WO2014045387A1

WO2014045387A1 - Fluorescent sensor

Info

Publication number: WO2014045387A1
Application number: PCT/JP2012/074178
Authority: WO
Inventors: 亮太田
Original assignee: テルモ株式会社
Priority date: 2012-09-21
Filing date: 2012-09-21
Publication date: 2014-03-27

Abstract

A fluorescent sensor (4) having: a substrate section (30) comprising a hole (40X); an indicator (17) arranged inside the hole (40X) and which receives excitation light (E) and generates fluorescent light (F) having an intensity corresponding to the concentration of an analyte (9); a light-emitting element (15) that generates the excitation light (E); and a cover section (18) covering the hole (40X) and comprising a semiconductor material having formed therein a through-hole (18X) through which the analyte (9) passes and a PD element (12) that converts the fluorescent light (F) to an electric signal.

Description

Fluorescent sensor

The present invention relates to a fluorescence sensor for measuring the concentration of an analyte in a solution, and more particularly to a fluorescence sensor having an indicator made of an analyte and a hydrogel that generates fluorescence by excitation light.

Various analyzers for measuring the concentration of an analyte in a solution, that is, a substance to be measured have been developed. For example, a fluorometer that measures the analyte concentration by injecting a solution to be measured containing a fluorescent dye and an analyte into a transparent container, irradiating excitation light, and measuring the fluorescence intensity from the fluorescent dye is known. Yes. The fluorescent dye changes its property due to the presence of the analyte, and generates fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light.
A small-sized fluorometer has a light source, a photodetector, and an indicator containing a fluorescent dye. And the excitation light from a light source is irradiated to the indicator in which the analyte in a to-be-measured solution can go in and out, and the photodetector receives the fluorescence which an indicator produces. The photodetector is a photoelectric conversion element and outputs an electrical signal corresponding to the received light intensity. The analyte concentration in the solution is calculated based on the electrical signal from the photodetector.

In order to measure an analyte in a very small amount of sample, a microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology has been proposed. Hereinafter, the microfluorometer is referred to as “fluorescence sensor”.

The fluorescent sensor 104 shown in FIGS. 1 and 2 is disclosed in International Publication No. 2010/119916. The sensor unit 110 which is a main functional unit of the fluorescence sensor 104 includes a silicon substrate 111 on which a photoelectric conversion element 112 is formed, a transparent intermediate layer 113, a filter layer 114, a light emitting element 115, a transparent protective layer 116, An indicator 117 and a light shielding layer 118 are provided. The analyte 9 passes through the light shielding layer 118 and enters the indicator 117. The filter layer 114 of the fluorescence sensor 104 blocks the excitation light E and transmits the fluorescence F. Further, the light emitting element 115 transmits the fluorescence F.

In the fluorescence sensor 104, when the excitation light E generated by the light emitting element 115 enters the indicator 117, the indicator 117 generates fluorescence F corresponding to the analyte concentration.

Part of the fluorescence F generated by the indicator 117 passes through the light emitting element 115 and the filter layer 114, enters the photoelectric conversion element 112, and is photoelectrically converted. The excitation light E emitted from the light emitting element 115 in the direction of the photoelectric conversion element 112 (downward) is attenuated by the filter layer 114 to a level that causes no problem in measurement as compared with the fluorescence intensity. The fluorescent sensor 104 has a simple configuration and can be easily downsized.

However, in the fluorescence sensor 104, since the photoelectric conversion element 112 is on the lower surface of the light emitting element 115, it cannot be said that the light reception efficiency of the fluorescence F by the photoelectric conversion element 112 is good. For this reason, a fluorescence sensor with higher detection sensitivity has been demanded.

An object of the present invention is to provide a fluorescent sensor with high detection sensitivity.

