HK1199659B - Fluorescent sensor and sensor system - Google Patents

Description

Fluorescence sensor and sensing system

Technical Field

The present invention relates to a fluorescence sensor for measuring the concentration of an analyte in a liquid and a sensing system having the fluorescence sensor, and more particularly, to a fluorescence sensor as a micro-fluorescence photometer manufactured by using a semiconductor manufacturing technique and an MEMS technique and a sensing system having the fluorescence sensor.

Background

Various types of analytical devices have been developed for measuring the concentration of an analyte, i.e., a test substance, in a liquid. For example, a fluorescence photometer is known which measures the concentration of an analyte by injecting a fluorescent dye and a solution to be measured containing the analyte into a transparent container, irradiating excitation light, and measuring the intensity of fluorescence from the fluorescent dye. The fluorescent dye changes in properties in response to the presence of the analyte, and when irradiated with excitation light, generates fluorescence having an intensity corresponding to the analyte concentration.

A compact fluorescence photometer has a light source, a photodetector, and an indicator containing a fluorescent dye. Then, excitation light from a light source is irradiated to an indicator that allows an analyte in a solution to be measured to freely enter and exit, and fluorescence generated by the indicator is received by a photodetector. The photodetector is a photoelectric conversion element and outputs an electric signal according to the light reception intensity. The concentration of the analyte in the solution is calculated based on the electrical signal from the photodetector.

In recent years, in order to measure an analyte in a trace amount of a sample, a micro fluorescence photometer manufactured by using a semiconductor manufacturing technique and an MEMS technique has been proposed. Hereinafter, the micro fluorescence photometer is referred to as a "fluorescence sensor".

For example, the fluorescence sensor 130 shown in fig. 1 and 2 is disclosed in the pamphlet of international publication No. 2010/119916. The sensor portion 110, which is a main functional portion of the fluorescence sensor 130, has a silicon substrate 111, a filter layer 114, a light-emitting device chip 115, a transparent protective layer 116, an indicator 117, and a light-shielding layer 118, wherein a photoelectric conversion device 112 is formed on the silicon substrate 111. Analyte 2 enters indicator 117 through light blocking layer 118. The filter layer 114 of the fluorescence sensor 130 blocks excitation light and allows fluorescence to pass therethrough. Further, the light-emitting element chip 115 allows fluorescence to pass therethrough.

In the fluorescence sensor 130, when excitation light generated by the light emitting element chip 115 is incident on the indicator 117, the indicator 117 generates fluorescence corresponding to the analyte concentration.

A part of the fluorescence generated by the indicator 117 passes through the light-emitting device chip 115 and the filter layer 114 and enters the photoelectric conversion device 112 to be photoelectrically converted. The excitation light emitted from the light-emitting device chip 115 in the direction of (below) the photoelectric conversion device 112 is attenuated by the filter layer 114 to such an extent that no problem occurs in measurement as compared with the fluorescence intensity. The fluorescence sensor 130 has a simple structure and is easily miniaturized.

However, the fluorescence sensor 130 can detect only fluorescence emitted downward in the direction toward the photoelectric conversion element 112, out of the fluorescence emitted from the indicator 117. Therefore, the fluorescence sensor 130 is small, but it is not easy to obtain high detection sensitivity.

An object of an embodiment of the present invention is to provide a fluorescent sensor which is small in size and high in detection sensitivity and a sensing system which is high in detection sensitivity.

Disclosure of Invention

The fluorescence sensor according to an aspect of the present invention includes: a detection substrate section having a photoelectric conversion element for converting fluorescence into an electric signal formed on a wall surface of a through hole penetrating through the 1 st principal surface and the 2 nd principal surface; an indicator that is disposed inside the through hole and generates the fluorescence with an intensity corresponding to the concentration of an analyte when receiving excitation light; a filter layer covering the photoelectric conversion element, allowing the fluorescence to pass therethrough and blocking the excitation light; a light shielding layer that covers an opening of the 1 st main surface of the through hole and allows the analyte to pass therethrough; and a light-emitting element chip that covers a region directly below the opening of the 2 nd main surface of the through hole and generates the excitation light.

A sensing system according to another aspect of the present invention includes a needle sensor having a sensing portion at a needle tip portion, and a calculation portion, the sensing portion including: a detection substrate section having a 1 st photoelectric conversion element for converting fluorescence into an electric signal formed on a wall surface of a through hole penetrating through the 1 st principal surface and the 2 nd principal surface, and a 2 nd photoelectric conversion element formed on the 2 nd principal surface; an indicator that is disposed inside the through-hole, reacts with an analyte, and generates the fluorescence with an intensity corresponding to a concentration of the analyte when receiving excitation light; a light shielding layer that covers an opening of the 1 st main surface of the through hole and allows the analyte to pass therethrough; a light-emitting element chip that covers the region directly below the opening of the 2 nd main surface and the region directly below the 2 nd photoelectric conversion element and generates the excitation light; the arithmetic unit corrects the electrical signal from the photoelectric conversion element using the electrical signal from the 2 nd photoelectric conversion element.

