JP2011163993A - Sample analysis chip and sample analysis system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a reproducible measurement value by preventing reduction of measurement precision by temperature change with an analysis chip having rapidness and easiness. <P>SOLUTION: A solution system reaction place is thermally brought into contact with a sensor, and sample and reagent solution is made to flow in the solution system reaction place as a fine flow channel. The temperatures of the reaction place, a detector, and the sample and reagent solution are set constant in a short time. A target molecule is measured rapidly and accurately. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a small apparatus for detecting or measuring an immune reaction or a gene reaction comprising a sensor chip integrated with a sensor and a signal processing function and a sample / reagent solution flow path.

  As a conventional technique, a color reaction or an agglutination reaction is used in an immunological reaction or chemical reaction detection system, and a light source (LED: Light Emitting Diode or LD: Laser Diode) and a sensor (PD: Photo Diode, A stationary apparatus using an optical system composed of a CCD (Charge Coupled Device) or a PMT (Photo multiplier tube) is known.

  In Patent Document 1, a probe for a biological material is fixed on a chip on which a functional block having a sensor and a wireless transmission / reception function is formed, a captured target is detected by the sensor, and a sensing result is transmitted to an external control device by the wireless transmission / reception function. A transmitting measuring device is disclosed.

  Patent Document 2 discloses a sensor chip in which a sensor, a signal processing function, and a wireless communication function are integrated.

  Non-Patent Documents 1 and 2 describe an analysis of the effect of flow velocity and flow channel shape on the efficiency with which sample molecules in a flow channel are captured by a probe fixed to the inner wall of the flow channel.

JP 2007-333695 A JP 2004-101253 A

Todd M Squires, Robert J Messinger & Scott R Manalis, “Making it stick: convection, reaction and diffusion in surface-based biosensors”, Nat. Biotechnol. 26, 417-426 (2008) Hesam Parsa, Curtis D. Chin, Puttisarn Mongkolwisetwara, Benjamin W. Lee, Jennifer J. Wang, and Samuel K. Sia, “Effect of volume- and time-based constraints on capture of analytes in microfluidic heterogeneous immunoassays” Lab Chip, 8 , 2062-2070 (2008)

In specimen testing of various proteins, viruses, and bacteria that serve as disease markers, centralized testing devices installed in large-scale hospitals and testing centers have been used to reduce costs through labor saving. On the other hand, POCT (Point of Care) for emergency tests and infectious disease tests that require quick results at the site of specimen collection, or self-tests that require simplicity and compactness (such as blood glucose levels performed at home) Testing) is becoming popular. With the expansion of use, POCT is required to have high measurement sensitivity in addition to quickness, simplicity and compactness. To meet this demand, a signal detection system using sensors using semiconductor integrated circuit technology and MEMS technology, and a solution reaction field that performs reactions (antigen-antibody reaction, enzyme reaction, nucleic acid hybridization reaction) to generate detection signals A POCT device that is miniaturized by combining it has been proposed. (For example, Patent Document 1)
The problem here is fluctuations in measured values caused by temperature fluctuations in the POCT detection system and reaction field. First, regarding the detection system, in an integrated sensor in which an amplifier and a control circuit are integrated in addition to a single sensor element, Joule heat generated by power supply causes temperature fluctuation. The power supply means for the integrated sensor may be either wired or wireless, but an example of wireless supply will be taken up.

  The device of Patent Document 1 wirelessly supplies electromagnetic energy from an external reader toward the POCT device. The sensor chip temperature rises as power is supplied by inductive coupling between the reader side coil and the sensor chip side coil. In general, the performance of a detection system that measures minute signals is strongly influenced by temperature. Although the Joule heat can be reduced by the technology for reducing the power consumption of the integrated sensor, it cannot be reduced to zero. Next, temperature fluctuations derived from the reaction field will be examined. The temperature fluctuates when a reagent solution or a sample solution is supplied from the outside to a reaction field where various chemical and biological reactions for detecting a target object are performed. Furthermore, depending on the reaction system, there is an influence of heat of reaction such as heat of mixing or chemical reaction. The temperature fluctuations derived from the detection system or reaction field described here affect sensor elements, amplifiers, control circuits, or chemical / biological reactions, cause fluctuations in measured values and require countermeasures.

