Sensor device

A sensor device includes a flow path and a metal layer disposed in the flow path. The flow path is configured to allow a sample containing analytes to flow and to allow a carrier to be disposed therein. The carrier has acceptors that are fixed on a surface thereof and specifically bound with the analytes for producing aggregates. The flow path includes an aggregate trapping section at which the analytes locally concentrate to the section. This sensor device has high detection sensitivity with a simple structure.

RELATED APPLICATIONS

This application is a national phase of International Application No. PCT/JP2013/000924, filed on Feb. 20, 2013, which in turn claims the benefit of Japanese Application No. 2012-047628, filed on Mar. 5, 2012, the disclosures of which Applications are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure relates to a sensor device to be used for detecting, e.g. viruses.

BACKGROUND ART

FIG. 22is a sectional view of sensor device600disclosed in Patent Literature 1 and to be used for detecting, e.g. viruses. Sensor device600includes prism601, metal layer602disposed on a lower surface of prism601and having a flat surface, insulating layer603disposed on a lower surface of metal layer602and having a flat surface and a predetermined dielectric constant, and acceptor604fixed to a lower surface of insulating layer603.

Surface plasmon wave (i.e. compression wave of electrons) exists at an interface between metal layer602and insulating layer603. Light source605is disposed above prism601and supplies P-polarized incident light to prism601under a condition of total reflection. This incident light causes an evanescent wave on surfaces of metal layer602and insulating layer603. The light totally reflected on metal layer602is received by detector606to detect an intensity of the light.

When a wave-number matching condition in which a wave number of the evanescent wave matches with a wave number of the surface plasmon wave is satisfied, the light energy supplied from light source605is used for exciting the surface plasmon wave, so that the intensity of the reflected light decreases. The wave-number matching condition depends on an incident angle of the light supplied from light source605. Therefore, while the incident angle is changed, an intensity of reflected light is detected with detector606. The intensity of the reflected light decreases at a certain incident angle.

A resonant angle at which the intensity of the reflected light takes a minimum value depends on the dielectric constant of insulating layer603. When a specific bound substance is formed on the lower surface of insulating layer603, the dielectric constant of layer603changes, and the resonant angle changes accordingly. This specific bound substance is produced by acceptor604and an analyte (i.e. a target to be measured in a sample) that are specifically bound together. By monitoring the change of the resonant angle, a binding strength of the specific bound substance or a speed of the binding can be detected.

CITATION LIST

Patent Literature

SUMMARY

A sensor device includes a flow path and a metal layer disposed in the flow path. The flow path is configured to allow a sample containing an analyte to flow therein and allow a carrier to be disposed therein. The carrier is configured to have acceptors fixed onto surfaces so that the acceptors are specifically bound with the analyte to produce an aggregate. The flow path includes an aggregate trapping section to allow the analytes to locally concentrate thereto. The sensor device has a high detection sensitivity with a simple structure.

DETAIL DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1Ais a top view of sensor device1in accordance with Exemplary Embodiment 1 of the present disclosure.FIG. 1Bis a sectional view of sensor device1at line1B-1B shown inFIG. 1A. Sensor device1is a metal insulator metal (MIM) type device.

Sensor device1includes inlet24configured to have a sample injected therein, reservoir25temporarily reserving the injected sample, flow path4allowing the injected sample to flow therein, reservoir26retaining the sample having undergone an examination and flown through flow path4, and metal layers2and3disposed on at least a part of flow path4. A user injects the sample to be examined with pipette27through inlet24into reservoir25. Flow path24includes holder5disposed at an upper section of sensor device1for holding metal layer2, holder6disposed at a lower section of sensor device1for holding metal layer3, side wall21, and side wall22. Flow path4includes specific region18sandwiched by metal layers2and3, input region15disposed before specific region18, and discharge region16disposed after specific region18. The sample reserved in reservoir25is input due to a capillary phenomenon into input region15of flow path4. The sample then flows in flow path4in a direction of arrow17, and flows through region18, then is discharged from discharge region16, and is finally retained in reservoir26. An analyte contained in the sample is trapped in region18of flow path4before being detected. Region18functions as an aggregate trapping section strapping an aggregate of the analyte.

An operation of sensor device1will be described below. A region of flow path4sandwiched between metal layers2and3constitutes a detector.FIGS. 2A and 2Bare a side sectional view and a top sectional view of an essential portion of sensor device1. As shown inFIG. 2A, metal layer3faces metal layer2across flow path4and is disposed under metal layer2. Metal layers2and3are made of metal, such as gold or silver. As shown inFIG. 2B, side wall21faces side wall22across flow path4. Lower surface2B of metal layer2constitutes an upper surface of flow path4, and upper surface3A of metal layer3constitutes a lower surface of flow path4. Side surface21A of side wall21constitute a first side surface of flow path4, and side surface22A of side wall22constitutes a second side surface of flow path4. Flow path4is thus constituted by these four surfaces. Carriers10are fixed physically by weak force, such as van der Waals force, and adheres onto at least one of lower surface2B of metal layer2and upper surface3A of metal layer3. Carrier10includes acceptors7which are fixed onto surfaces of a substance made of metal or resin and which are specifically bound with analyte8.

The substance made of metal or resin preferably has a size not larger than 10% of a wavelength of an incident electromagnetic wave supplied from above the sensor device1. The size of the substance refers to, e.g. the diameter of the substance. The wavelength refers to a wavelength that takes into account an influence of refraction index in flow path4. The size of the substance made of metal or resin exceeding 1/10 of the wavelength of the supplied electromagnetic wave increases an effect of Mie Scattering while the size is not larger than 1/10 of the wavelength increases an effect of Rayleigh Scattering. However, the scattering intensity of Rayleigh Scattering is so small because it is proportional to minus sixth-power of a radius of the substance, so that the scattering affects almost nothing. The size not greater than 1/10 of the wavelength thus can improve the sensitivity of sensor device1. Greater influence produced by the scattering will cause light to lose straightness, so that the light cannot be correctly observed. When visible light having a wavelength of ranging from 500 to 600 nm to be used for observation among others is used as the electromagnetic wave to be supplied from over the sensor device1, the size of the substance made of metal or resin is preferably not greater than 50 to 60 nm.