Drawings

Fig. 1 is an explanatory diagram showing a cross-sectional structure of a sensing portion of a conventional fluorescence sensor.

Fig. 2 is an exploded view for explaining the structure of a sensing part of a conventional fluorescence sensor.

Fig. 3 is an explanatory diagram for explaining a sensing system having the fluorescence sensor according to embodiment 1.

Fig. 4 is an exploded view of a sensing part for explaining the structure of the fluorescence sensor according to embodiment 1.

Fig. 5 is a schematic diagram showing a cross-sectional structure of a sensing portion of the fluorescence sensor according to embodiment 1.

Fig. 6A is a schematic diagram showing a cross-sectional structure of a sensing portion for explaining a method of manufacturing a fluorescence sensor according to embodiment 1.

Fig. 6B is a schematic diagram showing a cross-sectional structure of the sensing portion for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 6C is a schematic diagram showing a cross-sectional structure of the sensing portion for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 6D is a schematic diagram showing a cross-sectional structure of the sensing part for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 6E is a schematic diagram showing a cross-sectional structure of the sensing portion for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 6F is a schematic diagram showing a cross-sectional structure of the sensing portion for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 6G is a schematic diagram showing a cross-sectional structure of the sensing part for explaining the method of manufacturing the fluorescence sensor according to embodiment 1.

Fig. 7 is a schematic diagram showing a cross-sectional structure of a sensing portion of a fluorescence sensor according to a modification example of embodiment 1.

Fig. 8 is a schematic diagram showing a cross-sectional structure of a sensing portion of the fluorescence sensor according to embodiment 2.

Detailed Description

< embodiment 1 >

First, the fluorescence sensor 30 and the sensing system 1 according to embodiment 1 of the present invention will be described. As shown in fig. 3, the sensing system 1 has a fluorescence sensor 30, a main body portion 40, and a receiver 45 that receives and stores a signal from the main body portion 40. The transmission and reception of signals between the main body 40 and the receiver 45 are performed by a wireless or wired method.

The fluorescence sensor 30 includes a needle portion 34 for puncturing a subject and a connector portion 35 connected to a rear end portion of the needle portion 34. The needle portion 34 has an elongated needle main body portion 33 and a needle tip end portion 32 including the sensing portion 10 as a main functional portion. The needle tip portion 32, the needle main body portion 33, and the connector portion 35 may be integrally formed of the same material, or may be separately manufactured and joined together.

The connector portion 35 is detachably fitted to the fitting portion 41 of the main body portion 40. The connector portion 35 is mechanically fitted to the fitting portion 41 of the main body portion 40, whereby the plurality of wires 51 to 54 extending from the sensing portion 10 of the fluorescence sensor 30 are electrically connected to the main body portion 40.

The fluorescence sensor 30 is a needle-type sensor capable of measuring the analyte concentration for a predetermined period of time, for example, one week after the sensor unit 10 is inserted into the body. However, instead of inserting the sensor unit 10 into the body, the collected body fluid or the body fluid circulating through the extracorporeal circuit and the body may be brought into contact with the sensor unit 10 outside the body.

The main body 40 includes a control unit 42 that drives and controls the sensing unit 10, and an arithmetic unit 43 that processes a signal output from the sensing unit 10. The control unit 42 and the arithmetic unit 43 are each configured by an arithmetic circuit such as a CPU, but may be the same CPU. At least one of the control unit 42 and the arithmetic unit 43 may be disposed on the connector unit 35 of the fluorescence sensor 30 or the like, or may be disposed on the receiver 45.

Although not shown in the figure, the main body portion 40 also has a wireless antenna, a battery, and the like for transmitting and receiving wireless signals between the main body portion and the receiver 45. When receiving and transmitting a signal between the main body 40 and the receiver 45 by a wired method, the main body 40 includes a signal line instead of a wireless antenna. When the main body 40 has a memory portion with a sufficient capacity, the receiver 45 may not be required.

< Structure of sensing part >

Next, the structure of the sensing section 10, which is a main functional section of the fluorescence sensor 30, will be described with reference to fig. 4 and 5. It should be noted that the drawings are schematic diagrams for explanation, and the aspect ratio and the like are different from the actual ones, and some of the components may be omitted from the drawings. The Z-axis direction shown in fig. 4 and 5 is referred to as "upward".

