JP4987527B2 - Skin permeability measurement method, component concentration analysis method, skin permeability measurement device, and component concentration analysis device - Google Patents

Description

  The present invention relates to a skin permeability measurement method, a component concentration analysis method, a skin permeability measurement device, and a component concentration analysis device, and in particular, supplies a medium for holding tissue fluid containing a predetermined component of a subject to a medium container. The present invention relates to a skin permeability measuring method and a component concentration analyzing method including steps, and a skin permeability measuring apparatus and a component concentration analyzing apparatus including a medium container for holding a tissue fluid containing a predetermined component of a subject.

  2. Description of the Related Art Conventionally, there is known a blood sugar level analysis method including a step of supplying a medium for holding tissue fluid containing a predetermined component of a subject to a medium container (see, for example, Patent Document 1).

  In Patent Document 1, glucose is extracted from the skin of a subject by a so-called reverse iontophoresis method in order to analyze a blood glucose level without collecting blood. That is, physiological saline is supplied as a medium for holding glucose in a chamber placed on the subject's skin, and the skin is energized for a predetermined time via an electrode placed on the subject's skin. Thereby, the movement of ions existing in the tissue fluid of the subject occurs due to the potential gradient formed by energization. As the ionic substance moves, glucose contained in the tissue fluid also moves, so that the tissue fluid containing glucose extracted from the skin is retained in the physiological saline in the chamber. The glucose extraction rate is calculated by measuring the glucose amount in the chamber with a sensor and dividing the obtained glucose amount by the energization time. Moreover, in the said patent document 1, in order to correct | amend the extraction amount of glucose extracted percutaneously, the conductance of a test subject's skin is measured and the test subject's skin state is monitored by this conductance. Then, the permeability of glucose that correlates with the conductance (glucose permeability) is estimated from the conductance, and the blood glucose level of the subject is calculated based on the glucose extraction rate and the glucose permeability.

JP 2006-68492 A

However, in the above-mentioned Patent Document 1, since physiological saline is used as a medium for holding glucose-containing tissue fluid, conductance and glucose are caused by salts such as Na ⁺ and Cl ⁻ contained in the physiological saline. There is an inconvenience that the correlation with the transmittance deteriorates. Therefore, there is a problem that it is difficult to accurately estimate the glucose permeability. Moreover, since it is difficult to accurately estimate the glucose permeability, there is a problem that it is difficult to accurately calculate the blood sugar level calculated based on the glucose permeability.

  The present invention has been made in order to solve the above-described problems, and one object of the present invention is to measure the skin permeability that can more accurately estimate the transmittance of a predetermined component to the skin. A method and a component concentration analysis method capable of calculating the concentration of a predetermined component in a tissue fluid with higher accuracy.

  Another object of the present invention is to provide a skin permeability measuring apparatus capable of estimating the transmittance of a predetermined component to the skin with higher accuracy and to calculate the concentration of the predetermined component in tissue fluid with higher accuracy. It is to provide a possible component concentration analyzer.

Means for Solving the Problems and Effects of the Invention

A component concentration analysis method according to a first aspect of the present invention includes a step of supplying a low-conductivity medium as a medium for holding a tissue fluid containing a predetermined component of a subject to the medium container, and the medium container is disposed on the subject's skin. A step of placing the extraction fluid into the extraction site, a step of extracting the tissue fluid into the low-conductivity medium in the medium container through the extraction site, and the first electrode for supplying power to the extraction site and the skin other than the extraction site. A step of supplying power between the second electrodes for supplying power, and a step of measuring a value corresponding to the amount of a predetermined component contained in the tissue fluid extracted through the extraction site in the low-conductivity medium And calculating the concentration of the predetermined component in the tissue fluid based on the energization result of the power supplied between the first electrode and the second electrode and the measurement result of the value corresponding to the amount of the predetermined component. , The concentration of certain components in tissue fluid Calculating the conductance of the extraction site based on the energization result of the electric power supplied between the first electrode and the second electrode, and the measuring the conductance includes the tissue fluid in the low conductivity medium. After the step of extracting, conductance is measured with ions in the low-conductivity medium being substantially homogeneous in the low-conductivity medium .

In the component concentration analysis method according to the first aspect, as described above, a low-conductivity medium is supplied as a medium for holding a tissue fluid containing a predetermined component of a subject in the medium container, and thus the medium is physiological. Compared to the case where saline is used, the transmittance of the predetermined component held in the low-conductivity medium to the skin (extraction site) is based on the result of energization of the power supplied between the first electrode and the second electrode. It can be estimated with high accuracy. Further, by calculating the concentration of the predetermined component in the tissue fluid based on the energization result of the power supplied between the first electrode and the second electrode and the measurement result of the value corresponding to the amount of the predetermined component, The concentration of the predetermined component in the tissue fluid can be calculated based on the transmittance of the predetermined component with respect to the skin (extraction site) obtained more accurately by using the conductive medium. Therefore, the concentration of the predetermined component in the tissue fluid can be calculated with higher accuracy.
In addition, the conductance can be measured with higher accuracy than when the conductance is measured in a state where ions such as Na ⁺ are localized in the low-conductivity medium immediately after extracting the tissue fluid . Thereby, the density | concentration of the predetermined component in a tissue fluid can be calculated more accurately.

In the component concentration analysis method according to the first aspect, the predetermined component may contain glucose.

A skin permeability measuring device according to a second aspect of the present invention is a medium container that is disposed at an extraction site of a subject's skin and contains a low-conductivity medium for holding tissue fluid containing a predetermined component of the subject. A first electrode for supplying power to the extraction site, a second electrode for supplying power to a first site other than the extraction site of the subject's skin, and supplying power to the first electrode and the second electrode A conductance measuring unit that measures the conductance of the extraction site by supplying power from the power source to the first electrode and the second electrode, and in the medium containing unit, ions in the low conductive medium are contained in the low conductive medium. And homogenizing means for homogenizing .

In the skin permeability measuring apparatus according to the second aspect, as described above, by providing the medium container that stores the low-conductivity medium for holding the tissue fluid containing the predetermined component of the subject, the medium container is provided with the medium container. Compared with the case where physiological saline is stored, the correlation between the transmittance of the predetermined component held in the low conductive medium with respect to the skin (extraction site) and the conductance of the extraction site can be improved. Thereby, the transmittance | permeability with respect to the skin (extraction site | part) of a predetermined component can be estimated more accurately by measuring the conductance of an extraction site | part.
In addition, the ion in the low-conductivity medium, which is preferable as a state for measuring the conductance, from the state where the ions are localized in the low-conductivity medium immediately after the extraction of the tissue fluid by the homogenization means is homogeneous in the low-conductivity medium. It is possible to change to a converted state in a short time. Thereby, the measurement of conductance can be started promptly.

In the skin permeability measuring apparatus according to the second aspect, preferably, the power source is configured to be able to apply an alternating current between the first electrode and the second electrode, and the conductance measuring unit is configured to be the first by the power source. The conductance of the extraction part is measured based on the result of the alternating current applied between the electrode and the second electrode. If comprised in this way, the conductance of an extraction part can be measured by a comparatively simple structure and a comparatively short measurement time by applying alternating current only between the 1st electrode and the 2nd electrode.

The skin permeability measuring apparatus according to the second aspect preferably further includes a third electrode for supplying power to a second part other than the extracted part of the subject's skin, and the power source includes the first electrode and the second electrode. A direct current can be applied between the electrodes, between the first electrode and the third electrode, and between the second electrode and the third electrode, and the conductance measurement unit is configured to supply the first electrode and the second electrode by a power source. The conductance of the extraction part is measured based on the result of direct current applied between the electrodes, between the first electrode and the third electrode, and between the second electrode and the third electrode. If comprised in this way, compared with the case where conductance is measured by alternating current, the conductance of an extraction part can be measured comparatively stably.