When sensor device1is in operation, sample62is supplied into flow path4through input region15to fill flow path4, and then sample62is discharged from discharge region16. Sample62in flow path4is thus actually sandwiched between metal layers2and3. Sample62contains analyte8, non-specific specimen9, and medium61. Medium61is a fluid, such as liquid or gel, and carries analyte8and non-specific specimen9.

Metal layer2has a thickness not larger than 100 nm, so that it cannot maintain its shape by itself. Upper surface2A of metal layer2is fixed to lower surface5B of holder5for maintaining its shape. Metal layer3is fixed to upper surface6A of holder6to maintain its shape.

Electromagnetic wave91enters from upper surface2A of metal layer2. In the case that electromagnetic wave91is visible light and metal layer2is made of gold, metal layer2preferably has a thickness ranging from 10 nm to 45 nm.

In the case that metal layer3is made of gold, metal layer3preferably has a thickness not smaller than 100 nm. If the thickness is smaller than 100 nm, incident electromagnetic wave91of visible light passing through metal layer3, and decreases an amount of electromagnetic wave91reflected in flow path4.

Electromagnetic wave source92is disposed above upper surface2A of metal layer2, namely, it is opposite to metal layer3with respect to metal layer2. Electromagnetic wave source92supplies electromagnetic wave91from above upper surface2A to metal layer2.

Acceptor7refers to a trapper that is specifically bound with a designated analyte, and is, for example, antibody, receptor protein, aptamer, porphyrin, and polymer produced by molecular imprint technique.

As shown inFIG. 1B, filter23is preferably disposed between reservoir25and flow path4for removing unnecessary substance, such as dust, mixed in the sample.

An operation of sensor device1will be described below. According to Embodiment 1, electromagnetic wave91is light, and electromagnetic wave source92is a light source.

The electromagnetic wave enters from above metal layer2to upper surface2A at incident angle θ. A part of the wave reflects on upper surface2A and lower surface2B and propagates upward from metal layer2in a direction of reflection angle −θ. Incident angle θ is an angle between a normal line of the upper surface of metal layer2and an incident direction of the electromagnetic wave. The electromagnetic wave reflected on metal layer2and propagating upward from metal layer2at angle −θ is referred to as a first electromagnetic wave. Most of the electromagnetic wave not reflected on upper surface2A or lower surface2B of metal layer2passing through metal layer2propagates in flow path4and reaches upper surface3A of metal layer3. In the case that metal layer3has a thickness not smaller than 200 nm, the electromagnetic wave propagating from above metal layer3is entirely reflected on metal layer3, and propagates in flow path4again toward lower surface2B of metal layer2. Parts of the electromagnetic wave reaching lower surface2B of metal layer2passes through metal layer2and propagates upward from metal layer2at angle −θ. The electromagnetic wave passing through metal layer2from flow path4and propagating upward from metal layer2at angle −θ is referred to as a second electromagnetic wave. Most of the electromagnetic wave propagating from lower surface2B of metal layer2but not passing through metal layer2is reflected on lower surface2B and upper surface2A of metal layer2, and then propagates in flow path4downward. The first electromagnetic wave and the second electro-magnetic wave above metal layer2interfere with each other. The interference condition satisfies formula (1) or (2) with an integer m, the wavelength λ of the electromagnetic wave in vacuum, a thickness d of flow path4(i.e. a space d between the lower surface of metal layer2and the upper surface of metal layer3), a refraction index n within a hollow region, and the incident angle θ.
(m+½)×λ=2×n×d×cos θ  (Formula 1)
m×λ=2×n×d×cos θ  (Formula 2)

When space d satisfies formula (1), the first and second electromagnetic waves weaken each other. When space d satisfies formula (2), the first and second electromagnetic waves strengthen each other.

The interference condition can be controlled with the shapes (depending mainly on the thickness) of metal layers2and3, the space between metal layer2and metal layer3, dielectric constant (refraction index) of metal layer2, dielectric constant (refraction index) of metal layer3, and the refraction index in flow path4.

Detector94is disposed above upper surface2A of metal layer2and is configured to detect electromagnetic wave93, such as light. When sensor device1receives electromagnetic wave91supplied from electro-magnetic wave source92, detector94receives electromagnetic wave93, such as light, reflected or radiated from sensor device1. Detector94is may not necessary. In the case that electromagnetic wave91is visible light, the user can visibly sense a change in color or an intensity of electromagnetic wave91, hence providing simple and inexpensive sensor device1.

Holder5is made of material preventing electromagnetic wave91from attenuating so as to efficiently supply electromagnetic wave91to metal layer2. According to Embodiment 1, since electromagnetic wave91is light, holder5is made of transparent material, such as glass or transparent plastic, so as to allow the light to pass through holder5efficiently. Holder5preferably has a thickness as small as possible, and has a predetermined mechanical strength.

The supplied electromagnetic wave91, such as light, does not preferably pass through metal layer3so as to increase the sensitivity of sensor device1, so that holder6may be preferably made of material that cuts off electromagnetic wave91, such as light. For instance, holder6may be made of metal or semiconductor having a thickness not smaller than 100 nm.

In sensor device1, plural carriers10are disposed on lower surface2B of metal layer2facing flow path4. Each of carriers10includes plural acceptors7fixed onto a surface of a substance made of metal or resin.

When analyte8in sample62contacts one of acceptors7attached to carrier10, acceptor7is specifically bound with analyte8.FIG. 3is a schematic view of sensor device1according to Embodiment 1 for illustrating the specific binding of acceptor7and analyte8of carrier10. As shown inFIG. 3, sample62contains analyte8to be detected and non-specific specimen9. Acceptor7attached to carrier10is not specifically bound with non-specific specimen9, but is specifically bound only with analyte8, and then plural carriers10couple with each other via analyte8, thereby forming aggregate11. For instance, carrier10ahas plural acceptors fixed on a surface thereof, and one acceptor7aout of the plural acceptors is specifically bound with analyte8. Carrier10bincludes plural acceptors fixed on a surface thereof, and one acceptor7bout of the plural acceptors is specifically bound with analyte8. Two carriers10aand10bform one aggregate11with analyte8between carriers10aand10b. Each of carriers10aand10bincludes plural acceptors, so that these acceptors are specifically bound with other analytes for coupling a large number of carriers together, thereby providing a large size of aggregate. InFIGS. 2A and 2B, sensor device1has carriers10placed only on lower surface2B of metal layer2; however, carriers10may be placed on upper surface3A of metal layer3in addition to lower surface2B, or carriers10can be placed only on upper surface3, not on lower surface2B.

