Optical interference type surface stress sensor

Abstract

To provide within one chip, a plurality of sensor units which can detect different molecules.SOLUTION: A light interference type surface stress sensor 1 comprises: a semiconductor substrate 2; a hollow portion 3 which is provided in the semiconductor substrate; a movable film 5 which covers the hollow portion; an electro-conductive film 6 which is provided on the surface of the movable film; and a polymerization film 7 which has a molecular template. A sensor portion 11 which is the minimum unit of detection is configured for each hollow portion. The intensity of light having passed through the movable film changes by change of interference characteristic with respect to the template of the polymerization film due to molecular adsorption. The change of the light intensity is detected by a photodiode. The polymerization film 7 in which a template 9 of a molecule 8 is formed, can be selectively and locally formed in correspondence to the pattern of the electro-conductive film 6, and as a result, structure is obtained in which a plurality of types of polymerization films targeting different types of molecules are painted in different colors on the electro-conductive film.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to an optical interference type surface stress sensor that detects molecules based on the phenomenon in which, when a movable film covering a hollow portion of a semiconductor substrate is deformed due to the adsorption of molecules to a polymer film, the intensity of single-wavelength light transmitted through the movable film changes due to a change in the interference characteristics at the bottom of the movable film, and in particular, to an optical interference type surface stress sensor that can detect multiple types of molecules with a single element (chip) by coating multiple types of polymer films, each intended to detect different types of molecules, on the movable film in a desired pattern. [Background technology]

[0002] 7(a) and (b) are cross-sectional views schematically illustrating the structure of an optical interference surface stress sensor disclosed in Patent Document 1 below. In this sensor, the bottom of a hollow portion 101 formed in a semiconductor substrate 100 serves as the light-receiving surface of a photodiode (not shown). A movable film 102 is provided covering the hollow portion 101, and a Fabry-Perot interferometer is configured between this movable film 102 and the light-receiving surface of the photodiode. An antibody molecular adsorption layer 103 is provided on the movable film 102, and an antibody 104, which serves as a receptor for the antigen to be detected, is fixed to this antibody molecular adsorption layer 103. When this sensor is irradiated with light of a predetermined wavelength, as shown in FIG. 7(b), if a specific antigen 105 to be detected binds to the antibody 104, the movable film 102 deforms. Light of different wavelengths interferes depending on the deformation state of the movable film 102, and the transmittance for the specific wavelength changes. By measuring the change in the intensity of the transmitted light of that specific wavelength as a photocurrent output by the photodiode, the amount of change in the bending state of the movable film 102 can be determined, and this makes it possible to determine the binding state of the molecules. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. WO2013 / 047799 Summary of the Invention [Problem to be solved by the invention]

[0004] In the label-free sensor including the optical interference type surface stress sensor described in the above Patent Document 1, when the purpose is to detect a specific antigen, an antibody that contributes to the specific adsorption of the antigen can be used as a receptor molecule, as explained with reference to Fig. 7. However, in the case of an optical interference type surface stress sensor that detects molecules that do not have receptor molecules that contribute to specific adsorption, such as neurotransmitters, the structure as explained with reference to Fig. 7 may not be immediately adoptable. In other words, an optical interference type surface stress sensor with such a structure has a problem in that the types of molecules that can be applied are limited depending on the development status of receptor molecules.

[0005] 8 is a cross-sectional view schematically showing a process of modifying the surface of the movable film 102 with an antibody 104, which is a receptor, in the manufacture of the optical interference type surface stress sensor described with reference to FIG. 7. In this structural example of the optical interference type surface stress sensor, an insulating layer 110 is provided on a semiconductor substrate 100, and the portion surrounded by this insulating layer 110 is a hollow portion 101. The bottom of the hollow portion 101 is the light receiving surface of a photodiode 111 built in the semiconductor substrate 100. Wiring (not shown) connected to the photodiode 111 is provided in the insulating layer 110, and the movable film 102 is provided on the insulating layer 110 to cover the hollow portion 101.