A component concentration analyzer according to a third aspect of the present invention is disposed at an extraction site of a subject's skin, and a medium container that contains a low-conductivity medium for holding tissue fluid containing a predetermined component of the subject. A first electrode for supplying power to the extraction site; a second electrode for supplying power to the skin other than the extraction site; a power source for supplying power to the first electrode and the second electrode; Included in the energization result measurement unit that measures the energization result by supplying power to the first electrode and the second electrode, and the tissue fluid extracted through the extraction site in the low-conductivity medium supplied as a medium to the medium storage unit A component amount measuring unit that measures a value corresponding to the amount of the predetermined component to be determined, an analysis unit that calculates the concentration of the predetermined component in the tissue fluid based on the energization result and the value corresponding to the amount of the predetermined component , Medium container and first A main body device including an extraction cartridge including a pole, a first cartridge mounting portion for mounting the extraction cartridge, a second electrode, a power source, and an energization result measuring portion; and a second for mounting the extraction cartridge And a measuring device including a cartridge mounting unit, a component amount measuring unit, and an analyzing unit .

In the component concentration analyzer according to the third aspect, as described above, the medium container is provided with the medium container that stores the low-conductivity medium for holding the tissue fluid containing the predetermined component of the subject. Compared with the case of containing saline, the correlation between the transmittance of the predetermined component held in the low-conductivity medium with respect to the skin (extraction site) and the energization result can be improved. Thereby, the transmittance | permeability with respect to the skin (extraction site | part) of a predetermined | prescribed component can be estimated more accurately by an energization result. In addition, by providing an analysis unit that calculates the concentration of the predetermined component in the tissue fluid based on the energization result and the value corresponding to the amount of the predetermined component, it was obtained more accurately by using a low-conductivity medium. Based on the transmittance of the predetermined component to the skin (extraction site), the concentration of the predetermined component in the tissue fluid can be calculated. Therefore, the concentration of the predetermined component in the tissue fluid can be calculated with higher accuracy.

In the component concentration analyzer according to the third aspect, the energization result measurement unit is configured to measure the conductance of the extraction site based on the energization result of supplying power from the power source to the first electrode and the second electrode. May be.

In the component concentration analyzer according to the third aspect, preferably, the medium storage portion is formed in a sheet shape and is disposed so as to face the extraction site, and the sheet-shaped medium storage portion is 500 μm. It has the following thickness. With this configuration, the volume of the medium container can be reduced, so that the tissue fluid in which ions are localized in the vicinity of the first electrode can be obtained by waiting for a relatively short time compared to the case where the volume is large. From the state immediately after the extraction, the ion can be made uniform in the medium accommodating portion by diffusion. Accordingly, it is possible to quickly start energization of the first electrode and the second electrode and obtain an energization result.

  DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments embodying the present invention will be described below with reference to the drawings.

(First embodiment)
FIG. 1 is a block diagram showing the configuration of the glucose concentration analyzer according to the first embodiment of the present invention. First, the structure of the glucose concentration analyzer 100 according to the first embodiment of the present invention will be described with reference to FIG.

  As shown in FIG. 1, the glucose concentration analyzer 100 extracts a tissue fluid containing glucose, which is one of the biochemical components, from a living body, and analyzes the glucose contained in the extracted tissue fluid to obtain a blood glucose level. It is a device to calculate. In this glucose concentration analyzer 100, a tissue fluid is extracted from an extraction site by applying a direct current to the skin (extraction site) of a subject in which micropores are formed, and the amount of glucose (glucose extraction amount) is extracted from the tissue fluid by a glucose sensor. ) Since this glucose extraction amount changes depending on the depth of the micropores, etc., the conductance of the extraction site is calculated from the electrical information obtained by applying an alternating current to the subject's skin (extraction site). The state of the extraction site (depth of micropores, etc.) is monitored by conductance. In this way, by correcting the amount of glucose extracted by the conductance value, it is possible to accurately determine the glucose concentration. Since the glucose concentration contained in the tissue fluid is substantially equal to the blood glucose level, the blood glucose level of the subject can be measured without collecting the blood of the subject. Hereinafter, the structure of the glucose concentration analyzer 100 will be described in detail.

  The glucose concentration analyzer 100 includes a dry electrode 1 made of Ti arranged in a part 502 other than the extraction part 501 in the skin 500 of a subject, and a power supply unit 2 for applying alternating current and direct current by current control. A glucose sensor 3 composed of a semiconductor laser and a photodiode, a control / analysis unit 4 for controlling the power supply unit 2 and the glucose sensor 3, a voltmeter 5, and a subject measured by the glucose concentration analyzer 100 An input unit 6 including a button for instructing the start of the display and a display unit 7 for displaying a measurement result and the like. The glucose concentration analyzer 100 is also equipped with a disposable chip 200 that can be replaced for each measurement when analysis is performed.

  The disposable chip 200 includes a mesh sheet 201 soaked with pure water, a sensor member 202 disposed on the upper surface of the mesh sheet 201 and coated with a substance that reacts with glucose contained in the mesh sheet 201, and Ag / AgCl. A working electrode 203, a reference electrode 204 made of Ag / AgCl, and a masking tape 205 are included. With the disposable chip 200 disposed, the sensor member 202 is disposed below the glucose sensor 3, and the working electrode 203 and the reference electrode 204 are connected to the power supply unit 2 and the voltmeter 5, respectively.

  The mesh sheet 201 is configured to be able to hold about 3.5 μl of pure water. The mesh sheet 201 is made of nylon, has substantially no elasticity, and is configured so that the thickness does not change. Specifically, it is formed by weaving nylon fibers having a thickness of about 30 μm, and has a square network structure of about 33 μm in length and width. The mesh sheet 201 has a length of about 10 mm, a width of about 4 mm, and a thickness of about 50 μm.

  The mesh sheet 201 is contacted in a planar shape so as to face the extraction site 501 of the skin 500 of the subject. A sensor member 202 and a working electrode 203 are arranged on the surface of the mesh sheet 201 opposite to the extraction site 501.

Further, the surface of the sensor member 202 on the mesh sheet 201 side reacts with an enzyme (glucose oxidase) serving as a catalyst for glucose, an enzyme (peroxidase) serving as a catalyst for hydrogen peroxide (H ₂ O ₂ ), and active oxygen. Then, a coloring pigment that develops color is applied. As the coloring dye, for example, N, N-bis (2-hydroxy-3-sulfopropyl) tolidine dipotassium salt, 3,3 ′, 5,5′-tetramethylbenzylidene and the like can be used. .

The masking tape 205 is provided to reduce the pain of the subject due to the current flowing through the skin 500 by preventing the subject's skin 500 and the reference electrode 204 from directly contacting each other. The masking tape 205 is disposed on the lower surfaces of the mesh sheet 201 and the reference electrode 204. In addition, the masking tape 205, the opening 205a is provided approximately 7 mm ^2. The mesh sheet 201 and the extraction part 501 are configured to contact with each other through the opening 205a.

  In addition, with the disposable chip 200 attached to the glucose concentration analyzer 100, the power supply unit 2 applies current (DC current and AC current) to the skin 500 of the subject via the working electrode 203 and the dry electrode 1. It is configured. The power supply unit 2 has a function of applying a direct current to the skin 500 using the working electrode 203 and the dry electrode 1 as a cathode and an anode, respectively.

  The glucose sensor 3 detects the amount of glucose contained in the mesh sheet 201 by measuring the color intensity of the sensor member 202 and the like. The voltmeter 5 is a voltage between the dry electrode 1 and the reference electrode 204 when an electric current (alternating current) is applied to the skin 500 of the subject via the working electrode 203 and the dry electrode 1 by the power supply unit 2. Is configured to measure. In addition, the value measured by the voltmeter 5 and the amount of glucose measured by the glucose sensor 3 are configured to be input to the control / analysis unit 4.

  The control / analysis unit 4 has a function of calculating the impedance of the extraction region 501 using the voltage value input from the voltmeter 5 and calculating the conductance k of the extraction region 501 based on the impedance. Further, the control / analysis unit 4 determines the final glucose concentration of the tissue fluid, that is, the substantial blood sugar level, based on the amount of glucose in the mesh sheet 201 input from the glucose sensor 3 and the conductance k of the extraction site 501. It is configured to calculate.