  The problem described above is a problem peculiar to a sample analysis chip in which an integrated sensor chip, a solution reaction field, and a sample solution are in close contact with each other, which are suitable for realizing a small, inexpensive, and highly sensitive POCT. That is, it is required to suppress fluctuations in measured values by suppressing the influence of temperature fluctuation factors derived from the detection system and reaction field without impairing the POCT essential characteristics of small size and low cost.

  In order to solve the above-mentioned problems, a solution reaction field and a sensor are formed by causing a solution reaction field and a sensor to be in thermal contact with each other, and forming a solution reaction field by a flow path, and flowing a sample / reagent solution therein. A dynamic temperature equilibrium state is achieved in the sample solution in a short time. By measuring the target molecule within the period in which this dynamic temperature equilibrium state is achieved, rapid and highly accurate measurement is realized.

That is, the following is mentioned as an example of the said means.
(1) A first substrate, a detector provided on the first substrate, and an inlet and an outlet for a solution containing a sample provided on the first substrate. A sample analysis chip characterized in that a flow path formed to flow, a solution to be introduced, and a detector are arranged in thermal contact.
(2) The sample analysis chip includes, as detectors, a first detector that detects the reaction of the sample solution and a second detector that detects the temperature of the sample solution. A sample analysis system comprising: calculation means for correcting a signal from a solution acquired by the first detector using a temperature measurement value acquired by the second detector with respect to the temperature dependence data of the signal.

  Reduced fluctuations in measured values by suppressing the influence of temperature fluctuations of the entire measurement system due to heat generated from integrated detectors or reaction heat in solution reaction fields, within the limitations associated with the reduction in size and cost of POCT devices It becomes possible to do.

Diagram showing an example of the structure of a sample analysis chip with an optical sensor Diagram showing an example of the structure of a sample analysis chip equipped with a potential sensor The figure which shows the example of application of the integrated sensor which incorporates the optical sensor Diagram showing application example of integrated sensor with built-in optical sensor and wireless function Diagram showing fluctuations in temperature and sensor output in a sample analysis chip equipped with a potential sensor The figure which shows the example which applied the integrated sensor which built in the optical sensor and the wireless function to the immune measurement The figure which shows the example which applied the integrated sensor which built in the optical sensor and the radio function to gene measurement Diagram showing an example of applying an integrated sensor with a built-in potential sensor and wireless function to gene measurement Diagram showing an example of the structure of a sample analysis chip The figure which shows the example of the channel structure in a sample analysis chip The figure which shows the example of the structure of the sample analysis chip | tip which comprises a flow velocity control structure The figure which shows the example of the structure of the sample analysis chip | tip which comprises a parallel type flow velocity control structure The figure which shows the example of the structure of the sample analysis chip | tip which comprises a parallel type flow velocity control structure Diagram showing the relationship between the flow rate of the solution in the channel and the amount of analyte (antigen) captured by the immobilized antibody

  The basic part of the present invention will be described with reference to FIGS. In FIG. 1, the flow path 16 constituting the solution reaction field 10, the photodetector 11, and the flowing sample / reagent solution 12 are in thermal and optical contact. The reaction field refers to a part of the flow path where a substance to be detected reacts, and holds molecules that contribute to an antigen / antibody reaction or an enzyme reaction for detecting a sample. 1-4 corresponds to the area indicated by 10. Here, the solution in the flow path constituting the solution reaction field is flowing. The solution reaction field, the detector, and the sample / reagent solution are in thermal contact. Therefore, the photodetector 11 and the solution 12 are not necessarily in direct contact as shown in FIG. Thus, even when the substrate is sandwiched between the detector and the solution, the substrate may be formed of a heat conductive material or the like. Examples of the material constituting the flow path in this case include inorganic materials such as glass and silicon, and resin materials such as epoxy and acrylic. The heat conductivity of the heat conducting material is desirably 0.1 W / mK or more. In the case of a photodetector, if the material of the flow path constituting the solution reaction field 10 is transparent to the signal light so that the optical signal in the flow path can be observed, the light is sandwiched between the flow path materials. A detector can be arranged. Thermal and optical contact can be made more ideal by sandwiching a transparent filler or matching oil between the photodetector and the channel material.

  FIG. 2 shows a case where the potential detector 13 is used as a detector. In a potential detector, the detector surface must be brought into contact with a sample / reagent solution. The potential detector is kept in thermal contact with the solution reaction field 10.

