JP5243719B2 - Biological signal measuring tool and biological signal measuring method using the same - Google Patents

Description

  The present invention relates to a biological signal measuring instrument used for measuring a biological component concentration by a near infrared spectroscopic analysis method and a biological signal measuring method using the same.

  Near-infrared spectroscopy, which performs qualitative and quantitative analysis of biological tissue from spectral signals obtained by receiving diffusely reflected light inside the biological tissue when irradiated with near-infrared light, Information is attracting attention in many medical fields because information can be obtained immediately on the spot, non-invasively and without reagents.

  Especially regarding blood glucose measurement, not only is there a demand for blood glucose management in diabetics, but in recent years there has been a report that the mortality rate of patients will be significantly reduced by managing blood glucose within an appropriate range in the intensive care unit. Non-invasive continuous blood glucose monitoring has been attracting attention.

  In near-infrared spectroscopy, which is one of the technical means for non-invasively measuring blood glucose level, the absorbance changes due to the increase or decrease in glucose concentration at the glucose-specific absorption wavelength in the near-infrared spectrum. Japanese Patent Application Laid-Open No. 11-70101, Japanese Patent Application Laid-Open No. 2002-65645, and Japanese Patent Application Laid-Open No. 2006-87913 measure the spectrum of the signal from the body and detect the glucose concentration in the living body by multivariate analysis of the spectrum signal. It is shown in the gazette.

  FIG. 1 shows a non-invasive optical blood sugar level measuring system disclosed in Japanese Patent Laid-Open No. 2006-87913. Near-infrared light emitted from a halogen lamp 1 is a heat shielding plate 2 and a pinhole 3. Then, the light enters the living tissue 6 through the lens 4 and the optical fiber bundle 5. In the optical fiber bundle 5, one end of the measurement optical fiber 7 and one end of the reference optical fiber 8 are connected, the other end of the measurement optical fiber 7 is connected to the measurement probe 9, and the other end of the reference optical fiber 8 is The measurement probe 9 and the reference probe 10 are connected to a reference-side emission body 11 and a reference-side emission body 12 via optical fibers.

  The measurement probe 9 performs near-infrared spectrum measurement in a state in which the tip surface thereof is brought into contact with the surface of a living tissue 6 such as a forearm portion of a human body at a predetermined pressure. At this time, near-infrared light incident on the optical fiber bundle 5 from the light source 1 is transmitted through the measurement optical fiber 7 and is arranged on a concentric circumference from the tip of the measurement probe 9 as shown in FIG. The surface of the living tissue 6 is irradiated from the 12 light emitting fibers 20. The measurement light applied to the living tissue 6 is diffusely reflected in the living tissue 6, and then a part of the diffuse reflected light is received by the light receiving fiber 19 disposed at the center of the tip of the measurement probe 9. The received light is emitted from the measurement-side emitting body 11 through the light-receiving side optical fiber 19, is incident on the diffraction grating 14 through the lens 13, and is dispersed and then detected by the light-receiving element 15. The optical signal detected by the light receiving element 15 is AD converted by the A / D converter 16 and then manually operated by an arithmetic unit 17 such as a personal computer. The blood glucose level is calculated by analyzing the spectrum data.

  In the reference measurement, light reflected by a reference plate 18 such as a ceramic plate is measured and used as reference light. The reference probe 10 has the same configuration as the measurement probe 9 described above, and the optical fiber bundle from the light source 1 is provided. 5 is irradiated from the tip of the reference probe 10 to the surface of the reference plate 18 through the reference optical fiber 8. The reflected light from the reference plate 18 is emitted from the reference-side emitter 12 via the light receiving optical fiber 19 disposed at the tip of the reference probe 10.

  A shutter 22 is disposed between the measurement-side emitter 11 and the lens 13 and between the reference-side emitter 12 and the lens 13, and the light from the measurement-side emitter 11 is changed by opening and closing the shutter 22. One of the light from the reference-side emitter 12 is selectively passed and guided to the light receiving element 15.

  The end faces of the measurement probe 9 and the reference probe 10 are composed of 12 light emitting fibers 20 arranged on a circle and one light receiving fiber 19 arranged in the center as described above. The distance L between the centers of the light emitting fiber 20 and the light receiving fiber 19 is 650 μm. Further, the end faces of the measurement-side emitter 11 and the reference-side emitter 12 are arranged with the emission fiber 21 (the other end of the light receiving fiber 19) as the center as shown in the right figure of FIG.

  When performing quantitative and qualitative analysis by near infrared spectroscopy, usually perform multivariate analysis on the data set obtained by collecting data in advance, and create a calibration function when performing quantitative analysis, It is common to use a method for calculating the target component concentration. At this time, in order to obtain a robust calibration function, it is said that it is good to collect the widest possible and wide range of data and create the above data set. However, the time, labor, and cost associated with the collection of a wide range of data are considered. The burden is a big problem.

