TW567053B - Method and apparatus for minimizing spectral effects attributable to tissue state variations during NIR-based non-invasive blood analyte determination - Google Patents

Abstract

A method and apparatus for minimizing confounding effects in a noninvasive in-vivo spectral measurement caused by fluctuations in tissue state monitors a selected tissue state parameter spectroscopically and maintains the selected parameter within a target range, at which spectral effects attributable to the changes in the selected parameter are minimized. The invention includes means for both active and passive control. A preferred embodiment of the invention provides a method and apparatus for minimizing the confounding effects in near IR spectral measurements attributable to shifts in skin temperature at a tissue measurement site. Spectroscopic monitoring of skin temperature at the measurement site provides near-instantaneous temperature readings by eliminating thermal time constants. A thermistor positioned at the measurement site provides active control. The spectrometer and the temperature control device are incorporated into a single instrument for noninvasive measurement of blood glucose concentration.

Description

567053 A7 B7 V. Description of the Invention () Field of Invention ............: ά: (Please read the notes on the back before filling this page) This invention is about non-invasive tissue composition analysis More specifically, the present invention relates to a method and device that can minimize the spectral effect caused by the change of tissue state during the non-invasive non-invasive blood analysis and measurement of near-infrared light. Related Techniques: Printed near-infrared light (NIR) tissue spectroscopy by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics is a promising non-intrusive technology. Its principle is to use far infrared with a wavelength range of 700-2500 nm. Light illuminates the tissue measurement area. The light energy is concentrated in a skin area and measured using different scattering and absorption characteristics of different skin tissue areas. Therefore, the reflected and transmitted energy that escapes and is detected can provide information about the volume of tissue through which light passes. Attenuation of light energy at each wavelength is a function of structural characteristics and chemical composition. Different tissue layers contain special heterogeneous distributions, and different light scattering phenomena will affect the degree of light absorption. Chemical composition such as water, protein, fat, and blood analytes in their unique absorption wavelength or fingerprint region, the absorption will change in proportion to the concentration. Therefore, the measurement principle of tissue properties, characteristics, and composition is to measure the light attenuation caused by the tissue's unique scattering or absorption characteristics of light. When non-invasive near-infrared spectroscopy is used to measure analytes in blood, such as blood glucose concentration, tissue state variability, such as skin temperature, will increase the variability of spectral analysis and cause attenuation of the net analysis signal. , And it ’s hard to get useful signal information from it. Page 3 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public love) ---- 567053 A7 B7 V. Description of the invention () Because human tissue < contains up to 80% water, Therefore, the near-infrared light spectrum will cause a scientific shift phenomenon as a function of temperature. When the temperature increases, the water band will shift to a shorter wavelength due to the reduction of hydrogen bonds. When light illuminates the tissue and passes through the skin layers, the light will be scattered or absorbed by the skin components before leaving the skin and being used by the spectrometer. Detected. Changes in skin temperature can affect spectroscopic analysis in the form of rain. One is that the light signal that passes through the volume of tissue will contain spectral information about the tissue, and this information will be affected by the natural temperature gradient of the light path in the human tissue. Uniform body temperature. Therefore, the skin temperature of healthy people will fluctuate 5 degrees Fahrenheit throughout the day. These factors can cause variability in skin temperature when measured in different batches. Therefore, the water band shift caused by temperature changes will affect the data values in the same batch or different batches of measurement, and the data can be used to estimate the analyte concentration by using the multivariate school positive model. Variations in temperature between measurements in the same batch or in different batches can increase the complexity of multivariate analysis and make it difficult to obtain useful analytical information from them. When the temperature variability is large, the variability of the spectral analysis will also increase, resulting in attenuation of the net analysis signal. In addition, there is a high possibility that uncontrolled Piguang temperature changes may be correlated with the analytes to be measured. Such accidental correlations may cause calibration errors that may or may not be found. In previous techniques, Many spectroscopic methods or devices are dedicated to monitoring or changing the temperature of a sample. For example, in the embodiment, US Patent No. 56 1 5672 (April 1, 1 997) owned by j. Braig, D. G 1 dberger, B. Sterling, page 4 This paper standard is applicable to Chinese National Standard (CNS) A4 specifications (210x297 mm) (Please read the notes on the back before filling this page),-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A7 B7 V. Description of the invention Intrusive infrared light spectrum analyzer, this patent describes a self-luminous method for monitoring glucose. The monitor uses a non-invasive method to monitor the emission of glucose in the blood in the range of far infrared light near 100 nm The infrared light is used to measure the glucose concentration in the blood of the subject. The device described above uses infrared light emitted by blood or surrounding tissues to measure the absorption spectrum. A temperature sensing device for measuring the internal temperature of the subject's arm is also used to adjust the composition concentration measurement results affected by temperature-related effects. Because this device measures the infrared light emitted by the subject in the form of body heat, there is no need to prepare an infrared light source. The above device and method need to measure the internal temperature of the subject; however, the temperature measured by the probe is pico-temperature. Therefore, the calculation of the internal temperature to provide a spectral signal compensation method will become a significant source of error in estimating the analyte concentration. In addition, the thermal time constant of the probe can cause a hysteresis of up to 11/2 minutes during measurement. In addition, the device only calculates the part of the spectrum signal that needs to be compensated due to the temperature of the subject. It does not consider controlling the temperature in the target range and providing the optimal temperature of the sample to minimize the temperature-related spectral effects. Meanwhile, Braig, d α /. Mainly considers the range of the middle or far infrared light region. U.S. Patent No. 6002953 (December 1, 4, 199, 9) owned by M. Block is a non-invasive infrared light transmission method for measuring analytes in the eardrum. This patent describes non-invasive methods and devices for measuring blood. To measure the concentration of the analyte, the method is to extend the optical instrument into the external ear canal to transmit electromagnetic waves to the infrared light detection and analysis instrument. This method uses a method of cooling the eardrum to make it different from the temperature of the inner ear, so that the heat is lightly shot. Page 5 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the note on the back first) Please fill in this page for further details.) Order · Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed 56705 53. Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed A7 B7. Although it is not a non-invasive method to penetrate an optical instrument into the ear canal and cool the tympanic membrane ', this method is compared with other trauma-sampling methods such as venipuncture. This method can be regarded as the least invasive method. The Block method does not perform temperature measurement based on photometry in the measurement area. Cooling the tympanic membrane is also not used to reduce the spectral effects caused by changes in tissue state, but to help transfer thermal energy. Except for cooling the eardrum by non-traditional means, the block device cannot control the temperature in the measurement area. However, the block device provides a non-closed loop, which uses the temperature measurement method in spectroscopy to provide the feedback signal needed to control the temperature in the measurement area. j. Braig, C. Kramer, D. Sterling, D. Goldberger, P. Zheng, A. Shulenberger, R. Trebino, R. King, C. Barnes, US Patent 61 6 1028 (December 12, 2000) ) Is a method for measuring the concentration of analytes by periodic temperature adjustment and phase detection methods. This patent describes a method for measuring analyte concentration using a similar principle to a block device. The device has a temperature gradient of the test sample temperature and uses an infrared detector to measure the selected analyte absorption front and the reference wavelength. Braig et al. Used gradient spectroscopy to enable the temperature of the sample to have a temperature gradient to assist in the transfer of thermal energy so that more thermal radiation can be detected by the detector. This method does not pay attention to the problem of spectral effects caused by the change of tissue state in the measurement area and the interference caused by it to the net analysis signal. In addition to giving the sample temperature a temperature gradient, this method does not consider controlling the sample temperature in the target range to reduce the spectral effect caused by the sample temperature variation. Page 6 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page) Order · 567053 A7 B7 V. Description of the invention () In the previous art The unresolved problem must be resolved is the spectral effect caused by changes in tissue state, such as changes in skin temperature, in the measurement of near-infrared light non-invasive blood analytes. The solution can be to monitor the selected tissue state parameters and maintain the parameters within a predetermined target range to reduce the spectral effect. If the spectral method can be used to calculate the correlation between the selected tissue state parameter deviation and the observed spectral effect deviation by using the correction mode, eliminating all the time parameter problems of traditional detection devices will be a major advancement in the technology of monitoring tissue state. Therefore, if the calculated value provided by the closed loop can be used as a feedback signal, a method to determine how to control the selected organization state parameter will be expected. SUMMARY OF THE INVENTION The present invention provides a method and apparatus for reducing the spectral effects caused by tissue changes during non-invasive in vivo spectral measurements. Multivariate correction mode can be used to monitor the selected tissue state parameter by spectral monitoring by calculating the relationship between the spectral change and the selected tissue state parameter change. This method can achieve almost real-time measurement without an obvious time constant. presence. The parameter value target range can be selected from the experimental value of the spectrum experimental data to select the range that can minimize the spectral effect caused by the change of the selected parameter value. During the measurement process, the selected parameters are continuously monitored, and the calculated values are driven by a closed-loop device that maintains the selected tissue state parameters within a certain target range. This invention also includes a device that can actively or passively control tissue state parameters. A method and device provided in a preferred embodiment of the present invention is available on page 7 (please read the precautions on the back before filling out this page). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 567053 A7 ----- ---------- 5. Description of the invention () To reduce the interference effect caused by changes in skin temperature in the tissue area in non-invasive infrared light spectrum measurement. The temperature of the skin located in the measurement area can be calculated by the spectral monitoring method using a multivariate correction mode to calculate the correlation between the skin temperature change and the spectral change. In the present invention, a near-instant measurement can be obtained without the problem of the thermal time constant in the conventional temperature sensing device. The present invention also provides active and passive control methods. The passive control method is achieved by selectively covering and removing the thermal covering for sealing. The active control method is achieved by using a thermistor placed on the skin near the measurement area. Active and passive control methods can be used independently or complementary. In a specific preferred embodiment of the present invention, the control device is incorporated into the measurement device, and the skin temperature value calculated therein can be used as a return signal for a closed circuit for driving the control device. In other alternative embodiments, the temperature value is provided to the operator, and the operator decides to use an active or passive control method to keep the skin temperature within the target range. Using spectroscopic methods and active or passive control methods to monitor and control skin temperature can reduce the impact of skin temperature changes on near-infrared light measurement. The present invention is particularly suitable for measuring glucose concentration in blood. The Ministry of Economic Affairs ’Intellectual Property Bureau ’s employee consumer cooperatives printed a statement that the first form of the spectrum of light absorption and absorption of water was measured. The temperature was different. It is necessary to prepare the base spectrum light with two or more light sources; the spectrum surface light β accepts the absorption and band diagram of the receiver. Page 8 6 The Chinese standard (CNS) is used for the paper size. A4 specification (210 × 297 mm) 567053 A7 B7 V. Description of the invention () Figures 4 and 5 show the use of a spectroscopic device including at least a test subject interface made with a lens according to the present invention. Figure 3 shows the absorption spectrum measured by the subject; Figure 6 shows the difference spectrum obtained by subtracting the absorption spectrum from Figure 2 and Figure 3 of the present invention; Figure 7 shows the difference between Figure 4 and Figure 3 according to the present invention. The difference spectrum obtained by extinguishing the absorption spectrum in Fig. 5; Fig. 8 is a graph of the different wavelengths of light transitions measured by a diabetic patient according to the present invention; Figs. 9A to 1 1A are graphs according to the present invention. Spectral changes measured in households of three healthy subjects Mapping of different pairs of wavelengths; Figures 9B-11B are graphs obtained when the temperature of the three healthy subjects in Figures 9A-11A is minimized or greatly changed according to the present invention; Figures 12 and 13 are based on this Invented the relationship between the sample variation of three healthy subjects and two different light-emitting diode detectors in Figs. 9-11 by using a graph drawn by a bar graph; Fig. 14 is a measurement according to the present invention &Amp; Skin temperature method for measuring and controlling the organization's measuring area. Work flow chart printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Figure 15 shows the operation of a & flow chart. Detailed description of the invention The combination of near-infrared light spectrum measurement and skin temperature measurement and near-infrared light skin temperature