The fluorescence sensor 30 includes, as main functional elements, a detection substrate portion 11, an optical filter layer 14, an indicator 17, a Light shielding layer 18, and a Light Emitting Diode (LED) chip 15 as a Light Emitting element chip.

A through hole 21 is formed in the detection substrate portion 11 made of a semiconductor such as silicon to penetrate the 1 st main surface 11SA and the 2 nd main surface 11 SB.

A Photodiode (PD) element 12 as a photoelectric conversion element for converting fluorescence into an electric signal is formed on the wall surface 22 of the through hole 21. That is, the PD element 12 is provided so as to surround the indicator 17 disposed inside the through hole 21, and is disposed so that the light receiving surface faces the indicator 17. The PD element 12 may be formed on all four wall surfaces 22 of the rectangular through hole 21, or may be formed on only a part of the wall surfaces 22.

On the other hand, detection signal wires 51 and 52 for outputting detection signals from the PD element 12 are arranged on the 2 nd main surface 11SB of the detection substrate portion 11. The detection signal wiring 51 is connected to the light-receiving portion of the PD element 12 via the low-resistance region 12S of the same semiconductor impurity type as the light-receiving portion of the PD element 12, and the detection signal wiring 52 is connected to the low-resistance region 12H of the same semiconductor impurity type as the detection substrate portion 11.

Further, driving signal wires 53 and 54 for supplying driving signals to the driving signal electrodes 15A and 15B of the LED chip 15 are provided on the 2 nd main surface 11SB of the detection substrate portion 11.

The transparent protective layer 16 and the filter layer 14 are disposed so as to cover the PD elements 12 formed on the wall surface 22. That is, the protective layer 16 and the filter layer 14 are disposed on the light receiving surface side of the PD element 12 so as to cover the PD element 12. The filter layer 14 blocks excitation light having a wavelength of 375nm, for example, and allows fluorescence having a wavelength of 460nm, for example, to pass therethrough.

In the fluorescence sensor 30, the LED chip 15 is bonded to the detection substrate portion 11 via the transparent bonding layer 13. The LED chip 15 has a larger size in plan view than the opening size of the 2 nd main surface 11SB of the through hole 21. Thus, the LED chip 15 completely covers the region directly below the opening of the 2 nd main surface 11SB of the through hole 21. In other words, the bottom surface of the through hole 21 is constituted by the bonding layer 13 on the LED chip 15.

The bonding layer 13 is also a protective layer covering the surface of the LED chip 15 and the 2 nd main surface 11SB of the detection substrate section 11. As the bonding layer 13, an organic resin such as an epoxy resin, a silicone resin, or a transparent amorphous fluororesin, or a transparent inorganic material such as a silicon oxide film or a silicon nitride film can be used. The bonding layer 13 is selected from materials having characteristics such as electrical insulation, water resistance, and good transmittance for excitation light.

The bonding layer 13 may have an opening in a region directly below the opening of the 2 nd main surface 11SB of the through hole 21. In this case, the bottom surface of the through hole 21 becomes the surface of the LED chip 15. Further, as the material of the bonding layer 13, a material having a function of blocking excitation light is preferably used.

The indicator 17 disposed inside the through-hole 21 generates fluorescence having an intensity corresponding to the concentration of the analyte 2 by interaction with the analyte 2 that gradually enters and excitation light. The thickness of the indicator 17 is about several 10 μm to several 100 μm. The indicator 17 is composed of a base material containing a fluorescent dye that generates fluorescence having an intensity corresponding to the amount of the analyte 2 that enters the inside, that is, the analyte concentration in the measurement solution.

The light-shielding layer 18 covering the opening of the 1 st main surface 11SA of the through-hole 21 has a thickness of about several 10 μm. The light shielding layer 18 prevents the excitation light and the fluorescence from leaking to the outside and prevents the outside light from entering the inside. The light shielding layer 18 also has analyte permeability that does not prevent the analyte 2 from passing through.

The light leakage prevention layer 19 provided so as to cover the bottom surface (lower surface) and the side surfaces of the LED chip 15 prevents the excitation light emitted from the bottom surface and the side surfaces and the excitation light reflected by the 2 nd main surface 11SB of the detection substrate portion 11 from leaking to the outside. That is, the light leakage prevention layer 19 has a function similar to that of the light shielding layer 18, but does not require analyte permeability.

< method for manufacturing fluorescence sensor >

Next, a method for manufacturing the fluorescence sensor 30 will be described with reference to fig. 6A to 6G. Fig. 6A to 6G are partial cross-sectional views of the region of the sensing portion 10 of one fluorescence sensor 30, but in an actual process, the sensing portions 10 of a plurality of fluorescence sensors 30 are manufactured at once as a wafer process.

