Abstract:
This detection device has a holder and a heating unit. The holder holds a detection chip that has the following: a prism that has an incidence surface and a film-formation surface; a metal film formed on said film-formation surface; trapping bodies laid out on the surface of said metal film; and a substrate that is laid out on the surface of the metal film, and together with the metal film, forms a liquid collection section in which a liquid is collected. The heating unit heats at least one of the substrate, the prism, and the metal film either while in contact therewith or without contacting same. Also, the heating unit is positioned so as to avoid the path that excitation light takes from an excitation-light emission unit to the abovementioned incidence surface.

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to a detection device that detects a detection target substance using surface plasmon resonance, and also relates to a detection method using the detection device and to a detection chip used in the detection device. 
       BACKGROUND ART 
       [0002]    Highly-sensitive and quantitative detection of a minute amount of a detection target substance such as protein and/or DNA in laboratory tests or the like makes it possible to perform treatment while quickly determining the patient&#39;s condition. For this reason, the analysis device and the analysis method which can highly-sensitively and quantitatively detect a minute amount of a detection target substance have been in demand. 
         [0003]    Surface plasmon-field enhanced fluorescence spectroscopy (hereinafter abbreviated as “SPFS”) is known as a method which can detect a detection target substance with high sensitivity (see, for example, PTLs 1 and 2). 
         [0004]    PTLs 1 and 2 disclose an analysis device and an analysis method that utilize SPFS. 
         [0005]    In the analysis device and analysis method, a sensor chip including: a prism composed of dielectric; a metal film formed on one surface of the prism; and a capturing body (e.g., antibody) fixed onto the metal film, is used. When a sample containing a detection target substance is provided on the metal film, the detection target substance is captured by the capturing body (primary reaction). The captured detection target substance is further labeled by a fluorescent material (secondary reaction). In this state, when the metal film is irradiated with excitation light through the prism at an angle at which surface plasmon resonance occurs, localized-field light can be generated on the surface of the metal film. With this localized-field light, the fluorescent material used for labeling the captured detection target substance on the metal film is selectively excited, and the fluorescence emitted from the fluorescent material is observed. In the analysis device and analysis method, the fluorescence is detected to detect the presence or amount of the detection target substance. Normally, the analysis method using the analysis device is performed at room temperature. 
       CITATION LIST 
     Patent Literature 
       [0000]    
       
         PTL 1 
         Japanese Patent Application Laid-Open No. HEI 10-307141 
         PTL 2 
         WO 2012-042805 
       
     
       SUMMARY OF INVENTION 
     Technical Problem 
       [0010]    In general, the primary reaction and the secondary reaction vary depending on the surrounding temperature. When an antibody is used, the primary reaction and the secondary reaction are most promoted at around 37 degrees, which is higher than room temperature. Moreover, the intensity of fluorescence emitted from the fluorescent material also varies depending on the surrounding temperature. 
         [0011]    In the analysis device and analysis method disclosed in PTLs 1 and 2, however, the temperature of the reaction site is not managed, so that the temperatures of the reaction sites at the time of the primary reaction, the secondary reaction and the fluorescent detection have to be dependent on the installation environment of the analysis device. Accordingly, the analysis device and analysis method disclosed in PTLs 1 and 2 involve concern that there may be a change, depending on the surrounding temperature, in the rate of a detection target substance being captured by the capturing body in the primary reaction, the rate of a detection target substance being labeled by fluorescence in the secondary reaction, and the intensity of fluorescence at the time of fluorescent detection. Accordingly, there is concern that the analysis device and analysis method disclosed in PTLs 1 and 2 cannot detect a detection target substance contained in a sample, highly-sensitively and quantitatively. 
         [0012]    An object of the present invention is to provide a detection device capable of highly-sensitively and quantitatively detecting a detection target substance, using surface plasmon resonance. Still, another object of the present invention is to provide a detection method using this detection device. Yet, another object of the present invention is to provide a detection chip used in this detection device. 
       Solution to Problem 
       [0013]    To solve the above-mentioned problems, the detection device according to an embodiment of the present invention is a detection device that detects the presence or amount of a detection target substance contained in a sample, using surface plasmon resonance, the detection device including: a holder that holds a detection chip, the detection chip including: a prism including an incident surface and a film formation surface, a metal film disposed on the film formation surface; a capturing body disposed on the metal film; and a base body disposed to be flush with a surface of the metal film, the surface being where the capturing body is disposed, and the base body being configured to form, together with the metal film, a liquid reservoir section that reserves a liquid, an excitation light irradiation section that emits excitation light toward the incident surface; and a heating section that heats at least any one of the base body, the prism, and the metal film, in a contact state or a non-contact state, in which the heating section is disposed while avoiding a light path of the excitation light from the excitation light irradiation section to the incident surface. 
         [0014]    In addition, to solve the above-mentioned problems, the detection method according to an embodiment of the present invention is a detection method for detecting the presence or amount of a detection target substance contained in a sample, using surface plasmon resonance, the method including: preparing a detection chip comprising a detection section, the detection section including a prism including an incident surface and a film formation surface, a metal film disposed on the film formation surface, a capturing body fixed onto the metal film, and a base body disposed to be flush with a surface of the metal film, the surface being where the capturing body is disposed, and the base body being configured to form, together with the metal film, a liquid reservoir section that reserves the sample; heating at least any one of the base body, the prism, and the metal film of the detection chip; bonding a detection target substance contained in the sample to the capturing body by causing the sample to be in contact with the capturing body; and emitting excitation light to the metal film from a direction of the prism such that the excitation light is totally reflected at a surface boundary between the prism and the metal film. 
