Patent Application
20080208024
This application claims priority under 35 U.S.C. §119 to Japanese Patent Application Nos. JP2007-048262 filed Feb. 28, 2007 and JP2007-078375 filed Mar. 26, 2007, the entire contents of which are hereby incorporated by reference.
The present invention relates to a method for measuring skin permeability, method for analyzing component concentration, device for measuring skin permeability, and device for analyzing component concentration, and specifically relates to a method for measuring skin permeability which includes a process for supplying a medium for holding tissue fluid, which contains predetermined components of a subject, to a medium containing part, a method for analyzing the component concentrations, a device for measuring skin permeability which is provided with a medium containing part for receiving tissue fluid that contains predetermined components of a subject, and a device for analyzing the component concentrations.
The present invention further relates to a skin conductance measuring device, component concentration analyzing device, skin conductance measuring method, and component concentration analyzing method, and specifically relates to a skin conductance measuring device for measuring the conductance of the skin of a subject, a component concentration analyzing device for analyzing the concentrations of predetermined components contained in the tissue fluid of the subject using the measured skin conductance, a skin conductance measuring method, and a component concentration analyzing method.
Blood sugar level analyzing methods are know which are provided with a step of supplying a medium, which holds tissue fluid that includes predetermined components of a subject, to a medium containing part (US20060029991). Component concentration analyzers are also known which measure the conductance of the skin of a subject, and analyze the component concentrations of predetermined components contained in the tissue fluid of the subject using this conductance (US20060029991).
In US20060029991, glucose is extracted through the skin of a subject by so-called reverse iontophoresis for analyzing the blood sugar level without collecting blood. That is, physiological saline solution is supplied as a medium for holding the glucose within the chamber disposed on the skin of the subject, and an electric current is applied to the skin for a predetermined time through electrodes positioned on the skin of the subject. Ions present in the tissue fluid of the subject therefore migrate to the electric potential formed by the electric current. The glucose contained in the tissue fluid also migrates in conjunction with the migration of the ionic substance, and the tissue fluid containing the glucose extracted from the skin is holded in the physiological saline within the chamber. The amount of glucose within the chamber is measured by a sensor, and the glucose extraction speed is calculated by measuring the time during which the electric current was applied to obtain the glucose amount.
In US2006009991, the conductance of the skin of the subject is measured to correct the extraction amount of the transdermally extracted glucose, and the condition of the skin of the subject is monitored by this conductance. Then, the permeability of glucose through the skin (glucose permeability) in correlation with the conductance is estimated from the conductance, and the blood sugar level of the subject is calculated based on the glucose extraction rate and glucose permeability.
In US 20060029991, however, the conductance and glucose permeability may poorly correlate as a result of the salts such as Na+, Cl and the like contained in the physiological saline solution because physiological saline solution is used as the medium for holding the tissue fluid which includes glucose. Estimating glucose permeability with good accuracy is therefore difficult. Since it is difficult to accurately estimate glucose permeability, it is also difficult to accurately calculate the blood sugar level based on the since the calculation is based on the glucose permeability.
The component concentration analyzer disclosed in US20060029991 is provided with a switching circuit and three electrodes including a first electrode, second electrode, and third electrode disposed on the skin of a subject. The switching circuit is configured so as to be capable of switching the current flow pattern among a first current flow pattern in which a direct current flows to the skin for a predetermined time through the first electrode and second electrode, a second current flow pattern in which a direct current flows to the skin for a predetermined time through the second electrode and third electrode, and a third current flow pattern in which a direct current flows to the skin for a predetermined time through the third electrode and first electrode.
In US20060029991, the conductance of the skin is calculated based on a first electrical information, second electrical information, and third electrical information obtained by the respective first current flow pattern second current flow pattern, and third current flow pattern, and calculates the component concentration of a predetermined component contained in the tissue fluid of the subject based on the calculated conductance.
In the component concentration analyzer disclosed in US20060029991, however, a problem arises in that the current flow time is lengthened to calculate the conductance of the skin because the current must flow for predetermined times in the respective first current flow pattern, second current flow pattern, and third current flow pattern in order to obtain the first electrical information, second electrical information, and third electrical information necessary to calculate the conductance of the skin. A further problem arises in that electric power consumption is increased since a direct current is applied for a long time. A further problem is the complexity of the apparatus structure since switching circuits are necessary to switch the three electrodes and current flow patterns.
The scope of the present invention is defined solely by the appended claims, and is not affected to any degree by the statements within this summary.
To resolve above-mentioned problems, a first object of the present invention is to provide a method of measuring skin permeability capable of estimating, with greater accuracy, the permeability of predetermined components through the skin, and a method of analyzing component concentrations capable of calculating, with greater accuracy, the concentrations of predetermined components in tissue fluid.
A further object of the present invention is to provide a skin permeability measuring apparatus capable of estimating, with greater accuracy, the permeability of predetermined components through the skin, and a component concentration analyzer capable of calculating, with greater accuracy, the concentrations of predetermined components in tissue fluid.
A still further object of the present invention is to provide a method for measuring skin conductance, a method for analyzing component concentrations, skin conductance measuring apparatus, and component concentration analyzer capable of calculating the conductance of skin with a short current application time, low electric power consumption, and simplified apparatus structure.
The embodiments of the present invention are described hereinafter based on the drawings.
As shown in
The glucose concentration analyzer 100 is provided with a dry electrode 1 formed of Ti and disposed at a region 501 outside of the region 501 on the skin 500 of a subject, a power source 2 for supplying an alternating current and a direct current through current controls, a glucose sensor 3 configured by a semiconductor laser and photodiode, a control and analysis part 4 which controls the power source 2 and the glucose sensor 3, a voltmeter 5, an input part 6 on the glucose concentration analyzer 100 which is configured by buttons or the like for the subject to specify the start of measurement, and a display part 7 for displaying the measurement results and the like. A disposable chip 200, which is replaceable for each measurement when analysis is performed, is mounted on the glucose concentration analyzer 100.
The disposable chip 200 includes a mesh sheet 201 which is permeated with purified water, a sensor member 202 which is painted with a substance that reacts with the glucose contained in the mesh sheet 201 and which is disposed on the top surface of the mesh sheet 201, an electrode 203 formed of Ag/AgCl, a reference electrode 204 formed of Ag/AgCl, and a masking tape 205. When the disposable chip 200 is in the mounted state, the sensor member 202 is disposed at the bottom part of the glucose sensor 3, and the electrode 203 and reference electrode 204 are connected to the power source 2 and the voltmeter 5.
The mesh sheet 201 is configured so as to be capable of holding approximately 3.5 μl of purified water. The mesh sheet 201 is also made of nylon and substantially inelastic so that the thickness does not vary. Specifically, is formed of woven nylon fibers approximately 30 μm in thickness, and has a square net mesh structure approximately 33 μm on a side. The mesh sheet 201 is approximately 10 mm long, approximately 4 mm wide, and approximately 50 μm thick.
