JP2012225778A - Inspection chip and measurement device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inspection chip and a measurement device preventing an increase of manufacturing cost by heating or cooling reactants effectively.SOLUTION: A passage organizer, a dielectric medium and an electric conductor film are provided on an inspection chip. A junction region and an exposure region are provided in the surface of the passage organizer. A reactant storage space and a heat carrier storage space are formed on the passage organizer. The reactant storage space has an opening in the junction region and has a reactant entrance in the exposure region. The heat carrier storage space has a heat carrier entrance in the exposure region. An incoming region, a reflection region and an emission region are provided in the surface of the dielectric medium. Excitation light which has entered the incoming region is totally reflected in the reflection region and emitted from the emission region. A first principal plane of the electric conductor film is joined to the junction region. A second principal plane of the electric conductor film tightly adheres to the reflection region.

Description

  The present invention relates to a test chip used for measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance method, and a measurement apparatus that performs measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance method.

  When the excitation light traveling in the dielectric medium is totally reflected at the interface between the conductor film and the dielectric medium, the evanescent wave leaks from the interface, and the plasmon and the evanescent wave in the conductor film interfere with each other. To do. When the incident angle of the excitation light to the interface is set to the resonance angle and the plasmon and the evanescent wave resonate, the electric field of the evanescent wave is remarkably enhanced. This resonance is used in measurement by surface plasmon excitation fluorescence spectroscopy (SPFS) method or surface plasmon resonance (SPR) method.

  In the measurement by the SPFS method, an object to be measured is captured on the surface of the conductor film, and the captured object to be measured is fluorescently labeled. The enhanced electric field acts on the fluorescently labeled object to be measured, and surface plasmon excitation fluorescence is emitted from the fluorescently labeled object to be measured. Further, the amount of surface plasmon excitation fluorescence is measured, and the presence / absence of the object to be measured, the amount of the object to be measured, etc. are specified.

  In measurement by the SPR method, the substance to be measured is captured on the surface of the metal film. Further, the amount of reflected light, the amount of scattered light, the resonance angle, and all or part of these changes are measured, and the presence / absence of the object to be measured, the captured amount of the object to be measured, etc. are specified.

  For capturing the object to be measured and fluorescent labeling of the object to be measured, a reaction product such as a sample solution or a fluorescent labeling solution is accommodated in the inspection chip, and the reaction product is reacted inside the inspection chip. The progress of this reaction is affected by the temperature of the reactants. Therefore, depending on the temperature of the reaction product, the progress of the reaction is delayed, and the time required for measurement becomes longer. In addition, when the temperature of the reactant changes, the measurement result changes. For this reason, in the state where the temperature of the reactant is not controlled, the accuracy of measurement is reduced, and the measurement result is difficult to reproduce. Therefore, it is expected to adjust the temperature of the reaction product.

  On the other hand, there are cases where the reactants cannot be fully prepared. For example, when a specimen is collected from a human body, it is expected to reduce the amount of the specimen in order to reduce the load on the human body. In addition, when the reagent for processing the specimen is expensive, it is expected to reduce the amount of the reagent in order to reduce the cost of the test.

  If the reactants cannot be prepared well, the heat capacity of the reactants will be small, and even if the reactants are heated, heat will be taken away by the inspection chip having a large heat capacity, and it will be difficult to maintain the reactants at an appropriate temperature. . Alternatively, if the reactant is heated excessively in order to maintain the reactant at an appropriate temperature even when the inspection chip having a large heat capacity is deprived of heat, there is a risk that the reactant is deactivated by heat. These problems also occur when the reactants are cooled.

  In order to solve this problem, it is conceivable to adjust the temperature of the inspection chip. Patent Documents 1 to 3 are examples thereof.

JP 2010-276499 A JP 2010-203823 A JP 2008-139246 A

  However, as in Patent Documents 1 and 2, when there is a heat source outside the inspection chip and heat is transmitted from the outside of the inspection chip to the inspection chip, the heat is not sufficiently transmitted, and the inspection chip and the inside thereof are not transmitted. The reactants are not heated efficiently. In addition, a complicated mechanism for bringing the mechanism outside the inspection chip into close contact with the inspection chip is necessary for transferring heat.

  Moreover, when there exists a heat source inside a test | inspection chip like patent document 3, the manufacturing cost of a test | inspection chip will increase. Since the inspection chip is desired to be disposable in consideration of safety and efficiency of measurement work, an increase in the manufacturing cost of the inspection chip is often unacceptable.

  These problems arise not only when the reactants are heated, but also when the reactants are cooled.

  The present invention is made to solve these problems. An object of this invention is to provide the test | inspection chip and measuring device by which an internal reactant is heated or cooled efficiently and the increase in manufacturing cost is suppressed.

  The first to thirteenth aspects of the present invention are directed to a test chip used for measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance.

  In the first aspect of the present invention, a structure, a dielectric medium, and a conductor film are provided. A junction region and an exposed region are provided on the surface of the structure. In the structure, a reactant storage space and a heat medium storage space are formed. The reactant storage space has an opening in the junction region and a reactant inlet / outlet in the exposed region. The heat medium accommodation space has a heat medium entrance / exit in the exposed region.

  An incident area, a reflection area, and an emission area are provided on the surface of the dielectric medium. The incident area, the reflection area, and the emission area are arranged so that the excitation light incident on the incident area is totally reflected by the reflection area and emitted from the emission area.

  The first main surface of the conductor film is bonded to the bonding region. The second main surface of the conductor film is in close contact with the reflective region.

  The second aspect of the present invention adds further matters to the first aspect of the present invention. In the second aspect of the present invention, the heat medium inlet / outlet is the first heat medium inlet / outlet, and the heat medium accommodating space has the second heat medium inlet / outlet in the exposed region. The heat medium accommodation space is a flow path that extends from the first heat medium inlet / outlet to the second heat medium inlet / outlet through the inside of the structure.

  The third aspect of the present invention adds further matters to the second aspect of the present invention. In the third aspect of the present invention, the exposed area has an entrance / exit forming area facing a certain direction. The reactant inlet / outlet, the first heat medium inlet / outlet, and the second heat medium inlet / outlet are provided in the inlet / outlet forming region.

  The fourth aspect of the present invention adds further matters to the third aspect of the present invention. In the fourth aspect of the present invention, the entrance / exit formation region and the joining region face in opposite directions.

  The fifth aspect of the present invention adds further matters to any one of the second to fifth aspects of the present invention. In the fifth aspect of the present invention, the opening is the first opening, and the heat medium accommodation space has the second opening. The first surface has an opening forming region facing a certain direction. The first opening and the second opening are provided in the opening formation region.

  The sixth aspect of the present invention adds further matters to the second aspect of the present invention. In the sixth aspect of the present invention, the exposed region has an entrance / exit forming region facing a first constant direction, and the first surface has an opening forming region facing a second constant direction. The reactant inlet / outlet and the first heat medium inlet / outlet are provided in the inlet / outlet forming region. The opening and the second heat medium inlet / outlet are provided in the opening forming region.

  The seventh aspect of the present invention adds further matters to the first aspect of the present invention. In the seventh aspect of the present invention, the heat medium accommodation space is a reservoir having one heat medium inlet / outlet.

  The eighth aspect of the present invention adds further matters to the seventh aspect of the present invention. In the eighth aspect of the present invention, the exposed area has an entrance / exit forming area facing a certain direction. The reactant inlet / outlet and the heat medium inlet / outlet are provided in the inlet / outlet forming region.

  The ninth aspect of the present invention adds further matters to the eighth aspect of the present invention. In the ninth aspect of the present invention, the entrance / exit formation region and the joining region face in opposite directions.

  The tenth aspect of the present invention adds further matters to any of the seventh to ninth aspects of the present invention. In the tenth aspect of the present invention, the opening is a first opening, and the heat medium accommodation space has a second opening. The first surface has an opening forming region facing a certain direction. The first opening and the second opening are provided in the opening formation region. The second opening is closed by the closing body.

  The eleventh aspect of the present invention adds further matters to any one of the first to tenth aspects of the present invention. In the eleventh aspect of the present invention, the shape of the reactant inlet / outlet and the shape of the heat medium inlet / outlet are the same.

  The twelfth aspect of the present invention adds a further matter to any one of the first to eleventh aspects of the present invention. In the twelfth aspect of the present invention, two or more heat medium accommodating spaces separated from each other by a distance from the reactant accommodating space are formed.

  The thirteenth aspect of the present invention adds further matters to any one of the first to twelfth aspects of the present invention. In the twelfth aspect of the present invention, the total volume of the heat medium accommodating space is larger than the volume of the reactant accommodating space.

