectronic device of a single-chip microcomputer of the noninvasive blood glucose monitor according to an embodiment of the present invention.

Detailed Description

Fig. 1 is a block diagram of a non-invasive blood glucose monitor of the present invention. As shown in FIG. 1, the monitor of the present invention comprises a power supply 1-4 having two electrodes A and B, and reverse iontophoresis is achieved by applying a voltage to the skin 1-9 using the power supply 1-4, and the basic principle is that ions permeate out of the skin surface after a certain voltage is applied to the skin and a certain current is generated, glucose molecules in the permeated ions are absorbed by a gel disk containing glucose oxidase, and the glucose molecules are oxidized by the glucose oxidase to become glucose acid (glucose acid) and hydrogen peroxide, i.e., glucose oxidase

During this 7 minute period, with platinum at (-0.3) - - - - (-0.8) V relative to the Ag-Agcl electrode, the platinum sensor was activated and hydrogen peroxide decomposed into one oxygen molecule, two hydrogen ions and two free electrons, i.e., two hydrogen ions and two free electrons

This process is referred to as the "sensor activation" process.

Thus, as can be seen from the reaction formula, the number of glucose molecules can be indirectly measured by measuring any one of oxygen, hydrogen ions or electrons. In the present invention, this is done by measurement of electrons (current).

In a further preferred embodiment of the invention, the voltage applied to the skin by the power supply 1-4 is alternated in order to further increase the stability and accuracy of the measurement, thus avoiding a reduction of glucose molecule extravasation due to adaptation of the skin to electroosmosis.

A preferred embodiment of the present invention is described below with reference to fig. 2. As shown in FIG. 2, the output terminals of the power supplies 1-44 are input to a regulator circuit, preferably under the control of the control/processing modules 1-7. In other cases, the voltage regulator circuit 1-3 may not be needed if the output of the power supply 1-44 itself is sufficiently stable. The output end of the voltage stabilizing circuit is input to a polarity reversing circuit 1-2, so that the polarities of the electrodes A and B can be reversed. Preferably, the polarity inversion circuit is an H-bridge switching circuit, and the four switches of the H-bridge switching circuit are controlled to not only invert the polarity but also generate a zero output (equivalent to turning off the power supply). Under the control of the control/processing circuit, the polarity converter 1-2 can be used to change the polarity of the two electrodes or switch off. In one embodiment of the present invention, power sources 1-44 are lithium battery power sources. In the working process, for example, at the zero moment, the electrode A is a positive electrode, the electrode B is a negative electrode, and after 3 minutes, the power supply is turned off and the sensor is activated to measure; after 7 minutes of measurement, the electrode A is used as a negative electrode, and the electrode B is used as a positive electrode to perform reverse iontophoresis again; turning off the power supply to activate the sensor for measurement after 3 minutes of reverse iontophoresis; after 7 minutes of measurement, a new cycle can be carried out or ended. Thus every 10 minutes is a measurement period. The power supply 1-44 applies direct current to skin 1-9 via A, B electrodes, the current is about 0.3mA, the voltage is 0.3-0.8V, when the skin surface PH is neutral, the molecules of CI-, uric acid and ascorbic acid move to the positive pole, the glucose molecules 1-10 move to the negative pole along with Na +, which is called as reverse iontophoresis. Gel trays 1-6 are provided adjacent the ion inducing electrodes, and in one embodiment, between the electrodes and the skin. The gel tray 1-6 contains glucose oxidase, and glucose molecules which are produced by reverse iontophoresis are absorbed by the gel tray 1-6 between the ion-inducing electrode and the skin, and are oxidized by glucose oxidase to become gluconic acid (glucose acid) and hydrogen peroxide, and the reaction process is as described in the above reaction formula.

It is also clear from the above equation that if the amount of hydrogen peroxide (or electrons) is measured, the number of glucose molecules can be calculated, and the relative concentration of blood glucose can be easily known. Since the relationship between hydrogen peroxide (electrons) and blood glucose concentration can be obtained by counting a large number of people, the concentration of blood glucose can be known by measuring the amount of hydrogen peroxide (electrons).

The control/processing circuit 1-7 is electrically and physically connected with the sensor device 1-5 and the gel tray 1-6. The gel pads 1-6, by applying a voltage between the platinum electrode (-) and the Ag-AgCl (+), move the electrons to generate a current, which is amplified and processed to be displayed on the displays 1-8. In a preferred embodiment, the measurement can be integrated without stopping the measurement within a measurement time of 7 minutes. If necessary, 2 or more cycles may be measured, thereby improving accuracy. In a preferred embodiment, 2 cycles are measured, which takes about 20 minutes.