The mesh sheet 201 makes contact with the surface of the skin 500 of the subject opposite the extraction region 501. The sensor 202 and electrode 203 are disposed on the top surface of the mesh 201 on the opposite side from the extraction region 501.
On the side facing the mesh sheet 201, the sensor member 202 is painted with an enzyme (glucose oxidase) which acts as a catalyst for glucose, and enzyme (peroxidase) which acts as a catalyst for hydrogen peroxide (H2O2), and a color-producing agent which reacts with active oxygen. For example, N,N-bis(2-hydroxy-3-sulfopropyl)tolidene potassium salt,3,3′,5,5′-tetramethylbenzyldene and the like may be used as the color-producing agent.
The masking tape 205 is provided to prevent direct contact between the reference electrode 204 and the skin 500 of the subject, and to reduce the discomfort of the subject caused by the current flowing to the skin 500. The masking tape 205 is disposed on the bottom surface of the mesh sheet 201 and the reference electrode 204. The masking tape 205 is provided with an orifice 205a which measure approximately 7 mm2. The mesh sheet 201 is configured so as to make contact with the extraction region 501 through these orifices 205a.
When the disposable chip 200 is mounted on the glucose concentration analyzer 100, the power source 2 is configured to apply a current (direct current and alternating current) to the skin 500 of the subject through the electrode 203 and the dry electrode 1. The power source 2 applies a direct current to the skin 500 with the electrode 203 functioning as a negative electrode and the dry electrode 1 functioning as a positive electrode.
The glucose sensor 3 detects the amount of glucose contained in the mesh sheet 201 by measuring the color-producing agent and the like of the sensor member 202. The voltmeter 5 is configured to measure the voltage between the dry electrode 1 and electrode 204 when a current (alternating current) is applied to the skin 500 of the subject through the electrode 203 and dry electrode 1 from the power source 2. The value measured by the voltmeter 5 and the amount of glucose measured by the glucose sensor 3 are input to the control and analysis part 4.
The control and analysis part 4 calculates the impedance of the extraction region 501 using the voltage value received from the voltmeter 5, and calculates the conductance k of the extraction region 501 based on the calculated impedance value. The control and analysis part 4 also calculates the final glucose concentration, that is, essentially the blood sugar level, of the tissue fluid based on the conductance k of the extraction region 501 and the amount of glucose in the mesh sheet 201 which was received from the glucose sensor 3.
As shown in
When the blood sugar level is measured using the glucose concentration analyzer 100 of the first embodiment, micro extraction holes 501a are first formed in the skin 500 of the subject using the needle roller 600 (refer to
The subject installs the disposable chip 200 (refer to
The subject subsequently mounts the glucose concentration analyzer 100 on the skin 500 of the subject so that the extraction region 501, in which the extraction holes 501a have been formed, and the negative electrode (mesh sheet 201) are in surface contact. At this time the purified water contained in the mesh sheet 201 penetrates into the extraction holes 501a formed in the skin 500. The tissue fluid within the extraction holes 501a is then dispersed within the purified water held in the mesh sheet 201 when the tissue fluid exuded to the extraction holes 501a of the skin 500 mixes with the purified water from the mesh sheet 201. Tissue fluid from the corium is again exuded to the extraction holes 501a because the osmotic pressure within the extraction holes 501a is lower than the osmotic pressure of the corium of the skin. As a result, the tissue fluid exuded through the extraction holes 501a formed in the skin 500 is dispersed to a degree in the purified water held by the mesh sheet 201 before a current is applied from the power source 2. The subject subsequently issues a measurement start instruction by pressing a button (input part 6) of the glucose concentration analyzer 100.
In the glucose concentration analyzer 100, a determination is also made in step S2 as to whether or not a measurement start instruction has been issued. This determination is repeated when a measurement start instruction has not been issued. When a measurement start instruction has been issued, the power source applies a direct current of approximately 80 μA to the skin 500 for approximately 180 seconds in step S3. The charged ionic components (Na+ and the like) present in the extraction holes 501a therefore actively migrate. Glucose at a level which is detectable by the glucose sensor 3 (refer to
In the glucose concentration analyzer 100, the extraction rate (amount extracted per part time) of glucose extracted to the purified water collected in the mesh sheet 201 is measured in step S4.
Specifically, the glucose that reaches the sensor member 202 reacts with the glucose oxidase which acts as a catalyst, and the resulting product of this reaction, hydrogen peroxide (H2O2) reacts with the peroxidase which acts as a catalyst. Active oxygen is generated as a result. The color-producing agent painted on the sensor member 202 reacts with the active oxygen and produces a color. The color-producing agent thus produces a color the depth of which accords with the amount of glucose extracted from the living body.
Among the laser light irradiated from the semiconductor laser of the glucose sensor 3, on the other hand, there is a change in the intensity of the light which passes through the sensor member 202 sitting in contact with the mesh sheet 201 containing the purified water because the light intensity of the color produced by the color-producing agent accords with the amount of glucose extracted from the living body.
As a result, a light which has an intensity that accords with the amount of glucose arriving at the sensor member 202 impinges the photodiode of the glucose sensor 3, and a signal is output which corresponds to the intensity of the impinging light. The control and analysis part 4 then calculates the amount of extracted glucose based on the signal output from the photodiode of the glucose sensor 3. The control and analysis part 4 calculates the glucose extraction rate J by dividing the obtained amount of extracted glucose by the time (approximately 180 seconds) during which the power source 2 applied the direct current.
In step S5, the glucose concentration analyzer 100 waits for approximately 10 seconds after the application of the direct current for extracting glucose has terminated. That is, the ions of Na+ and the like disperse and become uniform throughout the mesh sheet 201 during the approximately 10 second waiting time because the ions of Na+ and the like are localized near the active electrode 203 of the mesh sheet 201 immediately after the direct current has been applied.
In the glucose concentration analyzer 100, the power source 2 applies an alternating current (approximately 500 Hz) of approximately ±30 μA to the skin 500 in step S6. This time the measurement value (impedance of the extraction region 501) of the voltmeter 5 is sent to the control and analysis part 4.
In step S7 in the glucose concentration analyzer 100, the conductance of the extraction region 501 is calculated based on the measurement value (impedance of the extraction region 501) of the voltmeter 5 obtained in step S6. That is, the measurement value of the voltmeter 5 approximates the sum of the voltage drop of the extraction region 501 and the voltage drop of the area 502. In the case of a high frequency alternating current (approximately 100 Hz or greater), the measurement value of the voltmeter 5 approximates the voltage drop of the extraction region 501 since the impedance of the area 502 is smaller compared to the impedance of the extraction region 501. The control and analysis part 4 calculates a reciprocal of the impedance of the extraction region 501 as the conductance k of the extraction region 501.
In step S8 the glucose concentration analyzer 100 calculates the glucose concentration (blood sugar level). That is, equation (1) below is established among the blood sugar level C, glucose extraction rate J, surface area S of the extraction region 501, and glucose permeability P of the skin 500 (extraction region 501).
J=S×C×P (1)
The blood sugar level C can therefore be expressed by equation (2) below.