The fluorescent sensor of one embodiment of the present invention includes a substrate portion having a hole, an indicator that is disposed inside the hole and receives excitation light and generates fluorescence having an intensity according to the concentration of the analyte, A cover portion made of a semiconductor material formed with a light emitting element that generates excitation light, a through-hole through which the analyte passes, covering the opening of the hole, and a photoelectric conversion element that converts the fluorescence into an electrical signal; Have

It is explanatory drawing which showed the cross-section of the conventional fluorescence sensor. It is the exploded view which showed the structure of the conventional fluorescence sensor. It is a block diagram of the sensor system of 1st Embodiment. It is a perspective view of the front-end | tip part of the fluorescence sensor of 1st Embodiment. FIG. 5 is an exploded cross-sectional view taken along the line VV of FIG. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 1st Embodiment. It is a perspective view of the cover part of the fluorescence sensor of 1st Embodiment. It is sectional drawing of the front-end | tip part of the fluorescence sensor of 2nd Embodiment. It is sectional drawing of the cover part of the fluorescence sensor of 2nd Embodiment. It is sectional drawing of the cover part of the modification of the fluorescence sensor of 2nd Embodiment. It is sectional drawing of the front-end | tip part of the fluorescence sensor of 3rd Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 3rd Embodiment. It is sectional drawing of the front-end | tip part of the fluorescence sensor of 4th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 4th Embodiment. It is sectional drawing of the front-end | tip part of the fluorescence sensor of 5th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 5th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 6th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 7th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 8th Embodiment. It is a cross-sectional schematic diagram for demonstrating operation | movement of the fluorescence sensor of 9th Embodiment.

<First Embodiment>
The fluorescence sensor 4 and the sensor system 1 according to the first embodiment of the present invention will be described. As shown in FIG. 3, the sensor system 1 includes a fluorescent sensor 4, a main body 2, and a receiver 3 that receives and stores a signal from the main body 2. Transmission / reception of signals between the main body 2 and the receiver 3 is performed wirelessly or by wire.

The fluorescent sensor 4 includes a needle portion 7 that is punctured by a subject and a connector portion 8 that is joined to the rear end portion of the needle portion 7. The needle part 7 has an elongated needle body part 6 and a needle tip part 5 including a sensor part 10 which is a main function part. Needle tip 5, needle body 6, and connector 8 may be integrally formed of the same material, or may be separately produced and joined.

The connector part 8 is detachably fitted to the fitting part 2A of the main body part 2. The plurality of wirings 60 extending from the sensor unit 10 of the fluorescent sensor 4 are electrically connected to the main body unit 2 when the connector unit 8 is mechanically fitted to the fitting unit 2A of the main body unit 2. .

Fluorescent sensor 4 is a needle-type sensor that can continuously measure the analyte concentration of a solution (body fluid) in a living body after inserting sensor unit 10 into the body for a predetermined period, for example, one week. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.

The main body unit 2 includes a control unit 2B that performs driving and control of the sensor unit 10, and a calculation unit 2C that processes a signal output from the sensor unit 10. Note that at least one of the control unit 2B and the calculation unit 2C may be disposed in the connector unit 8 of the fluorescent sensor 4 or may be disposed in the receiver 3.

Although not shown, the main body 2 further includes a radio antenna for transmitting and receiving radio signals to and from the receiver 3, a battery, and the like. When transmitting / receiving a signal to / from the receiver 3 by wire, the main body 2 has a signal line instead of a wireless antenna. Note that the receiver 3 may not be provided when the main body 2 includes a memory unit having a necessary capacity.

<Structure of sensor part>
Next, the structure of the sensor unit 10 which is a main functional unit of the fluorescence sensor 4 will be described with reference to FIGS. In addition, all the figures are schematic diagrams for explanation, and the vertical and horizontal dimensional ratios and the like are different from actual ones, and some components may not be shown. Further, the Z-axis direction shown in the figure is referred to as an upward direction.

The fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject. As shown in FIGS. 4 and 5, the sensor unit 10 includes a bonded substrate unit 30 in which the frame-shaped substrate unit 40 having the through hole 40X and the wiring substrate unit 20 are bonded, and an indicator disposed in the through hole 40X. 17 and the light emitting element 15, a cover portion 18 that covers the opening on the upper surface of the through hole 40 </ b> X, and a light shielding layer 19 that covers the cover portion 18.