  FIG. 2 is a perspective view showing a microneedle used when forming a fine extraction hole in the skin of a subject as a skin permeation promoting process. FIG. 3 is a cross-sectional view showing the state of the skin (extraction site) where the extraction holes by the microneedles shown in FIG. 2 are formed. Next, with reference to FIG. 2 and FIG. 3, the skin permeation promotion process as a pre-process at the time of measuring a blood glucose level with the glucose concentration analyzer 100 by 1st Embodiment is demonstrated.

  As illustrated in FIG. 2, the needle roller 600 includes an arm 601 and a plurality of rollers 602 that are rotatably supported by the arm 601. A plurality of minute needles 603 are formed on the outer peripheral surface of the roller 602 at a predetermined interval. The needle 603 does not reach the subcutaneous tissue when pressed against the skin, but has a protruding amount (about 0.3 mm) that can penetrate the epidermis including the stratum corneum of the skin. By performing the pretreatment using this needle roller 600, that is, the treatment of pressing the needle 603 against the extraction site 501, the skin penetrates the epidermis to reach the dermis and reaches the subcutaneous tissue as shown in FIG. A fine extraction hole 501a that does not reach is formed. In the first embodiment, tissue fluid containing glucose can be easily extracted from a living body through the plurality of extraction holes 501a by forming the extraction holes 501a. Therefore, when extracting glucose from a living body using the glucose concentration analyzer 100, it is possible to reduce the pain felt by the subject. In the first embodiment, a derma roller manufactured by Top-Rol is used as the needle roller 600.

  FIG. 4 is a flowchart for explaining the analysis operation of the glucose concentration analyzer according to the first embodiment shown in FIG. Next, with reference to FIGS. 1-4, the operation | movement procedure of the blood glucose level measurement using the glucose concentration analyzer 100 by 1st Embodiment of this invention is demonstrated.

When measuring a blood glucose level using the glucose concentration analyzer 100 according to the first embodiment, first, a fine extraction hole 501a is formed in the skin 500 of the subject using the needle roller 600 (see FIG. 2). Specifically, a plurality of fine extraction holes 501a as shown in FIG. 3 are formed by pressing the needle 603 against the extraction site 501 of the skin. The area S of the extraction site 501 is the area (about 7 mm ² ) of the opening 205a of the masking tape 205. The tissue fluid containing glucose that has originally accumulated in the dermis of the skin gradually oozes into the skin extraction hole 501a formed by the pretreatment (skin permeation promoting treatment) using the needle roller 600.

  Further, the test subject soaks pure water into the mesh sheet 201 of the disposable chip 200, and then attaches the disposable chip 200 (see FIG. 1) to the glucose concentration analyzer 100. At this time, in the glucose concentration analyzer 100, in step S1 of FIG. 4, it is determined by a sensor (not shown) whether or not the disposable chip 200 is attached to the apparatus. This determination is repeated when the disposable chip 200 is not attached to the apparatus. If the disposable chip 200 is attached to the apparatus, the process proceeds to step S2.

  Thereafter, the subject wears the glucose concentration analyzer 100 on the skin 500 of the subject so that the extraction site 501 in which the extraction holes 501a are formed and the cathode (mesh sheet 201) are in planar contact. At this time, pure water contained in the mesh sheet 201 enters the inside of the extraction hole 501 a formed in the skin 500. Then, the tissue fluid that has oozed into the extraction hole 501a of the skin 500 and the pure water from the mesh sheet 201 are mixed, so that the tissue fluid inside the extraction hole 501a is diffused into the pure water held in the mesh sheet 201. Thereby, since the osmotic pressure inside the extraction hole 501a becomes lower than the osmotic pressure of the dermis of the skin, the tissue fluid oozes out from the dermis into the extraction hole 501a again. As a result, before the current is applied from the power supply unit 2, the tissue fluid that has oozed out through the extraction hole 501a formed in the skin 500 is diffused to some extent in the pure water held in the mesh sheet 201. . Thereafter, the subject gives an instruction to start measurement by pressing a button (input unit 6) of the glucose concentration analyzer 100.

In the glucose concentration analyzer 100, it is determined in step S2 whether or not there has been an instruction to start measurement. This determination is repeated when there is no instruction to start measurement. If there is an instruction to start measurement, in step S3, the power supply unit 2 applies a direct current of about 80 μA to the skin 500 for about 180 seconds. As a result, charged ion components (such as Na ⁺ ) present in the extraction hole 501a are positively moved. Along with the movement of the ion component, an amount of glucose that can be detected by the glucose sensor 3 (see FIG. 1) is collected from the living body in the pure water held in the mesh sheet 201. Further, the glucose collected in the pure water reaches the sensor member 202 arranged on the upper surface of the mesh sheet 201.

  Next, in the glucose concentration analyzer 100, in step S4, the extraction rate (extraction amount per unit time) of glucose extracted into the pure water absorbed by the mesh sheet 201 is measured.

Specifically, glucose that has reached the sensor member 202 reacts with glucose oxidase as a catalyst, and hydrogen peroxide (H ₂ O ₂ ) generated as a result further reacts with peroxidase as a catalyst. As a result, active oxygen is generated. The coloring pigment applied to the sensor member 202 reacts with active oxygen and develops color. Therefore, the coloring pigment develops color with an intensity corresponding to the amount of glucose extracted from the living body.

  On the other hand, of the laser light emitted from the semiconductor laser of the glucose sensor 3, the intensity of the light passing through the sensor member 202 that is in contact with the mesh sheet 201 containing pure water is the amount of glucose extracted from the living body. It changes depending on the light intensity of the coloring dye that develops color accordingly.

  As a result, light having an intensity corresponding to the amount of glucose reaching the sensor member 202 is incident on the photodiode of the glucose sensor 3, and a signal corresponding to the intensity of the incident light is output. Based on the signal output from the photodiode of the glucose sensor 3, the control / analysis unit 4 calculates the glucose extraction amount. The control / analysis unit 4 calculates the glucose extraction rate J by dividing the obtained glucose extraction amount by the time during which the power supply unit 2 applied the direct current (that is, about 180 seconds).

The glucose concentration analyzer 100 waits for about 10 seconds after stopping application of the direct current for glucose extraction in step S5. That is, immediately after the direct current is applied, ions such as Na ⁺ are localized in the vicinity of the working electrode 203 of the mesh sheet 201. Therefore, by waiting for about 10 seconds, ions such as Na ⁺ diffuse and the mesh sheet diffuses. The state is made uniform in 201.

  Next, in the glucose concentration analyzer 100, in step S <b> 6, the power supply unit 2 applies an alternating current (about 500 Hz) of about 0 ± 30 μA to the skin 500. At this time, the measurement value (impedance of the extraction part 501) by the voltmeter 5 is input to the control / analysis unit 4.

  And in glucose concentration analyzer 100, in Step S7, conductance of extraction part 501 is computed based on a measurement value (impedance of extraction part 501) by voltmeter 5 obtained in Step S6. That is, the measured value by the voltmeter 5 can be approximated to the sum of the voltage drop at the extraction part 501 and the voltage drop at the part 502. Further, when the frequency of the alternating current is high (about 100 Hz or more), the impedance of the part 502 is smaller than the impedance of the extraction part 501, so that the measured value by the voltmeter 5 is used as the voltage drop of the extraction part 501. Can be approximated. The control / analysis unit 4 calculates the reciprocal of the impedance of the extraction part 501 as the conductance k of the extraction part 501.

  Next, in the glucose concentration analyzer 100, the glucose concentration (blood glucose level) is calculated in step S8. That is, the following formula (1) holds among the blood glucose level C, the glucose extraction rate J, the area S of the extraction site 501 and the transmittance P of glucose to the skin 500 (extraction site 501).

J = S × C × P (1)
Therefore, the blood glucose level C is expressed as the following formula (2).

C = J / (S × P) (2)
Here, it is experimentally obtained in Patent Document 1 described above that a predetermined relational expression holds between the glucose permeability P and the conductance k of the extraction portion 501 calculated in step S6. Based on this, the glucose permeability P is calculated. The glucose extraction rate J is obtained in step S4, and the area S of the extraction site 501 is the area of the opening 205a of the masking tape 205 (about 7 mm ² ). A blood glucose level C is calculated. The calculated blood glucose level is displayed on the display unit 7. As described above, the blood glucose level is analyzed by the glucose concentration analyzer 100 according to the first embodiment.