C=J/(S×P) (2)
A specific relational equation has been established experimentally for the glucose permeability P and the conductance k of the extraction region 501 calculated in step S6 and is described in US20060029991, and the glucose permeability P can be calculated based on this relational equation.
The glucose extraction rate J is obtained in step S4, and since the surface area S of the extraction region 501 is the surface area of the orifice 205a of the masking tape 205 (approximately 7 mm2), the blood sugar level C can be calculated based on equation (2) above. Furthermore, the calculated blood sugar level can be displayed on the display part 7. The analysis of the blood sugar level is performed as described above by the glucose concentration analyzer 100 of the first embodiment.
Comparative experiments are described below which verify the results using purified water as the medium for holding tissue fluid which contains glucose.
In the comparative experiments, the glucose extraction rate J and conductance k were measured a plurality of times for a plurality of subjects using the glucose concentration analyzer 100 and same measuring sequence as in the first embodiment. Furthermore, the blood sugar level C of the same subject was measured using a different blood sugar-level measuring apparatus (a model manufactured by Nipro Corporation, Ltd.) than the glucose concentration analyzer 100 of the first embodiment. The permeability P was calculated from the blood sugar level C, glucose extraction rate J, and surface area S using equation (1). Data (k, P) of the mutually corresponding glucose permeability P and conductance k were plotted on a coordinate map with the conductance k and permeability P on the horizontal axis and vertical axis, respectively.
The comparative experiments were performed using mesh sheets 201 saturated with media (examples 1˜4, and reference example 1) with different concentrations of NaCl concentrations. The concentrations of NaCl of the media used in examples 1˜4 and reference example 1 are shown in Table 1 below. Example 1 used purified water as an example of a medium with low conductivity used as the medium in the first embodiment, and reference example 1 used a conventional medium of physiological saline solution. Examples 2˜4 used examples of other media with low conductivity.
As shown in Table 1, example 1, which used a concentration of NaCl of 0 mM (purified water), had a conductivity of 0 (μS (seimens)/cm) and resistivity of 18300 (KΩ·cm). Example 2, which used a concentration of NaCl of 0.5 mM, had a conductivity of 59.72 μS/cm) and resistivity of 16.745 (KΩ·cm). 6 Example 3, which used a concentration of NaCl of 1 mM, had a conductivity of 119.44 (μS/cm) and resistivity of 8.372 (KΩ·cm). Example 4, which used a concentration of NaCl of 5 mM, had a conductivity of 597.2 (μS/cm) and resistivity of 1.674 (KΩ·cm). Reference example 1, which used a concentration of NaCl of 154 mM (physiological saline solution), had a conductivity of 18393.76 (μS/cm) and resistivity of 0.054 (KΩ·cm).
The results of the experiments performed using the examples 1˜4 and reference example 1 are shown in
Measurement errors were then determined in the experimental results of examples 1˜4 and reference example 1. The measurement errors of example 1 are described in detail below with reference to
Divergence rate=(actual permeability/estimated permeability)×100=(P/(112.84k+2.6793))×100 (3)
Thereafter, the standard deviation and average value are calculated from the divergence rate at each point, and the measurement error is calculated fusing equation (4) below.
Measurement error+(standard deviation/average value)×100 (4)
The measurement error was calculated in the manner for examples 1 through 4 and the reference example 1. The calculation results are shown in Table 2 below and in
As shown in Table 2, the measurement error of example 1 was 9.34057, and the measurement error of example 2 was 15.2159. The measurement error of example 3 was 18.143, and the measurement error of example 4 was 18.8571. Since the measurement error of reference example 1 was 24.0272, the measurement errors of examples 1 through 4 are clearly improvements over the measurement error of reference example 1. Thus, the measurement error becomes smaller as the concentration of NaCl becomes lower, as shown in Table 2 and
The mechanism by which the above experimental results were obtained is considered below.
The tissue fluid extracted from the skin (extraction region) of the subject contains sodium ion (Na+) as well as glucose. When a direct current is applied to extract the glucose, chloride ions (Cl—) and sodium ions (Na+) are forcibly diffused from the electrodes (Ag/AgCl) and the skin (extraction region) by the electric field which forms. Tissue fluid that contains glucose is extracted into the medium because the glucose also migrates in conjunction with the forcible diffusion of the sodium ions. Thus, the behavior of the sodium ions is thought to be closely associated with the mechanism by which glucose is extracted.
A current flows by means of the charges carried by the sodium ions and chloride ions. The percentage of the current flowing by the chloride ions as a medium at this time can be designated the transport rate tCl of the chloride ions, and the percentage of the current flowing by the sodium ions as a medium at this time can be designated the transport rate tNa of the sodium ions (tCl+tNa=1).
As shown in
When physiological saline solution is used as the medium (reference example 1), the medium contains large amounts of chloride ions (Cl—) and sodium ions (Na+), as shown in
In the first embodiment described above, excellent correlation can be attained between the permeability of glucose through the extraction region 501 and the conductance of the extraction region 501 by using purified water as the medium for holding tissue fluid that contains glucose, compared to using an electrically conductive medium such as physiological saline or the like which has low resistivity of approximately 0.054. The permeability of glucose through the extraction region can therefore be estimated with greater accuracy by measuring the conductance of the extraction region 501.
In the first embodiment described above, tissue fluid can be easily extracted through the extraction region 501 into the purified water within the mesh sheet 201 by forming micropores (extraction holes 501a) in the extraction region 501 as a preprocess.
In the first embodiment described above, the conductance of the extraction region 501 can be measured in a relatively short time using a relatively simple construction by applying an alternating current only between the electrode 203 and the dry electrode 1.
In the first embodiment described above uses a mesh sheet 201 of relatively small capacity of approximately 3.5 μl, and which has a relatively small thickness of approximately 50 μ, width of approximately 4 mm, and length of approximately 10 mm, as the medium for holding the purified water, so that ions can be uniformly diffused in the mesh sheet 201 immediately after extraction of the tissue fluid localized near the electrode 203 where the ions are present by implementing a relatively short waiting time compared to using a relatively large capacity of medium, thus, the conductance can be rapidly obtained by starting the current flow to the electrode 203 and the dry electrode 1.
The glucose concentration analyzer 300 of the second embodiment is configured by a conductance measuring apparatus 300a which is mounted on the skin 500 of a subject to calculate the conductance of the extraction region 501a and extract glucose to the mesh sheet 201, and a concentration analyzer 300b which calculates the glucose extraction rate from the mesh sheet 201 that contains glucose, and calculates the concentration of the glucose (blood sugar level) from the glucose extraction rate and the conductance calculated by the conductance measuring apparatus 300a.
The structure of the conductance measuring apparatus 300a is identical to the structure of the glucose concentration analyzer 100 of the first embodiment with the exception that the glucose sensor 3 is omitted, and the description is therefore abbreviated. When glucose is extracted in the conductance measuring apparatus 300a, a disposable chip 200a is mounted at the extraction region 501 similar to the first embodiment. The disposable chip 200a of the second embodiment has a configuration in which the sensor member 202 is omitted from the disposable chip 200 of the first embodiment.