FIGS. 4A and 4Bare side sectional views of sensor device1in accordance with Embodiment 1 for illustrating the operation. As shown inFIG. 4A, carriers10are physically adsorbed and fixed onto lower surface2B of metal layer2in advance in flow path4that is vacuumed or filled with air. Sample62of liquid containing non-specific specimen9and analyte8input into flow path4changes a status in flow path4, particularly the dielectric constant (refraction index) in flow path4. This allows the electromagnetic waves interfere with each other and strengthen or weaken each other above metal layer2according to formulae (1) and (2). The wavelengths λ of the electromagnetic waves interfering with each other changes, so that a frequency distribution of the electromagnetic wave detected by detector94changes. As discussed above, the detection of changes in the electromagnetic wave that propagates upward from metal layer2allows the user to realize the presence of the specific binding in flow path4.

As shown inFIG. 4B, sample62input in flow path4is forced by external force to flow along arrow17. Carriers10disposed on lower surface2B of metal layer2is physically fixed onto lower surface2B by weak force (e.g. van der Waals force), so that the flow can remove carriers10from lower surface2B. Carriers10are then suspended in flow path4and flow along arrow17. While carriers10flow in flow path4, acceptors7and analytes8of carriers10are specifically bound together, and other carriers10are also specifically bound with these analytes8. This process is repetitively performed, thereby forming aggregate11which is heavier than carrier10, non-specific specimen9, and medium61, so that aggregate11flows rather slowly. When aggregate11is trapped at specific region18(aggregate trapping section) in flow path4, a dielectric constant of region18changes, so that a dielectric constant (refraction index) of medium61disposed between metal layers2and3may change, thus changing a distribution of the dielectric constants. These changes the state of the electromagnetic wave propagating upward from metal layer2as derived from formulae (1) and (2). The detection of the changes in the electromagnetic wave propagating upward from metal layer2allows the user to realize the status of the specific binding between acceptors7and analytes8, to be more specific, the user will know strength of the specific binding and a speed of the binding.

The specific binding between acceptor7and analyte8changes the state of the electromagnetic wave propagating upward from metal layer2. This change will be described with a result of electromagnetic field simulation.FIG. 5is a schematic view of an analysis model of the electromagnetic field simulation of sensor device1according to Embodiment 1.

In analysis model501shown inFIG. 5, metal layer2is made of silver and has a thickness of 30 nm. Metal layer3is made of silver and has a thickness of 130 nm. Metal layer2is spaced away from metal layer3by 160 nm. Flow path4is filled with air having a relative dielectric constant of 1. A portion above upper surface2A of metal layer and a portion below lower surface3B of metal layer3are filled with air. In analysis model501, electromagnetic wave591enters into metal layer2at incident angle AN, and electromagnetic wave593propagates upward from metal layer2at angle BN (=−AN). These electromagnetic waves are analyzed by the simulation. In analysis model501, metal layers2and3and flow path4extend infinitely in horizontal directions.

Sensor device1detects not only a change in frequency or wavelength at which the first and second electromagnetic waves weaken each other, but also a change in reflectivity R501that is a ratio of the energy of the incident electromagnetic wave entering into metal layer2to the energy of the electromagnetic wave propagating upward from metal layer2. Use of two indexes (i.e. frequency or wavelength, and wavelength) simultaneously allows detecting a change in the state of the medium of flow path4, so that sensor device1can obtain high detective capability. The status of the medium refers to a status of the substance filling partially or entirely flow path4, for instance, a composition of the substance itself or a distribution of the substance in flow path4.FIG. 6shows a result of the analysis model shown inFIG. 5. InFIG. 6, the horizontal axis represents wavelength, and the vertical axis represents reflectivity R501. As shown inFIG. 6, an electromagnetic wave having a wavelength of about 340 nm satisfies formula (1) that allows canceling out two electromagnetic waves, so that a reflectivity decreases remarkably at the wavelength of about 340 nm.

Sensor device1can be used as a simple and home-use influenza-virus sensor. In this case, a sample containing human saliva is injected into flow path4. A home-use sensor device needs to have higher detection sensitivity and better usability than a professional-use sensor device. To achieve this need, analytes8concentrate locally to specific region18of flow path4, thereby increasing a density of analyte8in region18. Electromagnetic wave source92preferably employs a visible light source so that users can sense a change in wavelength easily without using a special detector expressly.

A structure of sensor device1according to Embodiment 1 for allowing analytes8to concentrate locally to the specific region in flow path4will be described below.FIGS. 7A and 7Bare side sectional views of the sensor device in accordance with Embodiment 1. In this sensor device, analytes concentrate locally.FIG. 7Ashows a status in flow path4just before a sample has been input.FIG. 7Bshows a status in flow path4after the sample is input and then a predetermined time has passed. Hereinafter, only analyte8is shown as sample62, and both of medium and specimen are not shown inFIGS. 7A and 7B, and figures thereafter.

As shown inFIG. 7A, plural carriers10concentrate locally at specific region18(aggregate trapping section) between lower surface2B of metal layer2and upper surface3A of metal layer3, and are fixed by physical adsorption. To be more specific, a density of carriers10physically adsorbed at region18is higher than other carriers10at further regions in flow path4. The physical adsorption is caused by van der Waals force acting on the interface between carriers10and each of metal layers2and3, and acting on the interface between carriers10. After sample62is input as shown inFIG. 7A, and the predetermined time lapses, then aggregate11including analytes8is formed. Specific region18is filled with aggregates11as shown inFIG. 7B. In other words, specific region18functions as an aggregate trapping section for trapping the aggregates. In this case, a large number of carriers10have been fixed at region18from the beginning, so that the dielectric constant at region18is not so much changed. The interference condition between the electromagnetic waves propagating upward from metal layer2does not change from before the aggregation to after the aggregation. As a result, no change is found in color of the reflection light between before and after the sample input. On the other hand, when sample62has no analytes, aggregate11cannot be formed, so that carriers10flow together with sample62in flow path4and are discharged from region18. The dielectric constant at region18changes more significantly than the case where analytes8form aggregates11, and the status of the interference between the electromagnetic waves propagating upward from metal layer2changes. As a result, the incident light including a visible-light band entering into sensor device1changes in color of the light propagating upward from metal layer2comparing with the color before inputting the sample. This color change can be sensed by human eyes, thereby recognizing the presence of analytes8in sample62. Thus, sensor device1allowing a user to realize easily at home whether or not analytes (e.g. virus) exist is provided. A structure for preventing aggregates11from flowing out easily from region18due to the flow of sample62along arrow17may be formed at region18. This structure retains the aggregates within region18, and is formed by, for instance, roughening at least one surface of metal layers2and3facing region18, thereby increasing a friction coefficient thereof.