In the fluorescence sensor 4, the cover portion 18 is made of a semiconductor material through which the analyte 9 passes, in which a photodiode element (hereinafter referred to as “PD element”) 12 that is a photoelectric conversion element that converts the fluorescence F into an electrical signal is formed. . That is, as shown in FIG. 7, the cover portion 18 is made of, for example, a silicon substrate having a minute through hole 18X, and the light receiving portion 12T of the PD element 12 is formed on one surface. The PD element 12 includes a light receiving portion 12T and a low resistance region 12H having a high conductivity in which impurities are partially introduced. Hereinafter, the light receiving portion 12T may be referred to as a PD element 12.

The minute through hole 18 </ b> X of the cover part 18 is an entry path through which the body fluid including the analyte 9 enters the indicator 17. That is, the body part can pass through the cover part 18.

The size, shape, position, and formation density of the minute through holes 18X of the cover portion 18 are appropriately selected according to the specifications. For example, the minute through holes 18X do not need to be arranged in an orderly manner as shown in FIG. Further, the shape of the opening when the minute through hole 18X is observed from the upper surface may be any of a circle, a rectangle, a polygon, and the like.

The cover portion 18 in which the minute through hole 18X is formed is produced by patterning the minute through hole 18X on a silicon plate or a silicon film, for example. Specifically, the minute through hole 18X can be formed by dry etching such as ICP-RIE after an etching mask is formed on the surface of a silicon plate or the like by photolithography or a self-assembled film. A machining method using a micro drill or the like may be used to form the minute through hole 18X.

Further, the cover portion 18 may be made of a porous semiconductor through which an analyte-containing solution can pass. The porous means a material having voids and pores connected to the outside in the structure. The size, distribution, and shape of the voids / pores need not be regular as long as the solution can pass through.

The open porosity of the cover part 18 is preferably 5 to 75% by volume, particularly preferably 20 to 50% by volume. If it is more than the said range, a bodily fluid will pass easily, and if it is below the said range, desired mechanical strength will be obtained. The open porosity is a value measured by Archimedes method.

The light shielding layer 19 prevents the excitation light E and the fluorescence F from leaking to the outside, and at the same time, prevents the external light G from entering the indicator 17.

The light shielding layer 19 has, for example, a submicron pore structure that does not prevent the analyte 9 from passing through the inside thereof and reaching the indicator 17. The light shielding layer 19 is made of a composite composition with an inorganic material such as metal or ceramic, or a hydrogel in which carbon black is mixed in a base material of an organic polymer such as polyimide or polyurethane, or a cellulose or polyacrylamide. A resin in which carbon black is mixed into an analyte-permeable polymer or a resin in which these are laminated is used.

The frame-like substrate portion 40 and the wiring substrate portion 20 are made of a resin material such as silicon, glass or metal having a Young's modulus of several tens to several hundreds of GPa, or polypropylene or polystyrene having a Young's modulus of about 1 GPa to 5 GPa. Use. The same silicon as the material of the cover portion 18A is particularly preferable.

The through hole 40X in which the indicator 17 and the light emitting element 15 are housed is a wiring board portion 20 on the lower surface, the cover portion 18 on the upper surface, and a concave portion of the frame-like substrate portion 40 on the side surface. The shape of the through hole 40X is a rectangular parallelepiped (quadrangular columnar shape), but may be a columnar shape, a polygonal columnar shape, or the like.

As will be described later, the side surface of the through hole 40X may be inclined with respect to the main surface. In addition, a reflective film that reflects fluorescence may be disposed on the side surface.

The wiring board portion 20 is provided with a wiring 51 that is connected to the external electrode 15T of the light emitting element 15 and supplies a driving signal. A wiring 61 for transmitting a signal of the PD element 12 among the wiring 60 is formed in the cover portion 18. The

wirings

51 and 61 are a part of the plurality of wirings 60.