         [0015]    Moreover, to solve the above-mentioned problems, the detection chip according to an embodiment of the present invention is a detection chip used in a detection device that detects the presence or amount of a detection target substance contained in a sample, using surface plasmon resonance, the detection chip including: a prism including an incident surface and a film formation surface; a metal film disposed so as to extend to an outer side of the film formation surface; a capturing body disposed on the metal film; and a base body disposed to be flush with a surface of the metal film, the surface being where the capturing body is disposed, and the base body being configured to form, together with the metal film, a liquid reservoir section that reserves a liquid. 
       Advantageous Effects of Invention 
       [0016]    According to the present invention, the temperature at the reaction site can be constant every time, so that a detection target substance can be highly-sensitively and quantitatively detected. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0017]      FIG. 1  is a schematic view of an SPFS device according to Embodiment 1; 
           [0018]      FIGS. 2A and 2B  are diagrams illustrating a configuration of a detection chip according to Embodiment 1; 
           [0019]      FIG. 3  is a flowchart of an operation procedure of the SPFS device according to 
           [0020]    Embodiment 1; 
           [0021]      FIGS. 4A to 4C  are diagrams illustrating a positional relationship between the detection chip according to Embodiment 1 and a heat block of a variation; 
           [0022]      FIGS. 5A to 5C  are diagrams illustrating a positional relationship between a detection chip according to Variation 1 of Embodiment 1 and each heat block; 
           [0023]      FIG. 6  is a diagram illustrating a configuration of a detection chip according to Variation 2 of Embodiment 1; 
           [0024]      FIG. 7  is a schematic diagram of an SPFS device according to Embodiment 2; 
           [0025]      FIG. 8  is a cross-sectional view taken along a long-side direction of a detection chip according to Embodiment 2; 
           [0026]      FIG. 9  is a flowchart illustrating an operation procedure of the SPFS device according to Embodiment 2; and 
           [0027]      FIG. 10  is a cross-sectional view taken along a long-side direction of a detection chip according to a variation of Embodiment 2. 
       
    
    
     DESCRIPTION OF EMBODIMENTS 
       [0028]    In the following, an embodiment of the present invention is described in detail with reference to the accompanying drawings. 
       Embodiment 1 
       [0029]    In Embodiment 1, a description will be given of an embodiment of an SPFS device which is a detection device according to the present invention. 
         [0030]    First, an outline of the SPFS device will be described. The SPFS device generates localized-field light (which is called “evanescent light” or “near-field light” in general) on a surface of a metal film by causing excitation light to enter the metal film on a prism composed of dielectric, at an angle at which surface plasmon resonance occurs. The SPFS device detects the presence or amount of a detection target substance by detecting, when a fluorescent material used to label a detection target substance disposed on the metal film is selectively excited by this localized-field light, the light amount of the fluorescence emitted from the fluorescent material. 
         [0031]      FIG. 1  is a schematic diagram illustrating a configuration of SPFS device  100  according to Embodiment 1. As illustrated in  FIG. 1 , SPFS device  100  includes excitation light irradiation section  110 , light detection section  120 , heating section  130 , and control section  140 . In detection of a detection target substance, SPFS device  100  is used in a state where detection chip  150  is attached to holder  150   a . For this reason, detection chip  150  will be described, first, and each configuration element of SPFS device  100  will be described, thereafter. 
         [0032]      FIGS. 2A and 2B  are diagrams illustrating a configuration of detection chip  150 .  FIG. 2A  is a perspective view of detection chip  150 , and  FIG. 2B  is a cross-sectional view taken along a long-side direction of detection chip  150 . Note that,  FIG. 2A  illustrates, using a broken line, heat block  131  to be described hereinafter. As illustrated in  FIG. 1  and  FIGS. 2A and 2B , detection chip  150  includes prism  151 , metal film  152 , reaction section  153 , and base body  154 . Normally, detection chip  150  is replaced every detection. The size of detection chip  150  is not limited in particular, and the length of each side of detection chip  150  is preferably about several millimeters to several centimeters. 
         [0033]    Prism  151  is composed of dielectric which is transparent with respect to excitation light α. Prism  151  includes incidence surface  161 , film formation surface (reflection surface)  162 , emission surface  163 , and bottom surface  164 . Incidence surface  161  is a surface through which excitation light α emitted from excitation light irradiation section  110  enters prism  151 . Film formation surface  162  reflects excitation light α that has entered prism  151 . Excitation light γ that has been reflected by film formation surface  162  becomes reflection light β. As will be described hereinafter, metal film  152  is disposed on film formation surface  162 . Emission surface  163  causes reflection light β to be emitted out of prism  151 . Bottom surface  164  is disposed to be opposite to film formation surface  162 . 
         [0034]    The shape of prism  151  is not limited in particular. In the present embodiment, the shape of prism  151  is a column having a trapezoidal bottom surface. In this case, the surface corresponding to a bottom side of the trapezoid is film formation surface  162  and the surface corresponding to the other bottom side of the trapezoid is bottom surface  164 , the surface corresponding to one of the legs is incidence surface  161 , and the surface corresponding to the other leg is emission surface  163 . Examples of the material of prism  151  include a resin and glass. Preferably, the material of prism  151  is a resin having a refractive index within a range from 1.4 to 1.6 and exhibiting a small birefringence. 