  On the other hand, for quantitative analysis of biological components, particularly blood glucose level measurement, the absorbance of the target component as a signal is very small. For example, when measuring the change in glucose signal with the device shown in the conventional example, it is clinically meaningful. The change in absorbance of the glucose signal with respect to the concentration change of 10 mg / dl required for a certain measurement is 100 μAU or less, which is extremely small (noise ratio is bad) compared to the noise related to biological changes and measurement reproducibility. It is difficult to obtain a useful calibration function even if the calibration function creation method performed in ordinary near infrared spectroscopy is used as it is for qualitative and quantitative analysis of biological components. Moreover, even if the calibration function is used, a calibration function is often created for each individual in order to eliminate noise caused by individual differences among subjects and enhance adaptability.

  However, in a medical facility such as an intensive care unit (ICU), it is practically impossible to prepare a calibration function by performing spectrum measurement on a patient prior to monitoring in treatment.

  On the other hand, what is disclosed in the above Japanese Patent Application Laid-Open No. 2006-87913 is a method of creating a calibration function without collecting spectrum data in advance, and here, a plurality of obtained from a living body or a simulation or the like. A plurality of differential absorbance spectra, which are differences between the near-infrared absorbance spectrum and a reference absorbance spectrum selected from these, are obtained, and a plurality of reference absorbance spectra of a subject measured in advance are combined with each of the difference absorbance spectra. A calibration function is created by obtaining a synthetic absorbance spectrum of the sample and performing multivariate analysis using the obtained plurality of synthesized absorbance spectra.

  In this case, a calibration model created by incorporating artificially selected disturbances can be used, but if changes in skin condition are not incorporated into the calibration model as disturbances, measurement is started until the skin condition stabilizes. You will have inadequate drawbacks. In some cases, it takes about 2 hours to stabilize the skin, which is a cause of restricting the use in actual use. An example is shown in FIG. In the figure, “a” is an estimated blood glucose level by near infrared light, and “b” is a blood glucose level by a blood sampling method.

Furthermore, as a continuous measurement of blood glucose level, an apparatus for measuring blood glucose level invasively has been developed. For example, an invasive continuous blood glucose monitor (CGMS) from Medtronic MiniMed (USA), which has received FDA approval from the United States, inserts a sensor needle into the body and measures the glucose concentration of bodily fluid in the subcutaneous tissue. Continuous measurement of time is possible. However, with this apparatus, it is necessary to wait for stabilization for about 2 hours after inserting the sensor needle into the body, and then calibrate the blood glucose level by collecting blood. The initial two hours are shorter than the 72 hours, which is the operation time, and this is a problem in usage forms such as blood glucose level history management for diabetic patients and blood glucose level management for patients past the acute phase. However, it is a cause that restricts the use in actual use.
JP 2006-87913 A

  The present invention was invented in view of the above-mentioned conventional problems, and in the measurement of biological components using near infrared light, particularly in the measurement of blood glucose level, the disturbance factor caused by the state change of the skin tissue is reduced. It is an object of the present invention to provide a biological signal measuring tool that can perform measurement with high accuracy without waiting for the skin state to stabilize and a biological signal measuring method using the same.

  In order to solve the above problems, a biological signal measuring instrument according to the present invention comprises a measuring probe for measuring a biological signal that irradiates a living body of a subject with near infrared light and receives reflected light or diffused light from the living body, A probe support that supports the measurement probe and contacts the living body, a drive means that is provided on the probe support and moves the measurement probe in a direction perpendicular to the surface of the living body, and a tip surface of the measurement probe; Contact detecting means for detecting contact with the living body surface, and the driving means is based on the position of the living body surface when no load is detected by the contact detecting means in a state where the probe support is in contact with the living body surface. The distal end surface is held within a range of a position where the distal end surface is 150 μm away and a position where the distal end surface protrudes 500 μm further toward the living body than the living body surface when no load is applied. It has a special feature.

  In particular, in order to detect the contact between the measurement probe and the surface of the living body and position the distal end surface of the measurement probe within the range based on this position, the position of the measurement probe with respect to the surface of the living body is more accurately and reproducible. Can be determined.

  In this case, as the contact detection means, the contact is electrically detected by an electrode disposed on the tip surface of the measurement probe, or the measurement probe is moved while being moved in a direction perpendicular to the surface of the living body by the drive means. What detects the contact state between the measurement probe and the surface of the living tissue by analyzing the change in the spectrum thus obtained can be suitably used.

It is also preferred to those with a vent for communicating the space surrounded by the front end surface and the probe support and the biological surface of the measuring probe to the outside air. The change in the properties of the measurement target portion in the living tissue can be suppressed by the ventilation through the vent, the living body surface can be kept in a good state, and the measurement accuracy can be improved.

  If the opening / closing means for opening and closing the vent is provided, it is possible to avoid noise caused by ventilation through the vent by closing the opening / closing means during measurement.

It may be a structure having an air blowing means for forcibly intake through the vent, in this case, it is possible to perform ventilation to ensure the space.

If the air blowing means also serves as the driving means, the number of parts can be reduced, and the apparatus can be made small and inexpensive.