First, as shown in fig. 6A, low-resistance regions 12S and 12H for outputting detection signals from the PD element 12 are formed on the 2 nd main surface 11SB of the silicon wafer (detection substrate) 11W by an impurity implantation process in a normal semiconductor process.

That is, the low-resistance region 12S is formed by introducing an impurity of the same semiconductor impurity type as the light-receiving portion of the PD element 12, and the low-resistance region 12H is formed by introducing an impurity of the same semiconductor impurity type as the silicon wafer 11. For example, when the light-receiving portion of the PD element is a P-type semiconductor, the low-resistance region 12S is formed by introducing boron, and the low-resistance region 12H is formed by introducing phosphorus, arsenic, or the like.

The material of the detection substrate portion 11 is preferably single crystal silicon in order to form the PD element 12 on the surface, but may be glass, ceramic, or the like. When the detection substrate portion is made of glass or the like, a semiconductor layer such as a silicone polymer (poly silicone) is formed on the wall surface 22 of the through hole 21 to form a photoelectric conversion element.

The photoelectric conversion element may be a photoresistor (photoconductor) element, a phototransistor (phototransistor) element, or the like.

Next, as shown in fig. 6B, through hole 21 is formed by etching silicon wafer 11W from the side of main surface 2 SB through mask layer 71 having an opening in the through hole forming portion. Various known methods can be used for etching. The low-resistance region 12S is removed by etching except for the region connected to the detection signal wiring 51.

The shape and size of the cross section of the through hole 21 are designed according to the specification of the fluorescence sensor 30. In order to provide the location where the sensing portion 10 is disposed on the needle tip portion 32, the size of the cross section of the through hole 21 is elongated, for example, 150 μm in the vertical direction and 500 μm in the horizontal direction. On the other hand, the cross-sectional shape (planar shape) of the through-hole 21 may be polygonal, circular, elliptical or the like, but is preferably rectangular in view of high opening efficiency and easy processing.

Next, as shown in FIG. 6C, PD elements 12 serving as light-receiving portions are formed on the wall surfaces 22 of the through-holes 21, that is, the silicon wafer 11W on which the mask layer 71 having the through-hole 21 forming region opened is disposed is inclined by 5 to 30 degrees, and ion implantation is performed from at least four directions, for example, when the silicon wafer 11W is of an N type, an acceleration voltage of 10 to 200keV and 1 × 10¹⁵～1×10¹⁶cm^－2Boron (B) is implanted at the right and left implantation doses. In this case, a thin oxide layer of 10 to 100nm may be formed on the surface of the wall surface 22 of the through hole 21. The PD element 12 connected to the low-resistance region 12S is formed on the wall surface 22 by heat treatment after ion implantation. After the heat treatment, the mask layer 71 is removed.

Next, as shown in fig. 6D, the protective layer 16 and the filter layer 14 are sequentially disposed by CVD or the like so as to cover the PD elements 12 on the wall surface 22 of the through hole 21 of the silicon wafer 11W.

The protective layer 16 is a single layer film of an inorganic insulating layer such as a silicon oxide layer or a silicon nitride layer, or a multilayer film in which the single layer films are stacked. As the protective layer 16, a silicon oxide layer having a high fluorescence transmittance, a silicon nitride layer, a composite layer laminate composed of a silicon oxide layer and a nitride layer, a silicone resin layer, or a transparent amorphous fluorine resin layer can be used.

The filter layer 14 may be a multiple interference filter layer, preferably an absorption filter layer, and may be a single-layer made of silicon, silicon carbide, silicon oxide, silicon nitride, an organic material, or the like, or a multilayer layer in which the single-layer layers are stacked. For example, the silicon layer and the silicon carbide layer have a transmittance of 10 at a wavelength of 375nm^－5% or less, and has a transmittance of 10% or more at a wavelength of 460nm and a transmittance selectivity (transmittance at an excitation light wavelength/transmittance at a fluorescence wavelength) of 6 digits or more. Filter layer 14 may be a band-pass filter that allows only fluorescence generated by indicator 17 to pass therethrough.

The filter layer 14 is preferably disposed not only on the wall surface 22 but also on the 2 nd main surface 11 SB. The filter layer 14 disposed on the 2 nd main surface 11SB has an effect of reducing the noise level of the PD element 12 to prevent the excitation light from entering the detection substrate section 11.

That is, the fluorescence sensor 30 having the filter layer 14 disposed on the 2 nd main surface 11SB has high sensitivity because the S/N ratio of the detection signal output from the PD element 12 is high.