  The fourteenth aspect of the present invention is directed to a measurement apparatus that performs measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance. In a fourteenth aspect of the present invention, an inspection chip, a heat medium supply mechanism, and a measurement mechanism according to the first aspect of the present invention are provided. The heat medium supply mechanism adjusts the temperature of the heat medium and supplies the heat medium whose temperature is adjusted to the heat medium accommodation space. The measurement mechanism causes excitation light to enter the incident region, and performs measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance.

  According to the first and fourteenth aspects of the present invention, the inspection chip is efficiently heated or cooled, and the reactant contained in the reactant accommodating space is efficiently heated or cooled. It is maintained at a temperature suitable for the reaction. In addition, an increase in the manufacturing cost of the inspection chip is suppressed.

  According to the second aspect of the present invention, the heat medium supply port and the recovery port are separated, and the heat medium is circulated efficiently.

  According to the third and eighth aspects of the present invention, the mechanism for supplying the reactant and the mechanism for supplying the heat medium are easily shared.

  According to the fourth and ninth aspects of the present invention, it becomes easy to provide a mechanism for supplying the reactant and a mechanism for supplying the heat medium on the opposite side of the dielectric medium, and the mechanism for supplying the reactant and the heat The mechanism for supplying the medium is difficult to prevent the dielectric medium from being irradiated with the excitation light.

  According to the fifth, sixth and tenth aspects of the present invention, the number of molds required when a structure is produced by injection molding is reduced, and the manufacturing cost of the inspection chip is reduced.

  According to the eleventh aspect of the present invention, the mechanism for supplying the reactant and the mechanism for supplying the heat medium are easily shared.

  According to the twelfth aspect of the present invention, the temperature is finely adjusted and the reactants are appropriately heated or cooled.

  According to the thirteenth aspect of the present invention, the heat medium contributing to heating or cooling of the inspection chip is increased, and the reactant is efficiently heated or cooled.

  These and other objects, features, aspects and advantages of the invention will become more apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

It is a schematic diagram of the measuring apparatus of 1st Embodiment. It is a perspective view of the test | inspection chip of 1st Embodiment. It is sectional drawing of the test | inspection chip of 1st Embodiment. It is a perspective view of the test | inspection chip of 1st Embodiment, and its periphery. It is a schematic diagram of the state by which the sample liquid was inject | poured into the reactant channel. It is a schematic diagram of the state by which the fluorescent labeling liquid was inject | poured into the reactant flow path. It is a flowchart of the procedure of measurement. It is sectional drawing of a reagent chip | tip. It is a perspective view of the test | inspection chip of 2nd Embodiment. It is sectional drawing of the test | inspection chip of 2nd Embodiment. It is a perspective view of the test | inspection chip of 3rd Embodiment. It is sectional drawing of the test | inspection chip of 3rd Embodiment. It is a perspective view of the test | inspection chip of 4th Embodiment. It is a perspective view of the test | inspection chip of 5th Embodiment. It is sectional drawing of the test | inspection chip of 5th Embodiment.

{First embodiment}
(Outline of measuring device)
The first embodiment relates to a measuring device and an inspection chip.

  The schematic diagram of FIG. 1 shows the measuring apparatus of the first embodiment. The schematic diagram of FIG. 2 is a perspective view of the test | inspection chip of 1st Embodiment. The schematic diagram of FIG. 3 shows the cross section of the test | inspection chip of 1st Embodiment.

  As shown in FIG. 1, the measurement apparatus 1000 according to the first embodiment includes an inspection chip 1002, a measurement mechanism 1004, a supply / recovery mechanism 1006, and a controller 1008. The measurement mechanism 1004 includes a laser diode 1010, a linearly polarizing plate 1012, a mirror 1014, a drive mechanism 1016, a low-pass filter 1018, a photomultiplier tube 1020, and a photodiode 1022. The supply and recovery mechanism 1006 includes a reaction liquid supply mechanism 1024, a reaction liquid recovery mechanism 1026, a heat medium circulation mechanism 1028, a reaction liquid supply pipe 1030, a reaction liquid recovery pipe 1032, heat medium supply pipes 1034a and 1034b, and a heat medium recovery pipe 1036a and 1036b.

  As shown in FIGS. 2 and 3, the test chip 1002 includes a gold film 1100, a prism 1102, an antibody solid film 1104, a flow path forming body 1106, and seals 1108a and 1108b.

(Outline of measurement)
The measurement apparatus 1000 performs measurement by surface plasmon excitation fluorescence spectroscopy (SPFS). The inspection chip 1002 is attached to the measurement apparatus 1000 and used for measurement by surface plasmon excitation fluorescence spectroscopy. The measuring device 1000 is mainly used for biochemical tests, immunological tests, and genetic tests.

  When measurement is performed, the sample liquid is supplied from the reaction liquid supply mechanism 1024 to the reactant flow path 1110 formed in the flow path forming body 1106, and the measurement target contained in the sample liquid is captured by the antibody solid layer film 1104. Is done. Further, a fluorescent labeling solution is supplied from the reaction solution supply mechanism 1024 to the reactant flow path 1110, and the captured measurement object is fluorescently labeled.

  At this time, the heat medium is supplied from the heat medium circulation mechanism 1028 to the heat medium flow paths 1112 a and 1112 b formed in the flow path forming body 1106. Thereby, the test chip 1002 is efficiently heated, and the sample solution or the fluorescent labeling solution stored in the reactant flow channel 1110 is maintained at a temperature suitable for the antibody-antigen reaction.

  In a state where the captured object to be measured is fluorescently labeled, the excitation light EL is irradiated to the prism 1102. The irradiated excitation light EL is totally reflected at the interface between the prism 1102 and the gold film 1100.

  When the excitation light EL is totally reflected at the interface between the prism 1102 and the gold film 1100, an evanescent wave leaks from the interface between the gold film 1100 and the prism 1102 to the gold film 1100 side. Plasmons and evanescent waves interfere. When the plasmon and the evanescent wave resonate, the electric field of the evanescent wave is remarkably enhanced. The enhanced electric field acts on the fluorescently labeled object to be measured, and surface plasmon excitation fluorescence FL is emitted from the fluorescently labeled object to be measured. The amount of surface plasmon excitation fluorescence FL is measured by a photomultiplier tube 1020. From the measurement result of the photomultiplier tube 1020, the controller 1008 calculates the presence / absence of the object to be measured, the capture amount of the object to be measured, and the like.

(Outline of inspection chip)
As shown in FIGS. 2 and 3, the antibody solid layer film 1104 is fixed on the first main surface 1114 of the gold film 1100. The first main surface 1114 of the gold film 1100 is bonded to the bonding region 1120 of the surface 1118 of the flow path forming body 1106. The second main surface 1116 of the gold film 1100 is in close contact with the reflection region 1128 of the surface 1124 of the prism 1102. The antibody solid layer film 1104 is accommodated in the reactant channel 1110. When the object to be measured can be adsorbed on the first main surface 1114 of the gold film 1100, the antibody solid layer film 1104 may be omitted.

  The gold film 1100 and the flow path forming body 1106 are bonded together by adhesion, laser welding, ultrasonic welding, clamp pressure bonding, or the like. However, the gold film 1100 and the flow path forming body 1106 may be joined by other methods.

(Gold film)
The gold film 1100 is a thin film. The film thickness of the gold film 1100 is desirably 30 to 70 nm. However, the film thickness of the gold film 1100 may be outside this range.

  The gold film 1100 is formed in the reflective region 1128 by sputtering, vapor deposition, plating, or the like. However, the gold film 1100 may be formed by other methods.

  The gold film 1100 may be replaced with a film made of a conductor other than gold. For example, the gold film 1100 may be replaced with a film made of a metal such as silver or aluminum or an alloy containing these metals.

(prism)
On the surface 1124 of the prism 1102, an incident area 1126 of the excitation light EL, a reflection area 1128, and an emission area 1130 are provided. The incident area 1126, the reflection area 1128, and the emission area 1130 are arranged such that the excitation light EL incident on the incident area 1126 is totally reflected by the reflection area 1128 and emitted from the emission area 1130.

  The prism 1102 is a trapezoidal column. Desirably, the prism 1102 is an isosceles trapezoidal column. When the prism 1102 is a trapezoidal column, one inclined side surface of the prism 1102 becomes the incident region 1126, the wide parallel side surface of the prism 1102 becomes the reflection region 1128, and the other inclined surface of the prism 1102 becomes the emission region 1130. become.

  The external shape of the prism 1102 is determined such that the excitation light EL enters the reflection region 1128 at an incident angle θ that is equal to or greater than the critical angle. As long as the excitation light EL is incident on the reflection region 1128 at an incident angle θ greater than the critical angle, the prism 1102 may be other than the trapezoidal column, and the prism 1102 may be replaced with a shape not included in the category of “prism”. . For example, the prism 1102 may be replaced with a plate.