         [0035]    Metal film  152  is disposed on film formation surface  162  of prism  151 . Thus, the interaction (surface plasmon resonance) occurs between the photons of excitation light α which has entered film formation surface  162  under the total reflection condition and the free electrons in metal film  152 , and thus localized-field light can be generated on the surface of metal film  152 . 
         [0036]    The material of metal film  152  is not limited in particular as long as the material is a metal that causes surface plasmon resonance. Examples of the material of metal film  152  include gold, silver, copper, aluminum, and their alloys. In the present embodiment, metal film  152  is a metal film. The formation method for metal film  152  is not limited in particular. Examples of the formation method for metal film  152  include sputtering, deposition, and plating. Preferably, the thickness of metal film  152  is within a range from 30 nm to 70 nm, but is not limited in particular. 
         [0037]    Reaction section  153  is disposed on a surface of metal film  152  where prism  151  is not disposed (top surface) among two surfaces (top surface and rear surface) of metal film  152 . Reaction section  153  contains a primary antibody (capturing body) for capturing a detection target substance and captures the detection target substance. The detection target substance captured by the primary antibody is labeled with fluorescence by a secondary antibody labeled by a fluorescent material. In such a situation, reaction section  153  excites the fluorescent material by localized-field light generated by irradiating metal film  152  with excitation light α, and fluorescence γ is emitted. 
         [0038]    Base body  154  is disposed on the surface of metal film  152  where prism  151  is not disposed (top surface). Base body  154  includes top surface  166 , side surface  167 , and bottom surface  168 . In this embodiment, base body  154  is disposed so as to cover reaction section  153  and is a substantially plate-shaped transparent member formed to have a size greater than film formation surface  162  of prism  151 . Channel groove  171  is formed in the surface of base body  154  that faces metal film  152  (bottom surface  168 ). Base body  154  is joined to metal film  152  or prism  151  by bonding using an adhesive or by laser welding, ultrasound welding, or pressure bonding using a clamp member, or the like, for example. In this embodiment, base body  154  forms, together with metal film  152 , channel  172  having liquid reservoir section  173 , by being bonded to metal film  152 . 
         [0039]    In addition to channel groove  171 , base body  154  includes first through hole  174  formed at one end of channel groove  171  and second through hole  175  formed at another end of channel groove  171 . First and second through holes  174  and  175  each have a cylindrical shape. Channel groove  171  becomes channel  172  when an opening section of channel groove  171  is closed by metal film  152 . In addition, when the opening section of channel  172  is closed by metal film  152 , first and second through holes  174  and  175  become injection port  176  and extraction port  177  to and from channel  172 , respectively. A liquid-feeding section (illustration is omitted) can be connected to injection port  176 . 
         [0040]    The sample is not limited to a particular kind. Examples of the sample include blood or serum, plasma, urine, nasal fluid, saliva, feces, coelomic fluid (spinal fluid, ascetic fluid, pleural effusion), and a diluted solution thereof. In addition, examples of the detection target substance contained in the sample include nucleic acid (single-stranded or double-stranded DNA, RNA, polynucleotide, oligonucleotide, peptide nucleic acid (PNA), nucleoside, nucleotide, or a modifier thereof), protein (polypeptide or oligopeptide), amino acid (including modified amino acid), carbohydrate (oligosaccharide, polysaccharide, or sugar chain), fat, or a modifier thereof, and a complex thereof or the like. More specifically, the detection target substance is carcinoembryonic antigen such as α fetoprotein (AFP), tumor marker, signal transducer, or hormone, or the like. 
         [0041]    The material of base body  154  is required to be well-formable (transferable, separable), highly-transparent, low in auto-fluorescence with respect to ultraviolet rays and visible light, and high in thermal conductivity, for example. For this reason, the material of base body  154  is favorably a transparent resin. Examples of the resin to be used as the material of base body  154  include polycarbonate, polymethylmethacrylate, polystyrene, polyacrylonitrile, polyvinyl chloride, polyethylene terephthalate, nylon  6 , nylon  66 , polyvinyl acetate, polyvinylidene chloride, polypropylene, polyisoprene, polyethylene, polydimethylsiloxane, and cyclic polyolefin. In terms of high refractive index, polycarbonate is favorable. The manufacturing method for base body  154  is not limited in particular, but injection molding using a mold is favorable in terms of manufacturing cost. 
         [0042]    As illustrated in  FIG. 1 , excitation light α enters prism  151  from incidence surface  161 . Excitation light α having entered prism  151  is incident on metal film  152  at a total reflection angle (an angle at which surface plasmon resonance is caused). Metal film  152  is irradiated with excitation light α at an angle which causes surface plasmon resonance in the above-mentioned manner, and thus it is possible to generate localized-field light on metal film  152 . With the localized-field light, the fluorescent material used for labeling the detection target substance on metal film  152  is excited, and fluorescence γ is emitted. By detecting the light amount of fluorescence γ emitted from the fluorescent material, SPFS device  100  detects the presence or amount of the detection target substance. 
         [0043]    Next, the configuration elements of SPFS device  100  are described. As described above, SPFS device  100  includes excitation light irradiation section  110 , light detection section  120 , heating section  130 , and control section  140 . Although no illustration is given in particular, SPFS device  100  may be covered by a transparent case. 
         [0044]    Excitation light irradiation section  110  emits excitation light α to metal film  152  of detection chip  150 . Excitation light α is totally reflected by metal film  152  and becomes reflection light β. Excitation light irradiation section  110  has a light source. The light source is turnable around a predetermined point in detection chip  150  and is capable of changing the incident angle of excitation light α with respect to metal film  152 . The light source is not limited to a particular type. Examples of the light source include a gas laser, solid-state laser, and semiconductor laser. For example, excitation light α is gas-laser light or solid-state laser light having a wavelength of 200 nm to 1000 nm or semiconductor laser light having a wavelength of 385 nm to 800 nm. 