  As described above, the sample reaction / reaction solution 10, the sample analysis chip substrate 51, the detectors 11, 13, and the sample / reagent solution 12 are brought into thermal contact with each other, and then the sample / reagent solution 12 is flowed. In a short time, a temperature equilibrium state can be dynamically achieved among the liquid reaction field 10, the detectors 11 and 13, and the sample / reagent solution 12.

  By performing measurement with a detector in a state where this equilibrium state is maintained, high-precision measurement is possible.

  A configuration example of the sample analysis chip when an integrated photodetector is used will be described with reference to FIG. An integrated detector 11 in which a flow path 16 is formed by a sample analysis chip substrate 51 made of resin or glass and a structure 60 that defines the upper shape of the flow path, and a photosensor is built in a part of the sample analysis chip substrate 51 As a solution reaction field 10 in the vicinity of the detector of the flow path 16, the optical signal generated here is detected. The configuration of the integrated detector is shown in FIG. 3 (b).

  The signal detected by the optical sensor is amplified by the analog circuit block 17, converted to AD (Analog-to-digital), encoded so that the digital signal can be transmitted by the control logic circuit block 18, the controller through the interface block 19 and the cable 26. 14 to analyze, display and store data. In the case of a signal with a short transmission distance and a large amplitude, it is also possible to send the output signal of the amplifier of the analog circuit block directly to the controller 14 on the cable 26. Since such an integrated detector amplifies and AD-converts the signal detected by the optical sensor on the spot, it is possible to minimize noise contamination during signal transmission.

  However, heat generated from the chip or module substrate on which these blocks are formed due to power for driving the analog circuit, the control logic circuit block, and the interface block becomes a problem. Here, by flowing the sample / reagent solution 12, the temperatures of the solution reaction field 10, the detector 11, and the sample / reagent solution 12 that are in thermal contact with each other in a shorter time than when not flowing are constant dynamic. Equilibrium temperature is reached. Assuming that the room temperature is always constant, the temperature of the sample / reagent solution is the same as that of the room temperature, and the power consumption of the integrated detector is always constant, the dynamic equilibrium temperature can be equal even in different measurements. In the measurement, it is confirmed that the dynamic equilibrium temperature has been reached, and a highly accurate measurement value can be obtained by reading the detector signal.

FIG. 4 shows an application example of an integrated optical sensor incorporating a sensor and a signal processing circuit and an integrated detector incorporating a wireless function. As shown in FIG. 4 (a), control signal transmission to the detector and data reception from the detector are performed wirelessly. As a general classification of wireless communication, there are an active type in which a detector is equipped with a battery and an oscillator and the detector itself generates a communication carrier wave, and a passive type in which wireless communication is received from an external reader. Any method may be applied.

  Hereinafter, a passive case in which a detector with a wireless function can be configured at low cost will be described. Patent Document 2 can be referred to for an integrated detector having a passive wireless function. FIG. 4B shows a configuration of an integrated detector having a radio reception function. Each circuit block included in the detector 21 is driven by electric power sent from the reader 23 via the reader coil 22. Through the sample analysis chip substrate 51, the solution reaction field 10, the detector 21, and the sample / reagent solution 12, which are three components related to the accuracy of the measurement value, are brought into thermal contact with each other, and then the solution 12 is added. The point of flowing is the same as in Example 1. And For example, if the channel thickness is 20 μm, the channel width is 5 mm, and the channel length is 6 mm, the solution can be flowed by capillary action when the interior is not filled with the solution. Here, the flow rate control structure shown in Example 7 described later is introduced in order to control the flow rate and cause the sample / reagent solution to flow continuously.

  FIG. 5 shows the time change of the temperature at the location of the detector and the dark state output of the photodetector when the sample analysis chip having this structure is operated. In order to examine variation for each measurement, three measurement results are shown in an overlapping manner. First, when electric power is supplied from the reader to the integrated detector in a state where the solution reaction field 10 is not filled with a solution (t = 0 s), the temperature rapidly rises by 20 ° C. or more. As the temperature rises, the measured value of the photodetector (corresponding to dark current because it is a dark state measurement) increases. Next, when solution flow starts at t = 380 s, the temperature decreases, and the output of the photodetector decreases correspondingly. It can be seen that the temperature and the output of the photodetector become stable after about 200 s in the solution flow state. When the solution flow is stopped at t = 800 s, the temperature and photodetector output begin to increase again. From the above, the effect of flowing the sample / reagent solution 12 can be confirmed after the solution reaction field 10, the detector 21 and the sample / reagent solution 12 are brought into thermal contact with each other.