  The prism 1102 is a dielectric medium made of a material transparent to the excitation light EL. Desirably, the prism 1102 is made of glass or resin having a refractive index of 1.40 to 1.75. When the prism 1102 is made of resin, the prism 1102 is preferably manufactured by injection molding. However, the prism 1102 may be manufactured by other than injection molding.

(Outline of flow path forming body)
In the flow path forming body 1106, a reactant flow path 1110 and heat medium flow paths 1112a and 1112b are formed. One of the heat medium flow paths 1112a and 1112b may be omitted. Additional heat medium channels separated from the heat medium channels 1112a and 1112b may be formed. The reactant channel 1110, the heat medium channel 1112a, and the heat medium channel 1112b are separated. Therefore, the sample solution or fluorescent labeling solution stored in the reactant flow channel 1110, the heat medium stored in the heat medium flow channel 1112a, and the heat medium stored in the heat medium flow channel 1112b are not mixed. When two or more separated heat medium flow paths are formed, the heat medium contributing to the heating of the test chip 1002 increases, and the sample liquid or the fluorescent labeling liquid is efficiently heated.

(Arrangement of reactant flow path and heat medium flow path)
The reactant flow path 1110 and the heat medium flow paths 1112a and 1112b are arranged in parallel to the bonding region 2220. Desirably, a reactant flow channel 1110 is formed between the heat medium flow channel 1112a and the heat medium flow channel 1112b. Thereby, heating is performed from both sides of the reactant flow channel 1110, and the sample solution or the fluorescent labeling solution is efficiently heated. However, the reactant channel 1110 may be formed at other positions.

(Surface of flow path forming body)
The outer shape of the flow path forming body 1106 is a rectangular parallelepiped or a cube, and the surface 1118 of the flow path forming body 1106 has an upper surface 1192, a side surface 1194, and a lower surface 1196. The surface 1118 of the flow path forming body 1106 is provided with a bonding region 1120, an exposed region 1122, and closed regions 1123a and 1123b. The bonding region 1120 is a region bonded to the first main surface 1114 of the gold film 1100 and occupies a part of the lower surface 1196. The exposed region 1122 is a region exposed to the outside of the inspection chip 1002 and occupies a part of the lower surface 1196, the upper surface 1192, and the side surface 1194. The closed regions 1123a and 1123b are regions to which the seals 1108a and 1108b are attached, respectively, and occupy a part of the lower surface 1196. The arrangement of the bonding region 1120, the exposed region 1122, and the closed regions 1123a and 1123b may be changed. The outer shape of the flow path forming body 1106 may be other than a rectangular parallelepiped and a cube.

(Reactant flow path)
The reactant flow channel 1110 extends from one reaction solution inlet / outlet port 1132 to the other reaction solution inlet / outlet port 1134 through the inside of the channel forming body 1106, and provides a reaction solution storage space for storing a sample solution or a fluorescent labeling solution. . Reaction liquid outlets 1132 and 1134 are provided in the exposed region 1122. Thereby, it is possible to supply the sample liquid and the fluorescent labeling liquid to the reaction liquid inlets / outlets 1132 and 1134 and to collect the sample liquid and the fluorescent labeling liquid from the reaction liquid inlets / outlets 1132 and 1134. The reaction liquid inlet / outlet 1132 and the reaction liquid inlet / outlet 1134 are separated. The reactant channel 1110 may be replaced with a reactant reservoir having one reactant inlet / outlet. The number of the reaction solution inlets and outlets may be increased to three or more.

  The reactant channel 1110 has a surface exposed channel 1138 and internal through channels 1140 and 1142.

  The surface exposed flow channel 1138 extends along the bonding region 1120 and has an opening 1144 in the bonding region 1120. As a result, when the sample liquid or the fluorescent labeling liquid is supplied to the surface exposed flow path 1138, the sample liquid or the fluorescent labeling liquid is supplied to the first main surface 1114 and fixed to the first main surface 1114, respectively. A sample solution or a fluorescent labeling solution contacts the antibody solid layer film 1104.

  One internal through channel 1140 extends from the reaction solution inlet / outlet port 1132 to one end of the surface exposed channel 1138. The other internal through channel 1142 extends from the reaction solution inlet / outlet 1134 to the other end of the surface exposed channel 1138. When the sample solution or the fluorescent labeling solution is supplied to the reaction solution inlet / outlet 1132 or 1136 by the internal through channels 1140 and 1142, the sample solution or the fluorescent labeling solution is supplied to the surface exposed channel 1138, respectively. The number of heat medium entrances / exits may be increased to 3 or more.

(Heat medium flow path)
The heat medium passages 1112a and 1112b extend from the heat medium inlet / outlet ports 1146a and 1146b to the heat medium inlet / outlet ports 1148a and 1148b through the inside of the flow passage forming body 1106, respectively, to provide a heat medium containing space for containing the heat medium. To do. When the heat medium accommodation space is provided as a heat medium flow path having two or more heat medium ports, the heat medium supply port and the recovery port are separated, and the heat medium is circulated efficiently.

  The heat medium inlet / outlet ports 1146a, 1146b, 1148a, and 1148b are provided in the exposed region 1122. As a result, the supply of the heat medium to the heat medium inlet / outlet 1146a, 1146b, 1148a and 1148b and the recovery of the heat medium from the heat medium inlet / outlet 1146a, 1146b, 1148a and 1148b become possible. The heat medium inlet / outlet 1146a and the heat medium inlet / outlet 1148a are separated. The heat medium inlet / outlet 1146b and the heat medium inlet / outlet 1148b are separated.

  The heat medium flow paths 1112a and 1112b desirably have the same shape. However, the heat medium flow paths 1112a and 1112b may have different shapes. One heat medium channel 1112a includes a surface exposed channel 1150a and internal through channels 1152a and 1154a. The other heat medium channel 1112b includes a surface exposed channel 1150b and internal through channels 1152b and 1154b.

  The surface exposed flow paths 1150a and 1150b extend along the closed regions 1123a and 1123b, respectively, and have openings 1156a and 1156b in the closed regions 1123a and 1123b. Both or one of the surface exposed flow paths 1150a and 1150b may be replaced with a flow path that does not have an opening through the flow path forming body 1106. In this case, the seals 1108a and 1108b are omitted.

  One of the internal through channels 1152a and 1152b extends from the heat medium inlet / outlet ports 1146a and 1146b to one end of the surface exposed channels 1150a and 1150b, respectively. The other internal through channels 1154a and 1154b extend from the heat medium inlet / outlet ports 1148a and 1148b to the other ends of the surface exposed channels 1150a and 1150b, respectively.

(Preferred arrangement of reaction liquid inlet / outlet and heat medium inlet / outlet)
Desirably, the reaction liquid inlets and outlets 1132 and 1134 and the heat medium inlets and outlets 1146a, 1146b, 1148a and 1148b are provided on the upper surface 1192 in a concentrated manner. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common. This can be understood by comparing with the case where, for example, the reaction liquid inlets / outlets 1132 and 1134 are provided on the upper surface 1192 and the heat medium inlets / outlets 1146a, 1146b, 1148a and 1148b are provided on the side surface 1194. More generally, when an inlet / outlet forming region facing in a certain direction such as the upper surface 1192 exists in the exposed region 1122, the reaction solution inlet / outlet 1132 and 1134 and the heat medium inlet / outlet 1146 a, 1146 b, 1148 a and 1148 b are in the inlet / outlet forming region. Concentrated on. The entrance / exit formation region is desirably a continuous surface, but may be divided into two or more regions by grooves, linear protrusions, or the like.

  The reaction liquid inlets and outlets 1132 and 1134 and the heat medium inlets and outlets 1146 a, 1146 b, 1148 a and 1148 b are provided on the upper surface 1192 facing the direction opposite to the bonding region 1120. Accordingly, it is easy to provide the supply / recovery mechanism 1006 on the opposite side of the prism 1102, and the supply / recovery mechanism 1006 is less likely to prevent the prism 1102 from being irradiated with the excitation light EL.

(Preferable arrangement of the reactant flow channel opening and the heat medium flow channel opening)
Desirably, the opening 1144 of the reactant flow channel 1110, the opening 1156a of the heat medium flow channel 1112a, and the opening 1156b of the heat medium flow channel 1112b are provided concentrated on the lower surface 1196. Thereby, when the flow path forming body 1106 is manufactured by injection molding, the number of molds that need to be processed such as the flow path is reduced, and the manufacturing cost of the inspection chip 1002 is reduced. However, the flow path forming body 1106 may be manufactured by other than injection molding.