  If temperature adjusting means for bringing the temperature of the air reaching the space through the vent close to the living body temperature is provided, it is possible to prevent the air sent into the space from causing the property change.

  Furthermore, when a control means for controlling at least one of the ventilation flow rate or the ventilation direction through the ventilation port based on the measured biological signal is provided, accurate measurement can be performed more reliably while suppressing the property change.

  The biological signal measuring method according to the present invention uses the above-described biological signal measuring instrument, and positions the distal end surface of the measurement probe within a range of 500 μm protruding from the position 150 μm away from the surface of the living body when unloaded to the living body side. In this state, it is characterized by irradiating the living body with near infrared light and receiving reflected light or diffused light.

  According to the present invention, there is almost no change that the measurement probe gives to the surface of the living body, so that disturbances due to changes in the living tissue can be removed, and accurate biological signal measurement can be performed at any time without waiting for the state change to stabilize. It can be performed.

  Hereinafter, the present invention will be described with reference to the embodiments shown in the accompanying drawings. The biological signal measuring device and the biological signal measuring method according to the present invention are for measuring biological component concentrations, particularly blood glucose concentration (blood glucose level). The spectrum measurement targets the dermis layer in a living tissue (skin).

  The skin tissue of a living body is mainly composed of three layers of the epidermis, dermis, and subcutaneous tissue. The epidermal tissue is a tissue including the stratum corneum, and the capillaries are not so developed in the tissue. The subcutaneous tissue is mainly composed of adipose tissue. Therefore, it is considered that the correlation between the water-soluble biological component concentrations contained in the two tissues, particularly, the glucose concentration and the blood glucose concentration (blood glucose level) is low. On the other hand, the dermal tissue has developed capillary blood vessels and the concentration of biological components with high water solubility, especially glucose has high permeability in the tissue. As is the case with fluid (ISF: Interstitial Fluid), it is considered to change following blood glucose level. For this reason, if spectrum measurement targeting the dermal tissue is performed, the concentration of biological signals, especially the spectral signal correlated with blood glucose level fluctuation, Measurement is possible.

  The measurement probe 9 composed of an optical fiber having a center-to-center distance L of 0.65 mm shown in FIG. 1 was developed to target this dermis layer. It can be used suitably. The near-infrared light irradiated from the incident optical fiber in the measurement probe 9 is diffusely reflected in the skin tissue, and a part of the light reaching the detection optical fiber is received and spectrum measurement is performed. The light propagation path in the skin has a shape called “banana shape”. When the distance between the centers is set to L, the light passing through the dermis layer reaches the detection optical fiber.

  In the present invention, when the measurement probe 9 irradiates near-infrared light to the skin surface (biological surface) and receives diffuse reflection light with the measurement probe 9, the tip surface of the measurement probe 9 is unloaded. By setting within the range of −150 μm to 500 μm from the position of the skin surface at the time, the skin state change caused by the contact between the measurement probe 9 and the skin is reduced, and the skin state caused by the contact between the measurement probe 9 and the skin By suppressing the change and shortening the time until the skin state is stabilized, accurate measurement can be performed at any time.

  In addition to glucose (blood glucose level), biological component concentrations expected to correlate with blood concentration include uric acid levels, cholesterol levels, triglyceride levels, albumin levels, globulin levels, oxygen saturation levels, hemoglobin levels, etc. .

  In the present invention, the measuring apparatus having the configuration shown in FIG. 1 was used. However, the measurement probe 9 is made to face the surface of the living tissue 6 using the probe support 21 shown in FIG. Here, the probe support 21 is formed by screwing a screw shaft 25 supported by a bearing 24 so as to freely rotate around an axis into a female screw hole provided in a slider 26 to which the measurement probe 9 is fixed. The slider 26 and the measurement probe 9 can be moved in the vertical direction in the figure by rotating the screw shaft 25 by the driving means 23. Here, the screw pitch of the screw shaft 25 is 250 μm. The measuring probe 9 can be moved by 250 μm by one rotation of the screw shaft 25.

  In the spectrum measurement, the bottom surface of the probe support 21 is brought into contact with the surface of the living tissue 6 and then the screw shaft 25 is rotated so that the distal end surface of the measurement probe 9 is −150 μm from the position of the skin surface when no load is applied. To 500 μm, and measurement is performed in this state. Here, the position of the skin surface when there is no load is the position of the skin surface in a state where no load is applied to the skin before the measurement probe 9 contacts the skin. Further, it is desirable that the position of the distal end face of the measurement probe 9 at the time of measurement is measured in the range of −150 μm to 30 μm. The living tissue 6 directly facing the distal end surface of the measurement probe 9 has a small change in skin condition such as compression and an increase in the amount of keratinous water, and can secure a near-infrared spectrum signal having a good SN ratio.