measurement technology and related skins Page 9 This paper applies Chinese National Standard (CNS) A4 (210X 297 mm) 567053 A7 B7 V. Description of the invention () The temperature reference measurement technology f is used to develop a near-infrared light temperature correction method, which only needs to scan the tissue with near-infrared light to predict the skin surface temperature. The development of correction techniques for spectral analysis requires a variety of multivariate analysis techniques that are familiar to those skilled in the art. Near-infrared skin temperature correction is achieved by using the relationship between the water band displacement at 1450nm and skin temperature changes. ° The correction mode uses displacement information hidden in the multivariate regression coefficient. Temperature measurement and tissue variation control are very important in near-infrared light measurement 'because it can simplify the problem that the analysis signal cannot be obtained due to the complex spectral overlap effect. Using near-infrared light temperature measurement can also save extra temperature measurement hardware costs and avoid the complexity of the analyzer. Compared with the traditional thermistor for measurement, near-infrared light measurement has the advantages of this measurement method without the problem of the traditional thermal time constant in the sensing hardware. When using a thermistor to measure a temperature gradient of 10 degrees Fahrenheit to change the condition of the piconet temperature, it usually takes up to 1 1/2 minutes to obtain a 95% sample temperature. Since it is not affected by the time constant in the traditional measurement methods in the past, it can use the near-instant skin temperature feedback signal to actively control the closed-loop temperature during the measurement. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Skin temperature correction for multiple persons can be established from the information of a single subject. The result can enable the instrument to establish a general skin temperature correction mode before shipment. The following are active and passive skin temperature control procedures. The skin is irradiated with near-infrared light and the biological analyte of the human subject is estimated from it. The negative effects of skin temperature fluctuations on near-infrared light have the following two aspects: · First, as shown on page 10, this paper applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 567053 Α7 ______ Β7 V. Description of the invention () If the skin / coverage interacts with the analyte, it may lead to erroneous calibration results. Second, large skin temperature fluctuations will reduce the net analysis signal. The following is a description of the device or process that can be used to actively or passively control the skin temperature to avoid the decrease of the net signal and the generation of real signals. The control program includes determining the target skin temperature, monitoring the real skin temperature, and using active or passive control methods to reach the target temperature. The purpose of the experiment is to: • Identify the effects of skin temperature fluctuations on the near-infrared light spectrum-see Experiment 1 and Experiment II below. • Identify skin temperature patterns during the day or between days and determine the target temperature-see Experiment II and Experiment m. • Test methods to control skin temperature changes to plus or minus 1 degree Fahrenheit. See Experiment III. Methods for controlling skin temperature Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs One of the basic functions of the skin is to keep the body temperature constant. The physiological response to external or internal stimuli will limit the control of skin temperature. Periodic monitoring is a key step in achieving good temperature control. With the present invention, a skilled operator can distinguish the trend of skin temperature and decide to perform passive or active control for temperature compensation, thus calling for keeping the skin temperature in the spectral measurement area stable. The skin temperature can be monitored with a temperature probe attached to the spectrum measurement area within 5 hours. As discussed in Experiment π, the skin temperature pattern is generally lowest in the morning and then gradually increased throughout the day. 11 pages of this paper are in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 567053 A7 B7 V. Description of the invention () The temperature pattern is a positive slope curve that gradually rises and stabilizes with time β as discussed in Experiment III The skin temperature paradigm of healthy and diabetic patients will eventually fall within the range of 90-92 degrees Fahrenheit, which is the representative temperature measured in the afternoon or near evening. The target temperature varies depending on the individual. The following methods are used to achieve or maintain the target range: Passive control Passive control is to wrap the subject's forearm with a heated wrap, which can make the subject's skin temperature quickly in the morning Reach the target temperature. This control method can make the skin temperature increase curve with a steep positive slope in the first hour, and then a more consistent skin temperature at other times of the day. The heating wrap covers the wrist to the elbow, which can increase the temperature of the entire forearm. The heat wrap can be adjusted for tightness or removed to keep the skin temperature within the target range. Active Control Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Active Control uses a copper heating tank with temperature control to quickly change the skin temperature. The heating set point of the copper heating bath can be adjusted to heat or cool the skin. Active control is placed on the area of the skin in contact with the heating tank, which is the same size as the interface of the subject-spectrum analyzer. If the skin temperature exceeds the target range too much before the spectral measurement, the arm is placed on the heating bath for one to two minutes before taking the measurement. The above method can be used as a supplement to keep the skin temperature within the target range. Page 12 This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 567053 Α7 Β7 V. Description of the invention () The temperature pattern is gradually increasing with The time-stable positive slope curve. As discussed in Experiment III, the skin temperature paradigm of healthy and diabetic patients will eventually fall within the range of the initial target skin temperature of 90-92 degrees Fahrenheit, which is the representative temperature measured in the afternoon or near evening. The target temperature varies depending on the individual. The following methods are used to achieve or maintain the target range: Passive control Passive control is to wrap the subject's forearm with a heated wrap, which can make the subject's skin temperature quickly in the morning Reach the target temperature. This control method can make the skin temperature increase the positive slope of the steep slope in the first hour, and then a more consistent skin temperature at other times of the day. The heating wrap covers the wrist to the elbow, which can increase the temperature of the entire forearm. The heat wrap can be adjusted for tightness or removed to keep the skin temperature within the target range. Active Control Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Active Control uses a copper heating tank with temperature control to quickly change the skin temperature. The heating set point of the copper heating bath can be adjusted to heat or cool the skin. Active control is placed on the area of the skin in contact with the heating tank, which is the same size as the interface of the subject-spectrum analyzer. If the skin temperature exceeds the target range too much before the spectral measurement, the arm is placed on the heating bath for one to two minutes before taking the measurement. The above method can be used as a supplement to keep the skin temperature within the target range. Page 12 This paper size is applicable to China National Standard (CNS) A4 (21 × 297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A7