[0006] As shown in Figure 8, in the process of fixing the antibody 104, which is a receptor, on the movable membrane 102, a cross-linking agent 112 (corresponding to the antibody molecule adsorption layer 103 in Figure 7) for adhering the antibody 104 is applied in advance to the surface of the movable membrane 102, and a solution containing the antibody 104 is supplied in the form of droplets 113 using an inkjet, dispenser, or the like, and the antibody 104 is fixed to the movable membrane 102 by a chemical reaction caused by the cross-linking agent 112. If it were possible to apply a different antibody 104 to each hollow portion 101, a useful optical interference surface stress sensor could be obtained in which a large number of sensor parts (sensor elements, which are the smallest unit of detection) for detecting different molecules are arranged on a chip made of a semiconductor substrate of about several millimeters square. However, with conventional technology, it was extremely difficult to precisely apply a different antibody 104 to each hollow portion 101. This is because it is technically extremely difficult to eject droplets 113 containing antibodies 104 of the required size, have them accurately reach and adhere to the desired positions, and adhere the antibodies 104 only to the surface of the movable membrane 102 directly above the desired hollow portion 101. In Figure 8, even if we attempt to adhere the antibodies 104 only to the surface of the movable membrane 102 directly above the central hollow portion 101, if the solution spreads irregularly on the movable membrane 102 and adheres to the surfaces of the movable membrane 102 corresponding to the adjacent hollow portions 101, 101, the adhesion of the antibodies 104 is difficult to control because it is a chemical reaction within the solution, and it is impossible to prevent the antibodies 104 from adhering to unwanted locations. Furthermore, the movable membrane 102 is only several hundred nanometers thick and is stretched over the hollow portion 101 without support except for its periphery, so there is a risk that the movable membrane 102 will be damaged if the droplets 113 of the solution collide with it. As described above, according to the conventional technology, even if the number of sensor parts, which are the minimum units, is increased in the optical interference type surface stress sensor formed on a chip made of one semiconductor substrate 100, there was a problem that it was difficult to make a structure capable of measuring many different types of molecules.

[0007] The present invention has been made in consideration of the conventional techniques described above, and aims to provide an optical interference type surface stress sensor that can be applied to the detection of any molecule, regardless of the presence or absence of a receptor molecule or the development status thereof, and that has multiple sensor units capable of measuring many different types of molecules within a single chip. [Means for solving the problem]

[0008] The optical interference type surface stress sensor according to claim 1 comprises: a semiconductor substrate; formed on the semiconductor substrate Height 0.4~4μm A hollow portion; The inside of the hollow portion is sealed in a liquid-tight state. Covering the hollow portion Made of Parylene C A movable membrane; a conductive film formed on the surface of the movable film so as to correspond to the hollow portion; a polymer film formed on the surface of the conductive film and having a template for a molecule to be detected; and a sensor unit that detects molecules based on a phenomenon in which the intensity of single-wavelength light transmitted through the movable film changes due to a change in interference characteristics caused by the adsorption of molecules to the polymer film, A plurality of such electrodes are formed on the semiconductor substrate.

[0009] The optical interference type surface stress sensor according to claim 2 comprises: a semiconductor substrate; formed on the semiconductor substrate Height 0.4~4μm A hollow portion; The inside of the hollow portion is sealed in a liquid-tight state. Covering the hollow portion Made of Parylene C A movable membrane; a conductive film formed on the surface of the movable film in a pattern corresponding to at least one of the hollow portion and the plurality of hollow portions; a polymer film provided on the surface of the conductive film so as to correspond to the pattern and having a template for a molecule to be detected formed thereon; and The molecule is detected based on the phenomenon in which the intensity of the single-wavelength light transmitted through the movable film changes due to a change in interference characteristics caused by the adsorption of the molecule to the polymer film.

[0010] The optical interference type surface stress sensor according to claim 3 is the optical interference type surface stress sensor according to claim 2, a plurality of sensor parts each having one of the hollow parts, and molecular templates different from each other are formed on the polymer film of the plurality of sensor parts; The present invention is characterized in that different molecules are detected simultaneously by the plurality of sensor parts.

[0011] The optical interference type surface stress sensor according to claim 4 is the optical interference type surface stress sensor according to claim 2, a sensor array having a plurality of the hollow portions, and a template of the same type of molecule is formed on the polymer film of the sensor array; The sensor array is characterized by detecting the same type of molecule simultaneously at multiple locations.

[0012] The optical interference type surface stress sensor according to claim 5 is the optical interference type surface stress sensor according to any one of claims 2 to 4, a first hollow portion that is set to be relatively large in order to detect molecules in a sample having a relatively low concentration of the molecules to be detected; a second hollow portion that is set to be relatively small in order to detect molecules in a sample having a relatively high concentration of the molecules to be detected; It is characterized by having the following. [Effects of the Invention]

[0013] According to the optical interference type surface stress sensor described in claim 1, since the conductive film can be formed into any pattern with high precision, by using a technique such as electrolytic polymerization, a polymerized film on which a molecular template is formed can be selectively and locally formed on the conductive film in accordance with the pattern of the conductive film. Therefore, it is possible to coat multiple types of polymerized films targeted at different types of molecules on the conductive film, and it is possible to realize a structure that detects multiple types of molecules on a single sensor chip.