FIGS. 8A and 8Bare side sectional views of sensor device1in which analytes8concentrate locally.FIG. 8Ashows a status in flow path4just before the sample is input to flow path4.FIG. 8Bshows a status in flow path4after the sample is input and then a predetermined time lapses. As shown inFIG. 8A, plural acceptors7concentrate locally and are fixed to specific region18on lower surface2B of metal layer2by chemical adsorption. Acceptors7do not exist at the other regions in flow path4. Plural carriers10are fixed onto lower surface2B by physical adsorption at a position from region18toward input region15. In the status shown inFIG. 8A, a sample containing analytes8is input into flow path4, and a predetermined time lapses. Then, as shown inFIG. 8B, the flow of sample removes carriers10from lower surface2B of metal layer2, and carriers10are suspended in flow path4to be specifically bound with analytes8, thereby forming aggregates11. Aggregates11follow the flow of the sample along arrow17, and are specifically bound with plural acceptors7disposed on lower surface2B via analytes8at region18(aggregate trapping section).

As a result, aggregates11containing analytes8are trapped at region18, thereby causing analytes8in the sample to concentrate locally at region18. In this case, since aggregates11containing analytes8are trapped at region18, the dielectric constant at region18is drastically different from dielectric constants of the other regions, so that sensitivity to the analytes increases. In other words, a status of the electromagnetic wave (e.g. a color of the visible light) propagating upward form metal layer2contacting region18of flow path4is different from that of the electromagnetic wave propagating upward from metal layer2contacting the regions other than region18. This phenomenon allows a user to visibly recognize easily at home whether the analytes exist or not. In the case of chemical adsorption, since acceptors7are adsorbed and fixed by covalent binding onto lower surface2B of metal layer2, acceptors7can be fixed to aggregates11more firmly than in the case of physical adsorption. Aggregates11can be thus fixed in more concentrated easily at region18where the analytes are expected to be detected, hence providing sensor device1with high sensitivity.

In conventional sensor device600shown inFIG. 22, analytes that are dispersed in a sample are specifically bound with acceptors fixed on a lower surface of insulating layer603, so that the detection sensitivity is insufficient.

A structure for facilitating the aggregating speed to form aggregates11will be described below.FIG. 9is a side sectional view of sensor device1shown inFIGS. 8A and 8Bfor illustrating the structure for facilitating the aggregation with ultrasonic wave. Sensor device1shown inFIG. 9further includes ultrasonic wave generator31adisposed on a portion of lower surface2B of metal layer2and ultrasonic wave generator31bdisposed on a portion of upper surface3A of metal layer3. Carriers10aand10babove flow path4are moved by the ultrasonic waves generated by ultrasonic wave generators31aand31bto be easily bound with analytes8. A standing wave of ultrasonic wave is generated between metal layers2and3, so that carriers10and analytes8concentrate at a predetermined region between layers metal2and3, accordingly increasing the possibility of binding carriers10with analytes8. Carriers10aand10bare thus specifically bound with analytes8to form aggregates11. Then, aggregates11then are trapped at region18via analytes8by acceptors7disposed on lower surface2B of metal layer2. The ultrasonic wave generated from an upper section and a lower section in flow path4facilitates the specific binding between carriers10and analytes8, hence facilitating the aggregation of analytes8. The ultrasonic wave generator may be disposed on only one of lower surface2B and upper surface3A. The ultrasonic wave generator may be disposed on side surface21A of side wall21or side surface22A of side wall22. These walls constitute flow path4. The ultrasonic wave generator can be disposed on a portion of lower surface5B of holder5at which metal layer2is not formed or on a portion of upper surface6A of holder6at which metal layer3is not formed.

FIG. 10is a side sectional view of sensor device1in which flow path4is heated to raise a temperature for facilitating the aggregation. Sensor device1shown inFIG. 10further includes heater32as a heat source disposed on upper surface5A of holder5. Heater32heats a sample in flow path4to increase kinetic energies of carriers10and analytes8, thereby facilitating the specific binding. For instance, facilitating of movements of carrier10a, carrier10b, and analyte8increases the possibility for them to contact each other, accordingly inviting them to be specifically bound with each other, and forming aggregates11. Carriers10aand10bare thus specifically bound with analytes8, and form aggregates11. Aggregates11are then trapped at region18via analytes8by acceptors7disposed on lower surface2B of metal layer2. The heating of flow path4of sensor device1encourages the specific binding between carriers10and analytes8, thereby facilitating the aggregation of analytes8. The location of heater32is not limited to a certain place as far as it can heat the sample.

FIG. 11is a side sectional view of sensor device1in which magnetic field is applied to flow path4for facilitating the aggregation. Sensor device1shown inFIG. 11further includes magnetic field generators33aand33bwhich are disposed near upper surface5A of holder5and lower surface6B of holder6, respectively. Magnetic field generators33aand33bgenerate magnetic field M1directing from an upper section of flow path4toward a lower section of flow path4. Carriers10are preferably made of magnetic material such that carriers10can be attracted along the direction of magnetic field M1. Carriers10aand10bmade of magnetic material move upward by magnetic field M1, and tend to be bound with analytes8. Carriers10aand10bare thus specifically bound with analytes8and form aggregates11. Aggregates11are then trapped at region18by acceptors7via analytes8. Magnetic field M1generated along the vertical direction of flow path4promotes the specific binding between carriers10and analytes8, thereby facilitating the aggregation of analytes8. Instead of providing sensor device1with magnetic field generators33aand33b, a user can hold a magnetic field generator with a hand and apply magnetic field M1to the flow path.