  FIG. 6 shows an example of performing immunoassay using the sample analysis chip of the present invention. An antibody 31 specific to the antigen to be measured is immobilized at a location corresponding to the upper part of the photodetector inside the flow path constituting the solution reaction field. Next, the sample solution is flowed to bind the antigen 33 to the immobilized antibody 31, and the labeled antibody 32 binds to the antigen 33 to form a sandwich structure. Luminescent substrate catalyzed by the last labeled enzyme, for example alkaline phosphatase, for example AMPPD: 3- (2'-spiroadamantane) -4-methoxy-4- (3 ”-phosphoryloxy) phenyl-1, 2-dioxetane disodium salt solution When the temperature reaches dynamic equilibrium, the measurement is performed.

  An example of carrying out gene measurement using the sample analysis chip of the present invention is shown in FIG. A DNA probe 41 complementary to the DNA to be measured is immobilized at a location corresponding to the upper part of the photodetector inside the flow path constituting the solution reaction field. Next, the sample solution is flowed to hybridize the DNA 42 to be measured with the probe. At this time, as shown in the inset of FIG. 7, all DNA in the sample solution is enzyme-labeled in advance, and after hybridization and washing, the luminescent substrate is flowed and the luminescence is observed by the detector 21. .

  FIG. 8 shows another example in which gene measurement is performed using the sample analysis chip of the present invention. A potential detector 25 incorporating a potential sensor is used as the detector. As the potential sensor, for example, an Ion Sensitive Field Effective Transistor (ISFET) in which the gate of a MOS transistor is floated and exposed on the surface of the detector chip can be used.

  The DNA probe 41 is fixed on the floating gate, and the target DNA 42 is hybridized to the probe by flowing the sample solution. Since DNA has a negative charge, when the target DNA is hybridized to the probe, the channel resistance of the MOS transistor that constitutes the potential sensor changes, so that the target DNA is detected by reading this.

  9 and 10 show configuration examples of the sample analysis chip. FIG. 9 shows an example in which the flow path 16 is formed on a sample analysis substrate 51 made of glass or resin. When the sample analysis substrate 51 is made of resin, polycarbonate, acrylic, COC (Cyclic Olefin Copolymer), PDMS (polydimethylsiloxane), or the like can be used. Integrated detectors 54 and 55 are fixed to the sample analysis substrate 51. As the sensor mounted on the integrated detector, the sensors shown in the third to fifth embodiments can be used. For example, 54 is an integrated detector equipped with an optical sensor for detecting signal light, and 55 is an integrated detector equipped with a reference optical sensor. The path 16 is formed above the integrated detectors 54,55.

Here, both 54 and 55 are integrated detectors equipped with optical sensors, and by taking the difference between the two outputs, only the optical signal corresponding to the sample captured by the probe 56 can be extracted. The probe can be composed of an antibody or DNA as described in the above examples. The sample or reagent solution is dropped and supplied from the supply solution reservoir 57 and discharged from the drain solution reservoir 58. These solution reservoirs 57 and 58 use an absorbent membrane (FIG. 9 (a)), or hold the solution by making the periphery of the solution reservoir convex or by making the solution reservoir concave. (a) (b)). As other forces for driving the solution flow in the flow path, an external pump, an electroosmotic flow, an electrowetting effect, or the like can be used.
As another example of the combination of the two integrated sensors 54 and 55, 54 is an integrated detector equipped with an optical sensor for detecting signal light, and 55 is an integrated detector equipped with a temperature sensor. Can be improved. As shown in FIG. 5, the dark current fluctuation due to the temperature fluctuation fluctuates depending on the presence or absence of the solution flowing through the flow path even during measurement. In the case of detecting a fine signal, it is essential to compensate for this temperature fluctuation. By measuring the temperature of the measurement system by providing a correction system that corrects the temperature dependence of the dark current inherent to the optical sensor acquired in advance and the temperature measurement value obtained by the 54 temperature sensors. Even when the fluctuation is large, an optical sensor output value faithful to the optical signal excluding the dark current fluctuation can be obtained.