  In the blood glucose measurement experiment, prior to blood glucose measurement, the blood glucose monitor is calibrated using the blood glucose level actually measured by blood collection. At the time of this calibration, a difference model obtained by the method described later is added to the absorption spectrum measured simultaneously with blood collection to synthesize a virtual data set, and a calibration model is created by performing PLS regression analysis from this data set. In this example, the near-infrared wavelength range used for preparing the calibration model is 1,430 nm to 1,850 nm, and the number of PLS factors is nine. After calibration, the blood glucose level measured by the near-infrared spectrum is obtained as a relative change value from the blood glucose level measured during calibration. Verification of the effect of the biological signal measuring instrument according to the present example was performed by measuring blood glucose level by near-infrared light and measuring blood glucose level by blood sampling as comparison data, and comparing both. The measurement was carried out for about 5 hours after the start of measurement.

  In this example, correction is performed based on the ratio between the feature quantity of the spectrum for creating the difference table and the feature quantity of the reference spectrum, but the creation of the difference table in this embodiment employs the Monte Carlo method as a light propagation simulation. I went. The Monte Carlo method is a statistical method that can accurately reproduce a target event using a function based on the probability distribution of the target event with respect to uniform random numbers in the range of 0 to 1 generated by a computer. When reproducing light propagation, the light incident on the medium is regarded as a collection of photons, and the behavior of each photon in the medium is determined based on the optical characteristic values of the medium (absorption coefficient, scattering coefficient, scattering phase function, refractive index). ) To track. As a result, light propagation can be statistically reproduced from the behavior of all photons.

  When the light propagation simulation is performed based on the Monte Carlo method, optical characteristic values such as the absorption coefficient, scattering coefficient, refractive index, and anisotropic scattering parameter of the epidermis layer, the dermis layer, and the subcutaneous tissue layer are required. As a variation factor used in the simulation, glucose, protein, lipid, moisture, and temperature are changed in 5 parameters in the body and scattering coefficient within the preset range so that the daily variation of the in vivo parameter is covered. The absorbance spectrum was prepared by repeating 64 combinations (maximum of 2 6) combining the maximum and minimum values of each parameter. The difference table is obtained by subtracting the average spectrum of the simulation spectra from the plurality of absorbance spectra obtained by simulating in this way, thereby obtaining a plurality of differential absorbance spectra.

  FIG. 3 shows the verification results when the spectrum measurement is performed in a state where the measurement probe 9 is 125 μm (half rotation) away from the bottom surface of the probe support 21. In the figure, “a” is an estimated blood glucose level by near infrared light, and “b” is a blood glucose level by a blood sampling method. Since changes in the skin condition such as compression of skin tissue and increase in the amount of keratinous water could be reduced, blood glucose levels could be estimated better than immediately after calibration.

  As a control experiment, an experiment was conducted in a state where the measurement probe 9 was pulled up by 200 μm from the bottom surface of the probe support 21 in contact with the surface of the living tissue 6. Except for the lifting distance, it is the same as that of the first embodiment. The blood glucose prediction value in the control experiment was able to be estimated well at an almost constant blood glucose level before the oral glucose load, but when the blood glucose level of the oral glucose load increased, the predicted value changed following the blood glucose level. It never happened. This is because the change in the skin state is small as in Example 1 under the experimental conditions in this control experiment, but the distance between the skin surface and the measurement probe 9 is too far away, and the signal due to the skin surface reflection increases. It is considered that the signal component propagated through the skin tissue is reduced and the SN ratio is deteriorated. Further, in the state where the measurement probe 9 protrudes from the bottom surface of the probe support 21 beyond 500 μm, that is, when the measurement probe 9 strongly presses the surface of the living tissue 6, the measurement is performed as shown in FIG. As a result.

  Therefore, setting the distal end surface of the measurement probe 9 within the range of −150 μm to 500 μm from the position of the skin surface at the time of no load makes it possible to perform a good spectrum measurement without deteriorating the SN ratio related to the biological component of the near infrared spectrum. It was a condition to perform.

  In this embodiment, a method using numerical simulation is shown as a method for creating a difference table. However, the method is not limited to this, and the difference table is actually obtained from a data set composed of absorbance spectra obtained by measuring human skin. Instead of the obtained difference table or the numerical simulation, a difference table obtained by measuring a simulated living body typified by intralipid may be used.

  Contact detection means for electrically detecting the contact state between the measurement probe 9 and the living tissue 6 is provided. As shown in FIG. It was made with Duracon manufactured by Polyplastics Co., Ltd., an insulator. Further, as shown in FIG. 4, the signal generator 28 and the monitor unit 29 are used to connect the electrode 30 of the measurement probe 9 with the conductive wire 31 and the contact surface with the living body measurement probe 9. The electrode 27 is brought into contact with another position and connected to the signal generator 28, so that the energized state between the measurement probe 9 and the living tissue 6 can be detected. Here, a function generator is used as the signal transmitter 28, an oscilloscope is used as the monitor unit 29, the frequency value emitted from the function generator 28 is 50 kHz, and the PP value of the voltage is 10V.