[0014] According to the optical interference type surface stress sensor of claim 2, the conductive film can be formed into any pattern with high precision, and by using a technique such as electrolytic polymerization, a polymerized film on which a molecular template is formed can be selectively and locally formed on the conductive film in accordance with the pattern. Therefore, multiple types of polymerized films targeted at different types of molecules can be applied separately to the conductive film. In this case, a different polymerized film can be applied to each conductive film formed corresponding to one hollow portion, or a different polymerized film can be applied to each conductive film formed corresponding to multiple hollow portions. Furthermore, different polymerized films can be applied to the conductive film corresponding to one hollow portion and the conductive film corresponding to multiple hollow portions. In either case, a structure that detects multiple types of molecules can be realized in a single sensor chip.

[0015] According to the optical interference type surface stress sensor described in claim 3, different molecules can be detected simultaneously by a single sensor chip using a plurality of sensor parts in which polymer films are applied to each conductive film formed corresponding to one hollow part.

[0016] According to the optical interference type surface stress sensor described in claim 4, in the sensor array, a polymer film is formed on a conductive film formed in a pattern corresponding to a plurality of hollow portions, so that the same type of molecule can be detected simultaneously at a plurality of locations using a single sensor chip. Therefore, by averaging a plurality of detection results obtained for the molecule, the accuracy of the detection result can be improved. Note that two or more sensor arrays having a conductive film and a polymer film formed in a pattern corresponding to a plurality of hollow portions can also be formed by applying different types of polymer films.

[0017] According to the optical interference type surface stress sensor described in claim 5, the ease of deformation of the movable film changes depending on the size of the hollow part, so by optimally setting the size of the hollow part according to the concentration of the molecule to be detected contained in the sample, the molecule can be detected reliably and accurately regardless of the concentration of the sample.

[0018] In the present invention, a photodiode provided at the bottom of the hollow portion or a spectrophotometer that measures the spectrum of reflected light from the polymer film can be used as a means for detecting the phenomenon in which the intensity of single-wavelength light that has passed through the movable film covering the hollow portion changes due to a change in interference characteristics associated with the adsorption of molecules to the polymer film. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is a cross-sectional view schematically showing the structure of an optical interference type surface stress sensor according to an embodiment. [Figure 2] FIG. 10 is a cross-sectional view schematically showing a process of locally forming a polymer film on the surface of a selected conductive film, on which a template of a molecule to be detected is formed, in the manufacture of an optical interference type surface stress sensor according to an embodiment. [Figure 3] 1A and 1B are diagrams for explaining the process of forming a polymerized film on the surface of a conductive film in the manufacture of an experimental device including the structure of an optical interference type surface stress sensor according to an embodiment, in which FIG. 1A is a cross-sectional view of the device in the middle of manufacture with conductive tape attached to the conductive film, FIG. 1B is a plan view of the device, and FIG. 1C is a diagram schematically showing the structure of an apparatus for forming a polymerized film on the surface of the conductive film of the device by electrolytic polymerization. [Figure 4] FIG. 2 is a schematic diagram for explaining the mechanism of forming a template for a molecule to be detected in a polymer film in the manufacture of an optical interference type surface stress sensor according to an embodiment. [Figure 5] It is a cross-sectional view of an experimental device manufactured to explain that the polymerized film of the optical interference type surface stress sensor of the embodiment can detect specific molecules, and is a diagram showing the structure (right) of the optical interference type surface stress sensor of the embodiment in which a polymerized film having a molecular template is provided on a conductive film on the upper surface of the movable film covering the hollow part of the semiconductor substrate, the structure (left) of Comparative Example 1 in which a polymerized film without a molecular template is provided on a conductive film, and the structure (center) of Comparative Example 2 in which a conductive film and a polymerized film are not formed. [Figure 6]6 is a graph showing the state in which the peak shift amount of the reflection spectrum from each structure changes over time when a dopamine solution is dropped onto the structure of the optical interference type surface stress sensor of the embodiment of the experimental device shown in FIG. 5 and the structures of Comparative Examples 1 and 2. [Figure 7] FIG. 1 is a cross-sectional view schematically showing the structure of an optical interference type surface stress sensor disclosed in Patent Document 1. [Figure 8] 1 is a cross-sectional view schematically showing a step of modifying the surface of a movable membrane with an antibody via an antibody molecule adsorption layer in the production of an optical interference type surface stress sensor disclosed in Patent Document 1. FIG. DETAILED DESCRIPTION OF THE INVENTION

[0020] Hereinafter, an embodiment of the present invention will be described with reference to FIGS. FIG. 1(a) is a schematic cross-sectional view showing the basic structure of the optical interference type surface stress sensor 1 of the embodiment, and FIG. 2 is a schematic cross-sectional view showing the electrolytic polymerization process for forming a polymer film 7 having a template of the molecule to be detected only in the required area in the manufacture of the optical interference type surface stress sensor 1 of the embodiment.