  Next, a comparative experiment that verifies the effect of using pure water as a medium for holding tissue fluid containing glucose will be described.

  In this comparative experiment, the glucose extraction rate J and the conductance k were measured a plurality of times by the glucose concentration analyzer 100 for each of a plurality of subjects in the same measurement procedure as in the first embodiment. Moreover, about the same test subject, the blood glucose level C was measured using the other blood glucose level measuring apparatus (Nipro Freestyle (made by Nipro Corporation)) different from the glucose concentration analyzer 100 according to the first embodiment. And the transmittance | permeability P was computed using the said Formula (1) from this blood glucose level C, the glucose extraction speed | rate J, and the area S. FIG. And the data (k, P) of the conductance k and glucose permeability P corresponding to each other were plotted on the coordinates with the conductance k and the permeability P as the horizontal axis and the vertical axis, respectively.

  Moreover, in this comparative experiment, the said experiment was conducted using the mesh sheet | seat 201 infiltrated with the medium (Examples 1-4 and Comparative Example 1) which has a several different NaCl density | concentration. The NaCl concentrations of the media of Examples 1 to 4 and Comparative Example 1 are shown in Table 1 below. In addition, Example 1 uses pure water as an example of a low-conductivity medium that is a medium according to the first embodiment, and Comparative Example 1 uses physiological saline that is a conventional medium. Examples 2 to 4 show other examples of low-conductivity media.

表１に示すように、ＮａＣｌ濃度が０ｍＭである実施例１（純水）は、０（μＳ（ジーメンス）／ｃｍ）の導電率および１８３００（ＫΩ・ｃｍ）の抵抗率を有する。また、ＮａＣｌ濃度が0．５ｍＭである実施例２は、５９．７２（μＳ／ｃｍ）の導電率および１６．７４５（ＫΩ・ｃｍ）の抵抗率を有する。また、ＮａＣｌ濃度が１ｍＭである実施例３は、１１９．４４（μＳ／ｃｍ）の導電率および８．３７２（ＫΩ・ｃｍ）の抵抗率を有する。また、ＮａＣｌ濃度が５ｍＭである実施例４は、５９７．２（μＳ／ｃｍ）の導電率および１．６７４（ＫΩ・ｃｍ）の抵抗率を有する。また、ＮａＣｌ濃度が１５４ｍＭである比較例１（生理食塩水）は、１８３９３．７６（μＳ／ｃｍ）の導電率および０．０５４（ＫΩ・ｃｍ）の抵抗率を有する。

As shown in Table 1, Example 1 (pure water) having a NaCl concentration of 0 mM has a conductivity of 0 (μS (Siemens) / cm) and a resistivity of 18300 (KΩ · cm). Moreover, Example 2 whose NaCl concentration is 0.5 mM has a conductivity of 59.72 (μS / cm) and a resistivity of 16.745 (KΩ · cm). Further, Example 3 in which the NaCl concentration is 1 mM has a conductivity of 119.44 (μS / cm) and a resistivity of 8.372 (KΩ · cm). Further, Example 4 having a NaCl concentration of 5 mM has a conductivity of 597.2 (μS / cm) and a resistivity of 1.673 (KΩ · cm). Moreover, the comparative example 1 (physiological saline) whose NaCl concentration is 154 mM has a conductivity of 18393.76 (μS / cm) and a resistivity of 0.054 (KΩ · cm).

The experimental results when the above-described experiment is performed for each of Examples 1 to 4 and Comparative Example 1 are shown in FIGS. As shown in FIGS. 5 to 9, it can be seen that the conductance k and the transmittance P are in a proportional relationship (correlation). In addition, the straight line shown in FIGS. 5-9 is a straight line (regression straight line) from which the difference with each point (k, P) calculated | required by the least square method becomes the minimum. For example, in FIG. 5, it is represented by P = 112.84k + 2.6793. Also, R ² in FIG. 5 to FIG. 9 is a so-called correlation coefficient, which indicates the magnitude of correlation between the conductance k and the glucose permeability P. The correlation coefficient R ² is, when the conductance k and glucose permeability P is directly proportional to takes a value of up to 0-1, show that the correlation as is a value close to 1 high. The correlation coefficient is 1 when all of the plurality of points (k, P) are on the same straight line. As shown in FIG. 5, in Example 1, the correlation coefficient is R ² = 0.8554, and it can be seen that the correlation between the conductance k and the glucose permeability P is high. Further, as shown in FIG. 9, in Comparative Example 1, the correlation coefficient is R ² = 0.1705, and it can be seen that the correlation between the conductance k and the glucose permeability P is low. Also, as shown in FIGS. 6 to 8, in Examples 2 to 4, the correlation coefficients are R ² = 0.5809, R ² = 0.6939, and R ² = 0.3301, respectively. It can be seen that the correlation between conductance k and glucose permeability P is higher than 1.

  Next, the measurement error was calculated | required about the experimental result of Examples 1-4 and the comparative example 1. FIG. With reference to FIG. 5, the case of Example 1 will be specifically described. First, the glucose permeability P (true permeability) at each point (k, P) is divided by the glucose permeability (estimated permeability) on the regression line ((k, 112.84k + 2.6793) in FIG. 5). , 100, the divergence rate of the glucose transmittance (true transmittance) at each point with respect to the estimated transmittance is calculated. That is, the divergence rate is expressed as the following formula (3).

Deviation rate = (true transmittance / estimated transmittance) × 100 = (P / (112.84k + 2.6793)) × 100 (3)
Thereafter, a standard deviation and an average value are calculated from the deviation rate of each point, and a measurement error is calculated by the following equation (4).

Measurement error = (standard deviation / average value) × 100 (4)
For Examples 1 to 4 and Comparative Example 1, the measurement error was calculated as described above. The calculation results are shown in Table 2 below and FIG.

表２に示すように、実施例１の測定誤差は、９．３４０５７であり、実施例２の測定誤差は、１５．２１５９であった。また、実施例３の測定誤差は、１８．１４３であり、実施例４の測定誤差は、１８．８５７１であった。比較例１の測定誤差は、２４．０２７２であるので、実施例１〜４の測定誤差は、比較例１の測定誤差よりも改善されていることが判明した。また、表２および図１０に示すように、ＮａＣｌ濃度を小さくするにしたがって、測定誤差も小さくなっている。特に、実施例１（純水）では、比較例１（生理食塩水）と比較して、大幅に測定誤差が小さくなっていることがわかる。

As shown in Table 2, the measurement error of Example 1 was 9.34057, and the measurement error of Example 2 was 15.2159. Moreover, the measurement error of Example 3 was 18.143, and the measurement error of Example 4 was 18.8571. Since the measurement error of Comparative Example 1 was 24.0272, it was found that the measurement errors of Examples 1 to 4 were improved over the measurement error of Comparative Example 1. Further, as shown in Table 2 and FIG. 10, the measurement error decreases as the NaCl concentration decreases. In particular, it can be seen that the measurement error in Example 1 (pure water) is significantly smaller than that in Comparative Example 1 (saline).

  Next, the mechanism by which the above experimental results were obtained will be considered. FIG. 11 and FIG. 12 are conceptual diagrams for explaining the behavior of ions in a medium when pure water (Example 1) and physiological saline (Comparative Example 1) are used as a medium for holding tissue fluid, respectively. It is.

The tissue fluid extracted from the subject's skin (extraction site) contains not only glucose but also sodium ions (Na ⁺ ). When a direct current is applied to extract glucose, an electric field is formed to force chloride ions (Cl ⁻ ) and sodium ions (Na ⁺ ) from the electrode (Ag / AgCl) and skin (extraction site), respectively. Is diffused. As sodium ions are forcibly diffused, glucose also moves, so that tissue fluid containing glucose in the medium is extracted. Thus, it is considered that the behavior of sodium ions is closely related to the glucose extraction mechanism.

