JPH06119B2 - Transdermal sensor for detecting organic matter and electrolytes in sweat - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a percutaneous sensor for detecting organic substances and electrolytes in sweat for detecting organic substances and electrolytes contained in sweat.

BACKGROUND OF THE INVENTION Conventional continuous measurement of glucose concentration in a living body is performed by inserting a sensor such as a glucose measuring device or an artificial pancreas into a blood vessel or a tissue (JP-A-59).
-8939, JP 59-8969, JP 59-14843, JP
59-14857). In addition, a method in which a sensor is brought into contact with blood guided outside the body from a catheter inserted into a blood vessel (Japanese Patent Laid-Open No. 52-13559)
No. 9, JP-A-54-82885).

In addition, intermittent measurement of glucose concentration is performed using a sensor after blood collection.

Each of these methods for measuring the glucose concentration is an effective method for knowing the blood glucose concentration (blood glucose level) and keeping the blood glucose level of a diabetic patient normal by diet therapy, exercise therapy, and insulin therapy. But on the other hand infection,
Various problems such as mental and physical distress, blood loss, performance deterioration due to factors of biological component adhesion, and lack of information due to intermittent measurement are occurring.

Therefore, the transcutaneous measurement of the partial pressure of blood gas (Japanese Patent Application Laid-Open No. 50-141186)
JP-A-53-137590 and JP-A-54-60788), a method of non-invasively measuring blood glucose concentration has been considered. In this transcutaneous blood gas partial pressure measurement method, the measurement target is oxygen or carbon gas. Oxygen and carbon gas easily permeate the skin, and non-invasive concentrations can be measured.

However, since it is difficult for blood glucose to penetrate the skin, it is difficult to directly adopt such a percutaneous measurement method.

Other problems with glucose include the in-vivo organic matter such as lactic acid, pyruvic acid, urea, and uric acid, sodium,
The same applies to in-vivo electrolytes such as potassium and calcium.

[Object of the Invention]

An object of the present invention is to provide a percutaneous sensor for detecting organic substances and electrolytes in sweat, which can easily and continuously detect organic substances and electrolytes contained in sweat.

[Outline of Invention]

The present inventors have conducted various studies on the correlation between organic matter contained in sweat, concentration of electrolytes and organic matter in blood, and concentration of electrolytes.

The examination will be described below.

As one of the methods for noninvasively measuring blood organic matter and electrolyte, it is possible to measure organic matter and electrolyte in sweat. However, the influence of blood organic matter, electrolyte concentration on organic matter in sweat, and electrolyte concentration has not been clarified in the past.In other words, the correlation between blood agriculture level and sweat concentration has not been clarified. Some measurement data has not been obtained yet. Therefore, the present inventor shows the correlation between the blood glucose concentration and the glucose concentration in sweat. Therefore, the glucose tolerance test measures changes in blood glucose and glucose concentration in sweat every 30 minutes, and obtains the correlation data between them. It was

The experiment for obtaining this data was carried out by performing a 50 g glucose tolerance test, and administration was performed on an empty stomach at 30 minutes, 60 minutes, 90 minutes, 1 minute after administration.
After 20 minutes, blood was collected from the cubital vein, and the blood glucose concentration was immediately measured with a dextrometer.

Since sweat could not be collected at the same time as blood collection, glucose tolerance tests for blood sampling and sweat collection were separately performed at intervals of 3 to 4 days, and each glucose tolerance test was started 12 hours after eating. Around each of the 5 time points, which is the timing of measuring blood glucose concentration, each was bathed in a high temperature sauna (116 ° C.) for 7 to 8 minutes, and sweat from the head was collected. The head was thoroughly washed and dried after each bath to prevent glucose and water from entering. Since sweat drops from the face are collected in a normal aluminum foil saucer, the sweat is immediately sealed in a polypropylene reagent bottle after perspiration, at -80 ° C.
It was frozen and stored in. The saucer was doubled and water was poured between them to cool the saucer to prevent evaporation of water from the collected sweat. Also. Sweat frozen and stored at −80 ° C. to prevent decomposition by bacteria etc. was subjected to sugar analysis by high performance liquid chromatography within 24 hours to determine the glucose concentration in sweat. The results are shown in FIG.