5. Description of the invention () Method s-The method chosen depends on the measured skin temperature and the available time before starting the spectral measurement. Deciding whether to use active or passive control depends on the difference between the measured skin temperature and the actual and target temperature. Passive control is suitable for situations where the time interval is more than 2 minutes, while active control is suitable for situations where rapid temperature rise and fall are required. Figure 14 is a flowchart of a general procedure for controlling skin temperature. As described in FIG. 14, the target temperature is an empirical value of 140 established based on the observational spectrum measurement. The empirical range is the temperature range where the spectral variation can be kept to a minimum. By performing a multivariate correction method on the spectral analysis, the near-infrared light spectrum measurement result 141 and the skin temperature value 142 can be collected and the relationship between the skin temperature variation and the spectral effect can be obtained. Estimate the measured temperature reading 143. If it is within the target range, no control program is required. If it exceeds the target range, passive control 1 44, active control i 45, or a combination of the two methods can be used to return the temperature. Into the target range. It can be seen from Figs. 14 and 15 that the present invention is a closed loop, and the control device can be driven by the echo signal provided by determining the spectral temperature. Fig. 15 is a spectroscopic instrument for implementing the present invention. The subject interface module 15 2 is combined with the tissue measurement area 5 1 on the subject's skin. The thermostat 1 5 9 built in the interface module of the test subject has a heating setpoint design within the target temperature range. The temperature is maintained at the set temperature by heating or cooling the skin. In a preferred embodiment of the present invention, the subject's interface includes at least one optical fiber probe. The subject interface module directs the light emitted from the light source 160 to the tissue measurement area. The light returned from the back of the measurement area is guided to one or more optical signals by the detection optical instrument such as the optical fiber in this example. Page 13 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ^^ ~

567053 A7 B7 V. Description of the invention () No. Detector 1 5 4. The optical signal is converted into a voltage by an analog electronic device, and then converted to a digital signal by the analog-to-digital converter 155. Finally, these digital values are used to calculate the absorption spectrum 156. The absorption spectrum is affected by the aforementioned pre-processing technique 157. Finally, a temperature value is calculated from the absorption spectrum by the aforementioned calibration mode, and the temperature value is transmitted to a controller connected to the thermistor 159 to provide a temperature feedback signal. Experiment I The effect of skin temperature on the near-infrared spectrum Summary The purpose of this preliminary experiment, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, was to consider the information contained in the water band in the near-infrared spectrum. Metrics, Inc., Tempe AZ, whether the optical configuration of the optical analysis equipment FOCSI (optical fiber combined scanning equipment) provided is better than the optical configuration of the DRACO spectral analysis equipment of the same company. The water band located at a wavelength of 1450nm will change with the temperature of the sample. 'This makes it difficult to detect samples with a wide range of temperature changes. The distribution of glucose in water and tissues. Therefore, the prediction of glucose in blood must be considered. Water band offset correction strategy to simplify model difficulty. Therefore, the optical design used to evaluate tissue temperature information has become an important design standard for non-invasive glucose monitoring. In this study, at different temperatures, FOCSI was significantly more stable than DRACO in achieving the expected spectral performance. This result may be due to the difficult to explain and correct the temperature effect of the highly variable sample measurement path when performing non-invasive measurements with DRACO. Page 14 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 567053 A7 B7 5. The invention statement printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs () Introduction 80% of human tissue is composed of water When the temperature of the sample rises, the water band of the near-infrared absorption spectrum will also shift. The water band shifts to shorter wavelengths due to the increase in the pH of the solution or the decrease in hydrogen bonding due to the increase in temperature. The first harmonic band of water in the transmission spectrum at 33 (11) and 4 1 (10) degrees Celsius is plotted in Figure 1, because in the living body measurement, the natural temperature of the living tissue in the optical sampling path The spectral effect caused by the change will appear in the measured wave science. Measuring glucose for this kind of thermal energy as a complex sample matrix is one of the challenges in performing near-infrared light spectroscopy in vivo measurement. Because the use of near-out light to measure tissue on the skin surface and tissue will have a localized effect, the most accurate tissue temperature compensation is derived from spectral measurements. However, the temperature needle cannot extend into the optical path without affecting the measurement, so the non-invasive temperature probe does not take into account the temperature gradient in the tissue. The most effective method for compensating for tissue temperature fluctuations requires sufficient spectral data on the position and shape of the water band. The shape of the water band is also affected by the light properties of the tissue, so it is more important to obtain a spectral scan with high information value. Based on the above considerations, because the instrumentation on the device or the sampling will affect the shape of the water band, special attention should be paid to this when designing a near-infrared non-invasive glucose measurement device. The degree of redness was used to enter the experimental section. Six subjects were scanned by FOCSI and DRACO spectrometers. Each subject underwent two experiments. The first set of experiments, the test subject page 15 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 × 297 mm)% Read Back * Note Note jn%

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V. Description of the invention () Scanning was performed under normal external skin temperature. In the second experiment, the subject's skin was pre-heated to 3.5 degrees Fahrenheit higher than normal skin temperature. Measurements before the study establish the following rules for spectral measurement: contact the arm with the device and the interface of the subject for three minutes before performing the spectral measurement, which can reduce the problem of rapid changes in body temperature and physiological phenomena. In the experiment, the skin temperature detector yellow spring OH with YSI, INC. YSI · 4000 type, the minimum reading of which is plus or minus 0.05 degrees Fahrenheit, is placed about 5 mm away from the measurement area, and the temperature is recorded every 30 seconds. The scan time took two minutes. The intensity is 80% of the standard reflection. The reference spectrum of the intensity is obtained directly before and after the in vivo measurement. ........... h 丨 丨 丨 · (Please read the notes on the back before filling out this page) The results and discussions printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs were passed on the six subjects. The scanning results obtained by the various spectroscopic devices are used to discuss temperature-dependent effects. In three of the remaining four patients who underwent a FOCSI scan, it was found that the temperature-related effects were consistent with changes in tissue sample temperature distribution, but compared to the results of the DRACO scan, the temperature-related effects were less pronounced. In Figures 2 and 3, FOCSI is used to measure two subjects at two different temperatures. One group of spectra was measured when the skin temperature was higher than that of the other group (2 ^. 