In order to prevent the excitation light E from entering the PD element 12, a filter that transmits the fluorescence F and blocks the excitation light E is disposed on the light receiving surface of the PD element 12, that is, the lower surface of the cover portion 18. May be. For example, a light absorption filter that blocks the excitation light E having a wavelength of 375 nm but transmits the fluorescence F having a wavelength of 460 nm is used. When a filter is provided, a minute through hole through which the analyte can pass is also formed in the filter. The external electrode 15T on the lower surface of the light emitting element 15 is preferably sealed with an insulating resin. Furthermore, the light emitting element 15 may be sealed with a transparent intermediate layer up to the upper surface. The resin-sealed light emitting element 15 is not easily affected by the moisture of the indicator 17.

The indicator 17 is made of a hydrogel having a fluorescent dye that generates fluorescence F having a wavelength longer than that of the excitation light E by the analyte 9 and the excitation light E. That is, the indicator 17 is composed of a hydrogel that contains the fluorescent dye that generates the fluorescent light F with a light amount corresponding to the analyte concentration in the sample and that allows the excitation light E and the fluorescent light F to pass therethrough satisfactorily. The indicator 17 may be the analyte 9 itself in which the fluorescent dye that does not include the fluorescent dye and generates the fluorescence F exists in the solution.

Hydrogel is water such as acrylic hydrogel produced by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel produced from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.

It is preferable that the hydrogel has a size that does not leave the sensor through the cover 18 and the light shielding layer 19. For this reason, it is preferable that the hydrogel has a molecular weight of 1,000,000 or more, or is in the form of particles having a diameter equal to or larger than the pore diameter of the cover portion 18, for example, 50 nm or larger, or is in a form in which it does not flow.

On the other hand, when measuring sugars such as glucose, phenylboronic acid derivatives having a fluorescent residue are suitable as fluorescent dyes. The fluorescent dye is prevented from detaching from the sensor by using a high molecular weight material or chemically fixing to a hydrogel.

The indicator is produced by polymerizing a phosphoric acid buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator in a nitrogen atmosphere for 1 hour. For example, as a fluorescent dye, 9,10-bis [N- [2- (5,5-dimethylborinan-2-yl) benzyl] -N- [6 ′-[(acryloyl polyethylene glycol-3400) carbonylamino ] -N-hexylamino] methyl] -2-acetylanthracene (F-PEG-AAm), acrylamide as the gel skeleton-forming material, sodium peroxodisulfate and N, N, N ′ as the polymerization initiator N'-tetramethylethylenediamine is used.

As the light emitting element 15, an element that transmits the fluorescence F is selected from light emitting elements that emit desired excitation light E such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element.

In addition, as the light emitting element 15, an LED element is used from the viewpoints of fluorescence transmittance, light generation efficiency, wide wavelength selectivity of the excitation light E, and generation of a light other than a wavelength having an excitation action. preferable. Furthermore, among LED elements, an ultraviolet LED element made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.

The light emitting element 15 emits pulsed excitation light having a center wavelength of around 375 nm at an interval of once every 30 seconds, for example. For example, the current of the drive signal to the light emitting element 15 is 1 mA to 100 mA, and the light emission pulse width is 1 ms to 100 ms.

As shown in FIG. 6, in the fluorescence sensor 4, the fluorescence F generated by the indicator 17 enters the PD element 12 on the upper surface of the indicator 17. For this reason, the fluorescence sensor 4 is more sensitive than the conventional fluorescence sensor 104.

Second Embodiment
Next, the fluorescence sensor 4A of the second embodiment will be described. Since the fluorescence sensor 4A is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals and description thereof is omitted.

As shown in FIG. 8, the fluorescence sensor 4A is the same as the fluorescence sensor 4 in that the PD element 12 is formed on the cover portion 18A, but differs in that the light shielding layer 19 is not provided. . In the fluorescence sensor 4A, the cover portion 18A has the function of the light shielding layer 19, that is, the function of preventing the entry of the external light G and the leakage of the excitation light E and the fluorescence F.