[0021] As shown in Figures 1(a) and 2, the optical interference type surface stress sensor 1 includes a semiconductor substrate 2, a hollow portion 3 (cavity) formed in the semiconductor substrate 2, a photodiode 4 (not shown in Figure 1(a)) provided on the semiconductor substrate 2 within the hollow portion 3, a movable film 5 covering the hollow portion 3, a conductive film 6 formed on the surface of the movable film 5 in a pattern corresponding to the hollow portion 3, and a polymerized film 7 which is a molecular imprint (MIP) film having a template of the molecule to be detected and formed only on selected surfaces of the conductive film 6, and a Fabry-Perot interferometer is configured between the movable film 5 and the light receiving surface of the photodiode 4. The photodiode 4 is an example of a deformation detection means which detects deformation of the polymerized film 7 due to adhesion of molecules by detecting a change in the intensity of incident light.

[0022] As shown in Figure 1(a), a template 9 for a specific molecule 8 to be detected is formed on the polymer film 7 of this optical interferometer surface stress sensor 1. Therefore, as shown in Figure 1(b), when the specific molecule 8 to be detected binds to the template 9 in the polymer film 7, the interaction between the molecule 8 and the polymer film 7 causes the polymer film 7 to expand or contract and deform. Figure 1(b) shows an example of the polymer film 7 expanding. When light of a specific wavelength is irradiated onto this optical interferometer surface stress sensor 1, light of different wavelengths interferes within the hollow portion 3 depending on the deformation state of the film portion, and the transmittance for the specific wavelength changes. By measuring the change in the transmitted light intensity of the specific wavelength as a photocurrent output by the photodiode 4 (shown in Figure 2), the amount of change in the deflection state of the movable film 5 can be determined, which makes it possible to grasp the binding state of the molecule to the polymer film 7, and thus determine whether the specific molecule has been adsorbed to the polymer film 7 and the amount of adsorbed molecule.

[0023] In the structural example of Fig. 1, hollow portion 3 is a recessed structure formed in semiconductor substrate 2 made of silicon or the like, but in the structural example of Fig. 2, it is configured by being surrounded by insulating layer 10 provided on the surface of semiconductor substrate 2. This insulating layer 10 fixes movable film 5 disposed thereon and also houses wiring, circuits, etc. (not shown) connected to photodiode 4 of semiconductor substrate 2. Hollow portion 3 shown in Figs. 1 and 2 is, as an example, a hollow cylindrical shape with an inner diameter of about 50 µm and a height of about 2.8 µm, but this is just an example, and the inner diameter can also be about 100 to 300 µm and the height can also be about 0.4 to 4 µm.

[0024] As shown in Figures 1 and 2, the movable film 5 covers the hollow section 3, sealing its interior. The movable film 5 must be elastic and optically transparent. Here, a 100-nm-thick Parylene-C film is used. However, a film of an appropriate thickness composed of SBS latex, a rubber-like material primarily composed of styrene-butadiene-styrene, can also be used. As mentioned above, a Fabry-Perot interferometer is configured between the movable film 5 and the light-receiving surface of the photodiode 4 at the bottom of the hollow section 3. Each hollow section 3 sealed with the movable film 5 constitutes a sensor section 11, i.e., a sensor element, which is the smallest unit for detecting molecules. Because the intrusion of liquid into the hollow section 3 changes the refractive index, altering the optical interference characteristics of the interferometer and affecting measurements, the movable film 5 must seal the hollow section 3 in a liquid-tight manner. Furthermore, since the air inside the hollow portion 3 does not affect the refractive index, it is preferable that the hollow portion 3 be in communication with the outside world so that the movable film 5 is not deformed due to at least a change in pressure inside the hollow portion 3. In Fig. 2, a common movable film 5 is provided for three hollow portions 3, which is advantageous in terms of manufacturing, but an independent movable film 5 may be provided for each hollow portion 3, i.e., for each sensor portion 11.

[0025] As shown in Figure 2, the conductive film 6 is formed on the surface of the movable film 5 in independent patterns corresponding to each of the multiple (three in the figure) hollow portions 3. The conductive film 6 is elastic and optically transparent. Here, a 40 nm thick gold thin film layer is used, but ITO (Indium Tin Oxide) can also be used.

