JP6939873B2 - Magnetic sensors, detectors and detection systems - Google Patents

Description

The present invention relates to magnetic sensors, detection devices and detection systems.

Radioimmunoassay (RIA (radio immunoassay), IRMA (immunoradiometric assay)) is known as a quantitative immunoassay. In this method, a competing antigen or antibody can be labeled with a radionuclide, and the antigen can be quantitatively measured from the measurement result of specific activity. The immunoassay is a method of indirectly measuring by labeling a target object such as an antigen. Although this method makes a great contribution to clinical diagnosis due to its high sensitivity, it has the disadvantage that it is necessary to ensure the safety of radionuclides and it requires dedicated facilities and equipment. Therefore, as a method that is easier to handle, for example, a method using a biosensor that uses magnetic beads or the like as a label has been proposed (see Patent Documents 1 to 4).

A conventional biosensor includes a substrate, a magnetoresistive element such as a GMR element provided on the substrate, and a protective film that covers the magnetoresistive element. When a magnetic field is applied after the magnetic beads having an affinity for biomolecules in the sample are captured on the protective layer via the biomolecules, a floating magnetic field is generated from the magnetic beads. When this stray magnetic field is input to the magnetoresistive element, the resistance value of the magnetoresistive element changes, and the biomolecule can be indirectly detected based on the change in the resistance value.

Japanese Patent No. 5161459 Japanese Patent No. 6043395 Japanese Patent No. 6101215 International Publication No. 2017/8227 Pamphlet

In the magnetoresistive element in the biosensor, a magnetoresistive film having a layer structure in which a non-magnetic film is sandwiched between two ferromagnetic films is formed on a substrate, and the magnetoresistive film is formed by using a resist pattern as a mask. It is produced by patterning. At the outer peripheral edge of the magnetoresistive element produced in this way, the magnetization of the ferromagnetic layer (free layer) becomes unstable. Therefore, the magnetic beads are trapped in the protective layer on the predetermined region including the outer peripheral edge of the magnetoresistive element, and the magnetic beads generate floating in the magnetoresistive element in which the magnetization of the ferromagnetic layer (free layer) is unstable. When a magnetic field is applied, noise is superimposed on the output from the biosensor. As a result, there is a problem that the detection accuracy of biomolecules is lowered.

In view of the above problems, it is an object of the present invention to provide a magnetic sensor, a detection device and a detection system including a magnetoresistive element capable of detecting a substance to be detected with high accuracy using magnetic beads.

In order to solve the above problems, the present invention comprises a magnetic sensor used for detecting a substance to be detected in a sample, a substrate having a first surface and a second surface facing the first surface, and a substrate. A magnetoresistive sensor that is provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a protective layer that covers the magnetoresistive sensor and can capture the substance to be detected. The magnetoresistive sensor is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. The height of the upper surface of the protective layer on the first region of the magnetoresistive sensor is the height of the upper surface of the protective layer on the second region of the magnetoresistive sensor. Provided is a magnetic sensor characterized by being higher than the above.

The present invention is a magnetic sensor used for detecting a substance to be detected in a sample, which is a substrate having a first surface and a second surface facing the first surface, and a substrate on the first surface of the substrate. The magnetoresistive sensor is provided on the It is configured in a line shape extending in the first direction in the above, has a first region located on the outer peripheral edge in a plan view, and a second region surrounded by the first region, and has the first region of the magnetoresistive sensor. The height of the upper surface of the protective layer on one region is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive sensor, and the magnetism in the first region of the magnetoresistive element. from the upper surface to the upper surface of the protective layer height of the resistive elements, to provide a magnetic sensor, characterized in der Rukoto than 40 nm.
The present invention is a magnetic sensor used for detecting a substance to be detected in a sample, which is a substrate having a first surface and a second surface facing the first surface, and a substrate on the first surface of the substrate. The magnetoresistive sensor is provided on the It is configured in a line shape extending in the first direction in the above, has a first region located on the outer peripheral edge in a plan view, and a second region surrounded by the first region, and has the first region of the magnetoresistive sensor. The height of the upper surface of the protective layer on one region is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive sensor, and the first region of the magnetoresistive element is said. providing a magnetic sensor characterized by region der Rukoto above 40nm towards the edge of the upper surface of the magnetoresistive element inwardly perpendicular to the end sides.