As shown in FIG. 9A, in the fluorescence sensor 4A, since the size D of the minute through hole 18X of the cover portion 18A is equal to or less than the wavelength of the excitation light E, light leakage can be prevented. The lower limit value of the size D of the minute through hole 18X is equal to or larger than the size through which the analyte 9 can pass. Therefore, the size D of the minute through hole 18X is preferably 1 nm to 350 nm, more preferably 10 nm to 350 nm, and still more preferably 100 nm to 300 nm when the analyte 9 is glucose, for example. The size D of the minute through hole 18X is the maximum length of the opening, and is the diameter when the opening is circular, and is an average value calculated from an electron micrograph.

9B, in the cover portion 18A1 of the fluorescent sensor 4A1 according to the modification of the second embodiment, the cover portion 18a and the cover portion 18b are arranged so that the minute through holes 18X1 and 18X2 are alternately arranged. Are stacked via a predetermined gap 18c. The cover portion 18A1 having a laminated structure in which minute through-holes are staggered effectively blocks external light G, excitation light E, and fluorescence F, and allows body fluid to pass through. In addition, although cover part 18A1 has laminated | stacked the cover part 18a and the cover part 18b, you may laminate | stack three or more cover parts. Further, instead of the gap 18c, for example, a porous material through which a body fluid can pass may be used.

The sizes D1 and D2 of the minute through holes 18X1 and 18X2 of the cover portion 18A1 may exceed the wavelength of the excitation light E unlike the cover portion 18A. This is because even a cover portion having a small opening with a large opening has good light-shielding properties if the minute through-holes are alternately laminated. In particular, the cover portion having a laminated structure in which the thickness T of the gap 18c is smaller than the wavelength of the excitation light and larger than the size of the analyte 9 allows the analyte 9 to pass therethrough and has a very good light shielding property.

Fluorescent sensor 4A and fluorescent sensor 4A1 have the effect of fluorescent sensor 4 and have a simple structure.

<Third Embodiment>
Next, the fluorescence sensor 4B of the third embodiment will be described. Since the fluorescence sensor 4B is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals, and description thereof is omitted.

As shown in FIG. 10, the fluorescence sensor 4B is the same as the fluorescence sensor 4A in that the PD element 12 is formed on the cover portion 18A. However, the fluorescent sensor 4B is a second photoelectric conversion element on at least one side surface (wall surface) of the bottomed recess 30X that is a hole filled with the indicator 17, that is, on at least one side surface side of the indicator 17. The PD element 12B is formed, and the light emitting element 15 is disposed on the bottom surface of the recess 30X.

That is, the PD element 12B, which is the second photoelectric conversion element, is formed on the four wall surfaces of the concave portion 30X having a rectangular opening formed in the substrate portion 30B made of a semiconductor such as silicon, and the light emitting element is formed on the bottom surface of the concave portion 30X. 15 is disposed. Note that the opening surface of the recess 30X is wider than the bottom surface, and the side surface is inclined at a predetermined angle θ rather than perpendicular (90 degrees) to the bottom surface.

Although not shown, a plurality of through wirings are formed on the bottom surface of the recess 30X of the substrate part 30B, and a drive signal is transmitted to the light emitting element 15 and a signal of the PD element 12B is transmitted through the through wiring. .

Next, a method for manufacturing the fluorescence sensor 4B will be briefly described. In addition, although it may manufacture for every one fluorescence sensor 4B, it is preferable to manufacture many sensors collectively as a wafer process.

First, a mask layer having a plurality of openings is manufactured on the first main surface of a silicon wafer having an area where a plurality of elements can be manufactured. Then, a plurality of concave portions 30X having a bottom surface parallel to the first main surface is formed by an etching method.

As an etching method, a wet etching method using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution, or the like is preferable, but dry etching such as reactive ion etching (RIE) or chemical dry etching (CDE) is used. For example, when a silicon (100) plane is used as a silicon wafer, the etching speed of the (111) plane is anisotropic etching compared to the (100) plane, so the side surface of the recess Becomes the (111) plane, and the angle with the (100) plane (bottom surface) is 54.7 degrees.

Next, PD elements 12B are formed on the four side surfaces of the respective recesses 30X by a known semiconductor process. The concave portion 30X whose side surface is inclined not only has a larger area in which the PD element 12 can be formed, but also the PD element 12D can be easily formed on the side surface than the concave portion whose vertical side surface is vertical. If the inclination angle θ of the side surface is 30 to 70 degrees, the above effect is remarkable.