[0026] FIG. 2 schematically illustrates the process of manufacturing an optical interferometric surface stress sensor 1, in which a polymerized film 7, a molecularly imprinted (MIP) film with a template for the molecule to be detected, is selectively and locally formed only on the surface of a specific conductive film 6 using an electropolymerization technique. FIG. 2 shows three combinations of hollow sections 3 corresponding to sensor sections 11, the smallest unit of the sensor, and conductive films 6 independently provided for each hollow section 3. Each of the three conductive films 6 is connected to a power source 13 via a switch 12, allowing voltage to be selectively applied to each conductive film 6. Detailed processes, including specific examples, will be described later with reference to FIG. 3. The material for forming the polymerized film 7 is not particularly limited, as long as it is a polymerizable monomer. A solution 15 containing the monomer and the specific molecule to be detected is prepared, and the semiconductor substrate 2 is immersed in this solution 15. For example, to form a polymerized film 7 with a template for the specific molecule only on the top surface of the conductive film 6 on the right side of FIG. 2, only the switch 12 connected to the conductive film 6 on the right side is closed, while the other switches 12 are left open. When switch 12 is closed, a polymerized film 7 containing specific molecules is produced by electropolymerization on the conductive film 6. By removing the specific molecules from the polymerized film 7 in the next step, a polymerized film 7 containing a template for the specific molecule, i.e., a molecular imprinted (MIP) film that serves as a receptor film with a template for the specific molecule, can be selectively and locally formed only on the top surface of the specific conductive film 6. Figure 2 shows a schematic diagram of a polymerized film 7 containing specific molecules, indicated by a small circular pattern, formed on the top surface of the right conductive film 6. A molecular imprinted (MIP) film with a template for another molecule can also be formed on the remaining conductive films 6 using a similar process.

[0027] 3A and 3B are diagrams showing an experimental apparatus and the like for more specifically explaining the process of forming a polymerized film 7 on the surface of a conductive film 6 by electrolytic polymerization in the manufacture of a device including the structure of an optical interferometric surface stress sensor 1 according to an embodiment. FIGS. 3A and 3B show the device in this experimental system before the polymerized film 7 is formed. The device shown in FIGS. 3A and 3B is an element in which three different structures or portions are formed in three hollow portions 3 provided in a common semiconductor substrate 2 in order to compare three different structures: a polymerized film 7 (present invention) as a molecular imprint (MIP) film included in the present invention; a polymerized film 7 without a specific molecular template (comparison object 1); and a portion (comparison object 2) without a conductive film 6 on which the polymerized film 7 is formed. That is, FIGS. 3A and 3B do not show the optical interferometric surface stress sensor of the present invention manufactured as an actual product, but show a portion (present invention) that will become the optical interferometric surface stress sensor 1 of the present invention having a predetermined structure and two portions (comparison objects 1 and 2) that will be used for comparison with the present invention, formed on the same semiconductor substrate 2. Hereinafter, this device (or the same device before completion) will be referred to as experimental device 20.

[0028] As shown in the cross-sectional view of FIG. 3(a) taken along the XZ plane, the experimental device 20 has a semiconductor substrate 2. This semiconductor substrate 2 is provided on a PTFT plate 16. As will be described later, the PTFT plate 16 is a support substrate for clamping a conductive tape 17 with electrode clips during the manufacture of the experimental device 20. Therefore, when commercializing the optical interference type surface stress sensor 1 of the present invention, if the semiconductor substrate 2 is mounted on a printed circuit board and wired, the PTFT plate 16 will not be used. The semiconductor substrate 2 has three hollow portions 3, and a common movable film 5 is provided on the semiconductor substrate 2 to cover the hollow portions 3. A conductive film 6, which is a thin film of Au, is provided only in two places on the movable film 5 corresponding to the two left and right hollow portions 3. In other words, the conductive film 6 is not provided on the movable film 5 corresponding to the central hollow portion 3. In this experimental device 20, the hollow portion 3 of the portion that becomes the optical interference type surface stress sensor 1 of the present invention and the bottom of each hollow portion 3 of the two portions that are the comparison target of the present invention do not have a photodetector as shown in FIG. 2, and the deformation of the movable film 5 is measured by a spectrophotometer as described later.

[0029] 3(b), which is a plan view parallel to the XY plane, three hollow portions 3 (not shown in the figure) are lined up in the X direction, and conductive films 6 are provided directly above two hollow portions 3 on both sides in the X direction, with a movable film 5 appearing at a position directly above the central hollow portion 3 between them. One end of conductive tape 17 is attached to each of the two conductive films 6 in order to apply an electric potential from the outside, and each conductive tape 17 extends in the Y direction with the other end extending onto the PTFT plate 16.

[0030] FIG. 3(c) shows an electropolymerization apparatus 30 for forming a polymerized film 7 by electropolymerization on the conductive film 6 of the experimental device 20 shown in FIGS. 3(a) and 3(b). The electropolymerization apparatus 30 includes a container 31 for storing a solution to be electropolymerized, and three electrodes disposed within the container 31: a working electrode 32, a reference electrode 33 made of Ag / AgCl, and a counter electrode 34 made of Pt. The working electrode 32 is connected to the negative electrode of a variable power supply 35, the reference electrode 33 is connected to the negative electrode of the variable power supply 35 via a voltmeter 36, and the counter electrode 34 is connected to the positive electrode of the variable power supply 35 via an ammeter 37. Each of the electrodes 32, 33, and 34 includes a clip for holding the metal serving as the electrode or the experimental device 20.