The concentration analyzer 300b is provided with a receiving part 301 for receiving the mesh sheet 201 which contains the glucose obtained in the conductance measuring apparatus 300a, a glucose sensor 302 for measuring the amount of glucose extracted from the mesh part 201, a control and analysis part 303 for calculating the glucose extraction rate from the amount of extracted glucose obtained by the glucose sensor 302, an input part 304 configured by buttons or the like for starting the analysis by the concentration analyzer 300b, and a display part 305 for displaying analysis results and the like. A sensor member 306, which has a configuration identical to that of the sensor member 202 of the first embodiment, is disposed on the glucose sensor 302 side of the receiving part 301 when performing the analysis of glucose concentration in the concentration analyzer 300b.
The control and analysis part 303 is connected by wire or wirelessly to the control and analysis part 4 of the conductance measuring apparatus 300a, and is capable of receiving the conductance value and the current application time of the direct current applied to extract the tissue fluid from the control and analysis part 4 of the conductance measuring apparatus 300a.
When the blood sugar level is measured using the glucose concentration analyzer 300 of the second embodiment, extraction holes 501a (refer to
The subject installs the disposable chip 200a in the conductance measuring apparatus 300a of the glucose concentration analyzer 300. At this time, the conductance measuring apparatus 300a determines whether or not a disposable chip 200a is installed in the apparatus in step S1 of
Thereafter, the conductance measuring apparatus 300a is mounted on the skin 500 of the subject so that the extraction region 501 in which the extraction holes 501a have been formed, and the negative electrode (mesh sheet 201 of the disposable chip 200a) are in contact. The subject subsequently issues a measurement start instruction by pressing the button (input part 6) of the conductance measuring apparatus 300a.
The conductance measuring apparatus 300a also determines whether or not a measurement start instruction has been issued in step S12. This determination is repeated when a measurement start instruction has not been issued. When the measurement start instruction has been issued, a direct current is applied to the skin 500 in step S13 in the same manner as step S3 of the first embodiment (refer to
The conductance measuring apparatus 300a waits approximately 10 seconds in step S14 immediately after the application of the direct current for extracting glucose has been terminated similar to step S5 of the first embodiment (refer to
In the conductance measuring apparatus 300a, an alternating current is subsequently applied to the skin in step S15 and the conductance of the extraction region 501 is calculated in step S16 similar to steps S6 and S7 of the first embodiment (refer to
In step S17, the conductance measuring apparatus 300a sends the conductance of the extraction region 501 calculated in step S16 from the control and analysis part 4 of the conductance measuring apparatus 300a to the control and analysis part 303 of the concentration analyzer 300b. The operation of the conductance measuring apparatus 300a thus ends.
The subject then removes the disposable chip 200a from the conductance measuring apparatus 300a, and installs the disposable chip 200a in the concentration analyzer 300b.
The concentration analyzer 300b first determines whether or not a sensor member 306 is installed in step S21. This determination is repeated when the sensor member 306 has not been installed. When a sensor member 306 has been installed the routine continues to step S22.
In step S22 the concentration analyzer 300b determines whether or not the disposable chip 200a has been installed. This determination is repeated when a disposable chip 200a is not installed. The routine continues to step S23 when a disposable chip 200a is installed.
The subject issues a measurement start instruction by operating the input part 304, which is configured by a button or the like, after the disposable chip 200a has been installed in the concentration analyzer 300b. In the glucose concentration analyzer 300a, a determination is also made in step S23 as to whether or not a measurement start instruction has been issued. This determination is repeated when a measurement start instruction has not been issued. When a measurement start instruction has been issued, the control and analysis part 303 calculates the amount of extracted glucose in step S24 based on the signal output from the photodiode to the glucose sensor 302 similar to step S4 of the first embodiment (refer to
In step S25, a determination is then made in the concentration analyzer 300b as to whether or not information such as the conductance of the extraction region 501 has been received from the conductance measuring apparatus 300a. This determination is repeated when information has not been received. When information has been received the routine continues to step S26. The information of conductance and the like includes the application time of the direct current applied to extract the glucose in step S13 (refer to
In step S26, the glucose concentration (blood sugar level) is calculated in the concentration analyzer 300b. That is, the control and analysis part 303 calculates the glucose extraction rate J by dividing the amount of extracted glucose obtained in step S24 by the application time of the direct current received in step S25. The control and analysis part 303 then calculates the glucose concentration (blood sugar level) of the tissue fluid based on the conductance k of the extraction region 501 and the glucose extraction rate.
Similar to the first embodiment, the second embodiment provides excellent correlation between the conductance and glucose permeability by using purified water as a medium for holding glucose. The blood sugar level can therefore be calculated with greater accuracy.
In the second embodiment described above, it is possible to prevent substances such as glucose oxidase, peroxidase, and color-producing agent contained in the sensor member 306, which are required to measure the amount of extracted glucose, from coming into contact with the skin of the subject by separating the conductance measuring apparatus 300a which measures conductance and extracts glucose, and the concentration analyzer 300b which is provided with the glucose sensor 302 that obtains the amount of extracted glucose while mounted on the skin of the subject. The safety of the subject s therefore increased.
The other effects of the second embodiment are identical to the effects of the first embodiment.
As shown in
The chamber 401 is capable of accommodating approximately 80 μl of purified water. The purified water supplied to the chamber 401 has the function of holding the glucose which is extracted from the extraction region 501. The glucose sensor 403 is configured by the glucose sensor 3 and the sensor member 202 of the first embodiment. The amount of glucose holded in the purified water of the chamber 401 is measured by the glucose sensor 403. The amount of glucose is sent to the control and analysis part 410.
The switching circuit 408 is capable of switching among a first current flow pattern in which a current flows through the electrodes 404 and 405 and the skin 500, a second current flow pattern in which a current flows through the electrodes 404 and 406 and the skin 500, and a third current flow pattern in which a current flows through the electrodes 405 and 406 and the skin 500.
The voltmeter 409 is provided to measure the voltage value in the current flow patterns which are respectively switched by the switching circuit 408. This current value is sent to the control and analysis part 410. The control and analysis part 410 is configured to calculate the resistance Ra of the extraction region 501 based on the voltage value, and calculate the conductance of the extraction region 501 based on the calculated resistance Ra.
Since the input part 411 and the display part 412 are identical to the input part 6 and display part 7 of the first embodiment, further description is omitted.
In the first current flow pattern as shown in
Rab=Ra+Rb+Rd (5)
Since the resistance of the tissue on the interior side of the skin 500 is sufficiently lower than the resistance of the skin 500, the relationships Rd<<Ra+Rb and 2Rd<<Ra+Rb are established. Equation (5) therefore approximates equation (6) below.
Rab=Ra+Rb (6)
In the second current flow pattern as shown in
Rac=Ra+Rc+2Rd=Ra+Rc (7)
In the third current flow pattern as shown in
Rbc=Rb+Rc+Rd=Rb+Rc (8)
From equations (6), (7), and (8), the resistance Ra of the extraction region 501 can be expressed by equation (9) below.