  While the measurement probe 9 held by the probe support 22 is gradually advanced, the contact detection means detects whether the tip surface of the measurement probe 9 is in contact with the surface of the living tissue 6, thereby measuring the measurement probe 9. It is possible to detect the point in time when the surface of the living tissue 6 is in contact with the surface of the living tissue 6 and to position the measurement probe 9 within the range of −150 μm to 500 μm with the measurement probe 9 at that position as a reference position. It is a thing. Note that the measurement probe 9 is placed at 0 μm at the reference position. In this state, spectrum measurement is performed in the same manner as in the previous embodiment, and after the measurement, the sample is placed in a standby state at a position sufficiently separated from the living body, as before measurement. The verification result is shown in FIG. In the figure, “a” is an estimated blood glucose level by near infrared light, and “b” is a blood glucose level by a blood sampling method.

  By electrically confirming whether or not the measurement probe 9 and the living tissue 6 are in contact with each other, it is possible to accurately grasp the positional relationship between them, so that the living tissue 6 is not compressed. In order to improve the reproducibility of the degree of contact of the measurement probe 9 with the living tissue 6, the relative position of the measurement probe 9 relative to the living tissue 6 can be improved even when the measurement is repeated over time. Almost no change can be eliminated, and good blood sugar estimation is possible.

  Here, the electrode 30 is formed on the mantle of the measurement probe 9 so that the current is supplied only when the measurement probe 9 comes into contact with the living tissue 6. However, the electrode 30 is not limited to the mantle and is not limited to the mantle of the measuring probe 9. It is sufficient that the contact surface with 6 can be energized.

  7 is provided with a protrusion 32 as a stopper that restricts the movement of the measurement probe 9 on the probe support 21. When the measurement probe 9 is brought close to the surface of the living tissue 6, the protrusion The tip end surface of the measurement probe 9 is lifted by a small distance from the surface of the living tissue 6 due to the contact with 32.

  As shown in FIGS. 8 and 9, the protrusion 32 may be provided on the outer periphery of the distal end surface of the measurement probe 9. At this time, if the protrusion 32 also serves as the electrode 30 in the contact detection means, It becomes easy to keep the tip surface of the measurement probe 9 away from the living tissue 6 by a predetermined minute height.

  Basically, it is the same as in the second embodiment, but here, the measurement is performed according to the following procedure. That is, the spectrum is measured in a state where the measurement probe 9 is positioned at the same position as the bottom surface of the probe support 21 by the driving means 23, and this is used as a reference spectrum. Note that the position of the measurement probe 9 at the time of measurement of the reference spectrum is not limited to the above position, and the position closer to the living body than the bottom surface of the probe support 21 by 0.5 mm, or conversely, 0.1 mm away from the living body. It is good also as a position.

  After the measurement of the reference spectrum, the measurement probe 9 is once moved away to a position where it does not contact the skin (for example, about 1 mm), and the next calibration model is created and calibrated in this state. Except when measuring the spectrum, the measurement probe 9 is not in contact with the skin, thereby minimizing changes in the skin condition such as compression of the skin tissue and an increase in the amount of keratin moisture, thereby stabilizing the skin condition. This is because measurement accuracy can be improved by making it possible to measure biological components at any time without waiting, and by reducing disturbance factors caused by changes in the state of skin tissue.

  The calibration model is created from the reference spectrum using the difference table. In addition, calibration is performed using blood glucose levels actually measured by blood collection.

  Next, a spectrum group for principal component analysis is calculated. This adds the difference table to the reference spectrum to calculate a spectrum group (hereinafter referred to as a principal component analysis spectrum group). As described above, the difference table is created by repeating 64 combinations of the maximum value and the minimum value of each of the six kinds of parameters of the absorbance spectrum by simulation. Therefore, the spectrum group for principal component analysis is composed of 64 spectrum groups. ing.

  Next, the spectrum is measured while bringing the measurement probe 9 close to the living body, and the principal component analysis is performed on the measured spectrum and the spectrum group for principal component analysis. At this time, the screw shaft 25 is rotated by, for example, 1/5 rotation to change the position of the measurement probe 9 by a minute value (corresponding to 50 μm when the screw pitch of the screw shaft 25 is 250 μm), and the spectrum is measured to be described later. If the result of determination is that the position of the measurement probe 9 needs to be changed, the screw shaft 25 is rotated to change the position of the measurement probe 9. Repeat and measure the spectrum.

  The determination is based on whether or not the measured spectrum score value is within the range of the score values of the principal component analysis spectrum group, and the principal component analysis spectrum group has 64 spectrum groups. Therefore, 64 score values are obtained, and 65 data groups are formed together with the score values of the measurement spectrum. When the score value of the measurement spectrum is within the range of 64 score groups of the principal component analysis spectrum, the blood glucose level is calculated, and when the score value is out of the range, the position of the measurement probe 9 is changed. In addition, when calculating the blood glucose level, the measuring probe 9 is moved away to a position where it does not contact the living body (for example, 1 mm).

  FIG. 11 shows an example of the result of displaying the calculated score values. Seven graphs in the figure have score values of 2 to 8 principal components on the Y axis. The X-axis is a score value with 1 main component. In addition, the points indicated by ◯ in each graph are the score values of the measured spectrum, and the other points are the score values of the spectrum group for principal component analysis.