  The reason why the number of molds that require processing such as the flow path is reduced is that the openings 1144 of the reactant flow path 1110 and the openings 1156a and 1156b of the heat medium flow paths 1112a and 1112b are concentrated on the lower surface 1196 where one mold is hit. This is because the reactant flow path 1110 and the heat medium flow paths 1112a and 1112b are formed by a mold on one side. More generally, when there is an opening forming region that faces in a certain direction, such as the lower surface 1196, on the surface 1118 of the flow path forming body 1106, the opening 1144 of the reactant flow path 1110 and the heat medium flow paths 1112 a and 1112 b Openings 1156a and 1156b are concentrated in the opening formation region. The opening formation region is desirably a continuous surface, but may be divided into two or more regions by grooves, linear protrusions, or the like.

(Opening blockage)
Seals 1108a and 1108b are attached to the closed regions 1123a and 1123b, respectively. Openings 1156a and 1156b are closed by seals 1108a and 1108b, respectively. As a result, the heat medium is held inside the flow path forming body 1106. The openings 1156a and 1156b may be closed by a closing body other than the seals 1108a and 1108b, respectively. For example, a sealing plate made of resin may be welded to the closed regions 1123a and 1123b. The openings 1156a and 1156b may be closed by the gold film 1100 or the prism 1102.

(Relationship between extending direction of reactant flow path and heat medium flow path)
Desirably, the surface exposed flow paths 1150a and 1150b of the heat medium flow paths 1112a and 1112b extend parallel to the surface exposed flow path 1138 of the reactant flow path 1110. The internal through channels 1152a and 1152b of the heat medium channels 1112a and 1112b extend in parallel to the internal through channel 1140 of the reactant channel 1110. The internal through channels 1154a and 1154b of the heat medium channels 1112a and 1112b extend in parallel to the internal through channel 1142 of the reactant channel 1110. The lengths of the surface exposed channels 1150a and 1150b of the heat medium channels 1112a and 1112b are the same as the surface exposed channels 1138 of the reactant channel 1110. The lengths of the internal through channels 1152a and 1152b of the heat medium channels 1112a and 1112b are the same as the internal through channels 1140 of the reactant channel 1110. The channel lengths of the internal through channels 1154a and 1154b of the heat medium channels 1112a and 1112b are the same as the internal through channels 1142 of the reactant channel 1110. Thereby, the heat medium flow paths 1112a and 1112b extend in parallel to the reactant flow path 1110, and the distance from the reactant flow path 1110 to each of the heat medium flow paths 1112a and 1112b becomes uniform. This contributes to heating the sample solution or fluorescent labeling solution uniformly and heating the sample solution or fluorescent labeling solution efficiently. However, both or one of the heat medium channels 1112a and 1112b may extend non-parallel to the reactant channel 1110.

(Relationship between volume of reactant flow path and heat medium flow path)
Desirably, the sum of the volumes of the heat medium channels 1112a and 1112b is greater than the volume of the reactant channels 1110. Thereby, the heat medium which contributes to the heating of the test | inspection chip 1002 increases, and a sample liquid or a fluorescent labeling liquid is heated efficiently.

(Combination of flow path forming body)
The flow path forming body 1106 is composed of one structure. However, the flow path forming body 1106 may be a combination of two or more structures. For example, the flow path forming body 1106 is a combination of the seal in which the surface exposed flow paths 1138, 1150a and 1150b are formed and the block in which the internal through flow paths 1140, 1422, 1152a, 1152b, 1154a and 1154b are formed. It may be.

(Supply and recovery mechanism)
The schematic diagram of FIG. 4 is a perspective view of an inspection chip and its periphery.

  As shown in FIGS. 1 and 4, when the sample solution or the fluorescent labeling solution is supplied to the reactant flow channel 1110, the sample solution or the fluorescent labeling solution is supplied to the reaction solution inlet / outlet 1132 by the reaction solution supply mechanism 1024 to react. The sample solution or the fluorescent labeling solution is collected from the reaction solution inlet / outlet 1134 by the solution collecting mechanism 1026. The reaction liquid supply mechanism 1024 and the reaction liquid recovery mechanism 1026 may be integrated. A sample solution or a fluorescent labeling solution may be circulated. The reaction liquid recovery mechanism 1026 may be omitted, and the sample liquid or the fluorescent labeling liquid may be discarded outside the measuring apparatus 1000. The reaction liquid supply mechanism 1024, the reaction liquid recovery mechanism 1026, the reaction liquid supply pipe 1030, and the reaction liquid recovery pipe 1032 are omitted, and the sample liquid or the fluorescent labeling liquid is supplied to the reaction liquid inlet / outlet port 1132 manually using a micropipette or the like. May be.

  The reaction solution supply mechanism 1024 and the reaction solution inlet / outlet port 1132 are connected by a reaction solution supply pipe 1030. The joint between the reaction liquid supply pipe 1030 and the reaction liquid supply mechanism 1024 is sealed with an O-ring 1200, and the joint between the reaction liquid supply pipe 1030 and the reaction liquid inlet / outlet 1132 is sealed with an O-ring 1202.

  The reaction liquid recovery mechanism 1026 and the reaction liquid inlet / outlet port 1134 are connected by a reaction liquid recovery pipe 1032. The joint between the reaction liquid recovery pipe 1032 and the reaction liquid recovery mechanism 1026 is sealed with an O-ring 1204, and the joint between the reaction liquid recovery pipe 1032 and the reaction liquid inlet / outlet 1134 is sealed with an O-ring 1206.

  When the heat medium is supplied to the heat medium channels 1112a and 1112b, the heat medium is supplied to the heat medium inlet / outlet 1146a and 1046b by the heat medium circulation mechanism 1028, and heat is supplied from the heat medium inlet / outlet 1148a and 048b by the heat medium circulation mechanism 1028. The medium is recovered and the heat medium is circulated. The heat medium circulation mechanism 1028 may be separated into the heat medium supply mechanism and the heat medium recovery mechanism, and the heat medium may not be circulated. The recovered heat medium may be discarded outside the measuring apparatus 1000. The temperature of the heat medium supplied to the heat medium flow paths 1112a and 1112b is desirably the same, but may be different.

  The heat medium circulation mechanism 1028 and the heat medium entrances 1046a and 1046b are connected by heat medium supply pipes 1034a and 1034b, respectively. The joints between the heat medium supply pipes 1034a and 1034b and the heat medium circulation mechanism 1028 are sealed with O-rings 1208a and 1208b, respectively. The joints between the heat medium supply pipes 1034a and 1034b and the heat medium inlet / outlet ports 1046a and 1046b are sealed with O-rings 1210a and 1210b, respectively.

  The heat medium circulation mechanism 1028 and the heat medium outlets 1048a and 1048b are connected by heat medium recovery pipes 1036a and 1036b, respectively. The joints between the heat medium recovery pipes 1036a and 1036b and the heat medium circulation mechanism 1028 are sealed with O-rings 1212a and 1212b, respectively. The joints between the heat medium recovery pipes 1036a and 1036b and the heat medium inlet / outlet ports 1048a and 1048b are sealed with O-rings 1214a and 1214b, respectively.

  All or part of the O-rings 1200, 1202, 1204, 1206, 1208a, 1208b, 1210a, 1210b, 1212a, 1212b, 1214a and 1214b may be replaced with other types of elastic seal members such as rubber packing.

(Heating of heating medium)
As shown in FIG. 1, the heating medium circulation mechanism 1028 includes a heating mechanism 1038. The heat medium supplied to the inspection chip 1002 is heated by the heating mechanism 1038. The heating mechanism 1038 includes, for example, a heating wire.

  Typically, the sample solution or fluorescent labeling solution is heated to improve the reactivity of the sample solution or fluorescent labeling solution. However, when the temperature of the environment in which the measuring apparatus 1000 is installed is high, or when the sample solution or the fluorescent labeling solution is vulnerable to heat, it is desirable to cool the sample solution or the fluorescent labeling solution. In that case, a cooling mechanism is built in the heat medium circulation mechanism 1028, and the heat medium supplied to the inspection chip 1002 is cooled by the cooling mechanism. The cooling mechanism includes, for example, a heat pump, a Peltier element, and the like. One of the sample solution and the fluorescent labeling solution can be heated and the other can be cooled. It is also permissible that one of the sample solution and the fluorescent labeling solution is heated or cooled and the other is neither heated nor cooled. The sample liquid or the fluorescent labeling liquid is allowed to be cooled after being heated. It is allowed that the sample solution or the fluorescent labeling solution is heated after being cooled.

  More generally, the heat medium circulation mechanism 1028 has a built-in temperature adjustment mechanism, and the heat medium supplied to the inspection chip 1002 is heated or cooled to adjust the temperature of a reaction product such as a sample solution or a fluorescent labeling solution. The

  The heat medium is typically a liquid such as water. However, the heat medium may be a gas such as air, carbon dioxide gas, or nitrogen gas.

  In addition to the heat medium, the temperature of the sample solution or the fluorescent labeling solution may be adjusted.