The light emitting elements 15 are respectively disposed on the bottom surfaces of the plurality of recesses 30X. Furthermore, the indicator 17 is filled in the concave portion, and the cover portion 18 on which the PD element 12 is formed is joined so as to close the opening of the concave portion 30X. Then, the silicon wafer on which the plurality of sensors are formed is separated into pieces, and the fluorescent sensor 4B is completed.

As shown in FIG. 11, in the fluorescence sensor 4B, the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61. The fluorescent light F2 emitted from the indicator 17 to the lateral side is received by the PD element 12B, and a signal is transmitted through the wiring 62 (60).

The fluorescence sensor 4B has the same effect as the fluorescence sensor 4A and the like, and further, the PD element 12B as the second photoelectric conversion element is also formed on the side surface side of the indicator 17, so that the sensitivity is higher.

<Fourth embodiment>
Next, the fluorescence sensor 4C of the fourth embodiment will be described. Since the fluorescence sensor 4C is similar to the fluorescence sensor 4B and the like, the same components are denoted by the same reference numerals and description thereof is omitted.

Compared with the fluorescent sensor 4B, the fluorescent sensor 4C shown in FIG. 12 is a second photoelectric conversion element on the side where the PD element 12 is formed in the cover portion 18A and the hole filled with the indicator 17. This is the same in that the PD element 12B is formed.

However, in the fluorescence sensor 4C, the hole is a through hole 30X1 formed in the substrate portion 30C, and the light emitting element 15 is disposed so as to cover the opening on the lower surface of the through hole 30X1. When the substrate portion 30C is made of silicon, the through hole 30X1 is formed by etching, and the PD element 12B is formed by a known semiconductor process. When the substrate portion 30C is not a semiconductor, a silicon film is formed on the wall surface after the through hole is formed, for example, by a CVD method.

Although not shown, an electrode pad for mounting the light emitting element 15 is disposed on the bottom surface 30SB of the substrate portion 30C, and the electrode pad is connected to the wiring 51 disposed on the bottom surface 30SB. A wiring 62 for transmitting a signal from the PD element 12B is also provided on the bottom surface 30SB.

As shown in FIG. 13, the fluorescence sensor 4C has higher sensitivity because the PD element 12B, which is the second photoelectric conversion element, is formed on the side surface of the indicator 17 as well as the fluorescence sensor 4B. Furthermore, since it is not necessary to form a through wiring, the manufacturing is easier than the fluorescent sensor 4B.

<Fifth Embodiment>
Next, the fluorescence sensor 4D of the fifth embodiment will be described. Since the fluorescence sensor 4D is similar to the fluorescence sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.

14 is the same as the fluorescence sensor 4A in that the PD element 12 is formed in the cover portion 18A as compared with the fluorescence sensor 4A. However, the substrate part 30D of the fluorescence sensor 4D is made of a semiconductor such as silicon on which the frame-like substrate part 40D in which the second through hole 40X serving as a hole is formed and the PD element 12D which is the third photoelectric conversion element is formed. This is a bonded substrate portion to which the detection substrate portion 20D made of is bonded. And the light emitting element 15 is mounted in the detection board | substrate part 20D which comprises the bottom face of the through-hole 40X.

As shown in FIG. 15, in the fluorescence sensor 4D, the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61. The fluorescent light F3 emitted downward from the indicator 17 is received by the PD element 12D, and a signal is transmitted through the wiring 63 (60).

The fluorescence sensor 4D has the effect of the fluorescence sensor 4, and further has a higher sensitivity because the PD element 12D, which is the third photoelectric conversion element, is also formed on the bottom surface side of the through hole 40X.

<Sixth to ninth embodiments>
Next, the fluorescence sensor 4E of the sixth embodiment to the fluorescence sensor 4H of the ninth embodiment will be described. Since the fluorescence sensors 4E to 4H are similar to the fluorescence sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.