An electric current flows when the chloride ions and sodium ions carry charges. In this case, black percentage of the current flowing in the chloride ion as a medium and transport number t _Cl of chloride ions, and transport number t _Na sodium the ratio of current flowing through the sodium ions as a medium ions _{(t Cl + t Na = 1} ).

As shown in FIG. 11, when the medium is pure water (Example 1), chloride ions (Cl ⁻ ) and sodium ions (Na ⁺ ) are not contained in the pure water. When Cl ⁻ ) diffuses into the medium, sodium ions (Na ⁺ ) diffuse from the skin in order to maintain electrical neutrality in the medium. In this way, since sodium ions diffuse unilaterally from the skin, the sodium ion transport number t _Na in the vicinity of the skin (extraction site) is relatively less influenced by the skin condition (depth, size, etc. of micropores). It is considered that it is stable at a high value (t _Na = 1) without receiving. Thus, since the behavior of sodium ions responsible for glucose extraction is stabilized without being affected by the skin condition, in Example 1, the correlation between the glucose permeability P and the conductance k reflecting the skin condition is improved. It is thought.

As shown in FIG. 12, when the medium is physiological saline (Comparative Example 1), a large amount of chloride ions (Cl ⁻ ) and sodium ions (Na ⁺ ) are contained. Therefore, when chloride ions (Cl ⁻ ) diffuse from the electrode into the medium, sodium ions (Na ⁺ ) diffuse from the skin in order to maintain the electrical neutrality in the medium, There are two possible cases: chloride ion (Cl ⁻ ) enters the skin. For this reason, when physiological saline is used as a medium, the sodium ion transport rate t _{Na in the} vicinity of the skin (extraction site) is low depending on the state of the skin (depth and size of the micropores) (t _It is considered that variation occurs at _Na = 0.7. Thus, since the behavior of sodium ions responsible for glucose extraction varies due to the influence of the skin condition, it is considered that in Comparative Example 1, the correlation between the glucose permeability P and the conductance k reflecting the skin condition was deteriorated.

  In the first embodiment, as described above, by using pure water as a medium for holding tissue fluid containing glucose, a conductive medium such as physiological saline having a resistivity as low as about 0.054 is used. As compared with the above, the correlation between the transmittance of the glucose extraction site 501 and the conductance of the extraction site 501 can be greatly improved. Thereby, by measuring the conductance of the extraction part 501, the transmittance of glucose to the extraction part 501 can be estimated with higher accuracy.

  In the first embodiment, as described above, as a pretreatment, the microfluid (extraction hole 501a) is formed in the extraction part 501 so that the tissue fluid is passed through the pure water in the mesh sheet 201 through the extraction part 501. Can be easily extracted.

  In the first embodiment, as described above, by applying an alternating current only between the working electrode 203 and the dry electrode 1, the conductance of the extraction part 501 can be achieved with a relatively simple configuration and a relatively short measurement time. Can be measured.

  In the first embodiment, as described above, the medium for holding pure water is a relatively small mesh having a volume of about 3.5 μl, a length of about 10 mm, a width of about 4 mm, and a thickness of about 50 μm. By using the sheet 201, the ions are removed from the state immediately after the extraction of the tissue fluid in which the ions are localized in the vicinity of the working electrode 203 by waiting for a relatively short time compared to the case of using a medium having a relatively large volume. The mesh sheet 201 can be made uniform by diffusion. Thereby, it is possible to quickly start energizing the working electrode 203 and the dry electrode 1 to obtain conductance.

(Second Embodiment)
FIG. 13 is a block diagram showing a configuration of a glucose concentration analyzer according to the second embodiment of the present invention. In the second embodiment, unlike the first embodiment, an example will be described in which a conductance measuring device that calculates conductance and a concentration analyzer that calculates glucose concentration are divided. First, the structure of the glucose concentration analyzer 300 according to the second embodiment of the present invention will be described with reference to FIG.

  The glucose concentration analyzer 300 according to the second embodiment is attached to the subject's skin 500, calculates the conductance of the extraction site 501, and extracts the glucose into the mesh sheet 201, and the mesh sheet containing glucose. The concentration analysis device 300b calculates the glucose extraction rate from 201 and calculates the glucose concentration (blood glucose level) from the conductance calculated by the conductance measuring device 300a and the glucose extraction rate.

  The structure of the conductance measuring device 300a is the same except that the glucose sensor 3 is omitted from the structure of the glucose concentration analyzer 100 of the first embodiment, and a description thereof will be omitted. When glucose is extracted in the conductance measuring device 300a, the disposable chip 200a is disposed at the extraction site 501 as in the first embodiment. The disposable chip 200a of the second embodiment has a configuration in which the sensor member 202 is removed from the disposable chip 200 of the first embodiment.

  In addition, the concentration analyzer 300b includes a receiving unit 301 for receiving the mesh sheet 201 containing glucose obtained in the conductance measuring device 300a, a glucose sensor 302 for measuring the amount of glucose extracted from the mesh sheet 201, glucose A control / analysis unit 303 for calculating the glucose extraction rate from the glucose extraction amount obtained by the sensor 302, an input unit 304 including a button for instructing the concentration analyzer 300a to start the analysis, and the analysis result are displayed. And a display unit 305. In addition, when glucose concentration analysis is performed in the concentration analyzer 300b, a sensor member 306 configured similarly to the sensor member 202 of the first embodiment is installed on the glucose sensor 302 side of the receiving portion 301. .

  The control / analysis unit 303 is connected to the control / analysis unit 4 of the conductance measurement apparatus 300a by wire or wirelessly, and is used to extract conductance values and tissue fluid from the control / analysis unit 4 of the conductance measurement apparatus 300a. It is configured to be able to receive the application time of the applied direct current.

  14 and 15 are flowcharts for explaining the operations of the conductance measurement device and the concentration analyzer of the glucose concentration analyzer according to the second embodiment of the present invention, respectively. Next, an analysis operation of the glucose concentration analyzer 300 according to the second embodiment of the present invention will be described with reference to FIGS. 2 to 4 and FIGS. 13 to 15.

  When measuring a blood glucose level using the glucose concentration analyzer 300 according to the second embodiment, first, an extraction hole 501a (see FIG. 3) is formed in the skin 500 of the subject using the needle roller 600 (see FIG. 2). To do.

  The subject wears the disposable chip 200a on the conductance measuring device 300a of the glucose concentration analyzer 300. At this time, in the conductance measuring apparatus 300a, in step S11 of FIG. 14, it is determined by a sensor (not shown) whether or not the disposable chip 200a is attached to the apparatus. This determination is repeated when the disposable chip 200a is not attached to the apparatus. If the disposable chip 200a is attached to the apparatus, the process proceeds to step S12.

  Thereafter, the conductance measuring device 300a is attached to the skin 500 of the subject so that the extraction site 501 in which the extraction holes 501a are formed and the cathode (the mesh sheet 201 of the disposable chip 200a) are in contact with each other. Thereafter, the subject gives an instruction to start measurement by pressing a button (input unit 6) of the conductance measuring device 300a.

  In conductance measuring apparatus 300a, it is determined in step S12 whether or not there has been an instruction to start measurement. This determination is repeated when there is no instruction to start measurement. When an instruction to start measurement is given, a direct current is applied to the skin 500 in step S13 as in step S3 (see FIG. 4) of the first embodiment. Thereby, glucose is extracted to the mesh sheet 201.

In addition, in the conductance measuring apparatus 300a, in step S14, the application of the direct current for glucose extraction is stopped, and then the apparatus waits for about 10 seconds as in step S5 (see FIG. 4) of the first embodiment. . As a result, ions such as Na ⁺ are homogenized in pure water in the mesh sheet 201.

  Thereafter, in the conductance measuring apparatus 300a, in steps S15 and S16, an alternating current is applied to the skin and the conductance of the extraction region 501 is increased as in steps S6 and S7 (see FIG. 4) of the first embodiment. Calculated.

  Thereafter, in the conductance measurement device 300a, in step S17, the conductance of the extraction portion 501 calculated in step S16 is transferred from the control / analysis unit 4 of the conductance measurement device 300a to the control / analysis unit 303 of the concentration analyzer 300a. Sent. Thereby, the operation of the conductance measuring apparatus 300a is completed.