Next, as shown in fig. 6E, detection signal wirings 51 and 52 for outputting a detection signal from the PD element 12 and driving signal wirings 53 and 54 for supplying a driving signal to the LED chip 15 are provided by a sputtering method, a vapor deposition method, or the like.

As the material of the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54, Al, Cu, Au, Pt, W, Mo, or the like is used as a metal material, or a low-resistance silicone polymer containing impurities at a high concentration is used. The material of the interlayer insulating layer 59 is an inorganic insulating material such as a silicon oxide film or a silicon nitride film, or an organic insulating material such as polyimide.

In order to prevent excitation light generated by the LED chip 15 from entering the detection substrate portion 11, at least one of the detection signal wires 51 and 52 and the drive signal wires 53 and 54 may be arranged to have a wide width.

As shown in fig. 6E, in the fluorescence sensor 30, the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54 have a multilayer wiring structure disposed in different layers with an interlayer insulating layer 59 interposed therebetween. However, the detection signal lines 51 and 52 and the drive signal lines 53 and 54 may be formed in one wiring layer.

In the case of the multilayer wiring structure, an interlayer insulating layer 59 is formed between the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54 by a CVD method or the like. In this case, when the interlayer insulating layer 59 is formed also on the surface of the filter layer 14 on the wall surface of the through hole 21, the interlayer insulating layer 59 is preferably made of a transparent material such as silicon oxide similar to the protective layer 16. The interlayer insulating layer 59 formed on the surface of the filter layer 14 has a function as a protective layer of the filter layer 14.

Next, as shown in fig. 6F, the LED chip 15 is bonded via the bonding layer 13 so as to cover the opening on the 2 nd main surface 11SB side of the through hole 21 of the detection substrate portion 11.

The light-emitting element chip is not limited to the LED chip 15, and may be selected from chips on which light-emitting elements such as organic EL elements, inorganic EL elements, and laser diode elements are formed. Further, the LED chip 15 is preferable from the viewpoints of the fluorescence transmittance, the light generation efficiency, the wide range of wavelength selectivity of the excitation light, the generation of only a small amount of light having a wavelength other than ultraviolet rays which become the excitation light, and the like.

The bonding layer 13 is produced by applying a resin and then curing the resin, for example. Further, a transparent SiO2 layer, a silicon nitride layer, or the like may be provided in advance on the surface to be coated with the resin by a CVD method or the like. The driving signal electrodes 15A and 15B of the LED Chip 15 and the driving signal wires 53 and 54 are electrically connected using a conductive adhesive, Flip Chip bonding (Flip Chip bonding), or the like.

That is, when the LED chip 15 is bonded to the 2 nd main surface 11SB of the detection substrate portion 11, the driving signal electrodes 15A and 15B of the LED chip 15 are electrically connected to the driving signal wires 53 and 54. That is, the LED chip 15 and the detection substrate portion are electrically connected together at the same time of being physically connected, and therefore, the fluorescent sensor 30 is easy to manufacture. The bonding layer 13 also has a function of a sealing member that seals the electrical connection portion.

Then, the light leakage prevention layer 19 is disposed on the lower surface and the side surface of the LED chip 15. The light leakage prevention layer 19 may be made of the same material as the light shielding layer 18, or may be made of an organic resin mixed with carbon black, a metal, or a multilayer film or a composite film made of these materials. The LED chip 15 on which the light leakage prevention layer 19 is provided in advance may be bonded to the detection substrate portion 11.

When a metal film having a high reflectance such as aluminum or silver is used as the light leakage prevention layer 19, the function as a reflection film that reflects the excitation light emitted from the bottom surface and the side surface of the LED chip 15 upward, that is, in the direction of the indicator 17, may be added.

The light leakage prevention layer 19 may be disposed on the entire lower surface, side surfaces, and upper surface of the detection substrate portion 11 in a portion not covered with the light shielding layer 18. Further, a 1 st light shielding layer for covering the LED chip 15 and a 2 nd light shielding layer for covering the detection substrate portion 11 together with the 1 st light shielding layer may be provided (see fig. 7).

Next, as shown in fig. 6G, the silicon wafer 11W is turned upside down, and the indicator 17 is disposed inside from the opening of the 1 st main surface 11SA of the through hole 21.

The fluorescent dye is selected depending on the type of the analyte 2, and any analyte may be used if the fluorescent dye reversibly changes the intensity of fluorescence generated depending on the amount of the analyte 2. For the fluorescent dye of the fluorescence sensor 30, a substance reversibly bound to glucose, such as a ruthenium organic complex, a fluorescent phenylboronic acid derivative, or a protein-bound fluorescein, is used for the measurement of a saccharide such as glucose.