Fluorescent sensors 4E to 4H are all the same as fluorescent sensor 4 and the like in that each has a cover portion on which a PD element is formed.

As shown in FIG. 16, in the fluorescent sensor 4E of the sixth embodiment, one large through hole 18XE is formed in the approximate center of the cover portion 18E. That is, as already described, in the case where the light shielding layer 19 is present, the size and number of through holes in the cover portion are not limited.

As shown in FIG. 17, in the fluorescence sensor 4F according to the seventh embodiment, a through hole 12X is formed in the approximate center of the PD element 12F, which is a third light receiving portion disposed below the indicator 17. And the light emitting element 15 is arrange | positioned under PD element 12F.

In the fluorescence sensor 4F, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, and the fluorescence F2 emitted downward is detected by the PD element 12F.

The excitation light E from the light emitting element 15 enters the indicator 17 through the through hole 12X. A plurality of through holes 12X may be formed in the PD element 12F.

Although not described in detail, the fluorescent sensor 4F has an SOI (active layer (SOI layer)) that is disposed on a support substrate layer (substrate layer) via a buried silicon oxide film (Buried Oxide: BOX layer). It can be easily manufactured by using a silicon on insulator substrate. That is, the indicator 17 is disposed in the through via formed in the substrate layer of the SOI substrate, the through via 12X is formed in the active layer, and the PD element 12F is formed so as to surround the through via 12X.

As shown in FIG. 18, the fluorescence sensor 4G of the eighth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4D shown in FIG. 15 are combined.

That is, in the fluorescence sensor 4G, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, the fluorescence F2 emitted horizontally is detected by the PD element 12B, and the fluorescence F2 emitted downward is the PD element. Detected by 12D.

As shown in FIG. 19, the fluorescence sensor 4H of the ninth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4F shown in FIG. 17 are combined.

That is, in the fluorescence sensor 4H, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, the fluorescence F2 emitted horizontally is detected by the PD element 12B, and the fluorescence F2 emitted downward is the PD element. It is detected by 12F.

Each of the fluorescence sensors 4E to 4H has the effect of the fluorescence sensor 4, and further emits in another direction in addition to the PD element formed on the cover portion that receives the fluorescence emitted upward. Since it has a PD element that receives fluorescence, it has higher sensitivity.

In addition, although the shape of the sensor part of the fluorescence sensor demonstrated in the said several embodiment was a right-angled column shape, trapezoid shape, the shape where the side was curved, or a column shape etc. may be sufficient.

In addition, although a sensor that detects saccharides such as glucose has been described as an example, the fluorescence sensor is compatible with various uses such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye.

That is, the present invention is not limited to the above-described embodiments and modifications, and various changes and modifications can be made without departing from the scope of the present invention.

Claims

A substrate part with holes,
An indicator disposed inside the hole for receiving excitation light and generating fluorescence having an intensity corresponding to the concentration of the analyte;
A light emitting element for generating the excitation light;
A fluorescence sensor comprising: a through-hole through which the analyte passes covering the opening of the hole; and a cover portion made of a semiconductor material on which a photoelectric conversion element for converting the fluorescence into an electric signal is formed. .
The fluorescent sensor according to claim 1, further comprising a light-shielding layer that covers the cover portion and through which the analyte passes.
The fluorescent sensor according to claim 1, wherein a plurality of minute through holes having a size equal to or smaller than the wavelength of the excitation light are formed in the cover part.
The fluorescent sensor according to claim 1, wherein a second photoelectric conversion element is formed on a side surface of the hole.
The fluorescent sensor according to claim 4, wherein the hole of the substrate portion is a recess, and the light emitting element is disposed on a bottom surface of the recess.
The fluorescent sensor according to claim 4, wherein the hole of the substrate portion is a through hole, and the light emitting element is disposed so as to cover an opening on a lower surface of the hole.
The substrate portion is a bonded substrate portion in which a frame-shaped substrate portion in which a second through hole serving as the hole is formed and a detection substrate portion in which a third photoelectric conversion element is formed are bonded,
The fluorescent sensor according to claim 1, wherein the light emitting element is disposed on a bottom surface of the hole.