According to Embodiment 1, analytes8are specifically bound with acceptors7of carriers10in flow path4.FIG. 12is a side sectional view of sensor device1in which analytes8are specifically bound with carriers10outside flow path4to form aggregates11before analytes8and carriers10flow into region18. Aggregates11are then input in flow path4. In this case, aggregates11can be formed, e.g. before aggregates11are input into sensor device1, or analytes8and carriers10are specifically bound together in reservoir25for forming aggregates11. Sensor device1shown inFIG. 12allows analytes8and carriers10to be specifically bound together without fail, hence increasing detection accuracy. Acceptors7chemically adsorbed to metal layers2and3shown inFIG. 8Acan be disposed in sensor device1shownFIG. 12, and aggregates11can be trapped and fixed to concentrate locally at region18(aggregate trapping section).

FIGS. 13A and 13Bare top sectional views of sensor device100in accordance with Exemplary Embodiment 2. InFIGS. 13A and 13B, components identical to those of sensor device1according to Embodiment 1 are denoted by the same reference numerals. A side sectional view of sensor device100in accordance with Embodiment 2 is the same as that of sensor device1shown inFIG. 1B.FIGS. 14A and 14Bare a side sectional view and a top sectional view of sensor device100, respectively. Sensor device100includes flow path104surrounded by four surfaces, namely, lower surface102B of metal layer102, upper surface103A of metal layer103, side surface111A of side wall111, and side surface112A of side wall112. Lower surface102B of metal layer102constitutes an upper surface of flow path104, and upper surface103A of metal layer103constitutes a lower surface of flow path104. Side surface111A of side wall111constitutes a first side surface, and side surface112A of side wall112constitutes a second side surface of flow path104. Flow path104includes input region115configures to allow sample62to be input thereto, and discharge region116configured to allow sample62to be discharged. Flow path104tapers from input region115to discharge region116, namely, the interval between side surface111A and side surface112A decreases gradually from input region115toward discharge region116. A front tip (the left end inFIG. 13) of input region115has a width W1, a tail end (the right end inFIG. 13) of discharge region116has a width W3, and arbitrary position104ain flow path104has a width W2. Flow path104is configured such that these widths satisfy the relation of W1≧W2≧W3. Sample62is input into flow path104, and then, analytes8in sample62and acceptors7of carriers10are specifically bound together and form aggregates11. As sample62flows from input region115to discharge region116, aggregates11move from input region115toward discharge region116. Width W4of discharge region116is larger than a diameter of carrier10and is smaller than a diameter of aggregate11. In other words, width W4of discharge region116is larger than a first predetermined value not smaller than the diameter of carrier10, while width W4is not larger than a second predetermined value that is smaller than the diameter of aggregate11.

In flow path104, aggregates11are trapped at specific region118between input region115and discharge region116. Region118thus functions as an aggregate trapping section. Aggregate11trapped at region118block flow path104, so that other aggregates11coming next is stopped by the trapped aggregate11. As a result, aggregates11are accumulated together at specific region118. To be more specific, carrier10in sample62having a diameter not larger than the first predetermined value, non-specific specimen9having a diameter smaller than that of carrier10, and medium61can pass through region118. However, aggregate11in sample62and having a diameter larger than the second predetermined value cannot pass through region118.

FIG. 15is a schematic view of aggregate11. Aggregate11includes plural carriers10bound with each other via an analyte. Aggregate11may have various shapes. According to this embodiment, the diameter of aggregate11refers to maximum diameter R of aggregate11as shown inFIG. 15. In other words, the second predetermined value is smaller than maximum diameter R.

As discussed above, sensor device100in accordance with Embodiment 2 traps aggregates11containing analytes8at specific region118of flow path104, so that the dielectric constant at region118may change more significantly than at other regions. A status of the electromagnetic wave (e.g. color of visible light) propagating upward form metal layer102contacting region118of flow path104is different from that of the electromagnetic wave propagating upward from metal layer102contacting regions of the flow path other than region118. This operation allows a user at home to visibly recognize presence of anayltes easily. In other words, sensor device100in accordance with Embodiment 2 has higher detection sensitivity than a sensor device in which aggregates11are not trapped but are uniformly distributed in flow path104.

Sample62flows from input region115to discharge region116to cause aggregates11to be trapped at the specific region in flow path104. Sensor device100shown inFIG. 13Bincludes absorber113near discharge region116of flow path104for absorbing sample62. The absorption of sample62into absorber113causes sample62to flow from input region115to discharge region116, so that aggregates11and carriers10can flow toward discharge region116. Aggregates11are then trapped at region118, and carriers10are discharged from discharge region116to the outside of flow path104. Absorber113shown inFIG. 13Bis added to sensor device100shown inFIG. 13A. Absorber113can be used also in sensor devices other than sensor device100shown inFIG. 13Afor enlarging the flow of the samples in flow paths4and104similarly to sensor device100shown inFIG. 13B.

In sensor device100shown inFIG. 13A, width W2of flow path104decreases continuously from the front tip of input region115to the tail end of discharge region116. Width W2may decrease discontinuously from the front tip of input region115to the tail end of discharge region116. The width of region118may decrease continuously. The width of at least one of input region115and discharge region116can be constant.