The indicator 17 is made of, for example, a hydrogel that is easily hydrated as a matrix material, and the fluorescent dye is contained in or bonded to the hydrogel. As the hydrogel component, polysaccharides such as methylcellulose and dextran; an acrylate hydrogel prepared by polymerizing a monomer such as (meth) acrylamide, methacrylamide, or hydroxyethyl acrylate; or polyurethane hydrogel made of polyethylene glycol and diisocyanate.

The indicator 17 may be bonded to the wall surface 22 of the through hole 21, the light shielding layer 18 on the upper surface, the bonding layer 13 on the lower surface, or the like via an adhesive layer made of a silane coupling agent or the like. When the bonding layer 13 has an opening in a region directly below the through-hole 21, the indicator 17 may be bonded to the surface of the LED chip 15 constituting the bottom surface of the through-hole 21.

The indicator 17 may be prepared by filling the through hole 21 with an indicator containing a gel skeleton-forming material before polymerization, covering the opening with the light-shielding layer 18, and then polymerizing the indicator. For example, a phosphoric acid buffer solution containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator is injected into the through-hole 21, and the indicator 17 is prepared by leaving the solution under a nitrogen atmosphere for 1 hour. As the fluorescent dye, 9, 10-bis [ N- [2- (5, 5-dimethylborolan-2-yl) benzyl ] -N- [6' - [ (acryloylpolyethylene glycol-3400) carbonylamino ] -N-hexyl ] methyl ] -2-acetylanthracene (F-PEG-AAm) was used; acrylamide is used as a gel skeleton-forming material; as the polymerization initiator, sodium persulfate and N, N, N ', N' -tetramethylethylenediamine were used.

Finally, the light shielding layer 18 is disposed so as to cover the opening of the 1 st main surface 11SA of the through hole 21. The light-shielding layer 18 may be an inorganic thin film made of a porous structure of submicron order, such as metal or ceramic; or a composite structure of a hydrogel and carbon black mixed in a base material of an organic polymer such as polyimide or polyurethane; or a resin obtained by mixing carbon black with a cellulose-based or polyacrylamide-based analyte-permeable polymer; or a resin obtained by laminating them.

Then, the wafer 11W is divided into individual pieces, thereby producing a plurality of sensing portions 10 at a time. Then, the sensing portion 10 is joined to a separately manufactured tip portion of the needle body portion 33 extending from the connector portion 35, thereby completing the fluorescence sensor 30.

The method of manufacturing the fluorescence sensor is not limited to this, and for example, the silicon wafer 11W in the state shown in fig. 6E may be divided into individual pieces, and the LED chips 15 may be bonded to the detection substrate sections 11.

Further, the silicon wafer 11W may be processed so that the needle main body portion 33 of the needle portion 34 is constituted by the extended portion of the detection substrate portion 11, and then joined to the connector portion 35.

As described above, the fluorescent sensor 30 can be mass-produced at a time by a wafer process. Therefore, the fluorescence sensor 30 can provide stable quality at low cost.

< action of fluorescent sensor >

Next, the operation of the fluorescence sensor 30 will be described.

The LED chip 15 emits excitation light having a center wavelength of about 375nm in pulses at intervals of, for example, 1 time for 30 seconds. For example, the pulse current to the LED chip 15 is 1mA to 100mA, and the pulse width of light emission is 1ms to 100 ms.

Excitation light generated by the LED chip 15 is incident on the indicator 17 through the bonding layer 13. The indicator 17 emits fluorescence with an intensity corresponding to the concentration of the analyte 2. Note that the analyte 2 enters the indicator 17 through the light shielding layer 18. The fluorescent dye of the indicator 17 generates fluorescence of, for example, a wavelength of 460nm longer than the wavelength of the excitation light of, for example, 375 nm.

A part of the fluorescence generated by the indicator 17 passes through the filter layer 14 and the protective layer 16 and enters the PD element 12. The fluorescence is photoelectrically converted in the PD element 12 to generate a photoelectric charge, and is output as a detection signal.

In the fluorescence sensor 30, the arithmetic unit 43 of the main body unit 40 performs arithmetic processing based on the detection signal, that is, based on the current caused by the photo-induced charges from the PD element 12 or the voltage caused by the accumulated photo-induced charges, and calculates the analyte amount.

The fluorescence sensor 30 detects fluorescence using the PD element 12 formed on the wall surface 22 surrounding the indicator 17. That is, among the fluorescent light emitted in the six directions in total from the indicator 17 in the two vertical directions and the four directions on the side surface, the fluorescent light emitted in the four directions is detected. Therefore, the fluorescence sensor 30 is small in size and has high detection sensitivity. Similarly, the sensing system 1 including the fluorescence sensor 30 has high detection sensitivity.