5 degrees Fahrenheit (2 1, 3 0). "Obviously, the higher the temperature during scanning, the higher the absorption wavelength at 1450nm and 1 650 -1700nm < The greater the difference in the intensity of the lowest absorption wavelength. The edge of the spectral peak measured at high temperature falls within the low-temperature spectrum and its position is the length of the 145Onm water band. The skin length range β is heated by heating The narrowing of the water temperature range in the organization. Page 16 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm). Order 567053 A7 B7 5. When the invention description (), the spectral differences also have consistent changes Therefore, sharper peaks can be obtained. According to the scattering theory, tissue scattering will increase with increasing temperature. The most severe scattering phenomenon in the spectral region is the short wavelength range of the second overtone region at 1100-1 300 nm. After the second overtone region, the scattering phenomenon will disappear rapidly. The ability of the sample to absorb light will be suppressed due to the increase in temperature. This phenomenon is consistent with the originally expected optical characteristics of the tissue. The phenomenon that the increase of the absorbance decreases as the result of the increase is most obvious in the first harmonic region, but it is also obvious in the first harmonic region where there is a strong absorption spectrum characteristic, such as the maximum absorption of the water band. The cooperative prints Figure 4 and Figure 5, which are the corresponding scans 40, 50, 41, and 51 obtained by DRACO. As mentioned earlier, the temperature effect is not as good as in Figures 2 and 3. The effect of the spectrum on the spectrum is obvious. Based on the skin temperature of the subject, the calculated different spectra should contain relevant spectral information about tissue temperature changes. Consistent measurements should be available on different subjects Similar graphs were obtained in the measured spectra. Figure 6 shows the spectrum obtained by subtracting the measured spectrum of DRACO from the subject at different picotemperatures, and Figure 7 shows the same as the FOCSI measurement. The result obtained after subtraction. The graph obtained by subtracting the spectrum measured at high temperature from the spectrum measured at low temperature. The spectrum measured by FOCSI is more consistent than that obtained by DRACO. In the second harmonic region The temperature-induced scattering effect observed nearby is consistent with the scattering research done on FOCSI. 'Because the positive residual spectrum obtained by subtracting the high-temperature spectrum from the low-temperature spectrum, we can know that the tissue scattering caused by the temperature rise is showing an increasing trend. Figures 6 and 7 also clearly show that the measurement on page 17 is based on the Chinese paper standard (CNS) A4 specification (21〇297297) on the paper scale. 567053 A7 B7 5. The spectrum of the invention () It is more difficult to interpret the spectral measurement results at normal temperature and high temperature than FOCSI. It may be because the sensor positioning and pressure in the DRACO optical system make the DRACO optical system more sensitive to tissue sampling and surface reflection. The Intellectual Property Bureau employee consumer cooperative printed in the temperature test, the results can be determined that using the FOCSI test subject interface module to collect and identify living body spectral measurement data, will be more efficient than using the DRACO test subject interface module. The spectral gap measured at normal temperature or heated tissue is two digits below the decimal point of the absorption unit value, so that under these conditions, the spectrum measured by the DRACO detector will be impossible due to the noise of the DRACO detector. Compare. The biggest difference between different devices is in the optical sampling system: between the single optical device and the sample and between the sample and the detector. DRACO uses a traditional lens system and FOCSI uses an optical fiber transmission system. The influence of reflection variation and large-scale optical path distribution will lead to the phenomenon of widening the water band and the uncertainty of the band shape at the wavelength of 145 nm. For a discussion of this phenomenon, please refer to JD Hardy, HT Hammel, D Murgatroyd, J. Appl. Phvsiol .. 9: 257 (1 956) 〇The FOCSI system is not affected by the wide surface reflection changes, and the optical path distribution is also narrow. . These optical differences between DRACO and FOCSI will result in less information in the water band when measured with DRACO ^ In addition, other less important determinants may limit the interpretation of temperature-dependent spectral changes , But may also be better explained as a result. Page 18 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 567053 A7 ____ B7_ V. Description of the invention () Excitingly, the spectral variation and contrast obtained by scanning with F 0 C SI The expected spectral shifts of water and human tissues are consistent with optical scattering characteristics. Obviously, the relationship between the spectral variation of the system obtained by the DRACO experiment and the skin temperature does not have such a consistent result. The reason may be the result of the variation of the skin surface reflection between the samples. Unfortunately, even the smallest variation in surface reflections in measurements between different batches of the same subject can cause variations in the size and shape of the water band, making it impossible or difficult to interpret temperature-dependent spectral variations. Temperature, pressure, physiological response, and sample position are all related to scattering phenomena of living samples and related changes in the average optical path. To compensate for temperature, it is necessary to separate temperature-related changes from other effects. However, it is more difficult to separate the Pi Guang temperature status from other information on DRACO instrument measurement, because the spectral variation caused by non-temperature factors during DRACO measurement is greater than F 0 C SI. The consistency of the information obtained in this experiment with the results shows that the fiber-based equipment has a better performance in providing compensation for the spectral changes caused by temperature. 0 Experiment 2 Skin Temperature Model Introduction The purpose of this experiment is to identify uncontrolled Or the skin temperature paradigm when passively controlling the skin temperature. In both cases, the Piguang temperature was the lowest in the morning and then gradually increased to a stable temperature. The passively controlled or uncontrolled skin temperature patterns are similar to each other in temperature change process, but the situation of passive control is less likely to happen suddenly. Page 19 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 567053 A7 B7 V. Description of the invention () Experiment Eight subjects were divided into a rain group ', each group consisting of three males and one female. Each subject measured the Piguang temperature model under uncontrolled and passive control conditions every three hours from 9 am to 6 pm for three consecutive days. The first set of skin temperature is a THERMAX wrap covering the measurement area of the forearm to passively control the skin temperature. In the second group, the first day was covered with THERMAX, and the second and third days were covered with wool for the entire forearm. In both groups, uncontrolled temperature measurements were taken using the subject's other uncoated forearm. The skin temperature is measured using the YSI4000 temperature probe. Results and discussion The observation results showed that the initial skin temperature was related to the subject's clothing. The subjects