FIG. 3 is a structural relationship of an electrode for reverse iontophoresis of a blood glucose monitor and a gel disk according to a preferred embodiment of the present invention. In one embodiment of the invention, the tray contains agar, glucose oxidase and NaCl, pH neutral, as shown in FIG. 3. The A ion induction electrode 2-1 and the B ion induction electrode 2-4 are Ag-AgCl electrodes with the width of 1 mm and are round, and gel discs 1-6 cover the electrodes. It should be ensured that the gel tray 1-6 has a good contact with the skin 1-9 during use. The gel tray 1-6 is preferably covered on the skin facing side of the electrodes, which also facilitates the replacement of the gel tray. As shown, the A gel tray 2-2 and the B gel tray 2-3 are preferably two separate, independent, circular gel trays insulated from each other. The distance between the two Ag-AgCl electrodes is 1-4 cm, preferably 2-3 cm. The gel plate A2-2 and the gel plate B2-3 are two mutually insulated circular gel plates. The ion inducing electrodes 2-1, 2-4 surrounding the periphery thereof are mounted on the same base, and the leads thereof are soldered to the base. The base 2-5 is made of a glass fiber printed circuit board, called glucose molecule collection layer. The platinum electrode of the A sensor 2-7 was inserted into the 2-2 gel layer, the platinum electrode of the B sensor 2-8 was inserted into the 2-3gel layer, and the reference electrode was Ag-AgCl (note that the reference electrode was used as a counter iontophoresis electrode during the counter iontophoresis process).

In the reverse iontophoresis process, a voltage is applied between two Ag-AgCl electrodes, so that the two electrodes, the gel pads 1-6 under the electrodes and the skin 1-9 are connected in series to form a passage, and a small current flows in the passage. The glucose that is counter-iontophoresed out is collected in a gel tray under the electrodes.

In the measuring process, a potential can be applied between the platinum electrode and the Ag-AgCl electrode, so that the potential difference of the platinum electrode relative to the Ag-AgCl electrode is from minus 0.3V to minus 0.8V. Thus, under the catalytic action of platinum and the oxidation action of glucose oxidase, glucose molecules are oxidized into hydrogen peroxide and then hydrogen ions and electrons are generated.

The specific measurement process is as follows:

the A iontophoresis electrifying time is 3 minutes, the A sensor is activated for 7 minutes, the B iontophoresis electrifying time is 3 minutes, and the B sensor is activated for 7 minutes. The results of the two or more acquisition electrons are added and displayed on a display via a control/processing device. The activation time of the counter-iontophoresis and the sensor can obviously be adjusted as long as it is ensured that sufficient glucose molecules are iontophoretically eluted and that the glucose molecules are sufficiently oxidized.

At a certain time, A is a positive electrode and B is a negative electrode. The next time, A is the negative and B is the positive, polarity was changed every 10 minutes. The electrodes act on the skin 1-9 with a distance of 2-3 cm, the skin in the interval is covered with a gel tray 1-6, glucose molecules 1-10 attracted by the negative electrode are oxidized by the gel tray 1-6, generated electrons are detected by a platinum electrode of a sensor, the output end of the sensor is connected with a control/processing device 1-7, the glucose is displayed on a display 1-8 after amplification, digitization and calculation, and the control/processing device 1-7 is connected with the display 1-8.

The measurement can be performed in other manners, for example, a capacitor is charged with a predetermined amount of electricity, the charged capacitor is connected between a platinum electrode and an Ag-AgCl electrode, and the amount of electricity remaining on the capacitor is measured after a certain period of time, so that the amount of electricity in the gel tray can be measured, and the measurement accuracy experiment of this manner shows that the amount of electricity is the highest.

Another measurement method is to add a voltage between the platinum electrode and the reference electrode and connect a resistor in series, and by measuring the voltage on the resistor, the magnitude of the current can be known and the blood glucose concentration can be calculated.

In summary, various prior art methods of measuring the electrical quantity (concentration of ions) in the gel tray can also be used without departing from the scope of the present invention.

Fig. 4 is a one-chip microcomputer microelectronic device of a blood glucose monitor implemented according to the present invention. As shown in FIG. 4, it comprises a sensor 3-1, an amplifier 3-2, a single chip 3-3, a latch 3-4, a real-time clock 3-5, a program memory 3-6, a data memory 3-7, a reset circuit 3-8, a key 3-9, and a display 3-10. The single chip 3-3 contains A/D converter and CPU sensor including platinum electrode and Ag-AgCl electrode and connected acquisition circuit, and the amplifier is low noise and high sensitivity amplifier.