  FIG. 10 is an example specifically showing the flow path forming method. (a) is a top view, and (b) and (c) are cross-sectional views taken along lines A-A ′ and B-B ′ in (a). The channel 16 is formed by a sample analysis chip substrate 51 and a channel shape defining structure 60 installed thereon. The substrate 51 and the flow path shape defining structure 60 are in contact with each other via the contact surface 52. It is desirable that an adhesive, a filler, a highly adhesive sheet, or the like is inserted into the contact surface 52 so that the solution does not penetrate. In addition, when the flow path is provided by the recess on the substrate on which the sensor as shown in FIG. 10B-2 is provided, the flow path can be formed without providing the flow path shape defining structure 60 on the upper part. There is also.

  FIG. 11-13 shows a configuration example of a structure for controlling the flow velocity in the flow path. Although it has been described above that giving a constant flow rate is effective for equalizing the temperature of the measurement system and the reaction system, a certain amount of time is required for the molecules to diffuse into the probe fixing part and react in the flow path. Necessary, and if the flow rate is too high, the reaction efficiency decreases and the amount of sample / reagent consumption increases. In order to avoid a decrease in reaction efficiency, it is necessary to suppress the flow rate to 10 μL / min even if it is large, and a structure for that purpose is required. In FIG. 11 (a), a flow rate limiting structure 59 is provided between the detector 54 and the drain reservoir 58 as a flow rate control means. Here, the flow rate limiting structure 59 may be configured by a solution permeable membrane or a channel having a smaller cross-sectional area compared to the channel near the reaction field. Nitrocellulose, nylon, polyether sulfone, glass fiber, etc. can be used as the membrane material.

  The flow rate limiting structure 59 may be disposed on the downstream side of the detector 54 as shown in FIG. 11 (a) or on the upstream side of the detector 54 as shown in FIG. 11 (b). The flow rate can be arbitrarily set according to the length and width of the flow rate restricting structure 59.

FIGS. 12 and 13 show structures in the case where a plurality of targets are simultaneously measured by a plurality of probes. In order to make the concentration of the solution uniform on each probe, it is desirable to arrange the probe in a direction perpendicular to the flow rate direction, and the width of the channel is increased. At this time, by providing the flow rate limiting structure 59 in parallel as shown in FIG. 12 (a), the flow rate can be made constant in the flow path. FIG. 12 (b) shows an example of a construction method of the flow rate limiting structure. The flow rate limiting structure is parallelized by hydrophobizing part 61 of the membrane.
When the flow restricting structure 59 is provided, for example, by providing an opening to the atmosphere in a portion indicated by 63 in FIG. 13, it is possible to prevent bubbles from staying in the flow path.

  To achieve a dynamic temperature equilibrium in the solution reaction field, sensor and sample solution in a short time, it is advantageous to increase the flow rate. However, it is generally known that the use efficiency of the analyte (antigen) in the sample solution decreases as the flow rate increases. Since the amount of sample solution that can be used is limited in actual use, it is necessary to restrict the flow rate to ensure the efficiency of use of the analyte (antigen) in the reagent.

  FIG. 14 shows the relationship between the flow rate of the solution in the channel and the amount of analyte (antigen) captured by the immobilized antibody by simulation (Non-patent Document 2). This relationship varies depending on the type of antigen / antibody and the shape of the flow path, but as a general trend, when the flow rate exceeds a certain level as shown in Fig. 14 (b), the amount of analyte captured by the immobilized antibody is Decrease. In order to shorten the temperature equilibrium arrival time without impairing the trapping amount, it is necessary to set the maximum flow rate within a range where the trapping amount does not change with respect to the flow rate.

  In a measuring apparatus for measuring a biological sample targeted by the present invention, for example, a sensor, a signal processing circuit, and a wireless communication circuit are combined with an integrated detector integrated on a silicon chip and a flow path to reduce the size. Cost reduction is possible. At the same time, it is possible to perform highly accurate measurement at the site where samples are collected. POCT devices that measure infectious diseases, pathogens in food, agricultural chemicals, etc. are promising applications.