  Then, the subject removes the disposable chip 200a from the conductance measuring device 300a and installs it on the concentration analyzer 300b.

  First, in the concentration analyzer 300b, it is determined in step S21 whether or not the sensor member 306 has been installed. This determination is repeated when the sensor member 306 is not installed. If the sensor member 306 is installed, the process proceeds to step S22.

  Next, in the concentration analyzer 300b, it is determined in step S22 whether or not the disposable chip 200a has been installed. This determination is repeated when the disposable chip 200a is not installed. If the disposable chip 200a is installed, the process proceeds to step S23.

  In addition, the subject places the disposable chip 200a on the concentration analyzer 300b, and then instructs the start of measurement by operating the input unit 304 including buttons and the like. At this time, the concentration analyzer 300a determines in step S23 whether or not there is an instruction to start measurement. This determination is repeated when there is no instruction to start measurement. When an instruction to start measurement is given, control is performed in step S24 based on the signal output from the photodiode of the glucose sensor 302, as in step S4 (see FIG. 4) of the first embodiment. The glucose extraction amount is calculated by the analysis unit 303.

  Next, in step S25, the concentration analyzer 300b determines whether information such as the conductance of the extraction site 501 has been received from the conductance measurement device 300a. If no information is received, this determination is repeated. If the information is received, the process proceeds to step S26. The information such as conductance includes the application time of the direct current applied at the time of glucose extraction in step S13 (see FIG. 14).

  Next, in the concentration analyzer 300b, the glucose concentration (blood glucose level) is calculated in step S26. That is, the control / analysis unit 303 calculates the glucose extraction rate J by dividing the glucose extraction amount obtained in step S24 by the DC current application time received in step S25. Then, the control / analysis unit 303 calculates the glucose concentration (blood glucose level C) of the tissue fluid based on the glucose extraction rate J and the conductance k of the extraction site 501.

  Also in the second embodiment, the correlation between the conductance and the glucose permeability can be improved by using pure water as a medium for holding glucose, as in the first embodiment. Thereby, a blood glucose level can be calculated more accurately.

  In the second embodiment, as described above, the conductance measurement device 300a that is attached to the skin of the subject and performs conductance measurement and glucose extraction, and the glucose sensor 302 for obtaining the glucose extraction amount are provided. By separating the concentration analyzer 300b, it is possible to prevent substances such as glucose oxidase, peroxidase, and coloring dye contained in the sensor member 306 necessary for measuring the amount of glucose extracted from touching the subject's skin. Can do. Thereby, a test subject's safety | security can be improved.

  Other effects of the second embodiment are the same as those of the first embodiment.

(Third embodiment)
FIG. 16 is a block diagram showing a configuration of a glucose concentration analyzer according to the third embodiment of the present invention. In the third embodiment, unlike the first and second embodiments, an example in which conductance is measured by a direct current will be described. First, the structure of the glucose concentration analyzer 400 according to the third embodiment of the present invention will be described with reference to FIG.

  As shown in FIG. 16, the glucose concentration analyzer 400 according to the third embodiment includes a chamber 401 disposed in an extraction site 501 of a subject's skin 500, a syringe 402 for supplying pure water to the chamber 401, and a chamber 401, a glucose sensor 403 provided in 401, an electrode 404 disposed in chamber 401, and electrodes 405 and 406 disposed in regions 502 and 503 other than extraction region 501 of skin 500, respectively. Further, the glucose concentration analyzer 400 measures the output of the power supply unit 407 for applying a direct current to the skin 500 via the electrodes 404 to 406, the switch circuit 408 for switching the energization pattern, and the power supply unit 407. And a control / analysis unit 410 for controlling the glucose sensor 403, the power supply unit 407, the switch circuit 408, and the like, an input unit 411, and a display unit 412.

  The chamber 401 is configured to be able to store about 80 μl of pure water. The pure water supplied to the chamber 401 has a function of holding tissue fluid containing glucose extracted from the extraction site 501. The glucose sensor 403 includes the glucose sensor 3 and the sensor member 202 of the first embodiment. The glucose sensor 403 measures the amount of glucose retained in the pure water in the chamber 401. This amount of glucose is input to the control / analysis unit 410.

  In addition, the switch circuit 408 includes a first energization pattern that energizes through the electrode 404, the electrode 405, and the skin 500, a second energization pattern that energizes through the electrode 404, the electrode 406, and the skin 500, and the electrode 405 and the electrode 406. It is also possible to switch to the third energization pattern that energizes through the skin 500.

  The voltmeter 409 is provided for measuring the voltage value in each energization pattern switched by the switch circuit 408. This voltage value is input to the control / analysis unit 410. The control / analysis unit 410 is configured to calculate the resistance Ra of the extraction region 501 based on the voltage value, and to calculate the conductance of the extraction region 501 based on the calculated resistance Ra.

  Moreover, since the input part 411 and the display part 412 are the structures similar to the input part 6 and the display part 7 of the said 1st Embodiment, respectively, detailed description is abbreviate | omitted.

  17 to 19 are equivalent circuit diagrams for explaining the first energization pattern, the second energization pattern, and the third energization pattern of the glucose concentration analyzer shown in FIG. 16, respectively. Next, with reference to FIGS. 17 to 19, the principle of measuring conductance of the glucose concentration analyzer 400 according to the third embodiment will be described.

  As shown in FIG. 17, in the first energization pattern, the output value of the voltmeter 409 is a resistance value Rab between the extraction part 501 and the part 502. In addition, the resistance value Rab between the extraction part 501 and the part 502 is greater than the resistance value Ra of the extraction part 501, the resistance value Rb of the part 502, and the skin 500 (extraction part 501, part 502, and part 503). It is represented by the sum of the resistance value Rd of the inner tissue. This resistance value Rab is expressed as the following equation (5).

Rab = Ra + Rb + Rd (5)
Here, since the resistance of the tissue inside the body than the skin 500 is sufficiently smaller than the resistance of the skin 500, Rd << Ra + Rb and 2Rd << Ra + Rb are established. Therefore, the above equation (5) can be approximated as the following equation (6).

Rab = Ra + Rb (6)
As shown in FIG. 18, in the second energization pattern, the output value of the voltmeter 409 becomes a resistance value Rac between the extraction part 501 and the part 503. This resistance value Rac can be approximated by the following equation (7), as in the case of the first energization pattern.

Rac = Ra + Rc + 2Rd = Ra + Rc (7)
As shown in FIG. 19, in the third energization pattern, the output value of the voltmeter 409 is a resistance value Rbc between the part 502 and the part 503. This resistance value Rbc can be approximated by the following equation (8), as in the case of the first energization pattern.

Rbc = Rb + Rc + Rd = Rb + Rc (8)
From the above formulas (6), (7), and (8), the resistance Ra of the extraction portion 501 is expressed as the following formula (9).

Ra = (Rab + Rac−Rbc) / 2 (9)
As described above, the resistance Ra of the extraction portion 501 can be calculated from the output values of the voltmeter in each of the first energization pattern, the second energization pattern, and the third energization pattern. In addition, the conductance k of the extraction part 501 is the reciprocal of the resistance Ra of the extraction part 501 and is represented by the following equation (10).

k = 1 / Ra (10)
In this way, the conductance is calculated in the glucose concentration analyzer 400 according to the third embodiment.

  FIG. 20 is a flowchart for explaining the analysis operation of the glucose concentration analyzer 400 according to the third embodiment. Next, the analysis operation of the glucose concentration analyzer 400 will be described with reference to FIGS. 3 and 4 and FIGS.

  When measuring a blood glucose level using the glucose concentration analyzer 400 according to the third embodiment, the subject first extracts the extraction hole 501a (see FIG. 3) as a pretreatment on the extraction site 501 as in the first embodiment. ).

  Thereafter, the subject wears the glucose concentration analyzer 400 on the skin 500 of the subject so that the chamber 401 is disposed at the extraction site 501 in which the extraction hole 501a is formed. Then, about 80 μl of pure water is supplied into the chamber by the syringe 402. Thereafter, the subject gives an instruction to start measurement by pressing a button (input unit 411) of the glucose concentration analyzer 400.