         [0045]    Light detection section  120  detects fluorescence γ emitted from metal film  152 . Light detection section  120  is disposed so as to face a surface of metal film  152  of detection chip  150  held by holder  150   a , and this surface of metal film  152  is the surface not facing prism  151 . Light detection section  120  includes first lens  121 , filter  122 , second lens  123 , and light sensor  124 . 
         [0046]    First lens  121  and second lens  123  form a conjugate light system which is less likely to be influenced by stray light. The light proceeds between first lens  121  and second lens  123  becomes substantially parallel light. First lens  121  and second lens  123  form an image of fluorescence γ emitted from metal film  152  on a light reception surface of light sensor  124 . 
         [0047]    Filter  122  is disposed between first lens  121  and second lens  123 . Filter  122  contributes to improving the accuracy and sensitivity of fluorescence detection by light sensor  124 . Filter  122  is, for example, an optical filter or cut filter. Examples of the optical filter include a neutral density (ND) filter and a diaphragm lens or the like. The cut filter removes outside light (illumination light other than the device), a transparent component of excitation light α, stray light (scattering component of excitation light α), plasmon scattering light (scattering light originated from excitation light α and generated due to the influence of an attachment on the surface of detection chip  150 ), and a noise component such as auto-fluorescence of each member. Examples of the cut filter include an interference filter and a color filter or the like. 
         [0048]    Light sensor  124  detects fluorescence γ emitted from detection chip  150  and passed through filter  122 . Examples of light sensor  124  include an ultrasensitive photomultiplier tube, and a CCD image sensor capable of multipoint measurement or the like. 
         [0049]    Heating section  130  indirectly heats a liquid at the reaction site, which has been reserved in liquid reservoir section  173 , via base body  154 . Heating section  130  includes heat block  131  and heat source  132 . Heat block  131  heats the liquid at the reaction site in a contact state or non-contact state with base body  154  to a temperature at the time of analysis. In this embodiment, heat block  131  is a cuboid shape and in contact with base body  154  at least during heating. More specifically, heat block  131  is in contact with bottom surface  168  of base body  154  while avoiding prism  151 , and is disposed at both end portions of channel  172  in the width direction of channel  172  (see  FIG. 2A ). In addition, heat block  131  is disposed while avoiding a light path of excitation light α emitted from excitation light irradiation section  110 . Note that, SPFS device  100  may be configured to monitor the temperature of the liquid at the reaction site using a temperature sensor. 
         [0050]    The material of heat block  131  is not limited in particular as long as the material allows heat block  131  to heat base body  154 , but a metal having a good heat conductivity may be favorably used, for example. The material of heat block  131  is copper or aluminum, for example. The number of and size of heat blocks  131  are not limited in particular and may be appropriately set in accordance with the amount of liquid at the reaction site to be heated. 
         [0051]    Accordingly, heat block  131  does not interfere with the functions of SPFS device  100 . Moreover, a design taking into account the usability (avoiding burn injury and/or attachment and removal of detection chip  150 ) can be simply implemented as compared with the case where another surface of base member  154  is heated (see  FIG. 4A ). In addition, since heat block  131  does not approach the reaction site, a detection error due to a temperature change unlikely occurs. Furthermore, since heat block  131  and prism  151  are not brought into contact with each other, generation of internal stress of prism  151 , i.e., of birefringence is suppressed to keep a good excitation light polarization state. 
         [0052]    Heat source  132  is connected to control section  140  and heats heat block  131 . As with heat block  131 , heat source  132  is disposed while avoiding the light path of excitation light α emitted from excitation light irradiation section  110 . More specifically, heat section  130  is disposed while avoiding the light path of excitation light α emitted from excitation light irradiation section  110 . Heat source  132  is by no means limited to a particular kind, and includes a cartridge heater, rubber heater, infrared heater such as a ceramic heater and a Peltier device or the like. The temperature of heat source  132  is not limited to a particular temperature as long as the temperature allows the liquid at the reaction site in liquid reservoir section  173  to be heated to a temperature of 34 degrees to 40 degrees (temperature at the time of analysis). In Embodiment 1, the temperature of heat source  132  is 40 degrees to 50 degrees. 
         [0053]    Heat block  131  heated by heat source  132  heats base body  154 . In addition, the heat conducted from the contact position with heat block  131  (bottom surface  168  of base body  154 ) is conducted to the entirety of base body  154 . At this time, the heat conducted to base body  154  is conducted to the liquid of liquid reservoir section  173  of channel  172 . Thus, the liquid at the reaction site in liquid reservoir section  173  is heated to the temperature at the time of analysis by heating section  130 . 
         [0054]    Control section  140  comprehensively controls excitation light irradiation section  110 , light detection section  120 , and heating section  130 . Control section  140  includes, for example, a known computer or a microcomputer or the like having an arithmetic device, a controller, a storage, an input unit and an output unit. 
         [0055]    Next, a detection operation of SPFS device  100  (detection method according to Embodiment 1 of the present invention) will be described.  FIG. 3  is a flowchart illustrating an example of an operation procedure of SPFS device  100 . 
         [0056]    First, detection chip  150  is installed in holder  150   a  of SPFS device  100  (S 100 ). At this time, detection chip  150  is installed such that heat block  131  of heating section  130  is in contact with bottom surface  168 . 