(Injection of sample solution and fluorescent labeling solution into flow channel)
The schematic diagram of FIG. 5 shows a state in which the sample solution is injected into the reactant flow path. The schematic diagram of FIG. 6 shows a state in which the fluorescent labeling solution is injected into the reactant flow path.

  As shown in FIG. 5, when the sample solution 1300 is injected into the reactant flow channel 1110, the antigen 1302 contained in the sample solution 1300 and the antibody 1304 contained in the antibody solid layer film 1104 are combined by an antigen-antibody reaction, The antigen 1302 is captured by the antibody solid film 1104. Further, when the fluorescent labeling solution 1306 is injected into the reactant flow channel 1110 in a state where the antigen 1302 is captured by the antibody solid layer film 1104, the antigen 1302 captured by the antibody solid layer film 1104 is shown in FIG. And the fluorescently labeled antibody 1308 contained in the fluorescently labeled solution 1306 are bound by an antigen-antibody reaction, and the antigen 1302 captured by the antibody solid layer film 1104 is fluorescently labeled on the fluorescently labeled antibody 1308.

(Sample solution and fluorescent labeling solution)
The sample liquid 1300 is typically a collected material from a human such as blood, but may be a collected material from a non-human organism or a non-living material. Pretreatments such as dilution, blood cell separation, and reagent mixing may be performed on the collected material.

  Instead of the sample solution 1300 and the fluorescent labeling solution 1306, a sample made of a gas or a fluid solid and a fluorescent labeled antibody-containing material may be injected into the reactant flow channel 1110, respectively.

(Antibody solid film)
The antibody solid layer film 1104 is made of a non-fluid. Therefore, even if the sample liquid 1300 or the fluorescent labeling liquid 1306 contacts the antibody solid layer film 1104, the antibody solid layer film 1104 does not move.

  The antibody 1304 is uniformly distributed. The capturing body for capturing the object to be measured is changed according to the object to be measured.

  The antibody solid film 1104 is patterned by, for example, a rubber applicator. The diameter of the antibody solid film 1104 is typically 2 mm, and the thickness of the antibody solid film 1104 is typically 100 nm or less.

(Laser diode)
As shown in FIG. 1, the laser diode 1010 emits excitation light EL. Desirably, the excitation light EL emitted from the laser diode 1010 is parallel light, linearly polarized light, and monochromatic light.

  The laser diode 1010 may be replaced with other types of light sources. For example, the laser diode 1010 may be replaced with a light emitting diode, a mercury lamp, a laser other than the laser diode, or the like. When the light emitted from the light source is not a parallel light beam, the light is preferably converted into a parallel light beam by a lens, a mirror, a slit, or the like. When the light emitted from the light source is not linearly polarized light, the light is preferably converted into linearly polarized light by a polarizer or the like. When the light emitted from the light source is not monochromatic light, the light is preferably converted into monochromatic light by a diffraction grating or the like.

(Linear polarizing plate)
The linearly polarizing plate 1012 is on the optical path of the excitation light EL, and converts the excitation light EL into linearly polarized light. The polarization direction of the excitation light EL is selected so that the excitation light EL is p-polarized with respect to the reflection region 1128. As a result, evanescent wave leakage increases, surface plasmon excitation fluorescence FL increases, and measurement sensitivity improves.

  The excitation light EL emitted from the laser diode 1010 is reflected by the mirror 1014. The light reflected by the mirror 1014 is applied to the prism 1102. The light irradiated to the prism 1102 enters the incident area 1126, is reflected by the reflection area 1128, and exits from the emission area 1130. The incident angle θ of the excitation light EL to the reflection region 1128 satisfies the total reflection condition. Therefore, when the excitation light EL is incident on the reflection region 1128, the excitation light EL is totally reflected on the reflection region 1128, and as shown in FIG. 6, the evanescent wave 1310 leaks to the gold film 1100 side, and the evanescent wave is emitted. 1310 is enhanced and surface plasmon excitation fluorescence FL is emitted.

  In order to adjust the incident angle θ of the excitation light EL to the reflection region 1128, the position and orientation of the mirror 1014 are adjusted by the drive mechanism 1016 as shown in FIG. The driving mechanism 1016 includes a driving force source such as a motor or a piezoelectric actuator. The drive mechanism 1016 rotates the mirror 1014 and adjusts the attitude of the mirror 1014. The drive mechanism 1016 moves the mirror 1014 on the linear stage and adjusts the position of the mirror 1014.

  The prism 1102 may be irradiated with excitation light EL emitted from the laser diode 1010 by another type of optical system. For example, the mirror 1014 may be replaced with another type of bending optical element such as a prism. Optical elements other than the mirror 1014 may be provided. Instead of the drive mechanism 1016 that adjusts the position and orientation of the mirror 1014, or in addition to the drive mechanism 1016 that adjusts the position and orientation of the mirror 1014, a drive mechanism that adjusts the position and orientation of optical elements other than the mirror 1014 is provided. A mechanism for adjusting the position and posture of the laser diode 1010 may be provided.

(Photomultiplier tube)
The photomultiplier tube 1020 is on the optical path of the surface plasmon excitation fluorescence FL, and measures the amount of light of the surface plasmon excitation fluorescence FL. The photomultiplier tube 1020 may be replaced with another type of light quantity sensor. For example, the photomultiplier tube 1020 may be replaced with a charge coupled device (CCD) sensor.

(Photodiode)
The photodiode 1022 is on the optical path of the excitation light EL emitted from the emission region 1130, that is, the reflected light RL, and measures the amount of the reflected light RL. However, the photodiode 1022 may be replaced with another type of light amount sensor. For example, the photodiode 1022 may be replaced with a photoresistor or a phototransistor.

(Low-pass filter)
The low pass filter 1018 transmits light having a wavelength longer than the cutoff wavelength, and attenuates light having a wavelength shorter than the cutoff wavelength. The cutoff wavelength is selected within a range from the wavelength of the excitation light EL to the wavelength of the surface plasmon excitation fluorescence FL. For example, when the wavelength of the excitation light EL is about 640 nm and the wavelength of the surface plasmon excitation fluorescence FL is 670 nm, 650 nm is selected as the cutoff wavelength. When the low-pass filter 1018 is inserted in the optical path of the surface plasmon excitation fluorescence FL, the scattered light is attenuated by the low-pass filter 1018 and a small part of the scattered light reaches the photomultiplier tube 1020, but the surface plasmon excitation fluorescence FL Passes through the low-pass filter 1018, and most of the surface plasmon excitation fluorescence FL reaches the photomultiplier tube 1020. Thereby, when the light quantity of the surface plasmon excitation fluorescence FL with a relatively small light quantity is measured, the influence of the scattered light with a relatively large light quantity is suppressed, and the measurement accuracy is improved.

(Measurement device operation)
The flowchart in FIG. 7 shows the operation of the measurement apparatus.

  As shown in FIG. 7, a test chip 1002 and a reagent chip 1400 are prepared, and the test chip 1002 and the reagent chip 1400 are attached to the measuring device 1000 (step S101).

  The schematic diagram of FIG. 8 shows a cross section of the reagent chip.

  A sample 1412 is accommodated in the sample container 1402 of the reagent chip 1400. Diluent 1414, fluorescent labeling liquid 1306, cleaning liquid 1416, and buffer liquid 1422 are previously stored in the diluent container 1404, fluorescent labeling liquid container 1406, cleaning liquid container 1408, and buffer liquid container 1420 of the reagent chip 1400, respectively. It is planned that the sample liquid 1300 is accommodated in the dilution container 1410 of the reagent chip 1400.

  After the inspection chip 1002 and the reagent chip 1400 are attached, the specimen 1412 is diluted and the sample liquid 1300 is prepared (step S102). When the specimen 1412 is diluted, the specimen 1412 is sent from the specimen container 1402 to the dilution container 1410, and the diluent 1414 is sent from the diluent container 1404 to the dilution container 1410. In some cases, the sample 1412 may be directly used as the sample solution 1300 without being diluted.

  After the sample liquid 1300 is prepared, the heat medium is supplied to the heat medium channels 1112a and 1112b (step S103). When the heat medium is supplied to the heat medium flow paths 1112a and 1112b, the heat medium circulation mechanism 1028 is controlled by the controller 1008. Thereby, the whole inspection chip 1002 is heated, and the temperature of the inspection chip 1002 is adjusted to the target temperature. Since the amount of the heat medium is sufficiently large and the contact between the heat medium, which is a fluid such as liquid or gas, and the inner surfaces of the heat medium flow paths 1112a and 1112b is good, the heat quickly moves from the heat medium to the inspection chip 1002. Then, the temperature of the inspection chip 1002 is quickly adjusted. The heat medium may be supplied to the heat medium flow paths 1112a and 1112b before the sample liquid 1300 is prepared or in parallel with the preparation of the sample liquid 1300.