  Here, the upper left graph of FIG. 11 shows that the score values of the principal component number 1 and the principal component number 2 of the measurement spectrum are within the range of the 64 score groups of the principal component analysis spectrum. It shows that the score value of the measured spectrum is within the range of 64 score groups of the spectrum for principal component analysis with respect to the score value of the number of principal components on the X-axis and the number of principal components on the Y-axis. ing. In this case, the measured spectrum is determined that the principal component analysis spectrum is within the range of score values of 1 to 8 principal components. On the other hand, FIG. 12 shows another example of the result of calculating the score value. Here, the number of principal components 1 to 7 is within the range, but the number of principal components 8 is outside the range. From this, it is determined that it is out of range.

  FIG. 13 shows the case where the blood glucose level is obtained by performing the spectrum measurement as described above, that is, the drive means 23 so that the measured spectrum is within the range of the score group of the principal component analysis spectrum when the number of principal components is 1 to 8. This is a result of measurement by moving the measurement probe 9. It can be seen that better blood glucose estimation is possible immediately after calibration without waiting for the stable state of the skin.

  In addition, the number of PLS factors when creating a calibration model is 9, as described above, but the number of principal components in the score group of the principal component analysis spectrum ranges from 1 to 7 when the measured spectrum is in the number of principal components from 1 to 8. If the number of principal components is 8 and the number of principal components is out of the range, the estimated value may be calculated using a calibration model created with the number of PLS factors set to 7. In this case, it is possible to obtain an accuracy equal to or higher than that when the estimated value is calculated by setting the PLS factor to 9.

  This is substantially the same as the embodiment of Example 2 except that the contact state between the measurement probe 9 and the living tissue 6 is detected by analyzing the change in the shape of the absorbance spectrum. In order to analyze the change in the shape of the absorbance spectrum, a value obtained by subtracting the absorbance value at 1655 nm from the absorbance value at the water absorption peak at 1450 nm is defined as a “water peak height value”. By analyzing the change in the water peak height value, the contact state between the measurement probe 9 and the surface of the living tissue 6 is detected.

  That is, when the spectrum is measured, the bottom surface of the probe support 21 is brought into contact with the living body, and then the measurement probe 9 is gradually moved away from the living body, and the absorbance spectrum is continuously measured. A water peak height value is calculated from each obtained absorbance spectrum, and the measurement probe 9 is moved until a large change described later can be confirmed in the water peak height value. If the change is confirmed, the position immediately before that is used as a correct measurement position, and the absorbance spectrum measured at that position is used as a true value for blood glucose estimation.

  Specifically, when the first measurement shown in FIG. 14 is used as an example, measurement is performed while the measurement positions A, B, C... And the measurement probe 9 are moved away from the living body, and the water peak height value is small. Since the water peak height value is small at the measurement position E (the difference in the water peak height value between the measurement position D and the measurement position E = 0.032 AU, the water at the other measurement position The change in peak height value is less than 0.005 AU), the position immediately before the water peak height value becomes small, that is, the measurement position D is the correct measurement position, and blood glucose estimation is performed using the absorbance spectrum measured at this measurement position D. went.

  The verification result is shown in FIG. Since the correct measurement position is identified from the change in the measured spectrum, the distance between the living tissue 6 and the measurement probe 9 can be accurately grasped, and reproducible spectrum measurement can be performed. An estimate is obtained.

  Note that the measurement probe 9 may be moved not in the direction away from the living body but in a direction closer to the living body.

  Substantially the same as the embodiment of Example 2, but after the measurement probe 9 is moved 30 μm away from the position where it is detected that the measurement probe 9 and the living tissue 6 are in contact with each other, spectrum measurement is performed to determine the blood glucose level. lead. FIG. 16 shows the verification result. Since the spectrum is measured in a state where the measurement probe 9 is not in contact with the living tissue 6, changes in the skin properties can be suppressed to a very small level, and good blood glucose estimation is possible.

  Substantially the same as the embodiment of Example 2, but after pushing the measuring probe 9 by 30 μm from the position where it was detected that the measuring probe 9 and the living tissue 6 contacted, the spectrum measurement was performed to determine the blood glucose level. lead. FIG. 17 shows the verification result.

  FIG. 18 shows another example of the biological signal measuring tool. The basic configuration is the same as that shown in the first embodiment, but here, the probe support 21 is provided with a vent 33 for communicating the space α surrounded by the measurement probe 9, the living tissue 6, and the probe support 21 to the outside. Is formed. Such a vent 33 may be provided in the measurement probe 9 as shown in FIG. 19, or may be formed so as to penetrate the probe support 21 and the slider 26, and a plurality of vents 33 may be formed. By making one the inflow side and the other the discharge side, the air flow can be improved.

  In any case, the presence of the vent 33 makes it possible to expose the portion of the living tissue 6 facing the distal end surface of the measuring probe 9 to the outside air when the measuring probe 9 is not in contact with the living tissue 6. Therefore, changes in skin properties such as sweating can be suppressed to a small level, and therefore, good blood sugar estimation is possible.