         [0057]    Next, control section  140  operates heat source  132  and heats heat block  131  (S 110 ). Thus, the liquid at the reaction site in liquid reservoir section  173  is heated to a temperature at the time of analysis. In Embodiment 1, the temperature of the liquid at the reaction site at the time of analysis is 37 degrees and is an optimum temperature for the primary reaction and the secondary reaction. 
         [0058]    Next, a sample that may contain a detection target substance is fed through channel  172  (S  120 ). In channel  172 , a pump is driven to reciprocate the sample in channel  172  in order for a capturing body (primary antibody) fixed to reaction section  153  to surely capture the detection target substance (in order to cause antigen-antibody reaction). At this time, since the inside of liquid reservoir section  173  is adjusted to the same temperature as the temperature at the time of analysis, the sample fed through channel  172  (liquid reservoir section  173 ) is heated to the temperature at the time of analysis immediately after being fed. The detection target substance contained in the sample is surely captured by the capturing body (primary antibody). Subsequently, the sample in channel  172  is removed, and the inside of channel  172  is cleaned using a cleaning liquid. 
         [0059]    Subsequently, a reagent containing the secondary antibody labeled by a fluorescent material is fed through channel  172  via a pump (S 130 ). In this case as well, the reagent fed through channel  172  is heated to the temperature at the time of analysis immediately after being fed. The secondary antibody labeled by a fluorescent material contained in the reagent is surely bonded to the detection target substance. Note that, a sample and reagent may be previously mixed together, and the liquid is fed through a channel in a state where the detection target substance and the secondary antibody are previously bonded to each other. Accordingly, the detection target substance is labeled by a fluorescent material. Subsequently, the reagent (labeling solution) in channel  172  is removed, and the inside of channel  172  is cleaned using a cleaning liquid. 
         [0060]    Subsequently, detection chip  150  is irradiated with excitation light α from the light source in order for excitation light α to be incident on metal film  152  at a specific incident angle (see  FIG. 1 ) (S 140 ). With this localized-field light, the fluorescent material used for labeling the detection target substance captured on reaction section  153  is efficiently excited, and fluorescence γ is emitted. 
         [0061]    The presence or amount of the detection target substance of the sample can be detected by the above procedure. 
         [0062]    (Variations) 
         [0063]    An SPFS device according to a variation of Embodiment 1 is different from SPFS device  100  according to Embodiment 1 in the configuration of the heat block. In this respect, the portion different from SPFS device  100  according to Embodiment 1 will be mainly described. 
         [0064]      FIGS. 4A to 4C  are diagrams illustrating a positional relationship between detection chip  150  and the heat block of the variations.  FIG. 4A  is a diagram illustrating the positional relationship between detection chip  150  and heat block  131   a  of Variation 1,  FIG. 4B  is a diagram illustrating the positional relationship between detection chip  150  and heat block  131   b  of Variation 2, and  FIG. 4C  is a diagram illustrating the positional relationship between detection chip  150  and heat block  131   c  of Variation 3. 
         [0065]    As illustrated in  FIG. 4A , heat block  131   a  may be configured to heat base body  154  from top surface  166 , side surface  167 , and bottom surface  168 . In this case, heat block  131   a  is divided into bottom-side heat block piece  131   a ′ and top-side heat block piece  131   a .″ Bottom-side heat block piece  131   a ′ heats base body  154  from bottom surface  168  and side surface  167 . Top-side heat block piece  131   a ″ heats base body  154  from top surface  166 . At this time, bottom-side heat block piece  131   a ′ and top-side heat block piece  131   a ″ heat base body  154  while holding base body  154  in between with pressure. Accordingly, detection chip  150  can be effectively heated as compared with heat block  131  according to Embodiment 1. Note that, although no illustration is given in particular, heat block  131  may be configured to heat base body  154  while pushing base body  154  only from side surface  167 , or may be configured to heat base body  154  while pushing base body  154  only from top surface  166 . When configured to heat base body  154  while pushing base body  154  only from top surface  166 , heat block  131  is disposed so as to avoid the fluorescent light path. 
         [0066]    As illustrated in  FIG. 4B , heat block  131   b  may be configured to perform heating from the bottom side of detection chip  150 . In this case, recess portion  133  is formed in heat block  131   b , which is in contact with bottom surface  168  of base body  154 , bottom surface  164  of prism  151 , incident surface  161  of prism  151 , and emission surface  163  of prism  151 . Heat block  131   b  includes first heat block  131   b ′ on the side of extraction port  177  and second heat block  131   b ″ on the side of injection port  176 . In this variation, first heat block  131   b ′ and second heat block  131   b ″ are formed in an identical shape and disposed so as to avoid the light path of excitation light α from excitation light irradiation section  110  to incident surface  161 . Moreover, as illustrated in  FIG. 4C , heat block  131   c  may be configured to heat bottom surface  164  of prism  151 . In this case, a design taking into account the usability (avoiding burn injury or the like and/or attachment and removal of detection chip  150 ) can be simply implemented as compared with heat block  131   a  indicated in  FIG. 4A . Thus, detection chip  150  can be effectively heated as compared with heat block  131  according to Embodiment 1. In addition, the temperature difference among points in prism  151  is made small, so that it is made easier to avoid deformation of prism  151  caused by thermal stress and also to avoid a change in optical characteristics. 