  In a state where the heat medium is accommodated in the heat medium channels 1112a and 1112b, the buffer liquid 1422 is injected into the reactant channel 1110 (step S104). When the buffer liquid 1422 is injected into the reactant flow path 1110, the reaction liquid supply mechanism 1024 and the reaction liquid recovery mechanism 1026 are controlled by the controller 1008. The reaction liquid supply mechanism 1024 supplies the buffer liquid 1422 pumped from the buffer liquid container 1420 to the reactant flow path 1110. The buffer solution 1422 is recovered from the reactant flow channel 1110 by the reaction solution recovery mechanism 1026.

  In a state where the buffer liquid 1422 is accommodated in the reactant flow channel 1110, the incident angle θ is set to the measurement angle θm (step S105). The incident angle θ may be set to the measurement angle θm before the sample solution 1300 is prepared or in parallel with the sample solution 1300 being prepared. When the incident angle θ is set to the measurement angle θm, the drive mechanism 1016 and the photodiode 1022 are controlled by the controller 1008. The position and orientation of the mirror 1014 are adjusted by the drive mechanism 1016, and the incident angle θ is scanned in the vicinity of the expected resonance angle θr. In parallel with the scanning of the incident angle θ, the light quantity of the reflected light RL is measured by the photodiode 1022. The measured value of the light amount of the reflected light RL is transferred to the controller 1008. The resonance angle θr, which is the incident angle θ at which the amount of the reflected light RL is minimized, is specified, and the measurement angle θm is determined from the resonance angle θr. Since the resonance angle θr and the incident angle θ at which the electric field enhancement becomes maximum are slightly different, it is desirable that the measurement angle θm is determined by adding or subtracting the minute angle to the resonance angle θr.

  In a state where the incident angle θ is set to the measurement angle θm and the heat medium is stored in the heat medium flow paths 1112a and 1112b, the sample liquid 1300 and the fluorescent labeling liquid 1306 are sequentially injected into the reactant flow path 1110 (step). S106). When the sample liquid 1300 and the fluorescent labeling liquid 1306 are sequentially injected into the reactant flow channel 1110, the reaction liquid supply mechanism 1024 and the reaction liquid recovery mechanism 1026 are controlled by the controller 1008. The reaction liquid supply mechanism 1024 supplies the sample liquid 1300 pumped from the dilution container 1410 to the reactant flow path 1110 and supplies the fluorescent label liquid 1306 pumped from the fluorescent label liquid container 1406 to the reactant flow path 1110. . The sample liquid 1300 and the fluorescent labeling liquid 1306 are recovered from the reactant flow channel 1110 by the reaction liquid recovery mechanism 1026. As a result, the sample solution 1300 and the fluorescent labeling solution 1306 are sequentially supplied to the antibody solid layer film 1104, and the fluorescently labeled antigen 1302 is captured by the antibody solid layer film 1104. The sample liquid 1300 and the fluorescent labeling liquid 1306 are heated, and the temperature of the sample liquid 1300 and the fluorescent labeling liquid 1306 is adjusted to a temperature suitable for the antigen-antibody reaction. Reagents other than the sample solution 1300 and the fluorescent labeling solution 1306 may be supplied as reactants, and biochemical reactions other than antigen-antibody reactions may be performed.

  After the sample solution 1300 and the fluorescent labeling solution 1306 are injected into the reactant flow channel 1110, the light quantity of the surface plasmon excitation fluorescence FL is measured (step S107). When the light quantity of the surface plasmon excitation fluorescence FL is measured, the photomultiplier tube 1020 is controlled by the controller 1008. The amount of surface plasmon excitation fluorescence FL is measured by a photomultiplier tube 1020. The measurement value of the light amount of the surface plasmon excitation fluorescence FL is transferred to the controller 1008.

  The measurement mechanism 1006 may perform measurement by the surface plasmon resonance (SPR) method instead of the measurement by the SPFS method. When the measurement mechanism 1006 performs measurement by the SPR method, the change in the resonance angle θr is measured instead of the light amount of the surface plasmon excitation fluorescence FL.

{Second Embodiment}
(Outline of inspection chip)
The second embodiment relates to a test chip that is employed instead of the test chip of the first embodiment.

  The schematic diagram of FIG. 9 is a perspective view of the test | inspection chip of 2nd Embodiment. The schematic diagram of FIG. 10 shows the cross section of the test | inspection chip of 2nd Embodiment.

  As shown in FIGS. 9 and 10, the test chip 2002 of the second embodiment includes a gold film 2100, a prism 2102, an antibody solid film 2104, a flow path forming body 2106, and seals 2108a and 2108b. The gold film 2100, the prism 2102, the antibody solid film 2104, and the seals 2108a and 2108b of the second embodiment are the same as the gold film 1100, the prism 1102, the antibody solid film 1104, and the seals 1108a and 1108b of the first embodiment, respectively. Is. The reactant channel 2110 formed in the channel forming body 2106 of the second embodiment is the same as the reactant channel 1110 formed in the channel forming body 1106 of the first embodiment.

(Differences between the first embodiment and the second embodiment)
The difference between the first embodiment and the second embodiment is that the heat medium flow path 1112a is replaced with heat medium flow paths 2112a to 2112d, and the heat medium flow path 1112b is replaced with heat medium flow paths 2112e to 2112h. .

(Accommodating heat media at different temperatures)
The heat medium flow paths 2112a to 2112h are separated. Therefore, the heat medium accommodated in the heat medium flow paths 2112a to 2112d is not mixed. Moreover, the heat medium accommodated in the heat medium flow paths 2112e to 2112h is not mixed. This makes it possible to store heat media having different temperatures in the heat medium channels 2112a to 2112d and to store heat media having different temperatures in the heat medium channels 2112e to 2112h. Although the number of heat medium channels may be increased or decreased, two or more heat medium channels separated from each other by a distance from the reactant channel 2110 are provided.

  The distance from the reactant flow path 2110 to each of the heat medium flow paths 2112a to 2112d is different, and the distance from the reactant flow path 2110 to each of the heat medium flow paths 2112e to 2112h is different. Heat media having different temperatures are supplied to the heat medium channels 2112a to 2112d. In addition, heat media having different temperatures are supplied to the heat medium channels 2112e to 2112h.

  When the sample solution 1300 or the fluorescent labeling solution 1306 is heated, a relatively low-temperature heat medium is desirably supplied to the heat medium channel relatively close to the reactant channel 2110, and the relative flow from the reactant channel 2110 The heat medium having a relatively high temperature is accommodated in the heat medium flow path far away from the heat medium. That is, the further away from the reactant flow path 2110, the higher the temperature of the heat medium supplied to the heat medium flow path.

  For example, the fourth heat medium flow channel 2112a and 2112e are supplied to the reactant flow channel 2110 with the fourth highest heat medium flow rate, and the second closest heat medium flow channel 2112b and 2112f are three with the third heat medium flow channel 2112b and 2112f. The second highest heat medium is supplied to the reactant flow path 2110, the second highest heat medium is supplied to the heat medium flow paths 2112c and 2112g, and the fourth highest heat medium is supplied to the reactant flow path 2110. The first high-temperature heat medium is supplied to the flow paths 2112d and 2112h.

  Thereby, the temperature is finely adjusted, and the sample solution 1300 or the fluorescent labeling solution 1306 is appropriately heated. This means that when a high-temperature heat medium is supplied to all of the heat medium flow paths 2112a to 2112h, the temperature rises faster but a temperature overshoot occurs, and the sample liquid 1300 or the fluorescent labeling liquid 1306 is excessive. It is understood from the fact that it may be deactivated by a simple heating. This can also be understood from the fact that when a low-temperature heat medium is supplied to all of the heat medium flow paths 2112a to 2112h, the temperature rises slowly and the time required for measurement becomes long. However, the heat medium having the same temperature may be supplied to all of the heat medium flow paths 2112a to 2112h.

  Conversely, when the sample liquid 1300 or the fluorescent labeling liquid 1306 is cooled, a relatively high-temperature heat medium is desirably supplied to the heat medium flow path relatively close to the reactant flow path 2110, and the reactant flow path 2110. The heat medium having a relatively low temperature is accommodated in the heat medium flow path relatively far from the heat medium. That is, the temperature of the heat medium supplied to the heat medium flow path decreases as the distance from the reactant flow path 2110 increases.

  When the inspection chip 2002 of the second embodiment is adopted instead of the inspection chip 1002 of the first embodiment, the heat medium circulation mechanism 1028 desirably supplies heat media having different temperatures.

(Arrangement of reactant inlet / outlet and heat medium inlet / outlet)
The reactant channel 2110 extends from the reactant inlet / outlet 2132 to the reactant inlet / outlet 2134 via the inside of the channel forming body 2106 and provides a reactant accommodating space for accommodating the reactant. The reactant channel 2110 has an opening 2144.