[0031] The electropolymerization apparatus 30 shown in FIG. 3(c) employs cyclic voltammetry (CV) as a method for forming the polymerized film 7 by electropolymerization. By going through the steps described below, receptor films with different properties, i.e., polymerized films 7 that are multiple types of molecular imprinted (MIP) films on which templates for different types of molecules to be detected are formed, can be selectively and locally applied to the conductive film 6 on the movable film 5.

[0032] In FIG. 3(a), first, a polymerized film 7 with a template of dopamine (DA) as a specific molecule is formed only on the conductive film 6 corresponding to the hollow portion 3 on the right side of the experimental device 20. To perform electropolymerization, a solution of 100 mM KCl, 1 mM DA, and 10 mM Pyrrole diluted with pure water is prepared. As shown in FIG. 3(c), a container 31 is filled with the solution, and the conductive tape 17 and PTFT plate 16 of the conductive film 6 are clamped with the clip of the working electrode 32. The experimental device 20 is immersed in the solution in the container 31 and a current is applied. A polypyrrole (PPy) film as the polymerized film 7 grows on the conductive film 6, and dopamine molecules are incorporated into the PPy film as shown in the left diagram of FIG. After the polypyrrole film was grown, the experimental device 20 was immersed in ethanol for 30 minutes, and the incorporated dopamine molecules were extracted from the polypyrrole film, forming a dopamine template within the polypyrrole film, as shown in the right diagram of Figure 4.

[0033] Next, by changing the type of molecule added to the electropolymerization solution and performing electropolymerization on the conductive film 6 corresponding to the hollow portion 3 on the left side of the experimental device 20 shown in FIG. 3(a) in the same manner as described above, a polymerized film 7 having a template for a specific molecule other than dopamine molecules can be formed. This allows different types of sensor units 11 capable of detecting different molecules to be formed on the same semiconductor substrate 2. However, in this example, to compare the polymerized film 7, which is a molecularly imprinted (MIP) film of the embodiment, with a template-free polymerized film 7, a polypyrrole film without a template for a specific molecule, such as dopamine molecules, is formed on the other conductive film 6. To perform electropolymerization, a solution containing 100 mM KCl and 10 mM pyrrole diluted with pure water is prepared. The container 31 is filled with this solution. A working electrode 32 is attached to the conductive tape 17 of the target conductive film 6. The experimental device 20 is immersed in the solution in the container 31 and a current is applied. A template-free polypyrrole (PPY) film grows on the conductive film 6.

[0034] FIG. 5 is a cross-sectional view showing the structure of the experimental device 20 fabricated as described above. The experimental device 20 incorporates three measurement target regions with different properties. Specifically, a polypyrrole (Ppy) film 40 with a dopamine molecule template 9 is formed on the conductive film 6 corresponding to the hollow portion 3 on the right side of the experimental device 20. This is indicated as a "Ppy membrane forming a dopamine template" in the legend in FIG. 5. A polypyrrole (Ppy) film 41 without a template is formed on the conductive film 6 corresponding to the hollow portion 3 on the left side of the experimental device 20. This is indicated as a "Ppy-only membrane" in the legend in FIG. 5. The central hollow portion 3 of the experimental device 20 is covered by a movable membrane 5, but no conductive film 6 is present on its upper surface. The area without the conductive film 6 is indicated as "No Au" in FIG. 6, which shows the experimental results described below.

[0035] To detect and compare the dopamine (DA) adsorption reaction at three measurement target portions built into the experimental device 20 shown in Figure 5, a spectrophotometer is used to measure the intensity of reflected light at each wavelength from each measurement target portion of the experimental device 20. The experimental device 20, submerged in a buffer solution, is placed on a movable stage that can move in the X direction (the horizontal direction in Figure 5) and the Y direction (the direction perpendicular to the paper surface in Figure 5), and the spectrophotometer is placed above it. The spectrophotometer includes a light source that generates light of a predetermined wavelength, an optical path connected to the light source that guides the light from the light source to the experimental device 20 on the movable stage and also guides the reflected light from the experimental device 20, and a spectroscope connected to the optical path that measures the intensity of the reflected light from the experimental device 20 at each wavelength to obtain a spectrum.