That is, the fluorescence sensor 30 has the LED chip 15 adjacent to the indicator 17, and fluorescence generated from the indicator 17 is also detected by the PD element 12 formed on the adjacent wall surface 22. Therefore, the fluorescence sensor 30 has high detection sensitivity despite of being microminiature. In addition, since a plurality of fluorescence sensors can be manufactured at a time by processing one detection substrate, the processing steps of the fluorescence sensor 30 are easy and the cost is low.

< modification of embodiment 1 >

In the fluorescence sensor 30 according to embodiment 1, the wall surface 22 of the through hole 21 is substantially perpendicular to the 1 st main surface 11SA (the 2 nd main surface 11 SB). In contrast, as shown in fig. 7, in the fluorescence sensor 30A of the sensing system 1A according to the modification example of embodiment 1, the wall surface 22A of the through hole 21A of the detection substrate portion 11A of the sensing portion 10A has a tapered shape, that is, the wall surface is inclined at a predetermined angle θ with respect to the main surface, and the opening of the 1 st main surface 11SA is larger than the opening of the 2 nd main surface 11 SB. The through hole 21A having the tapered wall surface 22A can be formed by wet etching using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution, or the like.

For example, when silicon (100) is used as the silicon wafer 11W, the (111) plane is etched anisotropically at a lower etching rate than the (100) plane, so that the wall surface 22A of the through hole 21A is a (111) plane, and the angle θ is 54.7 degrees.

The through-hole 21A having the inclined wall surface 22A has a larger area for forming the PD element 12A than the through-hole 21 having the vertical wall surface 22A, and therefore, not only is the sensitivity higher, but also the productivity is high because the PD element 12A is easily formed on the wall surface 22A. The above effect is remarkable when the inclination angle θ of the wall surface 22A is 30 to 70 degrees.

As shown in fig. 7, in the fluorescence sensor 30A, the bonding layer 13A is made of a light-shielding material having substantially the same opening as the opening of the 2 nd main surface 11SB of the through hole 21A. The 1 st light leakage prevention layer 19 is made of aluminum having a high reflectance. The 2 nd light leakage prevention layer 19A made of a carbon-containing resin having a high light-shielding property covers the portion of the needle-tip portion 32 other than the upper portion of the light-shielding layer 18.

< embodiment 2 >

Next, the sensing system 1B and the fluorescence sensor 30B according to embodiment 2 will be described. The fluorescence sensor 30B and the like are similar to the fluorescence sensor 30 and the like, and therefore the same components are denoted by the same reference numerals and description thereof is omitted.

As shown in fig. 8, in addition to the PD element 12 as the 1 st photoelectric conversion element that detects fluorescence generated by the indicator 17, a PD element 12B as the 2 nd photoelectric conversion element that detects excitation light generated by the LED chip 15L is formed on the detection substrate portion 11B of the sensing portion 10B of the fluorescence sensor 30B. That is, the light-receiving portion of the 1 st PD element 12 is formed on the wall surface 22 of the through hole 21 of the detection substrate portion 11B, and the light-receiving portion of the 2 nd PD element 12B is formed on the 2 nd main surface 11 SB. The 1 st photoelectric conversion element and the 2 nd photoelectric conversion element are PD elements having the same configuration.

The LED chip 15L covers not only the region directly below the opening of the 2 nd main surface 11SB of the through hole 21 but also the region directly below the 2 nd PD element 12B. That is, the LED chip 15L has a size covering a region directly below the opening of the through hole 21 and also covering a region directly below the PD element 12B in a plan view.

The filter layer 14 is not provided on the surface of the PD element 12B. Therefore, the PD element 12B outputs an electric signal (detection signal) according to the intensity of the excitation light generated by the LED chip 15L.

The manufacturing method of the fluorescence sensor 30B is similar to that of the fluorescence sensor 30. In the step shown in fig. 6A, the low-resistance regions 12S and 12H having low resistance are formed by impurity implantation treatment, and the light-receiving portion of the PD element 12B is formed. The PD element 12 on the wall surface of the through hole 21 is formed by the process shown in fig. 6C, similarly to the fluorescent sensor 30.

A detection signal wiring 55 for transmitting a detection signal output from the PD element 12B is also disposed on the 2 nd main surface 11SB of the detection substrate portion 11B. The detection signal wiring 52 connected to the low-resistance region 12H is a common wiring for the PD element 12 and the PD element 12B.

The intensity of fluorescence generated by the indicator 17 increases or decreases not only by the influence of the analyte concentration but also by the influence of the intensity of the irradiated excitation light. However, in the sensing system 1B, the arithmetic unit 43 that processes the electric signal (detection signal) output from the fluorescence sensor 30B corrects the electric signal (detection signal) from the 1 st PD element 12 based on the electric signal from the 2 nd PD element 12B.