wearing long sleeves had higher initial skin temperature. All subjects were right-handed, and observations showed that the temperature of the right arm was higher. The skin temperature of the subject is not necessarily related to room temperature. Usually, the arm skin temperature rises rapidly in the morning, and then after the first stage, it shows a steady or final gradual decline, or it continues to increase in a gentler trend. In the passive control group, the subjects had the highest daily skin temperature, and seven out of eight had temperatures of about 9 1-93 degrees Fahrenheit. The minimum temperature measured daily is highly variable and may be related to irritating beverages such as coffee or soft drinks. When the skin temperature is controlled passively, it is less sensitive to sudden changes in external temperature, such as when the subject is out of the house. After the rapid temperature increase in the morning, control page 20 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Staff of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative 567053 A7 _ B7 V. Description of the invention () Please read the precautions on the back or the uncontrolled temperature model is generally consistent with the trajectory, and the distance between the trajectories of the time and the trajectory is also kept substantially constant. This phenomenon may be because the sympathetic nervous system stabilizes the temperature and the temperature of the uncontrolled arm. Finally, it can be observed that when the forearm is covered with a fleece sleeve, the skin temperature can increase by about 2-9 degrees Fahrenheit. Conclusion Skin temperature is affected by many environmental and physiological phenomena. The passive control method can reduce the fluctuation of the skin temperature to within plus or minus one degree Fahrenheit, and the passive temperature control can suppress the phenomenon of rapid skin temperature increase. Experiment 3: Preliminary effects of skin temperature on sample reproducibility Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This study focuses on the relationship between skin temperature and non-invasive spectrum, especially the impact of large skin temperature changes on sampling accuracy β In this experiment, non-invasive spectral data were collected on three subjects with large temperature changes and controlled temperature changes. Preliminary results show that the smallest change in skin temperature can lead to a reduction in the spectral variation of the wavelength in the range of 1500-600 nm. Foreword After collecting the skin temperature data of the first group of diabetic patients who received continuous oral glucose tolerance test several times, it can be found that the Chinese national standard (CNS) A4 specification (210X297 mm) is applied differently or the same as the paper on page 21. 567053 Α7 Β7 V. Description of the invention () The skin temperature measured after four hours has changed greatly. There can be several reasons for this temperature fluctuation, such as environmental or physiological factors. Therefore, it is necessary to understand the effect of large temperature changes on the stability between samples. In the second group of healthy subjects, it can be observed that the skin temperature change can be as large as 5 degrees Fahrenheit on normal working days. The tester obtained two sets of data. The first set of data included non-invasive measurement of samples with a temperature difference of up to 8 degrees Fahrenheit, and the other group measured samples with temperature differences controlled within two degrees Fahrenheit. Experimental procedure The three subjects involved in the experiment were one female and two males. Before the measurement, the measurement area was covered with room temperature vulcanized silicone rubber for 4 5 minutes. One was manufactured by Metrics, Inc. of Tempe AZ. F〇CSI9 (scanning equipment combined with optical fiber) spectroscopy equipment to collect data, optical bonding liquid (FLUORINERT FC-40) provided by 3M company St. Paul MN is used to connect the measurement area with the optical fiber probe of the spectrometer Closer integration. Each sample was subjected to a reference scan (80% standard reflection) and a scan of polyethylene. The YSI temperature probe provided by YSI, Inc. of Yellow springs 0H was printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. In the case of large or minimal changes in skin temperature, 5-8 samples were collected. The sample with minimized temperature fluctuations refers to the sample with technical temperature, which is the sample that measures the arm area to 91 degrees Fahrenheit by using a passive method using a small blanket. For uncontrolled samples with large temperature changes, the sample temperature range is 86-93 degrees Fahrenheit. Page 22 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297). 567053 A7 B7 V. Description of the invention () Data analysis preprocessing steps include baseline calibration before data collection, standardization of X-coordinate axis, and detection of disparity points Measurement and conversion of absorbance should be prepared before analysis. For each sample, 16 raster scans are performed and the flat chirp is added. A 35-point first-order Savitsky-Golay filter can be used to obtain the first derivative spectrum. The square root of the standard deviation of each group of samples is defined as the spectral variation. The smaller the spectral variation, the simpler the matrix for partial least squares mode. In addition, the mean root error is used to evaluate the sample repeatability of the controlled and uncontrolled samples. The wavelength available for the 彳 彳 detector (1.9 // m detector uses a wavelength of 1 1 00-1 7 00nm and 2 · 6 # m detector uses a wavelength of 1 40 0-2 400nm) is used to determine These values. Results Figure 8 is a plot of spectral variation and wavelength using clinical experimental data from the first group of subjects. The data includes samples from two different batches of clinical trials, and the samples are classified based on the picotemperature. The standard deviation of skin temperature is 0.3 8 degrees (80) and 2.73 degrees (81). When the skin temperature changes very little, the spectral variation of 1500-1600nm will be greatly reduced. The second set of tests also indicated that reducing skin temperature variation can reduce spectral variation. Figure 9-1 1 is a graph drawn based on the spectral changes detected by the 1 · 9 e m detector and the wavelengths irradiating the subjects 1-3. Figure 9A-1 丨 a shows the standard error in skin temperature of 2.73 degrees (90, 100, 10) and Fahrenheit on page 23. This paper applies Chinese National Standard (CNS) A4 (21GX297) (Please read the precautions on the back before # this page) Order-Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A7 B7 V. Description of the invention () Spectral variograms plotted separately at 0.38 degrees. Figure 9B-1 1B shows the corresponding controlled or uncontrolled temperature model. Similar results can be observed in the wavelength range 1 500-1600 nm used by the 2 · 6 // m detector. Figures 1, 2, and 3 are the values of the mean root error, which are used to indicate the repeatability of the sample data. When the temperature variation is controlled, the variability between different samples measured by the detectors 1 and 2 with i. 9 // m detector will be slightly reduced. Use 2 · 6 // m on the subjects 2 and 3 The inter-sample variability obtained by the detector will be lower. Both studies have shown that a smaller skin temperature variation can reduce the spectral variation of the spectral region used by the spectroscopic instrument. In addition to the skin temperature of a single subject changing over time, the skin temperature range between subjects also varies. For example, the outside temperature is warm, and at different times of the day, the contact with the device interface module of the device and the clothing, the intensity of the activity will affect the skin temperature of the person. Because many of these parameters are included, it is not possible to determine a standard temperature for non-invasive spectral data collection. However, it is possible to reduce the fluctuation of the skin temperature to reduce the spectral variation in the spectral range used by the detection instrument. To reduce spectral fluctuations, skin temperature can be maintained at 89-91 degrees Fahrenheit. Covering the forearm with a blanket or other heatable covering can raise the temperature before measurement without causing significant temperature changes. Other possible methods include placing the arm in a heated tank before scanning. Although the present invention is related to controlling skin temperature, the present invention can also be applied to control of other tissue state parameters such as hydrolysis or surface pH. In addition, the present invention is particularly suitable for non-invasive measurement of glucose in blood, page 24 f Please read the precautions on the back before filling this page}