Ra=(Rab+Rac−Rbc)/2 (9)
Thus, the resistance Ra of the extraction region 501 can be calculated from the output values of the voltmeter in the respective first current flow pattern, second current flow patter, and third current flow pattern. The conductance k of the extraction region 501 is a reciprocal of the resistance value Ra of the extraction region 501, and can be expressed by equation (10) below.
k=1/Ra (10)
The conductance calculation is thus performed in the glucose concentration analyzer 400 of the third embodiment.
When a blood sugar level is measured using the glucose concentration analyzer 400 of the third embodiment, the subject first forms extraction holes 501a (refer to
The subject thereafter installs the glucose concentration analyzer 400 on the skin 500 of the subject so that the chamber 401 is positioned on the extraction region 501 in which the extraction holes 501a have been formed. Then approximately 80 μl of purified water is supplied into the chamber 401 by the syringe 402. The subject subsequently starts the measurement by pressing a button (input part 411) of the glucose concentration analyzer 400.
In the glucose concentration analyzer 400, a determination is made in step S31 of
In step S33, the extraction rate J (amount extracted per part time) of the glucose extracted to the chamber 401 is measured by the glucose sensor 403 in the glucose concentration analyzer 400 similar to step S4 (refer to
In step S34, the glucose concentration analyzer 400 waits for approximately six minutes seconds after the application of the direct current for extracting glucose has terminated. That is, the waiting time is longer in the third embodiment than the waiting time (approximately 10 seconds) in the first embodiment due to the relatively large amount of purified water within the chamber 401. The ions therefore attain a uniform condition within the chamber 401.
In step S35 in the glucose concentration analyzer 400, the switching circuit 408 is switched to the first current flow pattern (refer to
In step S36 in the glucose concentration analyzer 400, the switching circuit 408 is switched to the second current flow pattern (refer to
In step S37 in the glucose concentration analyzer 400, the switching circuit 408 is switched to the third current flow pattern (refer to
In step S38 in the glucose concentration analyzer 400, the control and analysis part 410 calculates the resistance Ra of the extraction region 501 using equations (9) and (10), and calculates the conductance k which is a reciprocal of the resistance Ra. The glucose permeability P relative to the skin (extraction region 501) is then calculated based on the conductance k.
In step S39 in the glucose concentration analyzer 400, the control and analysis part 410 calculates the glucose concentration (blood sugar level). That is. The glucose concentration C is calculated based on the glucose extraction rate J obtained in step S33, the glucose permeability P and surface area S of the extraction region 501 obtained in step S38, and equation (2). The calculated glucose concentration (blood sugar level) is thereafter displayed on the display part 412. The glucose concentration is calculated as described above in the third embodiment.
Similar to the first embodiment, the third embodiment provides excellent correlation between the conductance and glucose permeability by using purified water as a medium for holding glucose. The blood sugar level can therefore be calculated with greater accuracy.
Conductance can be stably measured in the third embodiment by measuring the conductance of the extraction region 501 by applying a direct current in three current flow patterns using the three electrodes 404, 405, and 406, compared to measuring conductance using an alternating current as in the first and second embodiments.
As shown in
The glucose concentration analyzer 1000 is provided with an electrode 1001 which is formed of Ag/AgCl and is positioned on the extraction region 501 of the skin 500 of the subject, a dry electrode 1002 which is formed of Ti and is positioned on region 502 that is outside of the extraction region 501, and a power source 1003 which applies a controlled direct current and alternating current to the skin 500 of the subject through the electrode 1001 and dry electrode 1002. The power source 1003 applies a direct current to the skin 500 with the electrode 1003 functioning as a negative electrode and the dry electrode 1002 functioning as a positive electrode. Furthermore, disposed between the electrode 1001 and the extraction region 501 is a disposable chip 1006, which includes the integratedly configured mesh sheet 1004 that is saturated with purified water and a sensor member 1005 that is painted with substances which react with the glucose contained in the mesh sheet 1004 and is disposed on the top surface of the mesh sheet 1004. Above the disposable chip 1006 is positioned a glucose sensor 1007 that is configured by a semiconductor laser and photodiode. The amount of glucose contained in the mesh sheet 1004 is detected when the glucose sensor 1007 measured the color intensity of the sensor member 1005. The power source 1003 and the glucose sensor 1007 are controlled by a control and analysis part 1008. A reference electrode 1009, which is formed of Ag/AgCl and disposed in substantial contact with the extraction region 501, is configured to measure the voltage between the dry electrode 1002 and the reference electrode 1009 using a voltmeter 1010. The value measured by the voltmeter 1010 and the amount of glucose measured by the glucose sensor 1007 are input to the control and analyzing part 1008. The glucose concentration analyzer 1000 is also provided with an input part 1011 which is configured by a button or the like to allow a subject to start a measurement by the glucose concentration analyzer 1000, and a display part 1012 for displaying the measurement result and the like.
On the side facing the mesh sheet 1004, the sensor member 1005 is painted with an enzyme (glucose oxidase) which acts as a catalyst for glucose, and an enzyme (peroxidase) which acts as a catalyst for hydrogen peroxide (H2O2), and a color-producing agent which reacts with active oxygen. For example, N,N-bis(2-hydroxy-3-sulfopropyl)tolidene potassium salt,3,3′,5,5′-tetramethylbenzyldene and the like may be used as the color-producing agent.
The control and analyzing part 1008 calculates the impedance of the extraction region 501 using the voltage value received from the voltmeter 1010, and calculates the conductance k of the extraction region 501 based on the calculated impedance value. The control and analyzing part 1008 also calculates the final glucose concentration, that is, essentially the blood sugar level, of the tissue fluid based on the conductance k of the extraction region 501 and the amount of glucose in the mesh sheet 1004 which was received from the glucose sensor 1007.
In the fourth embodiment, a Derma roller, manufactured by Top-Rol, Ltd., may be used as the needle roller 600 shown in
When the blood sugar level is measured using the glucose concentration analyzer 1000 of the fourth embodiment, micro extraction holes 501a are first formed in the skin 500 of the subject using the needle roller 600 (refer to
The subject installs the disposable chip 1006 (refer to
The glucose concentration analyzer 100 is thereafter mounted on the skin 500 of the subject so that the negative electrode (mesh sheet 1004) is in contact with the extraction region 501 in which the extraction holes 501a have been formed. At this time the purified water contained in the mesh sheet 1004 penetrates into the extraction holes 501a formed in the skin 500. The tissue fluid within the extraction holes 501a is then dispersed within the purified water held in the mesh sheet 1004 when the tissue fluid exuded to the extraction holes 501 a of the skin 500 mixes with the purified water from the mesh sheet 1004. Tissue fluid from the corium is again exuded to the extraction holes 501a because the osmotic pressure within the extraction holes 501a is lower than the osmotic pressure of the corium of the skin. As a result, the tissue fluid exuded through the extraction holes 501a formed in the skin 500 is dispersed to a degree in the purified water held by the mesh sheet 1004 before a current is applied from the power source 1003. The subject subsequently starts the measurement by pressing a button (input part 1011) of the glucose concentration analyzer 1000.