The present invention is a magnetic sensor used for detecting a substance to be detected in a sample, which is a substrate having a first surface and a second surface facing the first surface, and a substrate on the first surface of the substrate. The magnetoresistive sensor is provided on the It is configured in a line shape extending in the first direction in the above, has a first region located on the outer peripheral edge in a plan view, and a second region surrounded by the first region, and has the first region of the magnetoresistive sensor. The height of the upper surface of the protective layer on one region is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive sensor, and in the first region of the magnetoresistive element, the said. height adjustment layer to provide a magnetic sensor characterized that you have provided between the magnetoresistive element and the protective layer. A lead electrode electrically connected to each of both ends of the magnetoresistive element in the longitudinal direction is further provided, and the height adjusting layer may be made of the same material as the lead electrode, or may be made of an insulating material. It may be configured.

The present invention is a magnetic sensor used for detecting a substance to be detected in a sample, which is a substrate having a first surface and a second surface facing the first surface, and a substrate on the first surface of the substrate. The magnetoresistive sensor is provided on the It is configured in a line shape extending in the first direction in the above, has a first region located on the outer peripheral edge in a plan view, and a second region surrounded by the first region, and has the first region of the magnetoresistive sensor. The height of the upper surface of the protective layer on one region is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive sensor, and the height of the first region of the magnetoresistive element. but to provide a magnetic sensor characterized by higher Ikoto than the height of the second region of the magnetoresistive element. As the magnetoresistive element, a GMR element can be used, and the substance to be detected may be a biomolecule.

The present invention provides a detection device including the magnetic sensor and a support portion that supports the magnetic sensor. A probe capable of specifically binding to the substance to be detected may be present on the surface of the protective layer.

The present invention includes the detection device, a magnetic field generating unit, and a holding unit capable of holding the sample, so that the detection device can bring the magnetic sensor into contact with the sample held by the holding unit. The detection system is provided, wherein the magnetic field generating unit is provided so that a magnetic field is applied to the magnetic sensor that comes into contact with the sample held by the holding unit.

According to the present invention, it is possible to provide a magnetic sensor, a detection device and a detection system including a magnetoresistive element capable of detecting a substance to be detected with high accuracy using magnetic beads.

FIG. 1 is a cut end view showing a schematic configuration of a biosensor according to an embodiment of the present invention. FIG. 2 is a partially enlarged cut end view showing a schematic configuration of a biosensor according to an embodiment of the present invention. FIG. 3 is a cut end view showing a schematic configuration of a magnetoresistive element according to an embodiment of the present invention. FIG. 4 is a perspective view showing a schematic configuration of a biosensor according to an embodiment of the present invention. FIG. 5 is a cut end view for explaining an outline of a method for detecting a biomolecule using a biosensor according to an embodiment of the present invention. FIG. 6 is a partially enlarged cut end view showing a schematic configuration of another aspect (No. 1) of the height adjusting layer according to the embodiment of the present invention. FIG. 7 is a partially enlarged cut end view showing a schematic configuration of another aspect (No. 2) of the height adjusting layer according to the embodiment of the present invention. FIG. 8 is a partially enlarged cut end view showing a schematic configuration of another aspect (No. 3) of the height adjusting layer according to the embodiment of the present invention. FIG. 9A is a cut end view showing one step of the biosensor manufacturing step according to the embodiment of the present invention. FIG. 9B is a cut end view showing a step following the step shown in FIG. 9A. FIG. 9C is a cut end view showing a step following the step shown in FIG. 9B. FIG. 9D is a cut end view showing a step following the step shown in FIG. 9C. 9E is a cut end view showing a step following the step shown in FIG. 9D. 9F is a cut end view showing a step following the step shown in FIG. 9E. FIG. 10 is a cut end view showing a schematic configuration of a detection system according to an embodiment of the present invention.

Embodiments of the present invention will be described with reference to the drawings. In the present embodiment, a biosensor used for detecting a biomolecule as a substance to be detected will be described as an example of a magnetic sensor, but the present embodiment is not limited to this embodiment. The substance to be detected that can be detected by the magnetic sensor may include, for example, various organic compounds such as volatile organic compounds (VOCs) contained in contaminated water and the like, in addition to biomolecules.