[0036] By using a spectrophotometer while moving the movable stage in a timely manner, it is possible to irradiate light onto each measurement target portion of the experimental device 20 submerged in a buffer solution, and obtain a spectrum by dispersing the reflected light from the measurement target portion. To capture the movement of the movable membrane 5 of the measurement target portion due to dopamine (DA) adsorption, we obtained a spectrum when dopamine (DA) was reacted with the measurement target portion, and evaluated the change in peak shift over time. Figure 6 is a graph showing the change in peak shift (Peak Shift [nm], vertical axis) over time (Time [min], horizontal axis) of the reflection spectrum obtained when dopamine (DA) was dropped into each of the three measurement target portions to a final concentration of 10 μM. When the reflected light from the measurement target portion of the experimental device 20 is output by the spectroscope of the spectrophotometer, an optical interference peak determined by the length of the air gap in the hollow portion 3 is observed. The value indicating the movement of this interference peak is the peak shift, and depending on which side of ± it has moved, it can be determined whether the movable membrane 5 has expanded or contracted.

[0037] Figure 6 shows that the template-free polypyrrole film 41 (PPy-only membrane, the topmost row of dots in the figure) and the movable membrane 5 made of Parylene-C without gold deposition (No Au, the second row of dots in the figure) did not exhibit a shift in the interference peak due to the drop of dopamine (DA) because of the absence of a dopamine (DA) template. On the other hand, the template-containing polypyrrole film 40 (PPy membrane forming a dopamine template, the bottommost row of dots in the figure) exhibited a shift in the interference peak toward shorter wavelengths. This is thought to be due to the adsorption of dopamine (DA) into the template and the contraction of the membrane. These results demonstrate that label-free detection of neurotransmitters such as dopamine (DA) using molecularly imprinted (MIP) membranes and the application of multiple MIP membranes targeting different molecules are possible through patterning of a conductive film 6 and electropolymerization.

[0038] As described above, according to the optical interference type surface stress sensor 1 of the present invention, the conductive film 6 on the movable film 5 can be formed with high precision in any pattern by a technique such as photolithography. For example, the conductive film 6 can be accurately formed only at the position directly above each hollow portion 3, making it possible to separate the conductive film 6 for each sensor portion 11. In addition, the polymerized film 7, which is a molecular imprint (MIP) film formed on the conductive film 6, is also formed in a pattern corresponding to the conductive film 6. By repeating the manufacturing procedure by electrolytic polymerization with different electrolyte solutions, it is possible to apply multiple types of polymerized films 7, each detecting a different molecule, to the conductive film 6 of each sensor portion 11 on a single chip. This allows multiple types of receptor films, each detecting a different molecule, to be formed for each of the multiple sensor portions 11 (sensor elements, which are the smallest unit of detection) included in one optical interference type surface stress sensor 1 made of a single semiconductor substrate 2, and enables simultaneous detection of different molecules using one device.

[0039] Furthermore, according to the present invention, in a single sensor chip, i.e., a single optical interference type surface stress sensor 1 fabricated on a single semiconductor substrate 2, the conductive film 6 may be formed in a large pattern corresponding to multiple hollow portions 3. That is, if a set of multiple sensor portions 11 that detect the same molecule is referred to as a sensor array, the conductive film 6 may be provided in a continuous pattern for each sensor array. Furthermore, when the conductive film 6 is provided for each sensor array, the conductive film 6 can be accurately formed directly above the multiple hollow portions 3 included in the sensor array, and wiring can be formed in a pattern that connects the multiple conductive films 6 formed directly above the hollow portions 3 to each other. Alternatively, the conductive film 6 may be formed in a solid pattern over the entire area included in the sensor array. Furthermore, if the conductive film 6 is fabricated by photolithography, unlike the prior art described above with reference to FIG. 8, the movable film 5 is not subjected to mechanical shock, and therefore there is no risk of damaging the movable film 5.

[0040] According to the optical interference type surface stress sensor 1 having a sensor array, the same type of molecule can be detected simultaneously at multiple locations using a single sensor chip, i.e., a single optical interference type surface stress sensor 1 built into one semiconductor substrate 2. Therefore, by performing appropriate data processing such as averaging multiple detection results obtained for the molecule, it is possible to improve the accuracy of the detection results and obtain results with high numerical accuracy. Note that two or more sensor arrays coated with different types of polymer films 7 may be formed within a single sensor chip.

[0041] Thus, according to the optical interference type surface stress sensor 1 of the present invention, in a single sensor chip, that is, a single optical interference type surface stress sensor 1 built into one semiconductor substrate 2, a plurality of sensor units 11 that detect the same molecule as the detection target can be provided, a plurality of sensor units 11 that detect a plurality of different molecules as the detection target can be provided, a sensor array that detects the same molecule as the detection target can be provided, or another sensor array that detects a different molecule as the detection target can be provided, and further, a configuration can be adopted in which a plurality of sensor units 11 as described above and one or more sensor arrays as described above are mixed.