         [0067]    (Variation of Detection Chip) 
         [0068]    Detection chips  150 ′ and  150 ″ according to the variations used in SPFS device  100  of Embodiment 1 are different from detection chip  150  according to Embodiment 1 in size or the like of metal film  152 ′. Thus, the portion different from detection chip  150  according to Embodiment 1 will be mainly described. 
         [0069]      FIG. 5A  is a diagram illustrating the positional relationship between detection chip  150 ′ of Variation 1 and heat block  131 ,  FIG. 5B  is a diagram illustrating the positional relationship between detection chip  150 ′ of Variation 1 and heat block  131   a  of Variation 1, and  FIG. 5C  is a diagram illustrating the positional relationship between detection chip  150 ″ of Variation 1 and heat block  131   a  of Variation 2.  FIG. 6  is a diagram illustrating the positional relationship between detection chip  150 ″ of Variation 2 of Embodiment 1 and heat block  131   a  of Variation 1. 
         [0070]    As illustrated in  FIG. 5A , metal film  152 ′ of detection chip  150 ′ of Variation 1 is disposed so as to extend to the outer side of film formation surface  162 . In addition, base body  154  is disposed so as to cover metal film  152 ′. In Embodiment 1, bottom surface  168  of base body  154  and metal film  152 ′ are identical in outer diameter. In this case, metal film  152 ′ is heated by heating section  130 . More specifically, metal film  152 ′ is heated directly from the side (bottom side) of prism  151  by heat block  131  of heating section  130 . Thus, the heating time of the liquid at the reaction site in liquid reservoir section  173  can be shortened. Note that, a through hole may be formed in base body  154 , and heating section  130  may heat metal film  152 ′ from the top side. Moreover, metal film  152 ′ may be smaller in outer diameter than bottom surface  168  of base body  154 . 
         [0071]    As illustrated in  FIG. 5B , when detection chip  150 ′ of Variation 1 is heated by heating section  130  having heat block  131   a  of Variation 1, bottom-side heat block piece  131   a ′ heats base body  154  from metal film  152 ′ and side surface  167 . In addition, top-side heat block piece  131   a ″ heats base body  154  from top surface  166 . 
         [0072]    As illustrated in  FIG. 5C , when detection chip  150 ′ of Variation 1 is heated by heating section  130  having heat block  131   b  of Variation 2, heat block  131   b  performs heating from metal film  152 ′, bottom surface  164  of prism  151 , incident surface  161  of prism  151 , and emission surface  163  of prism  151 . In this case, heat block  131   b  has first heat block  131   b ′ on the side of extraction port  177  and second heat block  131   b ″ on the side of injection port  176 . 
         [0073]    As illustrated in  FIG. 6 , in detection chip  150 ″ of Variation 2, a transparent conductive film (ITO) or sealing seal  175   a  made of metal or carbon is disposed so as to cover at least injection port  176 . The raw material of sealing film  175   a  is favorably a highly heat-conductive raw material, and the material having a thermal conductivity equal to or greater than 280 W/(m·K) is favorable. Copper, gold, and aluminum, for example, are favorable as the metal-made sealing seal. In Embodiment 1, sealing seal  175   a  is disposed on the entirety of top surface  166  of base member  154 . In a case where detection chip  150 ″ of Variation 2 is heated by heating unit  130  having heat block  131   a  of Variation 1, bottom-side heat block piece  131   a ′ heats base body  154  from metal film  152 ′ and side surface  167 . In addition, heating section  130  (top-side heat block piece  131   a ″) heats base body  154  by heating sealing seal  175   a . Thus, heating the raw material having a high thermal conductivity can shorten the heating time of the liquid at the reaction site in liquid reservoir section  173 . Note that, sealing film  175   a  may be disposed only near injection port  176 . 
         [0074]    As has been described above, SPFS device  100  according to Embodiment 1 adjusts the reaction of the capturing body and detection target substance, the reaction of the detection target substance and fluorescent material, and the temperature around the fluorescent material from which fluorescence is emitted, to be constant, so that SPFS device  100  can detect the detection target substance with high accuracy and high sensitivity. 
         [0075]    Note that, in Embodiment 1, a description has been given of the case where each of heat blocks  131 ,  131   a , and  131   b  heats base body  154  in a contact state, but heat blocks  131 ,  131   a , and  131   b  may be configured to heat base body  154  in a non-contact state. In this configuration, the distance between each of heat blocks  131 ,  131   a , and  131   b  and base body  154  is not limited to any particular distance as long as base body  154  can be heated from the heat from each of heat blocks  131 ,  131   a , and  131   b . However, it is favorable that heat blocks  131 ,  131   a , and  131   b  be positioned as close to base body  154  as possible. In addition, heating section  130  may be configured to heat metal film  152  by induction heating (IH). In this case, an IH coil is disposed in place of each of heat blocks  131 ,  131   a , and  131   b.    
       Embodiment 2 
       [0076]    SPFS device  200  according to Embodiment 2 is different from SPFS device  100  according to Embodiment 1 in having reagent storage section  250  and second heating section  230  configured to heat reagent storage section  250 . In this respect, the portion different from SPFS device  100  according to Embodiment 1 will be mainly described. 
         [0077]      FIG. 7  is a diagram illustrating a configuration of SPFS device  200  according to Embodiment 2. As illustrated in  FIG. 7 , SPFS device  200  according to Embodiment 2 includes excitation light irradiation section  110 , light detection section  120 , first heating section  130  (heating section in Embodiment 1), second heating section  230 , moving section  280 , liquid-feeding section  290 , and control section  240 . As in Embodiment 1, in detection of a detection target substance, SPFS device  200  is used in a state where detection chip  350  is attached to holder  150   a . For this reason, detection chip  350  will be described, first, and each configuration element of SPFS device  200  will be described, thereafter. 