FIG. 1 (A) shows blood glucose concentration, and FIG. 1 (B) shows sweat glucose concentration. In FIG. 1, (1) shows the result of the test, and (2) shows the result of the test after one week. As described above, since the morphologies of the graphs in (1) and (2) are almost the same, it is assumed that the reproducibility of the test results is sufficient.

In this way, by comparing the blood glucose concentration and the sweat glucose concentration from FIG. 1, it is possible to obtain data showing a correlation between the two. Therefore, it is possible to know the blood glucose concentration by measuring the glucose concentration in sweat and adding a correction based on the correlation data to the measured value. With this, the blood glucose concentration can be measured non-invasively, and the burden on the patient can be eliminated. Then, such a correlation can be obtained by individually testing various organic substances in blood other than glucose and inorganic substances.

The present invention has been made based on such findings,
According to the present invention, a porous film having a thickness of 1 to 10 μm, which is larger than an occupied area of the sensitive film and whose peripheral end face is open, is provided on the outer surface of the sensitive film of the measuring sensor, and the porous film and the sensitive film are provided between the porous film and the sensitive film. An interfering substance removal film is placed, the porous film is fixed to the skin, and the temperature control mechanism placed on the measurement sensor promotes perspiration only in the measurement part, and the permeation from the skin surface is retained by the porous film. , The organic matter and electrolyte concentration in sweat are continuously measured while removing interfering substances, and the organic matter and electrolyte concentration in blood are estimated from the correlation data of organic matter in sweat, organic matter in blood and organic matter and electrolyte concentration A percutaneous sensor for detecting organic substances in sweat and electrolytes.

Example of Invention

 Next, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

FIG. 2 is a schematic sectional view showing the basic welfare of an embodiment of the transcutaneous sensor according to the present invention.

In FIG. 2, on the skin 3 side of the biochemical sensor 1 for measuring organic substances and electrolytes, a porous membrane 2 made of a porous substance is provided.
Is provided. The porous membrane 2 is made of a so-called sponge. The peripheral end surface of the porous membrane 2 is not covered by the sensor 1 and is open.

The porous film 2 of the sensor 1 is fixed to the surface of the skin 3 with a double-sided tape, a surgical tape or the like.

Sweat leached from the surface of skin 3 is absorbed in porous film 2. Since sweat evaporates from the peripheral end surface of the porous film 2,
Sweat that is continuously leached from the skin 3 flows back inside the porous membrane 2. As a result, fresh sweat is continuously supplied to the sensitive surface of the sensor 1, and organic substances and electrolytes in sweat can be continuously measured.

When the porous membrane 2 is provided, even if the porous membrane 2 is temporarily separated from the surface of the skin 3, the sensor 1 continuously measures organic substances and electrolytes in the sweat in order to retain the sweat leached from the skin 3. It is possible.

If such a porous material is not used, it is necessary to take a method such that the sensor 1 is always fixed to the skin 3. For this purpose, a method may be adopted in which the central part of the sensor is made to project from the peripheral part and is fixed to the skin with tape or the like, or the repulsive force of a spring is used to bring the sensor 1 into close contact with the skin. it can.

As a result of providing the porous film 2 between the sensor 1 and the skin 3 as described above, even if the contact state between the surface of the skin 3 and the sensitive surface of the sensor 1 changes due to body movement or the like, the output of the sensor fluctuates. It can be prevented and stable measurement values can be obtained.

In order to cause sweating on the surface of the skin 3 with which the porous film 2 is in contact, a sauna or the like is used.

Next, an example of a detection sensor having a skin heating mechanism will be described. FIG. 3 is a schematic sectional view showing the basic structure thereof.

In the transcutaneous sensor according to the present embodiment, a heater 4 is provided around the sensor 1, and the heater 4 is provided with a temperature sensor 5 such as a thermistor for controlling a motor to maintain an appropriate temperature. The sensor 1, the heater 4, and the thermistor 5 are covered with a heat insulating material 6 in order to prevent heat from being released into the outside air. The porous membrane 2 is configured to be larger than the sensitive surface of the sensor 1, and has a size similar to that of the heat insulating material 6 on the outer side, and the peripheral portion is open.

In this embodiment, since the temperature control mechanism is provided, it is possible to heat the skin surface in a range where inflammation does not occur, for example, up to about 43 ° C. As a result, sweat is forcibly leached from the surface of the skin 3, and the blood organic matter and electrolyte concentrations can be measured without using a sauna or the like. As a result, it is possible to easily measure electrolytes and organic substances in sweat.