FIGS. 16A and 16Bare a side sectional view and an enlarged side sectional view of sensor device200in accordance with Exemplary Embodiment 3, respectively. A top view of sensor device200is the same as that of sensor device1in accordance with Embodiment 1 shown inFIG. 1A. As shown inFIG. 16A, sensor device200includes flow path204constituted by four surfaces surrounding flow path204, namely, two side surfaces of two side walls similar to side walls21and22according to Embodiment 1, lower surface202B of metal layer202, and upper surface203A of metal layer203. The two side surfaces constitute first and second side surfaces of flow path204, lower surface202B of metal layer202constitutes an upper surface of flow path204, and upper surface203A of metal layer203constitutes a lower surface of flow path204. Flow path204includes input region215configures to allow sample62to be input thereto, discharge region216configures to allow sample62discharged, and region218disposed between input region215and discharge region216. Region218functions as an aggregate trapping section. Flow path204includes flow path204b(first flow path) and flow path204c(second flow path). Flow path204bincludes input region215and region218(aggregate trapping section). Flow path204cincludes discharge region216. An interval between lower surface202B and upper surface203A is referred to as a depth of flow path204. A depth of flow path204bis denoted by D1and the depth of flow path204cis denoted by D2. Depth D1is an interval between lower surface202B of metal layer202and upper surface203A of metal layer203in flow path204b, and depth D2is an interval between them in flow path204c. Flow path204is configured such that intervals D1and D2satisfy the relation of D1>D2. Upon sample62being input into flow path204, analytes8in sample62are specifically bound with acceptors7of carriers10to form aggregates11. Following the flow of sample62from input region215to discharge region216, aggregates11thus move toward discharge region216.

The depth (interval D2) of flow path204cis larger than the diameter of carrier10and smaller than the diameter of aggregate11. To be more specific, the depth (interval D2) of flow path204cis larger than a first predetermined value that is not smaller than the diameter of carrier10and that is not larger than a second predetermined value that is smaller than the diameter of aggregate11.

In flow path204, aggregate11is trapped at specific region218of flow path204, and then, aggregates11coming next are tacked together at specific region218since the trapped aggregate11blocks the flow path.FIG. 16Bis an enlarged view of region218at which aggregate11is trapped. Carriers10in sample62and having a diameter not larger than the first predetermined value, non-specific specimen9having a diameter smaller than that of carrier10, and medium61can pass through region218. However, aggregate11having a diameter larger than the second predetermined value cannot pass through region218.

Sensor device200in accordance with Embodiment 3 traps aggregates11containing analytes8at specific region218of flow path204, so that the dielectric constant of region218may change significantly larger than the dielectric constant of other regions. A status of the electromagnetic wave (e.g. color of the visible light) propagating upward form metal layer202contacting region218of flow path204changes, and a status of the electromagnetic wave (e.g. color of the visible light) propagating upward from metal layer202contacting the regions other than region218also changes. These phenomena allow a user at home to easily recognize visibly the presence of analytes. In other words, sensor device200has higher detection sensitivity than a sensor device in which aggregates11are not trapped but are uniformly distributed in the flow path.

An absorber may be disposed near discharge region216to form a flow of sample62in flow path204similarly to the absorber according to Embodiment 2. The absorber allows sample62to flow from input region215toward discharge region216of flow path204, so that aggregates11and carriers10may flow toward discharge region216. As a result, aggregates11are trapped at region218, and carriers10are discharged from discharge region216to the outside of flow path204.

FIG. 17shows a distribution of electromagnetic field intensity in sensor device200in accordance with Embodiment 3. As shown inFIG. 17, an interference state between the electromagnetic waves propagating upward from metal layer202contacting flow path204bcan be almost identical to an interference state between the electromagnetic waves propagating upward from metal layer202contacting flow path204c. To be more specific, flow path204band flow path204care configured such that these two paths satisfy formula 1 or formula 2. Note that integer m in formulae (1) and (2) is different from flow path204band flow path204c. In other words, interval D1between the upper surface and lower surface of flow path204band interval D2between the upper surface and the lower surface of flow path204csatisfy one of relations (a) or (b) with integers m1 and m2, a wavelength λ of the electromagnetic wave in vacuum, a refraction index n in flow path204, and an incident angle θ of the electromagnetic wave:
(m1+½)×λ=2×n×D1×cos θ, and (m2+½)×λ=2×n×D2×cos θ  (a)
m1×λ=2×n×D1×cos θ, andm2×λ=2×n×D2×cos θ  (b)

When light in a visible light band is supplied from above metal layer202of sensor device200, the condition discussed above allows the color of the light reflected on the region contacting flow path204bof metal layer202and the color of the light reflected on the region contacting flow path204cof metal layer202to be almost equal to each other. Therefore, analytes8and acceptors7of carriers10are specifically bound together to form aggregates11. Aggregates11are then trapped and stacked at aggregate trapping section218(region218). Then, the light reflected on the region contacting aggregate trapping section218of metal layer202changes remarkably, so that a user at home can visibly recognize the presence of analytes easily with this sensor device200.

Sensor device200allows the user to detect a change in color for detecting the presence of analytes, so that the light source preferably employs a light source of a visible light band. The visible light band refers to a wavelength band containing light visible by human eyes. This wavelength band is not smaller than 380 nm and not larger than 750 nm. For instance, sensor device200is configured such that the visible light band (i.e. colors of orange or red) having a wavelength ranging from 580 nm to 600 nm satisfies formula 2 when sample62not containing analytes8has been input in flow path204. Then, a sample containing analytes8is input into flow path204. This causes a change in refraction index (dielectric constant) of the aggregate trapping section218(region218). The material for the carriers can be selected appropriately, or a structure of aggregate trapping section218can be determined such that the light reflected on the region contacting aggregate trapping section218of metal layer202and having a wavelength not larger than 560 nm can satisfy formula 2. The above arrangement allow the specific binding to change the wavelength of the reflected light between a band shorter than the wavelength of yellow (about 560-580 nm) that shows a significant color difference for human eyes and a band larger than the wavelength. As a result, a user at home can visibly recognize the presence of the specific binding easily.

A filter allowing only a predetermined wavelength to pass through the filter may be disposed between sensor device200and human eyes of a user who observes sensor device200. In this case, a filter that blocks the wavelength shorter than 580 nm is disposed, then this filter allows the light having a wavelength not smaller than 580 nm to pass through when sample62contains no analytes, so that sensor device200looks bright to the user; however, when sample62contains analytes, the filter causes the wavelength that satisfies formula 2 to attenuate to cause sensor device200to look dark. A brightness change may be recognized more easily than a color change, so that the foregoing structure may be effective.