         [0078]      FIG. 8  is a cross-sectional view taken along a long-side direction of detection chip  350  according to Embodiment 2. Note that, hatching of first base body  354  and second base body  254  is omitted in  FIG. 8 . As illustrated in  FIG. 8 , detection chip  350  according to Embodiment 2 includes reagent storage section  250  in addition to the configuration elements of detection chip  150  in Embodiment 1. 
         [0079]    As illustrated in  FIG. 8 , detection well  273  is disposed in detection chip  350 . Reaction section  153  is disposed at the bottom portion of detection well  273 . Reagent storage section  250  includes second base body  254  and a plurality of wells  255 . Second base body  254  is a substantially plate-shaped transparent member. Second base body  254  is integrally formed with first base body  354  (base body  154  of Embodiment 1) as a single body. 
         [0080]    Well  255  stores a sample and/or a reagent used for the primary reaction and the secondary reaction described above. Well  255  is formed in second base body  254 . The shape of well  255  is not limited to a particular shape. Thus, the shape of well  255  is appropriately set in accordance with the amount of a sample or a reagent to be stored therein. 
         [0081]    As illustrated in  FIG. 7 , second heating section  230  indirectly heats, via second base body  254 , a liquid stored in reagent storage section  250 . Second heating section  230  includes second heat block  231  and second heat source  232 . Second heat block  231  heats a liquid to a predetermined temperature in a contact sate or a non-contact state with second base body  254 . In Embodiment 2, second heat block  231  is in contact with second base body  254  at least at the time of heating. More specifically, second heat block  231  is disposed at the lower side of well  255 . Moreover, for second heat source  232 , a heat source identical to first heat source  132  (heat source in Embodiment 1) can be used. The relationship between the temperature of the liquid in detection well  273  and the temperature of the liquid in well  255  is not limited in particular. For example, both of the temperature of the liquid in detection well  273  and the temperature of the liquid in well  255  may be 34 degrees to 40 degrees. Alternatively, the temperature of the liquid in detection well  273  may be 34 degrees to 40 degrees while the temperature of the liquid in well  255  may be 20 degrees to 30 degrees. In the latter case, the temperature of second heat source  232  is 20 degrees to 35 degrees. In addition, when SPFS device  200  is covered by a case, the temperature inside the case can be stabilized. 
         [0082]    Moving section  280  includes stage  281  and moving mechanism  282  that moves stage  281 . Stage  281  is formed in a plate shape, for example. First heat block  131  (heat block in Embodiment 1) of first heating section  130  and second heat block  231  of second heating section  230  are disposed on stage  281 . Detection chip  350  is disposed on stage  281  on which first heat block  131  and second heat block  231  are disposed. 
         [0083]    Moving section  280  moves detection chip  350  between the measurement position (position where fluorescence γ generated by emission of excitation light α by excitation light irradiation section  110  is detected by light detection section  120 ) and the liquid-feeding position (position where a sample or reagent is fed by liquid-feeding section  290 ). 
         [0084]    Liquid-feeding section  290  supplies the sample or reagent stored in reagent storage section  250  to detection well  273  of detection chip  350 . Liquid-feeding section  290  includes pipette  291  and pump  292 , for example. Suctioning and discharging the sample or reagent is quantitatively performed by driving pump  292 . 
         [0085]    Control section  240  comprehensively controls excitation light irradiation section  110 , light detection section  120 , first heating section  130 , second heating section  230 , moving section  280 , and liquid-feeding section  290 . 
         [0086]    Next, a detection operation of SPFS device  200  (detection method according to Embodiment 2 of the present invention) will be described.  FIG. 9  is a flowchart illustrating an example of an operation procedure of SPFS device  200 . 
         [0087]    First, detection chip  350  is installed in holder  150   a  positioned at an installation positon of detection chip  150  in SPFS device  200  (step S 200 ). At this time, detection chip  350  is installed so as to be in contact with first heat block  131  of first heating section  130  and second heat block  231  of second heating section  230 . 
         [0088]    Next, control section  240  operates a power supply of first heat source  132  and second heat source  232  to heat first heat block  131  and second heat block  231  (step S 210 ). Thus, the temperatures inside reagent storage section  250  and liquid reservoir section  173  liquid are raised to the same temperature as that of the liquid at the reaction site. In Embodiment 2, the temperature of the liquid at the reaction site is 37 degrees and is the optimum temperature for the primary reaction and the secondary reaction. 
         [0089]    Next, control section  240  operates moving mechanism  282  and moves detection chip  350  to the liquid-feeding position (step S 220 ). 
         [0090]    Subsequently, control section  240  operates liquid-feeding section  290  and introduces the sample in reagent storage section  250  into detection well  273  of detection chip  350  (step S 230 ). In detection well  273 , in order for the capturing body (primary antibody) fixed to reaction section  153  to surely capture the detection target substance (antigen-antibody reaction), pump  292  is driven to agitate the sample in detection well  273 . At this time, since the temperatures inside reagent storage section  250  and liquid reservoir section  173  are adjusted to the same temperature as the analysis temperature, the temperature of the liquid does not go down, and the reaction proceeds promptly. The detection target substance contained in the sample is then surely captured by the capturing body (primary antibody). Subsequently, the sample inside detection well  273  is removed, and the inside of detection well  273  is cleaned using a cleaning liquid. 