In the glucose concentration analyzer 1000, a determination is also made in step S42 as to whether or not a measurement start instruction has been issued. This determination is repeated when a measurement start instruction has not been issued. When a measurement start instruction has been issued, the power source 1003 applies a direct current of approximately 80 μA to the skin 500 for approximately 180 seconds in step S43. The charged ionic components present in the extraction holes 501 a therefore actively migrate. Glucose at a level which is detectable by the glucose sensor 1007 (refer to
In the glucose concentration analyzer 1000, the extraction rate (amount extracted per part time) of glucose extracted to the purified water collected in the mesh sheet 1004 is measured in step S44.
Specifically, the glucose that reaches the sensor member 1005 reacts with the glucose oxidase which acts as a catalyst, and the resulting product of this reaction, hydrogen peroxide (H2O2), reacts with the peroxidase which acts as a catalyst. Active oxygen is generated as a result. The color-producing agent painted on the sensor member 1005 reacts with the active oxygen and produces a color. The color-producing agent thus produces a color the depth of which accords with the amount of glucose extracted from the living body.
Among the laser light irradiated from the semiconductor laser of the glucose sensor 1007, on the other hand, there is a change in the intensity of the light which passes through the sensor member 1005 sitting in contact with the mesh sheet 1004 containing the purified water because the light intensity of the color produced by the color-producing agent accords with the amount of glucose extracted from the living body.
As a result, a light, which has an intensity that accords with the amount of glucose arriving at the sensor member 1005, impinges the photodiode of the glucose sensor 1007 and a signal is output which corresponds to the intensity of the impinging light. The control and analyzing part 1008 then calculates the amount of extracted glucose based on the signal output from the photodiode of the glucose sensor 1007. The control and analyzing part 1008 calculates the glucose extraction rate J by dividing the obtained amount of extracted glucose by the time (approximately 90 seconds) during which the power source 1003 applied the direct current.
In the glucose concentration analyzer 1000, the power source 1003 applies an alternating current (approximately 500 Hz) of approximately ±30 μA to the skin 500 in step S45. The measurement value of the voltmeter 1010 (impedance) is sent to the control and analysis part 1008 at this time.
In step S46 in the glucose concentration analyzer 1000, the conductance of the extraction region 501 is calculated based on the measurement value of the voltmeter 1010 obtained in step S45. That is, the measurement value of the voltmeter 1010 approximates the sum of the voltage drop of the extraction region 501 and the voltage drop of the area 502 as described later. In the case of a high frequency alternating current (approximately 100 Hz or greater), the measurement value of the voltmeter 1010 approximates the voltage drop of the extraction region 501 since the impedance of the area 502 is smaller compared to the impedance of the extraction region 501. The control and analyzing part 1008 calculates a reciprocal of the impedance of the extraction region 501 as the conductance k of the extraction region 501.
In step S47 the glucose concentration analyzer 1000 then calculates the glucose concentration (blood-sugar level). That is, equation (1) below is established among the blood sugar level C, glucose extraction rate J, surface area S of the extraction region 501, and glucose permeability P of the skin 500.
J=S×C×P (1)
The blood sugar level C can therefore be expressed by equation (2) below.
C=J/(S×P) (2)
A specific relational equation has been established experimentally for the glucose permeability P and the conductance k of the extraction region 501 calculated in step S6 and is described in US20060029991, and the glucose permeability P can be calculated based on this relational equation. The glucose extraction rate J was obtained in step S44, and the blood sugar level C can be calculated based on equation (2) since the surface area S of the extraction region 501 is known.
In the fourth embodiment described above, the impedance of the extraction region 501 can be obtained using two electrodes by providing the power source 1003 which applies an alternating current of approximately 500 Hz to the skin 500 of a subject through the electrode 1001 and the dry electrode 1002, and providing the voltmeter 1010 which obtains the impedance of the extraction region 501 by applying the alternating current from the power source 1003 to the skin 500. The conductance of the extraction region 501 of the subject can be calculated based on the impedance of the extraction region 501. Since the impedance of the extraction region 501 can be calculated by applying an alternating current to two electrodes, it is unnecessary to apply a direct current to three electrodes to form three current flow patterns, and thus the conductance of the extracting region can be calculated in a short time. Furthermore, since the conductance can be calculated by applying an alternating current for a short time, electric power consumption can be reduced compared to when a direct current is applied for a long time. The structure of the apparatus can be simplified since the conductance can be calculated using two electrodes, and it is unnecessary to provide a switching circuit for switching the current flow patterns.
In the fourth embodiment, tissue fluid which contains glucose can be easily extracted from the extraction region 501 by forming micro extraction holes 501a in the extraction region 501.
In the fourth embodiment, the voltage between the dry electrode 1002 and the extraction region 501 can be measured without including values which cause error such as the resistance of the mesh sheet 1004 and the resistance of the electrode 1001 and the like, by measuring the voltage between the dry electrode 1002 and the extraction region 501 using the reference electrode. The impedance of the extraction region 501 can be obtained using this voltage.
In the fourth embodiment, the glucose concentration in the tissue fluid can be calculated based on the conductance of the extraction region 501 and the amount of extracted glucose obtained by the glucose sensor 1007 by providing the glucose sensor 1007 which obtains the amount of glucose extracted from the tissue fluid, and the control and analysis part 1008 which calculates the glucose concentration in the tissue fluid based on the glucose extraction amount and the conductance of the extraction region 501. The blood sugar level of a subject can be obtained by the glucose concentration analyzer 1000 of the fourth embodiment since the glucose concentration in the tissue fluid is approximately equal to the blood sugar level.
In
Although Rpore is necessary for the calculation of the conductance of the extraction region 501, Rpore can not be measured directly. However, from the correspondence between Rpore and Zpore, which is the total impedance of Rpore and Cpore, it is possible to calculate the conductance of the extraction region 501 by measuring Zpore.
An alternating current (I) is applied by the power source 1003 in the circuit shown in
V=Rele−ref·i+Zintact·I+Zpore·I (3)
(Where each element Rele-ref, Zintact, Zpore, and I in the equation are vectors of a complex plane.)
Since the first item value (Rele-refxi) is small compared to the second item value (Zintact×I) and third item value (Zpore×I), the influence of the first item value on the measurement value B of the voltmeter 1010 is small compared to the second item value and third item value and can be ignored, so that equation (3) can essentially be expressed as equation (4) below.
V=Zintact·I+Zpore·I (4)
It has been experimentally confirmed that when the frequency of the alternating current of the power source 1003 increases, the Zintact value decreases. In this experiment, two dry electrodes were positioned on the skin of four human subjects, and an alternating current was applied through the two dry electrodes. Then the frequency of the alternating current was varied, and the impedance was measured between the two dry electrodes.