  Further, in the glucose concentration analyzer 400, it is determined in step S31 of FIG. 20 whether or not there has been an instruction to start measurement. This determination is repeated when there is no instruction to start measurement. In addition, when an instruction to start measurement is given, in step S32, the power supply unit 407 applies a direct current (DC) current of about 80 μA to the skin 500 for about 180 seconds with the electrode 404 and the electrode 405 as the cathode and the anode, respectively. To do. As a result, glucose is collected in the pure water held in the chamber 401 via the extraction site 501. Further, glucose collected in the pure water reaches a sensor member (not shown) of the glucose sensor 403 disposed on the upper surface of the chamber 401.

  Next, in the glucose concentration analyzer 400, the extraction rate J of glucose extracted into the chamber 401 by the glucose sensor 403 (unit time) in step S33, as in step S4 (see FIG. 4) of the first embodiment. Per extract).

  The glucose concentration analyzer 400 waits for about 6 minutes after stopping application of the direct current for glucose extraction in step S34. That is, in the third embodiment, since the amount of pure water in the chamber 401 is relatively large, the process waits for a longer time than the waiting time (about 10 seconds) of the first embodiment. As a result, ions are made uniform in the chamber 401.

  Next, in the glucose concentration analyzer 400, in step S35, the switch circuit 408 switches to the first energization pattern (see FIG. 17), and the power supply unit 2 applies a direct current of about 80 μA to the skin 500. At this time, a measured value (resistance value Rab) by the voltmeter 409 is input to the control / analysis unit 410.

  Next, in the glucose concentration analyzer 400, in step S36, the switch circuit 408 switches to the second energization pattern (see FIG. 18), and the power source unit 2 applies a direct current of about 80 μA to the skin 500. At this time, a measured value (resistance value Rac) by the voltmeter 409 is input to the control / analysis unit 410.

  Next, in the glucose concentration analyzer 400, in step S37, the switch circuit 408 switches to the third energization pattern (see FIG. 19), and the power source unit 2 applies a direct current of about 80 μA to the skin 500. At this time, the measured value (resistance value Rbc) by the voltmeter 409 is input to the control / analysis unit 410.

  Next, in the glucose concentration analyzer 400, in step S38, the control / analysis unit 410 calculates the resistance value Ra of the extraction portion 501 by the above formulas (9) and (10), and the reciprocal of the resistance value Ra. A conductance k is calculated. Further, the transmittance P of glucose to the skin (extraction site 501) is calculated based on the conductance k.

  Next, in the glucose concentration analyzer 400, the glucose concentration (blood glucose level) is calculated by the control / analysis unit 410 in step S39. That is, the glucose concentration C is calculated based on the glucose extraction rate J obtained in step S33, the glucose permeability P obtained in step S38 and the area S of the extraction site 501, and the above equation (2). The Thereafter, the calculated glucose concentration (blood glucose level) is displayed on the display unit 412. In the third embodiment, the glucose concentration is calculated as described above.

  In the third embodiment, as in the first embodiment, the correlation between conductance and glucose permeability can be improved by using pure water as a medium for holding glucose. Thereby, a blood glucose level can be calculated more accurately.

  In the third embodiment, as described above, the first and second electrodes 404, 405, and 406 are used to measure the conductance of the extraction region 501 by applying a direct current in three energization patterns. Compared with the case where the conductance is measured by an alternating current as in the second embodiment, the conductance can be measured stably.

  The embodiments and examples disclosed this time should be considered as illustrative in all points and not restrictive. The scope of the present invention is shown not by the above description of the embodiments and examples but by the scope of claims for patent, and includes all modifications within the meaning and scope equivalent to the scope of claims for patent.

  For example, in the first to third embodiments, an example using pure water having a NaCl concentration of 0 mM is shown. However, the present invention is not limited to this, and the saline is a low-conductivity medium having a NaCl concentration of 5 mM or less. May be used.

  In the first to third embodiments, an example in which the impedance of the cathode is obtained by measuring the voltage between the cathode and the anode by controlling the current of the power supply unit is shown. However, the impedance of the cathode may be obtained by controlling the voltage of the power supply unit and measuring the current between the cathode and the anode.

  Moreover, in the said 1st and 2nd embodiment, although the example which made the frequency of the alternating current of a power supply part about 500 Hz was shown, this invention is not restricted to this, Frequency other than 500 Hz may be sufficient. By appropriately selecting this frequency, measurement errors can be reduced.

In the first to third embodiments, the example in which the localized state of ions such as Na ⁺ is eliminated by waiting for a predetermined time after extracting glucose is shown. Not limited to this, pipetting may be performed, or the mixture may be actively stirred by a stirrer or the like. Thereby, ion can be equalized more quickly.

  Moreover, in the said 1st-3rd embodiment, although the example which formed the fine hole (extraction hole 501a) in skin with the needle roller 600 was shown as skin permeation promotion processing, this invention is not limited to this, Skin is Passive diffusion may be promoted by irradiating the extraction site with ultrasonic waves to reduce the barrier function of the skin, or alcohol or an interface that is an enhancer for promoting transdermal movement of tissue fluid to the extraction site of the skin An activator or the like may be added. Further, the barrier function of the skin may be lowered by irradiating the skin with a laser.

  In the first to third embodiments, an example in which tissue fluid containing glucose is extracted through the extraction portion 501 in which the microscopic hole (extraction hole 501a) is formed by the needle roller 600 (the skin permeation promoting process is performed). Although shown, this invention is not restricted to this, You may extract a tissue fluid from the extraction site | part which does not form a micropore (it does not give skin permeation promotion processing).

  Moreover, in the said 1st-3rd embodiment, although the example which accelerates | stimulates extraction of the tissue fluid containing glucose was shown by applying a direct current to skin, this invention is not limited to this, A direct current is applied to skin. Glucose may be extracted by passive diffusion without application. Also in the case of extraction by this passive diffusion, the correlation between conductance and skin permeability can be improved by using pure water as a medium for holding tissue fluid.

  In the first and second embodiments, the example in which the mesh sheet is used as the medium storage unit has been described. However, the present invention is not limited to this, and a sheet-like piece of paper may be used as the medium storage unit. Non-shaped paper pieces or nylon may be used. Moreover, you may use the collection medium which affixed the nonelectroconductive gel which consists of polyacrylic acid etc. on the plate-shaped member. Further, from the viewpoint of bringing the electrode and the skin closer, it is preferable that the medium housing portion is in a sheet form. By bringing the electrode close to the skin, the extraction rate of the analyte can be increased.

  In the first and second embodiments, an example using a mesh sheet having a thickness of about 50 μm is shown. However, the present invention is not limited to this, and the thickness of the mesh sheet may be about 500 μm or less.

  Moreover, although the said 1st-3rd embodiment demonstrated the example which applies this invention to the glucose concentration analyzer which extracts glucose from a biological body and calculates a blood glucose level, this invention is not limited to this, A biological body The present invention may also be applied to a component concentration analyzer that analyzes the concentration of analytes other than glucose. Examples of the analyte extracted by the component concentration analyzer to which the present invention is applicable include biochemical components and drugs administered to the subject. Examples of biochemical components include proteins such as albumin, globulin, and enzymes, which are a kind of biochemical components. Examples of biochemical components other than protein include creatinine, creatine, uric acid, amino acids, fructose, galactose, pentose, glycogen, lactic acid, pyruvic acid, and ketone bodies. Examples of the drug include digitalis preparations, theophylline, arrhythmic agents, antiepileptic agents, amino acid saccharide antibiotics, glycopeptide antibiotics, antithrombotic agents, and immunosuppressive agents.

  In addition, when the present invention is applied to the glucose concentration analyzer of the first to third embodiments or the component concentration analyzer that extracts an analyte other than glucose from a living body, HPLC (High Performance Liquid Chromatography) The control / analysis unit and the like may be configured to analyze proteins or biochemical components other than proteins and drugs using other measurement methods such as the method.