The fluorescence sensor 30B and the sensing system 1B have the effects of the fluorescence sensor 30, the sensing system 1, and the like, and can perform measurement with high accuracy even if the intensity of the excitation light changes due to fluctuation in the light emission efficiency of the LED chip 15L, variation in the amount of excitation light during operation, or the like.

In the fluorescence sensor 30B, the wall surface of the through hole is formed in a tapered shape, whereby the same effect as that of the fluorescence sensor 30A can be obtained.

In the above description, the fluorescent sensor 30 for detecting a saccharide such as glucose is described as an example, but various applications such as an enzyme sensor, a pH sensor, an immunosensor, and a microbial sensor can be dealt with depending on the selection of a fluorescent dye. For example, in the measurement of hydrogen ion concentration or carbon dioxide in a living body, a hydroxypyrene trisulfonic acid derivative or the like is used as the fluorescent dye, a phenylboronic acid derivative having a fluorescent residue or the like is used as the fluorescent dye in the measurement of sugars, and a crown ether derivative having a fluorescent residue or the like is used as the fluorescent dye in the measurement of potassium ions.

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

The present application is proposed based on the priority claim of Japanese patent application No. 2012-031964 filed on Japanese application on 2/16/2012, and the disclosure of the above Japanese application is incorporated in the specification, claims and drawings of the present application.

Claims (8)

1. A fluorescence sensor, comprising:

a detection substrate portion on which a photoelectric conversion element for converting fluorescence into an electric signal is formed;

an indicator that generates the fluorescence with an intensity corresponding to the concentration of the analyte when receiving the excitation light;

a filter layer covering the photoelectric conversion element, allowing the fluorescence to pass therethrough and blocking the excitation light; and

a light emitting element chip that generates the excitation light, the fluorescence sensor being characterized in that,

the photoelectric conversion element is formed on a wall surface of a through hole penetrating through the 1 st main surface and the 2 nd main surface of the detection substrate,

the indicator is disposed inside the through hole,

the light emitting element chip covers a region directly below the opening of the 2 nd main surface of the through hole,

the fluorescence sensor further includes a light shielding layer that covers an opening of the 1 st main surface of the through hole and allows the analyte to pass therethrough.

2. The fluorescence sensor of claim 1,

the fluorescent sensor is a needle-type sensor having a sensing portion including the detection substrate portion, the filter layer, the indicator, the light shielding layer, and the light-emitting device chip at a needle tip portion.

3. The fluorescence sensor of claim 2,

on the 2 nd main surface, a detection signal wiring connected to the photoelectric conversion element and a drive signal wiring connected to the light-emitting element chip are arranged.

4. The fluorescence sensor of claim 3,

the filter layer is also disposed on the 2 nd main surface.

5. The fluorescence sensor of claim 4,

the wall surface of the through hole is tapered.

6. The fluorescence sensor of claim 1,

a 2 nd photoelectric conversion element is formed on the 2 nd main surface,

the light-emitting element chip covers the region directly below the opening of the 2 nd main surface and the region directly below the 2 nd photoelectric conversion element.

7. The fluorescence sensor of claim 6,

and correcting the electrical signal from the photoelectric conversion element using the electrical signal from the 2 nd photoelectric conversion element.

8. A sensing system includes a needle sensor and an arithmetic section,

the needle sensor has a sensing portion at a tip portion of a needle, the sensing portion including:

a detection substrate portion on which a photoelectric conversion element for converting fluorescence into an electric signal is formed;

an indicator that reacts with the analyte and generates the fluorescence with an intensity corresponding to the concentration of the analyte when receiving the excitation light;

a filter layer covering the photoelectric conversion element, allowing the fluorescence to pass therethrough and blocking the excitation light; and

a light emitting element chip for generating the excitation light,

the induction system is characterized in that it is provided with,

the detection substrate section has a 1 st photoelectric conversion element for converting fluorescence into an electric signal formed on a wall surface of a through hole penetrating through the 1 st principal surface and the 2 nd principal surface, and a 2 nd photoelectric conversion element formed on the 2 nd principal surface,

the indicator is disposed inside the through hole,

the light emitting element chip covers a region directly below the opening of the 2 nd main surface and a region directly below the 2 nd photoelectric conversion element,

the sensing part further includes a light shielding layer covering an opening of the 1 st main surface of the through-hole and allowing the analyte to pass therethrough,

the arithmetic unit corrects the electrical signal from the 1 st photoelectric conversion element using the electrical signal from the 2 nd photoelectric conversion element.