Although there is large dispersion of the measurement values (impedance) of the four human subjects as shown in
V=Zpore·I (5)
It was experimentally confirmed that when the frequency of the alternating current of the power source 1003 is increased, the value of Zpore decreases. In the measurement system of this experiment the impedance (Zintact) of the positive electrodes (dry electrode 1002 and region 502) was set sufficiently small (less than approximately 0.5 kΩ), then the frequency of the alternating current was varied and the impedance was measured between the extraction region 501 and the positive electrode (dry electrode 1002 and region 502).
As shown in
The effect of a frequency change on measurement accuracy was determined by simulation. The dispersion of the impedance measured by the voltmeter 1010 (amount of change/average value) was determined when the negative electrode resistance (Rpore) was 5 kΩ, 10 kΩ, and 25 kΩ while varying the positive electrode capacitance component (Cintact), resistance component (Rintact), and the negative electrode capacitance component (Cpore) in this simulation. The simulation results are shown in
As shown in
When the negative electrode resistance (Rpore) was 10 kΩ, the measurement error was within 5% at frequencies greater than approximately 400 Hz and less than approximately 2000 Hz; and when the negative electrode resistance was 25 kΩ, the measurement error was within 5% at frequencies greater than approximately 200 Hz and less than 800 Hz. A measurement error within 5% can be obtained when the negative electrode resistance is greater than 10 kΩ and less than 25 kΩ insofar as the frequency is greater than 400 Hz and less than 800 Hz.
That is, the impedance (Zpore) of the extraction region 501 correlates significantly with the negative electrode resistance (Rpore) by selecting frequencies greater than 100 Hz and less than 6000 Hz, which are frequencies that decrease the influence of the impedance (Zintact) of the region 502 and the dry electrode 1002, and decrease the influence of the capacitance component (Cpore) of the impedance (Zpore) of the extraction region 501.
Thus, it is possible to calculate the reciprocal of the impedance of the extraction region 501 as the conductance k of the extraction region 501 as shown in equation (6) below by applying to the skin an alternating current, and particularly an alternating current which has a frequency within a range greater than 100 Hz and less than 6000 Hz.
k=1/Rpore∝1/Zpore (6)
In the fifth embodiment, the operation sin steps S51 and S52 of
In step S53 of the fifth embodiment, a current composed of an alternating current overlaid on a direct current of 80 μA+30 μA (500 Hz) is applied to the skin. Glucose is thus extracted from the extraction region 501 by the direct current component of the current applied to the skin 500. The impedance of the extraction region 501 can be obtained based on the measurement value measured by the voltmeter 1010 through the current applied to the skin 500.
In step S54, the amount of extracted glucose is measured by the glucose sensor 1007, and the control and analysis part 1008 calculates the glucose extraction rate J based on the amount of extracted glucose. The conductance k of the extraction region 501 can be calculated based on the impedance of the extraction region 501.
In step S55, the glucose concentration (blood sugar level C) is calculated based on the conductance k of the extraction region 501 and the glucose extraction rate J similar to step S7 of the fourth embodiment.
In the fifth embodiment, tissue fluid can be extracted by a direct current at the same time the impedance is obtained by an alternating current so as to calculate the conductance of the skin by applying a current composed of overlaid alternating current and direct current. The total time of the conductance measurement operation and the tissue fluid extraction operation is therefore reduced.
The other effects of the fifth embodiment are identical to the effects of the fourth embodiment.
The glucose concentration analyzer 1200 of the sixth embodiment is configured by a conductance measuring apparatus 1200a which is mounted on the skin 500 of a subject to calculate the conductance of the extraction region 501a and extract glucose to a mesh sheet 1004, and a concentration analyzer 1200b which calculates the glucose extraction rate from the mesh sheet 1004 that contains glucose, and calculates the concentration of the glucose (blood-sugar level) from the glucose extraction rate and the conductance calculated by the conductance measuring apparatus 1200a.
Since the structure of the conductance measuring apparatus 1200a is identical to the structure of the glucose concentration analyzer 1000 of the fourth embodiment with the exception that the sensor member 1005 and the glucose sensor 1007 are omitted, the description is abbreviated.
The concentration analyzer 1200b is provided with a receiving part 1201 for receiving the mesh sheet 1004 which contains the glucose obtained in the conductance measuring apparatus 1200a, a glucose sensor 1202 for measuring the amount of glucose extracted from the mesh part 1004, a control and analyzing part 1203 for calculating the glucose extraction rate from the amount of extracted glucose obtained by the glucose sensor 1202, an input part 1204 configured by buttons or the like for starting the analysis by the concentration analyzer 1200b, and a display part 1205 for displaying analysis results and the like. A sensor member 1206 which functions similar to the sensor member 1005 of the fourth embodiment is installed when the glucose sensor 1202 measures the amount of extracted glucose from the mesh sheet 1004.
The control and analyzing part 1203 is connected by wire or wirelessly to the control and analyzing part 1008 of the conductance measuring apparatus 1200a, and is capable of receiving the conductance value and the current application time of the direct current applied to extract the tissue fluid from the control and analyzing part 1008 of the conductance measuring apparatus 1200a.
When the blood-sugar level is measured using the glucose concentration analyzer 1200 of the sixth embodiment, extraction holes 501a (refer to
The subject also installs the mesh sheet 1004 in the conductance measuring apparatus 1200a of the glucose concentration analyzer 1200. In step S61 of
Thereafter, the conductance measuring apparatus 1200a is mounted on the skin 500 of the subject so that the negative electrode (mesh sheet 1004) is in contact with the extraction region 501 in which extraction holes 501a have been formed. The subject subsequently issues a measurement start instruction by pressing the button (input part 1011) of the conductance measuring apparatus 1200a.
The conductance measuring apparatus 1200a also determines whether or not a measurement start instruction has been issued in step S62. This determination is repeated when a measurement start instruction has not been issued. When a measurement start instruction has been issued, a direct current is applied to the skin 500 in step S63 similar to step S3 of the fourth embodiment. Thus, glucose is extracted to the mesh sheet 1004.
In the subsequent steps S64 and S65 in the conductance measuring apparatus 1200a, an alternating current is applied to the skin and the conductance of the extraction region 501 is calculated similar to steps S5 and S6 of the fourth embodiment.
In the following step S66, the conductance measuring apparatus 1200a sends the conductance of the extraction region 501 calculated in step S65 from the control and analyzing part 1008 of the conductance measuring apparatus 1200a to the control and analyzing part 1203 of the concentration analyzer 1200b.
The subject then removes the mesh sheet 1004 from the conductance measuring apparatus 1200a, and installs the mesh sheet 1004 in the concentration analyzer 1200b.
In step S71 in the concentration analyzer 1200b, a determination is made as to whether not the mesh sheet 1004 has been installed. This determination is repeated when a mesh sheet 1004 has not been installed. The routine continues to step S72 when the mesh sheet 1004 has been installed.
The subject installs the sensor member 1206 in the concentration analyzer 1200b after the mesh sheet 1004 has been installed in the concentration analyzer 1200b. The concentration analyzer 1200b determines at this time whether or not a sensor member 1206 is installed in step S72. This determination is repeated when the sensor member 1206 has not been installed. When a sensor member 1206 has been installed the routine continues to step S73.