FIG. 1 is a cut end view showing a schematic configuration of a biosensor according to the present embodiment, FIG. 2 is a partially enlarged cut end view showing a schematic configuration of a biosensor according to the present embodiment, and FIG. 3 is a partially enlarged cut end view. It is a cut end view which shows the schematic structure of the magnetoresistive element in this embodiment, and FIG. 4 is a perspective view which shows the schematic structure of the biosensor which concerns on this 1 Embodiment.

In the biosensor according to the present embodiment, "X-axis direction, Y-axis direction and Z-axis direction" are specified in some drawings as necessary. Here, the X-axis direction and the Y-axis direction are directions orthogonal to each other in the plane of the substrate (in the plane substantially parallel to the first and second surfaces of the substrate) in the present embodiment, and are the Z-axis directions. Is the thickness direction of the substrate (direction orthogonal to the first and second surfaces of the substrate).

The biosensor 1 according to the present embodiment includes a substrate 2 having a first surface 21 and a second surface 22 facing the first surface 21, a magnetoresistive element 3 provided on the first surface 21 of the substrate 2, and a magnetoresistive element. A height adjusting layer 4 located on the first region 3A located on the outer peripheral edge of the effect element 3 and a protective layer 5 covering the magnetic resistance effect element 3 are provided. In the biosensor 1 according to the present embodiment, the magnetic bead 10 is applied by applying a magnetic field H to the magnetic bead 10 in which the biomolecules in the sample are accumulated, which is captured by the protective layer 5 on the magnetoresistive element 3. the stray field H _S from by detecting at the magnetoresistive element 3, it is possible to detect the biomolecules.

The substrate 2 may have a rectangular shape on which the magnetoresistive element 3 can be mounted, and examples thereof include a semiconductor substrate such as a silicon wafer; a ceramic substrate such as an AlTiC substrate and an alumina substrate; a resin substrate; and a glass substrate. .. Depending on the type of the substrate 2, a base layer (not shown) containing _{Al 2} O ₃ or the like is provided on the first surface 21 of the substrate 2, particularly between the first surface 21 of the substrate 2 and the magnetoresistive element 3. May be. The thickness of the substrate 2 can be appropriately set from the viewpoints of the strength of the substrate 2, the thinning and weight reduction of the biosensor 1, and may be, for example, about 5 to 100 nm.

In the present embodiment, as the magnetoresistive element 3, a spin valve type GMR element or the like can be used. The magnetoresistive element 3 has an MR laminate 60 including an antiferromagnetic layer 61, a magnetization fixing layer 62, a non-magnetic layer 63, and a free layer 64, which are laminated in order from the substrate 2 side (see FIG. 3). The antiferromagnetic layer 61 is made of an antiferromagnetic material and plays a role of fixing the direction of magnetization of the magnetization fixing layer 62 by forming an exchange bond with the magnetization fixing layer 62. The magnetoresistive element 3 may have a configuration in which a free layer 64, a non-magnetic layer 63, a magnetization fixing layer 62, and an antiferromagnetic layer 64 are laminated in this order from the substrate 2 side. Further, the magnetized fixed layer 62 has a laminated ferromagnetic structure of a ferromagnetic layer / a non-magnetic intermediate layer / a ferromagnetic layer, and both ferromagnetic layers are antiferromagnetically coupled to form a so-called self-pinning fixed layer (Synthetic). The antiferromagnetic layer 61 may be omitted by using the Ferri Pinned layer and the SFP layer).

In the GMR element as the magnetoresistive element 3, the non-magnetic layer 63 is a non-magnetic conductive layer. In the GMR element, the resistance value changes according to the angle formed by the magnetization direction of the free layer 64 with respect to the magnetization direction of the magnetization fixed layer 62, and when this angle is 0 ° (the magnetization directions are parallel to each other). The resistance value becomes the minimum, and the resistance value becomes the maximum at 180 ° (the magnetization directions of each other are antiparallel).

In the magnetoresistive element 3, a plurality of line-shaped portions 31 extending along the X-axis direction (first direction) are arranged in parallel in the Y-axis direction (second direction), and between the ends of adjacent line-shaped portions 31. Is connected by the lead electrode 6 to form a meander shape (see FIG. 4). In FIG. 4, the height adjusting layer 4 and the protective layer 5 are not shown because the drawing becomes complicated.