FIG. 18Ais a top sectional view of sensor device300in accordance with Exemplary Embodiment 4.FIG. 18Bis a side sectional view of sensor device300at line18B-18B shown inFIG. 18A. InFIGS. 18A and 18B, components identical to those of sensor device1shown inFIGS. 2A and 2Bin accordance with Embodiment 1 are denoted by the same reference numerals. Sensor device300includes flow path304constituted by four surfaces surrounding flow path304: side surface311A of side wall311, side surface312A of side wall312, lower surface2B of metal layer2, and upper surface3A of metal layer3. Side surface311A of side wall311constitutes a first side surface of flow path304. Side surface312A of side wall312constitutes a second side surface of flow path304. Lower surface2B of metal layer2constitutes an upper surface of flow path304. Upper surface3A of metal layer3constitutes a lower surface of flow path304. Sensor device300includes plural pillars313extending in parallel to side surfaces311A and312A from lower surface2B of metal layer2to upper surface3A of metal layer3. Plural pillars313are disposed at specific region318of flow path304, and have a cylindrical shape according to Embodiment 4; however pillars313can have another shape. Interval p1between pillars313adjacent to each other, interval p2between side wall311and pillar313, and interval p3between side wall312and pillar311are determined such that carrier10can pass through between pillars313and side walls311,312; however, aggregates11can be trapped there. Interval p1is a distance between outer walls of two adjacent pillars313. Interval p2is a distance between side wall311A of side wall311and the outer wall of pillar313. Interval p3is a distance between side wall312A of side wall312and the outer wall of pillar313. Intervals p1, p2, and p3are larger than a diameter of carrier10, and smaller than a diameter of aggregate11. To be more specific, intervals p1, p2, and p3are larger than a first predetermined value not smaller than the diameter of carrier10, and is not larger than a second predetermined value smaller than the diameter of aggregate11. As discussed above, region318of flow path304functions as an aggregate trapping section for trapping aggregates11. The sample crosses pillars313perpendicularly to pillars313in flow path304; however, pillars313can slant toward the flow of the sample while they keep intersecting with the flow at right angles, namely pillars313can extend slantingly at a predetermined angle from side walls311and312.

FIG. 18Cis a top sectional view of another sensor device300A in accordance with Embodiment 4.FIG. 18Dis a side sectional view of sensor device300A at line18D-18D shown inFIG. 18C. InFIGS. 18C and 18D, components identical to those of sensor device300shown inFIGS. 18A and 18Bare denoted by the same reference numerals. Sensor device300A includes plural pillars313aand313binstead of pillars313of sensor device300. Pillars313aand313bextend in parallel to side surfaces311A and312A from lower surface2B of metal layer2to upper surface3A of metal layer3. Plural pillars313aand313bare disposed at specific region318of flow path304, and have a cylindrical shape according to Embodiment 4; however may have another shape. Pillars313aand313bare arranged alternately on two lines. An interval between adjacent pillars313aand313b, an interval between pillar313aand side surface311A, and an interval between pillar313aand side surface312A are determined such that carriers10can pass through the intervals between pillars313a,313band side wall311,312, but aggregates11are trapped at these intervals. Plural pillars313aand313bmay be arranged on three or more lines.

Multiple pillars313can be connected to side surface311A and312A instead of surfaces2B and3B of metal layers2and3, and can extend in parallel to surfaces2B and3B. In this case, an interval between pillars313adjacent to each other, and an interval between pillar313and upper surface3A of metal layer3, and an interval between pillar313and lower surface2B of metal layer2are determined such that carriers10can pass through the intervals between pillars313and metal layers2and3; however, aggregates11can be trapped there.

As discussed above, sensor devices300and300A in accordance with Embodiment 4 allow specific region318of flow path304to trap aggregates11containing analytes8, so that the dielectric constant at region318can change more remarkably than other regions. These changes cause a change in a state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting region318as well as in a state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting other regions. A user at home thus can recognize the presence of analytes easily. In other words, sensor devices300and300A can have high detection sensitivity to analytes than a sensor device in which aggregates are not trapped but are distributed uniformly in a flow path.

InFIGS. 18A to 18D, the intervals between pillars313,313a, and313badjacent to each other can be different from each other.

FIG. 19Ais a top sectional view of sensor device400in accordance with Exemplary Embodiment 5.FIG. 19Bis a side sectional view of sensor device400at line19B-19B shown inFIG. 19A. InFIGS. 19A and 19B, components identical to those of sensor device1shown inFIGS. 2A and 2Bin accordance with Embodiment 1 are denoted by the same reference numerals. Sensor device400includes flow path404constituted by four surfaces surrounding path404: side surface411A of side wall411, side surface412A of side wall412, lower surface2B of metal layer2, and upper surface3A of metal layer3. Side surface411A of side wall411constitutes a first side surface of flow path404. Side surface412A of side wall412constitutes a second side surface of flow path404. Lower surface2B of metal layer2constitutes an upper surface of flow path404. Upper surface3A of metal layer3constitutes a lower surface of flow path404. Sensor device400includes plural fibrous substances413disposed at specific region418of flow path404. Fibrous substances413tangle with each other and form a mesh having apertures. The minimum value of aperture widths of the mesh is determined such that carrier10can pass through the apertures but aggregate11cannot pass through the apertures. In other words, the minimum diameter of the apertures is larger than a diameter of carrier10and smaller than a diameter of aggregate11. To be more specific, the minimum diameter of the aperture is larger than a first predetermined value not smaller than the diameter of carrier10, and is not larger than a second predetermined value smaller than the diameter of aggregate11. The mesh structure having the apertures and formed of tangled fibrous substances413is disposed at specific region418of flow path404.

The foregoing structure traps aggregates11, as a result of filtration, having a diameter larger than the minimum diameter of the apertures among fibrous substances413. On the other hand, carriers10having a diameter smaller than the minimum diameter of the apertures pass through fibrous substances413. Region418thus functions as an aggregate trapping section for trapping aggregates11. Fibrous substances413having the mesh structure may be made of silicon dioxide nano-fiber.

Sensor device400in accordance with Embodiment 5 allows specific region418of flow path404to trap aggregates11containing analytes8, so that the dielectric constant of region418changes more remarkably than other regions. These changes cause a change in state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting region418as well as in state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting other regions. A user at home thus can recognize the presence of analytes easily. In other words, sensor device400can have higher detection sensitivity to analytes than a sensor device in which aggregates are not trapped but distributed uniformly in a flow path.