  It is also preferable to provide a filter in the vent 33 so that dust and dirt do not adhere to the tip surface of the measurement probe 9 from the outside.

  The vent 33 is not always opened, but it is also preferable that the vent 33 can be opened and closed by an on-off valve 36 as shown in FIG. By closing the on-off valve 36 at the time of measurement, it is possible to avoid that the inflow / outflow of air through the vent 33 becomes noise at the time of measurement.

  As shown in FIG. 21, air blowing means 35 is connected to the vent 33. As the air blowing means 35, a carbon dioxide gas cylinder or the like may be used in addition to the air pump. Since the air can be forcibly sent to the space α, a change in the properties of the living tissue 6, in particular, an increase in water content can be reliably suppressed. Note that it is preferable in terms of noise reduction to stop the blowing from the blowing means 35 when performing the measurement. In addition, although the vent 33 is provided in the probe support 21 here, it is needless to say that the vent 33 may be formed in another part as described above.

  In FIG. 22, it is possible to easily switch between when the measurement probe 9 is in contact with or close to the living tissue 6 and when the measurement is suppressed by using the vent 33. A receiving piece 26a projecting sideways is provided on the upper portion of the slider 26 (or the measurement probe 9) supported by the probe support 21 so as to be movable up and down.

  The probe support 9 is provided with an on-off valve 36 and a vent 33. In addition to the port 36a that opens on the vent 33 side, the on-off valve 36 has a port 36b that opens on the receiving piece 26a side. It also has. A rotating plate 38 that is rotatably supported by a shaft 39 is disposed in the probe support 9, and the rotating plate 38 contacts the lower end surface of the slider 26 when in the horizontal state. .

  Now, as shown in FIG. 22 (a), when air is supplied to the vent 33 through the on-off valve 36, the slider 26 is lifted by the air pressure of the receiving piece 26a and is separated from the living tissue 6. At this time, the rotating plate 38 is in a horizontal state and supports the lower end surface of the slider 26. The air that has entered the vent hole 33 comes into contact with the living tissue 6 and suppresses changes in the properties of the living tissue 6, and then is discharged to the outside.

  When the on-off valve 36 is closed or the air supply is stopped, the slider 26 (measurement probe 9) descends while rotating the rotating plate 38, and the measurement probe 9 approaches the living tissue 6 as shown in FIG. Or contact. Measurement is performed in this state.

  If air is supplied again through the on-off valve 36, the slider 26 is lifted by pressing the receiving piece 26a with air pressure. Note that the rotation of the rotating plate 38 is prevented by the slider 26 until the slider 26 completes raising, so that air does not leak out from the vent 33 side and the raising of the slider 26 is not hindered.

  When the slider 26 finishes moving up, the rotating plate 38 rotates to return to the state shown in FIG. 22A in order to open the flow path for sending air to the living tissue 6.

  FIG. 23 shows that air having a small temperature difference from the surface temperature of the living tissue 6 can be sent into the space α through the vent 33, and the vent 33 has a longer path so that the probe support 21 can be extended. In addition to being provided in a loop shape that goes around the inside, a heater wire 43 is disposed around the vent 33. An air temperature detecting means 45 is provided near one end of the vent 33 on the outside air side, and a living body temperature detecting means 46 such as a thermocouple is provided on the contact surface of the probe support 21 with the living tissue 6.

  The air temperature detecting means 45 and the living body temperature detecting means 46 are connected to a heater control circuit 44 that controls the heat generation of the heater wire 43, and the heater control circuit 44 detects the living body temperature detected by the living body temperature detecting means 46. Based on the temperature difference from the air temperature detected by the air temperature detecting means 45, the amount of heat generated is suppressed when the temperature difference is small, and the amount of heat generated is increased when the temperature difference is large. The temperature of the air entering α is set to a temperature close to the living body temperature. When cold air touches the living tissue 6, a change in properties occurs in the living tissue 6, which can be suppressed.

  FIG. 24 shows that the properties of the living tissue 6 are changed when the measurement value is greatly changed from the previous measurement value when the measurement is continuously performed a plurality of times at different times. Take action to restore. For this reason, here, the arithmetic unit 17 is provided with a biological variation detection unit 38, and the blower 35 and the flow rate adjustment valve 37 can be controlled by the output of the biological variation detection unit 38.

  For example, the value of the above-mentioned “water peak height” is used for the detection of the biological variation by the biological variation detector 38. In this case, the reference value of the water peak height value and the allowable fluctuation amount of the water peak height value are set in advance. The permissible fluctuation amount is an allowable value of the amount of change from the reference value of the water peak height value. If there is a change in the water peak height value that exceeds the permissible fluctuation amount, the biological tissue 6 is characterized. Judge that there was a change.

  Specifically, spectrum measurement is first performed, the measured spectrum is taken into the arithmetic unit 17, and a water peak height value is calculated. In addition, the water peak height value calculated from the first spectrum at the start of measurement is used as the reference value.