[0042] In the description of the embodiments of the present invention, when the movable film 5 covering the hollow portion 3 of the semiconductor substrate 2 deforms due to the adsorption of molecules to the polymer film 7, the interference characteristics of light change in the hollow portion 3, causing a change in the intensity of light transmitted through the movable film 5. As a means for detecting this phenomenon, in the structural example shown in Figure 2, a photodiode 4 is provided at the bottom of the hollow portion 3, and in the structural example of the experimental device 20 shown in Figures 3 to 6, a spectrophotometer is used. However, in short, any means capable of measuring the deformation of the film from changes in the interference characteristics of light in the hollow portion 3 will suffice, and this is not limited to means based on a specific principle.

[0043] According to the optical interference type surface stress sensor 1 of the present invention, the movable film 5 is stretched over the opening of the hollow portion 3, so the deformability of the movable film 5 varies depending on the size of the hollow portion 3. More specifically, since the hollow portion 3 in the embodiment is hollow and cylindrical, the deformability of the movable film 5, i.e., its sensitivity as a sensor, increases in proportion to the square of the diameter of the hollow portion 3. Therefore, by optimally setting the size of the hollow portion 3 according to the concentration of the molecules to be detected contained in the sample, the molecules can be reliably and accurately detected regardless of the concentration of the molecules in the sample. Increasing the diameter of the hollow portion 3 makes the movable film 5 more deformable, increasing the detection sensitivity of the molecules, so that the molecules can be properly detected even in samples with low concentrations of the molecules. Reducing the diameter of the hollow portion 3 makes the movable film 5 less deformable, decreasing the detection sensitivity of the molecules, so that the molecules can be properly detected even in samples with high concentrations of the molecules.

[0044] The optical interference type surface stress sensor 1 of the present invention can also be used as a gas sensor that detects the presence and amount of a specific type of gas. When used as a gas sensor, the movable film 5 must be made of a material that is impermeable to at least the target gas, and must be configured to allow gas that has entered the hollow portion 3 to escape to the outside so that changes in pressure and refractive index do not occur within the hollow portion 3. [Explanation of symbols]

[0045] 1... Optical interference type surface stress sensor 2...Semiconductor substrate 3...Hollow part (cavity) 4...Photodiode 5... Movable membrane 6...Conductive film 7...Polymerized film 8...Specific molecules to be detected 9...Mold 11...Sensor section 20...Experimental device 30…Electrolytic polymerization equipment

Claims

1. a semiconductor substrate; a hollow portion having a height of 0.4 to 4 μm formed in the semiconductor substrate; a movable membrane made of parylene C that covers the hollow portion so as to seal the inside of the hollow portion in a liquid-tight state; a conductive film formed on the surface of the movable film so as to correspond to the hollow portion; a polymer film formed on the surface of the conductive film and having a template for a molecule to be detected; and a sensor unit that detects molecules based on a phenomenon in which the intensity of single-wavelength light transmitted through the movable film changes due to a change in interference characteristics caused by the adsorption of molecules to the polymer film, An optical interference type surface stress sensor characterized in that a plurality of sensors are formed on the semiconductor substrate.

2. a semiconductor substrate; a hollow portion having a height of 0.4 to 4 μm formed in the semiconductor substrate; a movable membrane made of parylene C that covers the hollow portion so as to seal the inside of the hollow portion in a liquid-tight state; a conductive film formed on the surface of the movable film in a pattern corresponding to at least one of the hollow portion and the plurality of hollow portions; a polymer film provided on the surface of the conductive film so as to correspond to the pattern and having a template for a molecule to be detected formed thereon; and An optical interference type surface stress sensor characterized in that molecules are detected based on a phenomenon in which the intensity of single-wavelength light transmitted through the movable film changes due to a change in interference characteristics accompanying the adsorption of molecules to the polymer film.

3. a plurality of sensor parts each having one of the hollow parts, and molecular templates different from each other are formed on the polymer film of the plurality of sensor parts; 3. The optical interference type surface stress sensor according to claim 2, wherein different molecules are detected simultaneously by a plurality of said sensor portions.

4. a sensor array having a plurality of the hollow portions, and a template of the same type of molecule is formed on the polymer film of the sensor array; 3. The optical interference type surface stress sensor according to claim 2, wherein the sensor array detects the same type of molecules at a plurality of locations simultaneously.

5. a first hollow portion that is set to be relatively large in order to detect molecules in a sample having a relatively low concentration of the molecules to be detected; a second hollow portion set to be relatively small for detecting molecules in a sample having a relatively high concentration of the molecule to be detected; 5. The optical interference type surface stress sensor according to claim 2, further comprising:

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