FIG. 20Ais a top sectional view of sensor device500in accordance with Exemplary Embodiment 6.FIG. 20Bis a side sectional view of sensor device500at line20B-20B shown inFIG. 20A. InFIGS. 20A and 20B, components identical to those of sensor device1shown inFIGS. 2A and 2Bin accordance with Embodiment 1 are denoted by the same reference numerals. Sensor device500includes flow path504constituted by four surfaces surrounding flow path504: side surface511A of side wall511, side surface512A of side wall512, lower surface2B of metal layer2, and upper surface3A of metal layer3. Side surface511A of side wall511constitutes a first side surface of flow path504. Side surface512A of side wall512constitutes a second side surface of flow path504. Lower surface2B of metal layer2constitutes an upper surface of flow path504. Upper surface3A of metal layer3constitutes a lower surface of flow path504. Side surfaces511A and512A of flow path504meander such that recesses511P and512P are formed at specific regions518aand518b. While sample62flows through flow path504, aggregates11are trapped in recesses511pand512pformed at specific regions518aand518bwhich function as aggregate trapping sections for trapping aggregates11. Flow path504can meander such that one of side surface511A or512A can have a recess therein.

Sensor device500in accordance with Embodiment 6 allows specific region518of flow path504to trap aggregates11containing analytes8, so that the dielectric constant of region518changes more remarkably than other regions. These changes cause a change in a state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting regions518aand518bas well as in a state of electromagnetic wave (e.g. color of visible light) propagating upward from metal layer2contacting other regions. A user at home thus can recognize the presence of analytes easily. In other words, sensor devices500can have higher detection sensitivity to analytes than a sensor device in which aggregates are not trapped but are distributed uniformly in a flow path.

FIGS. 21A and 21Bare a sectional view and a perspective bottom view of sensor device700in accordance with Exemplary Embodiment 7, respectively. Sensor device700is an attenuated total reflection (ATR) type sensor device.

Sensor device700includes prism701, insulating layer703disposed on a lower surface of prism701, and metal layer702disposed on a lower surface of insulating layer703. Insulating layer703has a predetermined dielectric constant. The lower surface of insulating layer703is flat.

Insulating layer703of sensor device700is made of transparent insulating material, such as glass. Lower surface of insulating layer703has flow path704therein having a groove shape. Flow path704is constituted by three surfaces, side surface703C, side surface703D, and lower surface702B of metal layer702. Metal layer702is disposed on at least a part of lower surface703B of insulating layer703. Side surface703C constitutes a first side surface of flow path704. Side surface703D constitutes a second surface of flow path704. Lower surface702B of metal layer702constitutes an upper surface of flow path704.

Flow path704includes input region715configured to have a sample input thereto, discharge region716configured to have the sample discharged, and specific region718disposed between input region715and discharge region716. The sample flows in region718functions as an aggregate trapping section for trapping aggregates containing analytes in the sample. Flow path704has carriers adsorbed physically therein. Each carrier has plural acceptors fixed on a surface thereof. The acceptors are specifically bound with the analytes to produce an aggregate. Sensor device700shown inFIG. 21Ais actually used upside down.

The sample input into input region715flows toward discharge region716when a user squeezes out the sample with a pipette. The analytes in the sample are specifically bound with the carriers disposed in flow path704, thereby forming the aggregates. The aggregates are trapped at region718. Region718may be configured similarly to any one of specific regions18,118,218,318,418,518a, and518baccording to Embodiments 1, 2, 4, 5, and 6.

Surface plasmon wave (i.e. compression wave of electrons) is provided on an interface between metal layer702and insulating layer703. Light source705is disposed above prism701and supplies P-polarized incident light to prism701under a condition of total reflection. This incident light causes an evanescent wave on both the surfaces of metal layer702and insulating layer703. The light totally reflected on metal layer702is received by detector706which detects an intensity of the light.

When a wave-number matching condition in which a wave number of the evanescent wave matches wave number of the surface plasmon wave is satisfied, the light energy supplied from light source705is used for exciting the surface plasmon wave, so that the light intensity decreases. The wave-number matching condition depends on an incident angle of the light supplied from light source705. Therefore, an intensity of reflected light is detected with detector706while the incident angle changes, and then, the intensity of the reflected light decreases at a certain incident angle.

A resonant angle at which the intensity of the reflected light takes a minimum value depends on the dielectric constant of insulating layer703. A specific bound substance is produced by the acceptors and the analytes (i.e. an object to be measured in the sample) that are specifically bound together. When the specific bound substance is formed on the upper surface of insulating layer703, the dielectric constant of layer703changes, and the resonant angle also changes accordingly. Upon the change of the resonant angle being monitored, a binding strength of the specific binding between the analytes and the acceptors or a speed of the specific binding can be detected.

In sensor device700in accordance with Embodiment 7, specific region718of flow path704traps the aggregates containing the analytes, so that the dielectric constant at region718may change more remarkably than other regions of flow path704. Therefore, sensor device700has higher detection sensitivity to the analytes than conventional sensor device600shown inFIG. 22which does not trap aggregates but allows the aggregates to distribute uniformly in a flow path thereof.

As described above, each sensor device according to the present disclosure traps the aggregates containing the acceptors at the specific region in the flow path, so that the acceptors can locally concentrate to the specific region. The dielectric constant of the specific region thus changes more remarkably than other regions, and the acceptors in the sample can be detected at a higher sensitivity.

In Embodiments 1 to 7, the metal layer refers to not only a sheet-like layer but also a layer covered with fine metal particles.

In the sensor devices shown in, e.g.FIGS. 2A, 4A, 4B, 8A, 8B, 9, and 11, the carriers and the acceptors are disposed only on lower surface2B of metal layer2; however, the structure is not limited to this. For instance, the carriers and the acceptors may be disposed only on upper surface3A of metal layer3, or disposed both on lower surface2B and upper surface3A of metal layers2and3, providing the same effect.

In the embodiments, terms, such as “upper surface”, “lower surface”, “above”, “below”, indicating directions indicate relative directions depending on relative positional relations of structural elements, such as the flow path and the metal layers, of the sensor device, and do not indicate absolute directions, such as a vertical direction.

INDUSTRIAL APPLICABILITY

A sensor device according to the present disclosure has high detection sensitivity with a small and simple structure, so that it can be useful for small and inexpensive bio-sensors.