The sensor 3-1 is connected to the amplifier 3-2, the latter sends the analog signal to the A/D converter in the one-chip computer 3-3, the one-chip computer 3-3 couples to latch, the latter couples to program memory 3-6, the program memory 3-6 couples to latch 3-4, 3-3 of one-chip computer, data memory 3-7, the data memory 3-7 couples to latch 3-4, 3-3 of one-chip computer. The reset circuit 3-8, the key 3-9, the display 3-10 and the power control part 3-11 are respectively connected with the singlechip 3-3. In the working process, the power supply control parts 3-11 control the on-off and polarity change of the power supply under the unified control of the single chip microcomputer, and change the power supply voltage if necessary, thereby providing effective reverse iontophoresis. After the reverse iontophoresis, the oxidized free electrons are collected and displayed by a microcomputer consisting of a sensor, an amplifier, a single chip microcomputer (CPU, A/D), a latch, a real-time clock, a program memory, a data memory, a reset circuit, a key and a display.

In the installed device, the counter iontophoresis electrode and the sensor are installed on one side of the glass fiber printed circuit board, the single chip microcomputer circuit is installed on the other side of the glass fiber printed circuit board of the single chip microcomputer microelectronic layer 2-5, and the display 2-6 is attached to the single chip microcomputer circuit.

The measurement circuit is preferably disconnected during the reverse iontophoresis process to avoid the reverse iontophoresis process from interfering with the sensor activation process.

The measurement accuracy of the invention is 95 percent

The average absolute error is 13%

Correlation with fingertip blood sampling glucometer 0.9

Correlation between machines 0.94

If the blood glucose is measured by a fingertip blood sampling glucometer for 2 times every day, the hypoglycemia sensitivity is 14 percent

If the hypoglycemia sensitivity is 39% after 4 times of blood glucose sampling by a fingertip blood glucose meter every day

When the blood sugar is measured 3 times per hour and 72 times per day by using the blood sugar measuring device, the hypoglycemia sensitivity is 75 percent.

The present invention has been described in terms of the preferred embodiments thereof, but it will be apparent to those skilled in the art that various modifications, changes, and substitutions can be made in the teachings of the preferred embodiments within the spirit and scope of the present invention. For example, the time of reverse iontophoresis, the time of measurement can be adjusted, the voltage of reverse iontophoresis can be adjusted, etc. Moreover, the amplifying parts of the two sensing circuits can be time division multiplexed with the same set of circuits, and certainly, the amplifying parts can also be two sets of independent circuits. In the case of two circuits, independence of the two circuits should be ensured. Of course, the invention can also adopt only one sensor, and adopt a plurality of times of measurement, and then the certain time interval between two times of measurement, thus can also reach better effect.

Claims

1. A method of non-invasive blood glucose measurement, comprising the steps of:

performing reverse iontophoresis to electroosmose glucose through the skin;

oxidizing the electro-leached glucose to generate free electrons;

measuring the amount of free electrons generated; and

the concentration of blood glucose was estimated by the amount of free electrons.

2. The method of claim 1, wherein: the step of reverse iontophoresis includes the step of alternately applying a voltage.

3. The method of claim 1 or 2, wherein: the measuring step includes using a platinum electrode and an Ag-AgCl electrode as measuring electrodes, respectively, and an Ag-AgCl electrode as a reference electrode.

4. The method of claim 3, wherein: the reverse iontophoresis step and the measurement step are performed separately.

5. A non-invasive blood glucose monitor, comprising: a control/processing unit, a power supply controlled by the control/processing unit, a gel tray for collecting glucose molecules, a sensor circuit connected to the gel tray and the control/processing unit, respectively, and a display circuit connected to the control/processing unit, wherein the power supply has two output electrodes for applying a voltage to the skin for reverse iontophoresis, and the sensor circuit includes two electrodes inserted into the gel tray.

6. The blood glucose monitor of claim 5, further comprising a polarity reversing circuit, and wherein the control/processing means reverses the polarity of the two output electrodes of the power supply via the polarity reversing circuit.

7. Blood glucose monitor according to claim 5 or 6, wherein there are two gel pads, one around each of the two counter iontophoresis electrodes, and two sensing circuits,which operate alternately.