Next, an embodiment in which the route sensor described in FIGS. 2 and 3 is developed into a glucose measuring route sensor will be described. FIG. 4 is a sectional view showing the basic construction of the embodiment.

In this embodiment, a hydrogen peroxide electrode based on the polarographic principle is used as the glucose sensor.

The hydrogen peroxide electrode is composed of an anode 7 made of platinum or the like, a cathode 8 made of silver or the like, and an insulating material tank 11 such as an epoxy resin. On the skin 3 side surface of the hydrogen peroxide electrode, the porous film 2 that absorbs and recirculates sweat leaching from the skin 3 side, the immobilized glucose oxidase film 9, the hydrogen peroxide, oxygen, water, and salts are passed. An interfering substance removing film 10 having a function of removing a reducing substance which is an interfering substance is stretched. Further, a temperature sensor 5 such as a thermistor is provided in the insulating material tank 11 for temperature compensation. Each of these devices is covered with a cover 12, and a lead wire 13 for applying a voltage to the electrodes and obtaining an output current is provided. The lead wire 14 is used for the temperature sensor 5.

The interfering substance removal film 10 is made of acetyl cellulose having pores, and is porous so as to remove interfering substances having a large molecular weight.

The transcutaneous glucose sensor according to the present embodiment is attached to the chest, back, forehead, neck, etc. during thermal sweating due to local or whole-body heating or exercise to absorb and circulate perspiration into the porous membrane 2. The glucose concentration in sweat, which changes in correlation with the blood glucose level, is measured by a glucose sensor on the body surface. Thereby, the blood glucose concentration (blood sugar level) can be known non-invasively. Glucose in sweat to be contained in the porous membrane _{2 (C 6 H 12 O 6} ), oxygen, water in the immobilized glucose oxidase membrane 9, glucuronic acid cause the following chemical reaction by the action of oxygen (C ₆ It produces H ₁₂ O ₇ ) and hydrogen peroxide (H ₂ O ₂ ).

In this example, the hydrogen peroxide generated by the formula (1) is measured, but it is also possible to obtain the glucose concentration by detecting the consumed oxygen or the generated glucuronic acid concentration. The interfering substance removing film 10 does not allow reducing substances such as urea and ascorbic acid to pass therethrough, but allows hydrogen peroxide, oxygen, water, and salts to pass therethrough, so that the hydrogen peroxide is guided to the anode 7 and the cathode 8. be able to.

Between the cathode 8 and the anode 7 of the hydrogen peroxide electrode is 0.7-0.
When a voltage of 8 V is applied, hydrogen peroxide is oxidized on the anode 7 according to the following equation and becomes 2H ₂ O ₂ → 4H ++ 2O ₂ + 4e- (2), and oxygen is reduced on the cathode 8 according to the following equation. , 4H ++ O ₂ → 2H ₂ O-4e- (3). Therefore, a current proportional to the glucose concentration in sweat flows between both electrodes. The interfering substance removing film 10 and the immobilized glucose oxidase film 9 are described in US Pat. No. 4,307,195.
As described in detail in the above issue, the integrated substance acetyl cellulose is used, and the interfering substance removal film 10 side is made of pores,
It can be integrated by immobilizing glucose oxidase in the coarse pores on the side of the immobilized glucose oxidase membrane.

Next, the porous film 2 will be described in detail.

The sweat leached from the surface of the skin 3 permeates the porous film 2 and evaporates from the end surface 41 of the transdermal sensor. Since the amount of evaporation changes depending on the temperature of the transdermal sensor, the temperature of the atmosphere, and the humidity, the glucose concentration of the peripheral portion of the porous substance 2 and the sweat is also affected. Therefore, in order to remove this effect, the porous membrane 2
Of the glucose sensor is required to be larger than the reaction surface of the glucose sensor, that is, the area occupied by the immobilized glucose oxidase membrane 9.

If the thickness of the porous film is thick, the response of the sensor becomes slow and it becomes impossible to follow a sudden output change. On the other hand, if the film thickness is thin, it will not be able to be damaged or retain the amount of sweat necessary for measurement. Body surface temperature of approximately 43 ° C that can be continuously heated
The sweating rate below is 0.1 to 10 μl / min · cm ² , and there is no capillary phenomenon except the beginning of sweating, so sweat permeates into the porous material at a rate of 1 to 100 μm / min. . So, if you consider the response speed and the strength of the porous material,
Porous material is 1-100 μm, preferably 1-10 μm
Is desirable.