  Moreover, although the example which forms the extraction hole 501a in the test subject's skin 500 using the needle roller 600 was shown in the said 1st-3rd embodiment, this invention is not limited to this, It shows to FIG. 21 and FIG. A puncture device 700 according to a modification can also be used. The puncture device 700 is equipped with a sterilized microneedle chip 800 (see FIG. 22), and the microneedle 810 of the microneedle chip 800 is brought into contact with the skin of a living body (for example, the skin of a human body), It is an apparatus for forming body fluid extraction holes (micropores) in the skin of a living body. More specifically, the puncture tool 700 includes a spring for biasing the piston and a fixing mechanism for fixing the piston in a state of being biased by the spring. When using the puncture device 700, the puncture device 700 is set on the skin of the subject with the fine needle tip 800 attached to the lower part of the piston. Thereafter, when the fixing mechanism is removed by pressing the button portion 710, the fine needle tip 800 collides with the skin by the elastic force of the spring. Thereby, micropores are formed.

It is a block diagram which shows the structure of the glucose concentration analyzer by 1st Embodiment of this invention. It is the perspective view which showed the microneedle used when forming a micropore in a test subject's skin. It is sectional drawing which showed the state of the skin in which the micropore was formed with the microneedle shown in FIG. 3 is a flowchart for explaining an analysis operation of the glucose concentration analyzer shown in FIG. 1. It is a characteristic view which shows the relationship between the conductance in the case of Example 1, and glucose permeability. 6 is a characteristic diagram showing the relationship between conductance and glucose permeability in the case of Example 2. FIG. It is a characteristic view which shows the relationship between the conductance in the case of Example 3, and glucose permeability. It is a characteristic view which shows the relationship between the conductance in the case of Example 4, and glucose permeability. It is a characteristic view which shows the relationship between the conductance in the case of the comparative example 1, and glucose permeability. It is a bar graph which shows the measurement error of the glucose permeability in the case of Examples 1-4 and the comparative example 1. FIG. It is a schematic diagram for demonstrating the hypothesis at the time of considering the mechanism in which the effect of this invention was acquired. It is a schematic diagram for demonstrating the hypothesis at the time of considering the mechanism in which the effect of this invention was acquired. It is a block diagram which shows the structure of the glucose concentration analyzer by 2nd Embodiment of this invention. It is a flowchart for demonstrating the measurement operation | movement of the conductance measuring apparatus of the glucose concentration analyzer shown in FIG. It is a flowchart for demonstrating the analysis operation | movement of the concentration analyzer of the glucose concentration analyzer shown in FIG. FIG. 5 is a block diagram showing a configuration of a glucose concentration analyzer according to a third embodiment of the present invention. It is an equivalent circuit diagram for demonstrating the 1st electricity supply pattern of the glucose concentration analyzer shown in FIG. It is an equivalent circuit diagram for demonstrating the 2nd electricity supply pattern of the glucose concentration analyzer shown in FIG. It is an equivalent circuit diagram for demonstrating the 3rd electricity supply pattern of the glucose concentration analyzer shown in FIG. It is a flowchart for demonstrating the analysis operation | movement of the glucose concentration analyzer shown in FIG. It is an external view which shows the puncture tool by the modification used when forming a micropore in a test subject's skin. It is a perspective view which shows the fine needle chip | tip attached to the puncture device shown in FIG.

Explanation of symbols

1 Dry electrode (second electrode)
2,407 Power supply unit (power supply)
3, 302, 403 Glucose sensor (component amount measuring unit)
4,410 Control / analysis unit (analysis unit)
5, 409 Voltmeter (Energization result measurement part)
100, 300, 400 Glucose concentration analyzer (skin permeability measuring device, component concentration analyzer)
200 disposable chip (extraction cartridge)
201 Mesh sheet (medium container)
203 Working electrode (first electrode)
300a Conductance measuring device (skin permeability measuring device)
300b Concentration analyzer (measuring device)
301 Receiving part (second cartridge mounting part)
303 Control / analysis unit (analysis acquisition unit)
401 chamber (medium container)
404 electrode (first electrode)
405 electrode (second electrode)
406 Electrode (third electrode)
500 Skin 501 Extraction site

Claims (8)

Supplying a low-conductivity medium as a medium for holding tissue fluid containing a predetermined component of the subject in the medium container;
Disposing the medium container in an extraction site of the subject's skin;
Extracting the tissue fluid into a low conductivity medium in the medium container through the extraction site;
Supplying power between a first electrode for supplying power to the extraction site and a second electrode for supplying power to skin other than the extraction site;
Measuring a value corresponding to an amount of a predetermined component contained in the tissue fluid extracted through the extraction site in the low-conductivity medium;
Calculating the concentration of the predetermined component in the tissue fluid based on the energization result of the power supplied between the first electrode and the second electrode and the measurement result of the value corresponding to the amount of the predetermined component; Prepared ,
The step of calculating the concentration of the predetermined component in the tissue fluid includes the step of measuring the conductance of the extraction site based on the energization result of the power supplied between the first electrode and the second electrode,
The step of measuring the conductance includes the step of extracting the tissue fluid into the low-conductivity medium, and then conducting the conductance in a state where ions in the low-conductivity medium are substantially homogeneous in the low-conductivity medium. A component concentration analysis method including a measuring step . The predetermined component includes glucose, component concentration analyzing method according to claim 1. A medium container that is disposed at an extraction site of the subject's skin and contains a low-conductivity medium for holding tissue fluid containing a predetermined component of the subject;
A first electrode for supplying power to the extraction site;
A second electrode for supplying power to a first site other than the extracted site of the subject's skin;
A power supply for supplying power to the first electrode and the second electrode;
A conductance measurement unit that measures conductance of the extraction site by supplying electric power from the power source to the first electrode and the second electrode ;
A skin permeability measuring device, comprising: a homogenizing means for homogenizing ions in a low-conductivity medium in the low-conductivity medium in the medium container . The power source is configured to be able to apply an alternating current between the first electrode and the second electrode,
The conductance measuring unit is configured to measure the conductance of the extraction region based on the current results of the applied alternating current between the first electrode and the second electrode by said power source, according to claim 3 Skin permeability measuring device. A third electrode for supplying power to a second part other than the extracted part of the subject's skin;
The power supply is configured to be able to apply a direct current between the first electrode and the second electrode, between the first electrode and the third electrode, and between the second electrode and the third electrode. And
The conductance measurement unit is configured to apply a direct current applied between the first electrode and the second electrode, between the first electrode and the third electrode, and between the second electrode and the third electrode by the power source. The skin permeability measuring device according to claim 3 , wherein the device is configured to measure conductance of the extraction site based on a result of energization. A medium container that is disposed at an extraction site of the subject's skin and contains a low-conductivity medium for holding tissue fluid containing a predetermined component of the subject;
A first electrode for supplying power to the extraction site;
A second electrode for supplying power to the skin other than the extraction site;
A power supply for supplying power to the first electrode and the second electrode;
An energization result measuring unit for measuring an energization result by supplying electric power from the power source to the first electrode and the second electrode;
A component amount measuring unit that measures a value corresponding to the amount of a predetermined component contained in the tissue fluid extracted through the extraction site in the low-conductivity medium supplied as a medium to the medium containing unit;
An analysis unit that calculates the concentration of the predetermined component in the tissue fluid based on the energization result and a value corresponding to the amount of the predetermined component ;
An extraction cartridge including the medium accommodating portion and the first electrode;
A main body device including a first cartridge mounting unit for mounting the extraction cartridge, the second electrode, the power source, and the energization result measuring unit;
A component concentration analyzer comprising: a second cartridge mounting unit for mounting the extraction cartridge; a measuring device including the component amount measuring unit and the analyzing unit. The energization results measuring section, based on the current result of supplying power to said first electrode and said second electrode from said power source, and is configured to measure the conductance of the extraction region, according to claim 6 Component concentration analyzer. The medium accommodating portion is formed in a sheet shape and is arranged to face the extraction site,
8. The component concentration analyzer according to claim 6 , wherein the sheet-shaped medium accommodating portion has a thickness of 500 μm or less.

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