  Then, a difference between the water peak height value calculated from the next spectrum measurement and the reference value is obtained, and when this difference is smaller than the allowable fluctuation amount (for example, 10,000 μAU), the property change that needs to be dealt with is the biological tissue 6. When the allowable fluctuation amount is exceeded, the air blowing means 35 is operated and the flow rate adjusting valve 37 is opened to blow the surface of the living tissue 6.

  Here, it is preferable that the air blowing means 35 is one that can switch the air blowing direction, and the air blowing direction varies depending on which of the water peak height values has changed from the reference value. This is because if the air is blown onto the living tissue 6, the water peak height value can be reduced, and if the air is sucked up, the water peak height value can be increased by raising the moisture on the skin surface. Further, by controlling the flow rate with the flow rate adjusting valve 37 in accordance with the value of the fluctuation amount, it is possible to quickly and accurately return the property change.

  Although an example in which the water peak height value is used for detection of biological fluctuation has been shown, the present invention is not limited to this. For example, an absorbance value of one wavelength or a plurality of wavelengths of a spectrum to be measured may be used. The voltage signal value output from 15 may be used as it is.

The measuring apparatus used in this invention is shown, (a) is the schematic of the whole structure, (b) is the schematic of a probe structure. It is a schematic sectional drawing of an example of the probe support body used for this invention. It is explanatory drawing which shows the verification result of the Example of this invention. It is a schematic sectional drawing of the other example used for this invention. It is the schematic of a probe structure same as the above. It is explanatory drawing of a verification result same as the above. It is a schematic sectional drawing of another example of the probe support body used for this invention. (a) and (b) are a schematic sectional view and an end view of another example of the above. (a) and (b) are a schematic sectional view and an end view of still another example of the above. It is a flowchart of an example of other embodiment. It is explanatory drawing of the example of a display of a score value same as the above. It is explanatory drawing which shows the other example of a display of a score value same as the above. It is explanatory drawing which shows a verification result same as the above. It is explanatory drawing of another Example. It is explanatory drawing of a verification result same as the above. It is explanatory drawing which shows the verification result of another example. It is explanatory drawing which shows the verification result of another example. It is a schematic sectional drawing of the probe structure of another example. Furthermore, it is a schematic sectional drawing of another example. It is a schematic sectional drawing of other examples. It is a schematic sectional drawing of another example. (a) (b) is a schematic sectional drawing of another example. It is a schematic plan view which shows another example. It is a block diagram of a different example. It is explanatory drawing which shows an example of the verification result in a prior art example.

6 Living tissue 9 Measuring probe 21 Probe support 23 Driving means

Claims (11)

A measurement probe for measuring a biological signal that irradiates a subject's living body with near-infrared light and receives reflected light or diffused light from the living body; a probe support that supports the measurement probe and contacts the living body; A driving means provided on the probe support for moving the measurement probe in a direction perpendicular to the biological surface; and a contact detection means for detecting contact between the tip surface of the measurement probe and the biological surface;
The driving means includes a position where the tip surface is spaced 150 μm away from the position of the living body surface at the time of no load detected by the contact detecting means in a state where the probe support is in contact with the living body surface, and the tip surface is A biological signal measuring instrument that holds the tip surface within a range of a position protruding 500 μm to the living body side of the living body surface at the time of loading.   2. The biological signal measuring instrument according to claim 1, wherein the contact detection means is configured to electrically detect contact with an electrode disposed on a tip surface of the measurement probe.   The biological signal measuring tool according to claim 1, further comprising a protrusion that floats the distal end surface of the measurement probe from the biological surface. The contact detection means measures the spectrum by receiving reflected light or diffused light from the living body with the measuring probe while the measuring probe is moved in the direction orthogonal to the surface of the living body by the driving means, and measuring probe. biological signal measuring instrument according to claim 1, characterized in that for detecting contact between the moved was measured probe to analyze changes in spectra measured with the biological surface. The biological signal measurement according to any one of claims 1 to 4, further comprising a vent for communicating a space surrounded by the distal end surface of the measurement probe, the probe support, and the biological surface with the outside air. Ingredients.   6. The biological signal measuring instrument according to claim 5, further comprising opening / closing means for opening and closing the vent.   The biological signal measuring instrument according to claim 5 or 6, further comprising a blowing unit forcibly sucking and discharging through the vent.   8. The biological signal measuring tool according to claim 7, wherein the blowing means also serves as the driving means.   The biological signal measuring instrument according to any one of claims 5 to 8, further comprising temperature adjusting means for bringing the temperature of the air reaching the space through the vent close to the biological temperature.   The biological signal measuring instrument according to any one of claims 5 to 9, further comprising a control unit that controls at least one of an aeration flow rate or an aeration direction through the ventilation port based on the measured biological signal. .   The biological signal measuring instrument according to any one of claims 1 to 10, wherein the distal end surface of the measurement probe is positioned within a range of 500 μm projecting from the position 150 μm away from the living body surface when no load is applied to the living body side. In this state, the living body signal measuring method is characterized in that near-infrared light is irradiated on the living body and reflected light or diffused light is received.