Since the glucose oxidase film 9 is porous, it can also serve as the function of the porous film 2.
Can be omitted. However, since the porous membrane 2 has an area larger than that of the glucose oxidase membrane 9 as shown in FIG. 4, it cannot be said to be very effective in terms of cost.

Although the glucose transdermal sensor has been described in the present embodiment, when transdermally measuring the electrolyte in sweat, a sensor made of glass is used. Since the surface of this sensor is not porous, it is necessary to maintain the perspiration such as a porous material and to recirculate the perspiration.

Next, an example of a glucose transdermal sensor having a temperature control mechanism in the glucose transdermal sensor shown in FIG. 4 will be described. FIG. 5 is a sectional view showing the embodiment.

In FIG. 5, the insulating material 11 is covered with a good heat conductor 17, and the good heat conductor 17 is covered with a heat insulating material 16.
A pair of spaces is provided between the good heat conductor 17 and the heat insulating material 16, and the heater 4 is provided in the space. A lead wire 15 is connected to the heater 4 so that the heater 4 can be heated.

In the glucose transdermal sensor of the present embodiment, a temperature control circuit including a temperature sensor 5 such as a thermistor and a heater 4 sets and maintains a constant temperature, and the skin does not cause inflammation (about 43 ° C. or less on the skin surface). The skin surface is constantly sweated by being heated. The good conductor 17 of heat makes the heat conduction to the skin 3 good, and the heat insulating material 16 effectively conducts the heat to the skin 3 without letting it escape to the outside air. Other configurations are similar to those of the embodiment shown in FIG.

In the present embodiment, since the glucose transdermal sensor has a built-in heating mechanism, there is no need for local or whole-body heating or exercise, and it becomes possible to measure blood glucose non-invasively in a normal state, and a blood glucose measuring device or It can be used as a sensor for an artificial pancreas.

Although the glucose sensor is used as the biochemical sensor in each of the above examples, a sensor for measuring other organic substances or electrolytes can also be used as the transdermal sensor. Further, the number of biochemical sensors is not limited to one, and a plurality of biochemical sensors can be used as a transdermal sensor.

〔The invention's effect〕

According to the present invention, the temperature control mechanism promotes perspiration only in the measurement part, and the permeated sweat is held by the porous film, whereby the organic matter and electrolyte concentrations in the sweat can be continuously measured.

Further, the organic matter and electrolyte concentration in blood can be continuously estimated from the correlation data of the organic matter and electrolyte concentration in sweat and the organic matter and electrolyte concentration in blood.

[Brief description of drawings]

FIG. 1 is a graph showing changes in blood glucose and sweat glucose concentrations over time, FIG. 2 is a basic cross-sectional configuration diagram showing an embodiment of a transdermal sensor according to the present invention, and FIG. 3 is shown in FIG. FIG. 4 is a basic cross-sectional configuration diagram showing an embodiment provided with a temperature control mechanism, FIG. 4 is a cross-sectional configuration diagram of an embodiment of a glucose transdermal sensor which is an embodiment of the transdermal sensor according to the present invention, and FIG. FIG. 4 is a sectional configuration diagram showing an embodiment in which a temperature control mechanism is provided in FIG. 4. 1 ... Glucose sensor, 2 ... Porous substance, 4 ... Heater,
5 ... Temperature sensor, 7 ... Anode, 8 ... Cathode, 9 ... Immobilized glucose oxidase membrane, 10 ... Interfering substance removing membrane, 11 ...
Insulating material, 16 ... Insulating material, 17 ... Good conductor of heat.

Claims (1)

[Claims] 1. A porous film having a thickness of 1 to 10 μm, in which a peripheral end face is opened to the outer surface of a sensitive film of a sensor for measuring the concentration of organic matter and electrolytes in sweat, the peripheral end face being larger than the occupied area of the sensitive film, and the porous film. An interfering substance removing film that is disposed between the porous film and the sensitive film to remove a substance that interferes with the measurement, a heater that is disposed around the measuring sensor, and a temperature sensor that detects the temperature of the porous film. A percutaneous sensor for detecting organic substances in a sweat and an electrolyte, comprising a temperature control mechanism having the same.