The subject issues a measurement start instruction by operating the input part 1204, which is configured as a button or the like, after the mesh sheet 1004 and the sensor member 1206 have been installed in the concentration analyzer 1200b. In the concentration analyzer 1200b, a determination is also made in step S73 as to whether or not a measurement start instruction has been issued. This determination is repeated when a measurement start instruction has not been issued. When a measurement start instruction has been issued, the control and analysis part 1203 calculates the glucose extraction amount in step S74 based on the signals output from the glucose sensor 1202 and the photodiode similar to step S4 of the fourth embodiment.
In step S75, a determination is then made in the concentration analyzer 1200b as to whether or not information such as the conductance of the extraction region 501 has been received from the conductance measuring apparatus 1200a. This determination is repeated when information has not been received. When information has been received the routine continues to step S76. The information of conductance and the like includes the application time of the direct current applied to extract the glucose in step S63.
In step S76, the glucose concentration (blood sugar level) is calculated in the concentration analyzer 1200b. That is, the control and analysis part 1203 calculates the glucose extraction rate J by dividing the amount of extracted glucose obtained in step S74 by the application time of the direct current received in step S75. The control and analysis part 1203 then calculates the glucose concentration (blood sugar level C) of the tissue fluid based on the conductance k of the extraction region 501 and the glucose extraction rate J.
In the sixth embodiment described above, it is possible to prevent substances such as glucose oxidase, peroxidase, and color-producing agent contained in the sensor member 1206, which are required to measure the amount of extracted glucose, from coming into contact with the skin of the subject by separating the conductance measuring apparatus 1200a which measures conductance and extracts glucose and measures conductance, and the concentration analyzer 1200b which is provided with the glucose sensor 1202 that obtains the amount of extracted glucose while mounted on the skin of the subject. The safety of the subject s therefore increased.
The other effects of the sixth embodiment are identical to the effects of the fourth embodiment.
The embodiments and examples in this disclosure are only examples in all aspects, and are not to be considered limiting in any way. The scope of the present invention is defined by the scope of the claims and not by the embodiment or description of the embodiments, and includes all modifications within the scope of the claims and the meanings and equivalences therein.
For example, although a NaCl concentration of 0 mM was used in the first through third embodiment, the present invention is not limited to this use inasmuch as physiological saline solution which has a low conductivity and a NaCl concentration less than 5 mM may also be used.
Although examples are described in which the presence of ions such as Na+ and the like are localized by waiting a predetermined time after the glucose has been extracted in the first through third embodiment, the present invention is not limited to this mode inasmuch as active mixing may also accomplished by pipetting or stirring or the like. Thus, the ions may be made uniform more rapidly.
Although the first through third embodiments are described by way of examples in which tissue fluid which contains glucose is extracted through the extraction region 501 in which micropores (extraction holes 501 a) have been formed by the needle roller 600 (skin permeability facilitating treatment), the present invention is not limited to this mode inasmuch as tissue fluid may also be extracted from the extraction region without forming micropores (no skin permeability facilitating treatment).
Although the first through third embodiment are described by way of examples in which the extraction of tissue fluid containing glucose is facilitated by applying a direct current to the skin, the present invention is not limited to this mode inasmuch as glucose also may be extracted by passive diffusion without applying a direct current to the skin. The correlation between conductance and skin permeability can be improved by using purified water as the medium for holding the tissue fluid even when extraction is by passive diffusion.
Although a mesh sheet which has a thickness of approximately 50 μm is used in the first and second embodiments, the present invention is not limited to this configuration insofar as the thickness of the mesh sheet is less than 500 μm.
Although the first, second and fourth through sixth embodiments are described by way of examples in which the frequency of the alternating current of the power source is approximately 500 Hz, the present invention is not limited to this frequency inasmuch as a frequency other than 500 Hz may also be used. 500 Frequencies greater than 100 Hz and less than 6000 Hz are examples of such frequencies other than 500 Hz. Measurement errors can be reduced by suitably selecting the frequency.
Although the fourth through sixth embodiments have been described by ways of example in which purified water is included in the mesh sheet as a substance for holding glucose, the present invention is not limited to this mode inasmuch as a conductive medium such as physiological saline solution may also be used as the holding substance.
Although the impedance of the negative electrode is determined in the above embodiments by controlling the current of the power source and measuring the voltage between the negative electrode and positive electrode, the present invention is not limited to this mode inasmuch as the impedance of the negative electrode may also be determined by controlling the voltage of the power source and measuring the current between the negative electrode and positive electrode.
Although micropores are formed in the skin by a needle roller in the above embodiments, the present invention is not limited to this mode inasmuch as passive diffusion may be promoted by ultrasonically irradiating the extraction region of the skin to lower the barrier function of the skin, or alcohol and surface active agent may be applied as enhancers to promote transdermal movement of tissue fluid at the extraction region of the skin. The barrier function of the skin may also be lowered by irradiating the skin with a laser.
Although the examples of the above embodiments use a mesh sheet as a medium containing part or tissue fluid holding part, the present invention is not limited to this mode inasmuch as a sheet-like piece of paper may also be used as a medium containing part, or a non-sheet-like piece of paper or nylon or the like may be used. Furthermore, a collecting medium configured by a nonconductive gel such as polyacrylic acid or the like adhered to a plate-like member may also be used. It is desirable that the medium containing part is sheet-like from the perspective of being close to the electrode and skin. The analyte extraction speed can be increased by being having the electrode close to the skin.
Although the embodiments have been described by way of examples in which the present invention is applied to a glucose concentration analyzer that extracts glucose from a living body and calculates the blood sugar level, the present invention is not limited to this mode inasmuch as the present invention may also be applied to a component concentration analyzer that analyzes the concentration of analytes other than glucose extracted from a living body. The analytes extracted by the component concentration analyzer to which the present invention can be applied may be, for example, a biochemical component, or drug administered to the subject or the like. Examples of biochemical components include proteins such as albumin, globulin, enzymes and the like which are one type of biochemical component. Examples of biochemical components other than proteins include creatinine, creatine, uric acid, amino acid, fructose, galactose, pentose, glycogen, lactic acid, pyruvic acid, ketone bodies and the like. Examples of drugs include digitalis, theophylline, arrhythmia drug, anti-epileptic drug, amino glycoside antibiotic, glycopeptide antibiotic, antithrombic agent, immunosuppressant and the like.
The glucose concentration analyzer of the above embodiments, or a component concentration analyzer incorporating the present invention to extract analytes other than glucose from a living body, may also utilize a control and analysis part and the like to analyze proteins and non-protein biochemical components and drugs using measurement method other than HPLC (high performance liquid chromatography).
Although the above embodiment shave been described by way of examples in which extraction holes 501a are formed in the skin 500 of a subject using a needle roller 600, the present invention is not limited to this mode inasmuch as a modified puncture tool 700 shown in
The foregoing detailed description and examples have been provided by way of explanation and illustration, and are not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments will be obvious to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2007-048262 | Feb 2007 | JP | national |
| 2007-078375 | Mar 2007 | JP | national |