  The heat medium flow paths 2112a to 2112h extend from the heat medium inlet / outlet ports 2146a to 2146h to the heat medium inlet / outlet ports 2148a to 2148h via the inside of the flow path forming body 2106, respectively, and form heat medium storage spaces for storing the heat medium. provide. The heat medium flow paths 2112a to 2112h have openings 2156a to 2156h, respectively. The heat medium is supplied to the heat medium ports 2146a to 2146h, and is recovered from the heat medium ports 2148a to 2148h.

  The reactant inlets and outlets 2132 and 2134 and the heating medium inlets and outlets 2146a to 2146h and 2148a to 2148h are provided in the exposed region 2122 of the surface 2118 of the flow path forming body 2106, and preferably concentrated on the upper surface 2192 facing a certain direction. It is done. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common. Further, since the upper surface 2192 faces in the opposite direction to the bonding region 2120, it is easy to provide the supply / recovery mechanism 1006 on the opposite side of the prism 2102, and the supply / recovery mechanism 1006 irradiates the prism 2102 with the excitation light EL. It becomes difficult to block.

  The opening 2144 of the reactant channel 2110 and the openings 2156a and 2156e of the heat medium channels 2112a and 2112e are provided in the joining region 2120. The openings 2156b to 2156d and 2156f to 2156h of the heat medium flow paths 2112b to 2112d and 2112f to 2112h are provided in the closed regions 2123a and 2123b, respectively. Desirably, the openings 2144 and 2156a to 2156h are provided in a concentrated manner on the lower surface 2196 facing in a certain direction. Thereby, when the flow path forming body 2106 is manufactured by injection molding, the number of molds that need to be processed such as the flow path is reduced, and the manufacturing cost of the inspection chip 2002 is reduced.

(Shape of reactant inlet / outlet and heat medium inlet / outlet)
The shape of the reactant flow channel 2110 and the shape of each of the heat medium flow channels 2112a to 2112h are the same. For this reason, the shapes of the reactant inlets and outlets 2132 and 2134 and the heat medium inlets and outlets 2146a to 2146h and 2148a to 2148h are the same. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common.

  When the shape of the reactant channel 2110 and the shape of each of the heat medium channels 2112a to 2112h are the same, the volume of the reactant channel 2110 and the volume of each of 2112a to 2112h are the same. The total volume of the channels 2112a to 2112h is larger than the volume of the reactant channel 2110. Thereby, the heat medium which contributes to the heating of the test | inspection chip 2002 increases, and a sample liquid and a fluorescent labeling liquid are heated efficiently.

  According to the inspection chip 2002 of the second embodiment, the sample liquid and the fluorescent labeling liquid are efficiently heated or cooled, and an increase in manufacturing cost of the inspection chip 2002 is also suppressed.

{Third embodiment}
(Outline of inspection chip)
The third embodiment relates to a test chip that is employed instead of the test chip of the first embodiment.

  The schematic diagram of FIG. 11 is a perspective view of the test | inspection chip of 3rd Embodiment. The schematic diagram of FIG. 12 shows the cross section of the test | inspection chip of 3rd Embodiment.

  As shown in FIGS. 11 and 12, the test chip 3002 of the third embodiment includes a gold film 3100, a prism 3102, an antibody solid film 3104, a flow path forming body 3106, and seals 3108a and 3108b. The gold film 3100, the prism 3102, the antibody solid film 3104, and the seals 3108a and 3108b of the third embodiment are the same as the gold film 1100, the prism 1102, the antibody solid film 1104, and the seals 1108a and 1108b of the first embodiment, respectively. Is. The reactant flow path 3110 formed in the flow path forming body 3106 of the third embodiment is the same as the reactant flow path 1110 formed in the flow path forming body 1106 of the first embodiment.

(Differences between the first embodiment and the third embodiment)
The difference between the first embodiment and the third embodiment is that the heat medium flow path 1112a is replaced with a heat medium pool (well) 3112a, and the heat medium flow path 1112b is replaced with a heat medium pool 3112b.

(Arrangement of reactant inlet / outlet and heat medium inlet / outlet)
The reactant channel 3110 extends from the reactant inlet / outlet 3132 to the reactant inlet / outlet 3134 via the inside of the channel forming body 3106, and provides a reactant accommodating space for accommodating the reactant. The reactant flow path 3110 has an opening 3144.

  The heat medium reservoirs 3112a and 3112b have one heat medium inlet / outlet 3146a and 3146b, respectively, and provide a heat medium accommodating space for accommodating the heat medium. Heat medium reservoirs 3112a and 3112b have openings 3156a and 3156b, respectively. The heat medium is supplied to the heat medium ports 3146a and 3146b, and is recovered from the heat medium ports 3146a and 3146b.

  The reactant inlet / outlet ports 3132 and 3134 and the heat medium inlet / outlet ports 3146a and 3146b are provided in the exposed region 3122 of the surface 3118 of the flow path forming body 3106, and preferably are concentrated on the upper surface 3192 facing a certain direction. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common. Further, since the upper surface 3192 faces in the opposite direction to the bonding region 3120, it is easy to provide the supply / recovery mechanism 1006 on the opposite side of the prism 3102, and the supply / recovery mechanism 1006 irradiates the prism 3102 with the excitation light EL. It becomes difficult to block.

  An opening 3144 of the reactant channel 3110 is provided in the bonding region 3120. The openings 3156a and 3156b of the heat medium reservoirs 3112a and 3112b are provided in the closed regions 3023a and 3023b, respectively. The openings 3156a and 3156b of the heat medium reservoirs 3112a and 3112b are closed by seals 3108a and 3108b, respectively. Desirably, the openings 3144 of the reactant flow path 3110 and the openings 3156a and 3156b of the heat medium reservoirs 3112a and 3112b are concentrated on the lower surface 3196 facing a certain direction. Thereby, when the flow path forming body 3106 is produced by injection molding, the number of molds that need to be processed such as the flow path is reduced, and the manufacturing cost of the inspection chip 3002 is reduced.

  The sum of the volumes of the heat medium reservoirs 3112a and 3112b is larger than the volume of the reactant flow path 3110. Thereby, the heat medium which contributes to the heating of the test | inspection chip 3002 increases, and a sample liquid or a fluorescent labeling liquid is heated efficiently.

  According to the inspection chip 3002 of the third embodiment, the sample liquid and the fluorescent labeling liquid are efficiently heated or cooled, and an increase in manufacturing cost of the inspection chip 3002 is also suppressed.

{Fourth embodiment}
The fourth embodiment relates to an inspection chip that is employed instead of the inspection chip of the first embodiment.

  The schematic diagram of FIG. 13 is a perspective view of the test | inspection chip of 4th Embodiment.

  As shown in FIG. 13, the test chip 4002 of the fourth embodiment includes a gold film 4100, a prism 4102, an antibody solid film 4104, and a flow path forming body 4106. The gold film 4100, prism 4102 and antibody solid film 4104 of the fourth embodiment are the same as the gold film 1100, prism 1102 and antibody solid film 1104 of the first embodiment, respectively. The reactant flow path 4110 formed in the flow path forming body 4106 of the fourth embodiment is the same as the reactant flow path 1110 formed in the flow path forming body 1106 of the first embodiment.

(Difference between the first embodiment and the fourth embodiment)
The difference between the first embodiment and the fourth embodiment is that the heat medium flow paths 1112a and 1112b are replaced with a heat medium reservoir 4112. Unlike the heat medium reservoirs 3112a and 3112b of the third embodiment, the heat medium reservoir 4112 of the fourth embodiment makes a round around the reactant flow path 4110. Thereby, the sample solution or fluorescent labeling solution accommodated in the reactant flow path 4110 is efficiently heated.

(Arrangement of reactant inlet / outlet and heat medium inlet / outlet)
The reactant channel 4110 extends from the reactant inlet / outlet 4132 to the reactant inlet / outlet 4134 via the inside of the channel forming body 4106, and provides a reactant accommodating space for accommodating the reactant.

  The heat medium reservoir 4112 has one heat medium inlet / outlet 4146 and provides a heat medium accommodation space for accommodating the heat medium. The heat medium reservoir 4112 has no opening other than the heat medium inlet / outlet 4146. The heat medium is supplied to the heat medium inlet / outlet 4146 and is recovered from the heat medium inlet / outlet 4146.

  The reactant inlets / outlets 4132 and 4134 and the heat medium inlet / outlet 4146 are provided in the exposed region 4122 of the surface 4118 of the flow path forming body 4106, and preferably are concentrated on the upper surface 4192 facing a certain direction. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common. Since the upper surface 4132 faces in a direction opposite to the bonding region, it is easy to provide the supply / recovery mechanism 1006 on the opposite side of the prism 4102, and the supply / recovery mechanism 1006 is unlikely to hinder the irradiation of the excitation light EL to the prism 4102. .