         [0091]    Subsequently, control section  240  operates liquid-feeding section  290  and introduces the reagent (labeling solution) containing the secondary antibody labeled by a fluorescent material into detection well  273  of detection chip  350  (step S 240 ). In this case as well, since the reagent fed to detection well  273  is previously heated to the temperature at the time of analysis when the secondary antibody and detection target substance react with each other, the temperature does not go down. The secondary antibody labeled by the fluorescent material contained in the reagent is surely bonded to the detection target substance. Thus, the detection target substance is labeled by the fluorescent material. Subsequently, the labeling solution inside detection well  273  is removed, and the channel is cleaned using a cleaning liquid. 
         [0092]    Next, control section  240  operates moving mechanism  282  and moves detection chip  350  from the liquid-feeding position to the measurement position (step S 250 ). Detection chip  350  is irradiated with excitation light α from the light source in such a way that excitation light α is incident on metal film  152  at a specific incident angle (step S 260 ). 
         [0093]    The presence or amount of the detection target substance of the sample can be detected by the procedure mentioned above. 
         [0094]    As has been described, SPFS device  200  according to Embodiment 2 can further detect the detection target substance with high accuracy and high sensitivity as compared with SPFS device  100  according to Embodiment 1 because reagent storage section  250  is also heated. 
         [0095]    Note that, in Embodiment 2, a description has been given of the case where heating is performed while first heat block  131  and second heat block  231  are in contact with base body  154  and second base body  254 , respectively, but heating may be performed while first heat block  131  and second heat block  231  are not in contact with base body  154  and second base body  254 . In this case, the distances between first heat block  131  and base body  154 , and second heat block  231  and second base body  254  are not limited in particular as long as base body  154  and second base body  254  can be heated by the heat from first heat block  131  and second heat block  231 , respectively, but the shorter the better. 
         [0096]    Moreover, in Embodiment 2, reagent storage section  250  is heated by second heating section  230 , but may not be heated. In other words, in Embodiment 2, only detection well  273  may be heated. In this case, the proportion of detection chip  350  that is occupied by detection well  273  is so small that the reagent injected into detection well  273  increases in temperature right after the injection. Moreover, since second heating section  230  is not necessary, designing can be implemented easily as compared with Embodiment 2 in which detection well  273  and reagent storage section  250  are heated. Moreover, the temperature of detection well  273  goes up fast as compared with detection chip  350  according to Embodiment 2. 
         [0097]    Furthermore, in Embodiment 2, first and second heat blocks  131  and  231  are controlled by first and second heat sources  132  and  232 , respectively, but may be controlled by a single heating section. Thus, first and second heat blocks  131  and  231  can be controlled simply 
         [0098]    (Variation of Detection Chip) 
         [0099]      FIG. 10  is a cross-sectional view taken along a long-side direction of detection chip  350  of a variation of Embodiment 2. As illustrated in  FIG. 10 , metal film  152  of detection chip  350  of the variation of Embodiment 2 is disposed so as to extend to the outer side of film formation surface  162 . In this case, heat block  131  of heating section  130  can directly heat metal film  152 , so that the heating time of the liquid at the reaction site in liquid reservoir section  173  can be shortened. 
         [0100]    Note that, first and second heating sections  130  and  230  illustrated in  FIG. 7  may be configured to heat metal film  152  using induction heating (IH). In this case, an IH coil is disposed instead of each of heat blocks  131  and  231 . 
         [0101]    Although a description has been given of the SPFS devices in Embodiments 1 and 2, the detection device according to the present invention is not limited to an SPFS device. For example, the detection device according to the present invention may be an SPR device. In this case, the SPR device includes a light detection section configured to detect the excitation light reflected by a metal thin film and emitted from an emission surface. 
         [0102]    This application is entitled to and claims the benefit of Japanese Patent Application No. 2013-226952 filed on Oct. 31, 2013, the disclosure of which including the specification, and drawings is incorporated herein by reference in its entirety. 
       INDUSTRIAL APPLICABILITY 
       [0103]    The detection device, and detection method using surface plasmon resonance, and the detection chip used in the device and method, according to the present invention, enable highly reliable measurement of a detection target substance, so that they are useful in laboratory tests or the like, for example. 
       REFERENCE SIGNS LIST 
       [0000]    
       
           100 ,  200  SPFS device 
           110  Excitation light irradiation section 
           120  Light detection section 
           121  First lens 
           122  Filter 
           123  Second lens 
           124  Light sensor 
           130  Heating section (first heating section) 
           131  Heat block (first heat block) 
           132  Heat source (first heat source) 
           133  Recess section 
           140 ,  240  Control section 
           150 ,  350  Detection chip (detection section) 
           150   a  Holder 
           151  Prism 
           152  Metal film 
           153  Reaction section 
           154 ,  354  Base body (first base body) 
           161  Incident surface of prism 
           162  Film formation surface of prism 
           163  Emission surface of prism 
           164  Bottom surface of prism 
           166  Top surface of base body 
           167  Side surface of base body 
           168  Bottom surface of base body 
           171  Channel groove 
           172  Channel 
           173  Liquid reservoir section 
           174  First through hole 
           175  Second through hole 
           175   a  Sealing seal 
           176  Injection port 
           177  Extraction port 
           230  Second heating section 
           231  Second heat block 
           232  Second heat source 
           250  Reagent storage section 
           254  Second base body 
           255  Well 
           273  Detection well 
           280  Moving section 
           281  Stage 
           282  Moving mechanism 
           290  Liquid-feeding section 
           291  Pipette 
           292  Pump