10: Solution reaction field
11: Photodetector
12: Sample / reagent solution
13: Potential detector
14: Photodetector controller
15: Photosensor built in the photodetector
16: Flow path
17: Analog circuit block built into the photodetector
18: Control logic block built in photodetector
19: Interface circuit block built into the photodetector
21: Photo detector with built-in wireless function
22: Reader coil
23: Leader
24: Controller
25: Potential detector with built-in wireless function
26: Cable
31: Immobilized antibody
32: Labeled antibody
33: Antigen
41: Probe DNA
42: Target DNA
43: Modification enzyme
51: Sample analysis chip substrate
52: Flow path shape regulating structure and contact surface of sample analysis chip
54: Integrated detector
55: Integrated detector
56: Probe fixing area
57: Supply solution reservoir upstream of detector
58: Drain solution reservoir downstream of the detector
59: Flow rate limiting structure
60: Structure that defines the upper shape of the channel
61: Partially hydrophobized membrane
62: Convex part of the supply solution reservoir upstream of the detector
63: Open to the atmosphere

Claims (21)

A first substrate;
A detector provided on the first substrate;
A flow path provided on the first substrate, having an inlet and an outlet for a solution containing a sample, and formed so that the introduced solution flows;
A sample analysis chip, wherein the solution to be introduced and the detector are arranged in thermal contact with each other. The sample analysis chip according to claim 1, wherein the detector is a photodetector that detects light emitted by a reaction of a solution containing the sample.   The sample analysis chip according to claim 2, wherein the first substrate is transparent with respect to light to the photodetector.   2. The sample analysis chip according to claim 1, wherein the detector is a potential detector that detects a potential that changes when a solution containing the sample reacts.   The sample analysis chip according to claim 4, wherein the potential detector is provided on the first substrate so as to come into contact with the solution.   The sample analysis chip according to claim 1, wherein the detector is an integrated detector having a signal detector and a signal processor.   The sample analysis chip according to claim 1, wherein the detector is an integrated detector having a wireless communication unit.   2. The sample analysis according to claim 1, wherein an antibody corresponding to an antigen to be measured is provided on the detector of the first substrate, and the antigen contained in the introduced sample is measured. Chip.   2. The sample analysis according to claim 1, wherein a nucleic acid probe for hybridizing a nucleic acid to be measured is provided on the detector of the first substrate, and the nucleic acid contained in the introduced sample is measured. Chip.   The sample analysis chip according to claim 9, wherein the detector is a photodetector, and detects light emitted from an enzyme labeled with the hybridized nucleic acid.   10. The sample analysis chip according to claim 9, wherein the detector is a potential detector, and measures a potential change caused by hybridization of the nucleic acid.   2. The sample analysis chip according to claim 1, wherein a solution reservoir for the solution is provided at the introduction port and the discharge port.   13. The sample analysis chip according to claim 12, wherein an inlet side of the solution reservoir has a convex guide so that the solution is accumulated.   The flow rate control means for controlling the flow rate of the solution is provided between the solution reservoir on the introduction port side and / or the discharge port side and the flow path. Sample analysis chip.   15. The sample analysis chip according to claim 14, wherein the flow rate control means is any one of a narrow channel and a porous chamber material or a parallel arrangement of hydrophobic processed portions.   15. The sample analysis chip according to claim 14, further comprising: the flow rate control means on the discharge port side, and an opening to the atmosphere between the flow rate control means and the dew.   2. The sample analysis chip according to claim 1, wherein the detector is a first detector that detects a reaction of the sample solution and a second detector that detects a temperature of the sample solution.   2. The sample analysis chip according to claim 1, further comprising: a second substrate disposed opposite to the first substrate and constituting an upper portion of the flow path.   15. The sample analysis chip according to claim 14, wherein a surface of the second substrate facing the detector is formed in a concave shape so as to form the flow path.   2. The sample analysis chip according to claim 1, wherein a surface of the first substrate facing the detector is formed in a concave shape so as to form the flow path. A sample analysis chip according to claim 1;
The sample analysis chip includes, as the detector, a first detector that detects a reaction of the sample solution, and a second detector that detects the temperature of the sample solution,
Calculation for correcting the signal from the solution obtained by the first detector using the temperature measurement value obtained by the second detector with respect to the temperature dependence data of the signal of the first detector. And a sample analysis system.

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