  The volume of the heat medium reservoir 4112 is larger than the volume of the reactant flow path 4110. Thereby, the heat medium which contributes to the heating of the test | inspection chip 4002 increases, and a sample liquid or a fluorescent labeling liquid is heated efficiently.

  According to the inspection chip 4002 of the fourth embodiment, the sample liquid and the fluorescent labeling liquid are efficiently heated or cooled, and an increase in manufacturing cost of the inspection chip 4002 is also suppressed.

{Fifth embodiment}
The fifth embodiment relates to a test chip that is employed instead of the test chip of the first embodiment.

  The schematic diagram of FIG. 14 is a perspective view of the test | inspection chip of 5th Embodiment. The schematic diagram of FIG. 15 shows the cross section of the test | inspection chip of 5th Embodiment.

  As shown in FIGS. 14 and 15, the test chip 5002 of the fifth embodiment includes a gold film 5100, a prism 5102, an antibody solid layer film 5104, and a flow path forming body 5106. The gold film 5100, prism 5102 and antibody solid film 5104 of the test chip 5002 of the fifth embodiment are the same as the gold film 1100, prism 1102 and antibody solid film 1104 of the test chip 1002 of the first embodiment, respectively. is there. The reactant flow path 5110 formed in the flow path forming body 5106 of the fifth embodiment is the same as the reactant flow path 1110 formed in the flow path forming body 1106 of the first embodiment.

(Differences between the first embodiment and the fifth embodiment)
The difference between the first embodiment and the fifth embodiment is that the heat medium flow path 1112a is replaced with a heat medium flow path 5112a, and the heat medium flow path 1112b is replaced with a heat medium flow path 5112b.

(Arrangement of reactant inlet / outlet and heat medium inlet / outlet)
The reactant channel 5110 extends from the reactant inlet / outlet 5132 to the reactant inlet / outlet 5134 via the inside of the channel forming body 5106 and provides a reactant accommodating space for accommodating the reactant. The reactant flow path 5110 has an opening 5144.

  The heat medium flow paths 5112a and 5112b extend from the heat medium inlet / outlet ports 5146a and 5146b to the heat medium inlet / outlet ports 5148a and 5148b via the inside of the flow path forming body 5106, respectively. provide. The heat medium flow paths 5112a and 5112b do not have openings other than the heat medium inlet / outlet ports 5146a, 5146b, 5148a, and 5148b. The heat medium is supplied to the heat medium ports 5146a and 5146b, and is recovered from the heat medium ports 5148a and 5148b.

  The reactant inlet / outlet 5132 and 5134 and the heat medium inlet / outlet 5146a and 5146b are provided in the exposed region 5122 of the surface 5118 of the flow path forming body 5106, and preferably are concentrated on the upper surface 5192 facing a certain direction. Thereby, the mechanism for supplying the reaction liquid and the mechanism for supplying the heat medium can be easily made common. Further, since the upper surface 5192 faces in the direction opposite to the bonding region 5120, it is easy to provide the supply / recovery mechanism 1006 on the opposite side of the prism 5102, and the supply / recovery mechanism 1006 irradiates the prism 5102 with the excitation light EL. It becomes difficult to block.

  The opening 5144 is provided in the bonding region 5120. The heat medium entrances 5148 a and 5148 b are provided in the exposed region 5122. Desirably, the opening 5144 and the heat medium inlet / outlet ports 5148a and 5148b are concentrated on the lower surface 5196 facing a certain direction. Thereby, when the flow path forming body 5106 is produced by injection molding, the number of molds that need to be processed such as the flow path is reduced, and the manufacturing cost of the inspection chip 5002 is reduced.

  The sum of the volumes of the heat medium channels 5112a and 5112b is larger than the volume of the reactant channel 5110. Thereby, the heat medium which contributes to the heating of the test | inspection chip 5002 increases, and a sample liquid and a fluorescent labeling liquid are heated or cooled efficiently.

  According to the inspection chip 5002 of the fifth embodiment, the sample liquid and the fluorescent labeling liquid are efficiently heated or cooled, and an increase in manufacturing cost of the inspection chip 5002 is also suppressed.

  Although the present invention has been described in detail, the above description is illustrative in all aspects, and the present invention is not limited to the above description. Innumerable modifications not illustrated can be envisaged without departing from the scope of the present invention.

1002, 2002, 3002, 4002, 5002 Inspection chip 1110, 2110, 3110, 4110, 5110 Reactant flow path 1112a, 1112b, 2112a to 2112h, 5112a, 5112b Heat medium flow path 3146a, 3146b, 4146 Heat medium accumulation

Claims (14)

A test chip used for measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance method,
A first surface having a bonding region and an exposed region, a reactant storage space and a heat medium storage space are formed, and the reactant storage space has an opening in the bonding region; A structure having a reactant inlet / outlet in the exposed region, and wherein the heat medium accommodating space has a heat medium inlet / outlet in the exposed region;
The second surface has an incident area, a reflection area, and an emission area, and the excitation light incident on the incident area is totally reflected by the reflection area and emitted from the emission area. A dielectric medium in which the incident region, the reflective region, and the emitting region are disposed;
A conductor film having a first main surface and a second main surface, wherein the first main surface is bonded to the bonding region, and the second main surface is in close contact with the reflection region;
Inspection chip with. The inspection chip according to claim 1,
The heating medium inlet / outlet is a first heating medium inlet / outlet;
The heat medium accommodating space has a second heat medium inlet / outlet in the exposed region;
An inspection chip in which the heat medium accommodation space is a flow path extending from the first heat medium inlet / outlet through the inside of the structure to the second heat medium inlet / outlet. The inspection chip according to claim 2,
The exposed area has an entrance / exit forming area facing a certain direction;
An inspection chip in which the reactant inlet / outlet, the first heat medium inlet / outlet and the second heat medium inlet / outlet are provided in the inlet / outlet formation region. The inspection chip according to claim 3,
An inspection chip in which the entrance / exit formation region and the joining region face in opposite directions. In the inspection chip according to any one of claims 2 to 4,
The opening is a first opening;
The heat medium accommodating space has a second opening;
The first surface has an opening forming region facing a certain direction;
An inspection chip in which the first opening and the second opening are provided in the opening formation region. The inspection chip according to claim 2,
The exposed area has an entrance / exit forming area facing a first constant direction;
The first surface has an opening forming region facing a second constant direction;
The reactant outlet and the first heat medium inlet / outlet are provided in the inlet / outlet forming region;
An inspection chip in which the opening and the second heat medium inlet / outlet are provided in the opening formation region. The inspection chip according to claim 1,
An inspection chip in which the heat medium accommodation space is a reservoir having one heat medium entrance. The inspection chip according to claim 7,
The exposed area has an entrance / exit forming area facing a certain direction;
The inspection chip in which the reactant entrance and the heat medium entrance are provided in the entrance formation region. The inspection chip according to claim 8,
An inspection chip in which the entrance / exit formation region and the joining region face in opposite directions. In the inspection chip according to any one of claims 7 to 9,
The opening is a first opening;
The heat medium accommodating space has a second opening;
The first surface has an opening forming region facing a certain direction;
An inspection chip in which the first opening and the second opening are provided in the opening formation region. In the inspection chip according to any one of claims 1 to 10,
An inspection chip having the same shape of the reactant inlet / outlet and the shape of the heat medium inlet / outlet. In the inspection chip according to any one of claims 1 to 11,
An inspection chip in which two or more heat medium accommodation spaces separated from each other by a distance from the reactant accommodation space are formed. In the inspection chip according to any one of claims 1 to 12,
An inspection chip in which the total volume of the heat medium accommodation space is larger than the volume of the reactant accommodation space. A measurement device that performs measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance method,
A first surface having a bonding region and an exposed region, a reactant storage space and a heat medium storage space are formed, and the reactant storage space has an opening in the bonding region; A structure having a reactant inlet / outlet in the exposed region, and wherein the heat medium accommodating space has a heat medium inlet / outlet in the exposed region;
The second surface has an incident area, a reflection area, and an emission area, and the excitation light incident on the incident area is totally reflected by the reflection area and emitted from the emission area. A dielectric medium in which the incident region, the reflective region, and the emitting region are disposed;
A conductor film having a first main surface and a second main surface, wherein the first main surface is bonded to the bonding region, and the second main surface is in close contact with the reflection region;
A heat medium supply mechanism that adjusts the temperature of the heat medium and supplies the heat medium whose temperature is adjusted to the heat medium accommodation space;
A measurement mechanism for making excitation light incident on the incident region and performing measurement by surface plasmon excitation fluorescence spectroscopy or surface plasmon resonance method;
A measuring device comprising:

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