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567053

5. Description of the invention (The invention can also be applied to the measurement of other blood and tissue components, such as cholesterol, fat, blood urea nitrogen, and protein. In addition, the invention is also suitable for detecting foreign substances in the blood such as ethanol and Other drugs or toxic substances. Although the present invention is described here using some preferred embodiments, for those skilled in the art, there may be other applications without departing from the spirit and scope of the present invention. Therefore, the present invention is only The scope of patent applications is limited. (Please read the notes on the back before filling out this page) Fill in this f Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Page 25 (Mm)

Claims (1)

567053 A8 B8 C8 D8 Patent Application Scope 1. A method for controlling the spectral effect caused by tissue state changes during non-invasive non-invasive blood analysis and measurement of near-infrared light. The method includes at least the following steps: determining the selected tissue state parameters Target value range of; Provide means to modify the aforementioned tissue state parameters; Provide a correction mode 'which can calculate the correlation between the aforementioned tissue state parameter changes and spectral effects; use near-infrared light spectrum to monitor the aforementioned tissue state parameters and use the aforementioned corrections The mode calculates the values used for the spectral parameters; and if the calculated values exceed the target range, the aforementioned tissue state parameters need to be modified until the measured values are within the target range. 2. The method according to item 1 of the scope of patent application, wherein the tissue state parameter includes at least the skin temperature near the tissue measurement area on the body of the living subject. 3. The method according to item 2 of the scope of the patent application, wherein the spectral effect includes at least the shift of the absorption band peak of the water band in the near-infrared light spectrum, wherein the 'water band absorption peak will go when the skin temperature rises. The short wavelength shifts, and when the skin temperature decreases, the absorption band of the water band shifts to the long wavelength; the above shift will cause the attenuation of the net analysis signal. 4. According to the method described in item 3 of the scope of patent application, where the water band absorption is on page 26, this paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm (please read the precautions on the back first, (Please fill in this page again) p ^ l ^ -------- Order ---------: Printing of clothing by employees' cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A8 B8 C8 D8 The peak is located at a wavelength range of about 1450 nm. (Please read the precautions on the back before filling out this page) 5. The method described in item 3 of the 'Please Patent Range', where the target range includes at least the water band offset is The smallest range of skin temperature fluctuations' At this time, the attenuation of the net analysis signal can be minimized. 6. The method described in item 5 of the patent application range, wherein the target range mentioned is about 89 to 91 degrees Fahrenheit. 7. If The method described in item 3 of the scope of patent application, wherein the step of determining the target range includes at least: determining the target range by empirical values based on the spectrum obtained by observing the correction data set, and the range is when the water band offset can be kept to a minimum Temperature range The method described in item 2, wherein the method for modifying tissue state parameters includes at least one of the following or rain: a method of actively controlling the skin temperature; a method of passively controlling the skin temperature " Bureau of Intellectual Property, Ministry of Economic Affairs Printed by the employee consumer cooperative 9. The method described in item 8 of the scope of patent application, wherein the method of actively controlling the skin temperature and the method of passively controlling the skin temperature may be complementary methods to maintain the skin temperature within the target range. 27 The paper size of this page applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 567053 A8 B8 C8 D8 _ VI. Patent application scope 1 ° · The method described in item 9 of the patent application scope, where the active control The method of skin temperature is used to cause rapid changes in skin temperature. 1 1. The method described in item 8 of the scope of patent application, wherein the method of passively controlling skin temperature is used for relatively long time to change the skin temperature. 1 2 · The method described in item 8 of the scope of patent application, wherein the method for passively controlling the skin temperature includes at least wrapping around the body The body needs a heating wrap for the temperature-controlling part, which can increase the skin temperature at the beginning of the coating. 1 3 · The method described in item 12 of the patent application scope, wherein the skin temperature is maintained within the target range The methods include loosening, tightening or removing the aforementioned heating wrap. 1 4. The method according to item 8 of the scope of patent application, wherein the method for actively controlling the skin temperature includes at least one temperature-controllable heating tank. 1 5. The method as described in item 14 of the scope of patent application, wherein the heating tank has a heating set point that can maintain the temperature within the target range, and can be adjusted to heat or cool the skin to maintain the skin temperature within the target range. 28 pages of this paper are applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling in this page) Order .. Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A8 B8 C8 D8 Application for patent scope 1 6. According to the method described in item No. 14 of the patent scope, loading and lifting (the active control is placed in contact with the heating tank On the skin. 17. The method as described in item 3 of the scope of patent application, wherein the step of providing a calibration mode includes at least a correction developed by a correction team obtained by performing spectral measurements and related skin temperature reference measurements on a group of demonstration subjects. mode. Zhengguang 18. The method as described in item 17 of the scope of patent application, wherein the reference measurement range is approximately equal to or greater than the target range. 19. The method as described in item I? Of the scope of patent application, wherein the reference amount is a non-invasive warm needle that is placed near the tissue measurement area. 20. The method as described in item 17 of the scope of patent application, wherein the correction technique uses multivariate analysis techniques, wherein the multivariate regression coefficients in the model contain the aforementioned water band offset information. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 21. The method described in item 20 of the scope of patent application, wherein the step of monitoring the acoustic parameters of the tissue includes at least: Calculating an absorption spectrum for near-infrared light spectrum ; Selectively preprocessing the aforementioned absorption spectrum; and calculating the skin temperature using the aforementioned multivariate correction mode. Page 29 This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling in this page) Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 567053 A8 B8 C8 D8 VI. Application for Patent Scope 22 · The method as described in Item 21 of the Patent Application Scope, wherein the step of modifying the tissue state parameters includes at least the application of the foregoing to maintain the skin temperature Control method within target range. 23. A device capable of controlling the spectral effect caused by a change in tissue state during the non-invasive blood analysis and measurement of near-infrared light, the device includes at least a device for correcting a selected tissue state parameter; and provides near-infrared light in a tissue measurement area A device for measuring the spectrum. A correction mode that can calculate the correlation between the aforementioned spectral effect and the change in the state parameter of the tissue. The aforementioned spectrum can be used to calculate the value for the aforementioned parameter by the correction mode and use the near-infrared light spectrum to monitor the tissue. Device for state parameters; The organization state parameters can be corrected by the aforementioned correction device. If the calculated value exceeds the target range, the device can be used to correct it within the target range. 24. The device according to item 23 of the scope of patent application, wherein the tissue state parameters include at least the skin temperature near the tissue measurement area on the body of the living subject. Page 30 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) n_i ϋ it n J 1, I 111 I ϋ nnn «1« I Preface 567053 A8 B8 C8 D8 VI. Application for patent scope 25. As for the device described in the scope of the application for patent scope item 24, Gan's "The spectral effect is at least included in the near-infrared light spectrum with a hundred water bands and the spectrum received. With peaks (please read the precautions on the back and then fill out this page) shift. When the skin temperature rises, the water band absorbs η Η π to shift to a short wavelength, and when the skin temperature drops, the water The band absorption lead is shifted to a long wavelength; the above-mentioned shift will cause the attenuation of the net analysis signal. 26. The device as described in item 25 of the patent application range, wherein the water band absorption peak is located at a wavelength range of about 1450 nm. 2 7. The device as described in item 25 of the scope of patent application, wherein the target range includes at least the skin temperature fluctuation range when the water band shift is minimum, at which time the net analysis signal attenuation can be reduced to a minimum ^ 28 . If applying for a patent The equipment described in item 27, wherein the target range is approximately 89 to 91 degrees Fahrenheit. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 29. The device described in item 25 of the patent application scope, wherein the target range is based on observations. The spectrum obtained by calibrating the data set, the target range determined by empirical values is the temperature range at which the water band shift can be kept to a minimum. 30. The device described in item 24 of the scope of patent application, which is used to modify the organization The device of the status parameter contains at least one or two of the following: Page 31 This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs 567053 A8 B8 C8 _____ D8 ____-___ VI. Patent application device for actively controlling skin temperature; Device for passively controlling skin temperature ° 3 1 · The device described in item 30 of the patent application scope, in which device for actively controlling skin temperature and passively controlling skin The temperature device can be a complementary method to maintain the skin temperature within the target range. 3 2. As claimed in item 31 of the scope of patent application The device, wherein the device for actively controlling the temperature of the skin is used to cause rapid changes in the skin temperature. 3 3 · The device as described in item 30 of the scope of the patent application, wherein the device for passively controlling the temperature of the skin is used for a relatively long time When the skin temperature is changed. 3 4. The device according to item 30 of the scope of patent application, wherein the device for passively controlling the skin temperature includes at least a heating wrap wrapped around the body's temperature-controlling part, which can make the skin wide temperature It is raised 3 5 at the beginning of the coating. The device as described in item 34 of the scope of patent application, wherein the method of keeping the skin temperature within the target range is to open, seal or remove the aforementioned heating wrap. 3 6 · The equipment described in item 30 of the scope of the patent application, in which near-infrared page 32 is applicable to the China Standard & Standard (CNS) A4 specification (210 X 297 mm '" " " " " '' (Please read the precautions on the back before filling this page) -------- Order --------- line "567053 A8 B8 C8 D8 VI. Application Patent scope The device for optical spectrum measurement includes at least the above-mentioned spectroscopic equipment including at least near-infrared optical spectroscopy equipment and its testee interface modules. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 37. The device according to item 36, wherein the device for actively controlling the temperature of the skin includes at least one temperature-controlling heating tank. 38. As described in item 36 of the scope of patent application, the heating tank is the interface of the aforementioned test subject A part of the module is' in measurement '. The aforementioned heating tank will contact the tissue measurement area. 3 9. The device described in item 37 of the patent application scope', where the heating tank has a temperature maintained at the target The heating set point within the range can be adjusted to heat or cool the skin Maintain the skin temperature within the target range 0 40. The device as described in item 37 of the scope of patent application, wherein the active control is placed on the skin contacting the aforementioned heating tank. 1. As described in item 25 of the scope of patent application The above-mentioned equipment 'wherein the calibration mode includes at least the calibration mode developed by the calibration data group obtained by performing spectral measurement and related pico temperature reference measurement on a group of demonstration subjects. Page 33 (210 X 297 mm) (Please read the notes on the back before filling this page) • Line ‘567053 A8 B8 C8 D8 VI. Patent application scope 42 • The device described in item 41 of the patent application scope, where the reference measurement range is approximately equal to or greater than the target range. 43. The device described in item 41 of the Chinese Patent Application, where the reference measurement is a non-invasive temperature probe placed near the tissue measurement area. 44. The device as described in item 41 of the scope of patent application, wherein the correction is based on multivariate analysis technology, and the polyvariate regression coefficient in the model contains water band shift information. 45. The device according to item 44 of the scope of the patent application, wherein the tissue state parameters are monitored by: calculating an absorption spectrum for use by near-infrared light spectrum; optionally, pre-processing the aforementioned absorption light reading; Calculate skin temperature using the aforementioned multivariate correction mode. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)-line 46. The device described in item 44 of the scope of patent application, where the step of modifying the organization state parameter includes at least one of the foregoing Or all two devices that can keep the pico temperature in the target range. P.34 This paper is sized for China National Standard (CNS) A4 (210 X 297 mm)