Since the GMR element as the magnetoresistive element 3 generally has a relatively low element resistance value, in order to output a signal of a predetermined intensity from the biosensor 1, the line width of the GMR element is narrowed to make a line. The length needs to be increased. Then, by configuring the GMR element in the shape of the meander, the line width of the GMR element can be narrowed and the line length can be lengthened within a limited region on the first surface 21 of the substrate 2. The lead electrode 6 may be composed of, for example, a conductive material of one of Cu, Al, Au, Ta, Ti and the like, or a composite film of two or more kinds of conductive materials.

In the magnetoresistive element 3 composed of the plurality of line-shaped portions 31, the magnetization direction of the magnetization fixing layer 62 is substantially parallel to the lateral direction of each line-shaped portion 31. In the biosensor 1 according to the present embodiment, magnetism is applied to the magnetic beads 10 captured by the protective layer 5 on the magnetoresistive element 3 by applying a magnetic field H in a direction orthogonal to the first surface 21 of the substrate 2. stray field H _S is generated from the bead 10, it is applied to the magnetoresistance effect element 3 (see FIG. 5). By this stray magnetic field H _S is applied to the magnetoresistive effect element 3, the direction of magnetization is changed in the free layer 64, whereby the resistance value of the magnetoresistive effect element 3 is changed. By outputting the change in the resistance value as a signal, the biosensor 1 can detect the presence and abundance of biomolecules in the sample.

The length of the line-shaped portion 31 in the longitudinal direction can be appropriately set according to the size of the entire biosensor 1 and the sensitivity required for the biosensor 1, but may be, for example, about 10 to 500 μm. The length in the lateral direction may be, for example, about 0.2 to 10 μm.

In the plan view of the biosensor 1 according to the present embodiment, each line-shaped portion 31 of the magnetoresistive element 3 has a first region 3A located on the outer peripheral edge of each line-shaped portion 31 and an inside of the first region 3A. It is located in and has a second region 3B surrounded by a first region 3A. _{The first region 3A is a region having a predetermined width W 3A} that extends inward at right angles to each end edge from each end edge of the upper surface 32 of each line-shaped portion 31. The width W _3A is preferably 40 nm or more. As will be described later, the height adjusting layer 4 is provided in the first region 3A of the magnetoresistive element 3, so that the upper surface of the protective layer 5 in the first region 3A is the protective layer 5 in the second region 3B. It is configured higher than the top surface. _{More specifically, the height H 3A} of the upper surface of the protective layer 5 in the first region 3A is preferably 40 nm or more. This means that if the magnetic beads 10 are present in a region within a radius of 40 nm from the edge of the upper surface of the magnetoresistive element 3, noise is likely to be superimposed on the output of the biosensor 1. Therefore, if the width _{W 3A} of the first region 3A is less than 40 nm, the stray field _{H S} from the magnetic beads 10 trapped in the vicinity of the first region 3A in the second region 3B, noise output from the biosensor 1 May be easily superimposed. The upper limit of the width W _3A of the first region 3A may be less than 1/2 of the width of the upper surface of each line-shaped portion 31 of the magnetoresistive element 3 in the lateral direction, and the width in the lateral direction. It is preferably about 10% of the above.

In the biosensor 1 according to the present embodiment, the height adjusting layer 4 is provided in the first region 3A of the magnetoresistive element 3. By providing the height adjusting layer 4, the height of the upper surface of the protective layer 5 in the first region 3A can be made higher than the height of the upper surface of the protective layer 5 in the second region 3B. Since both ends in the longitudinal direction of the plurality of line-shaped portions 31 constituting the magnetoresistive element 3 are covered with the lead electrodes 6, the height adjusting layer 4 is provided at both ends in the point direction of the plurality of line-shaped portions 31. It may be provided in the first region 3A of the unit. In this case, the lead electrode 6 that covers both ends of each line-shaped portion 31 in the longitudinal direction can also function as the height adjusting layer 4.

The height adjusting layer 4 may be made of, for example, the same material as the lead electrode 6, or may be _{an insulating material such as SiO 2} , Al ₂ O ₃ , Si ₃ N ₄ , TiN, TaN, TaO, TiO, Al N, or the like. It may be composed of.

The thickness T ₄ of the height adjustment layer 4, the stray field H _S of the magnetic beads 10 to be trapped in the protective layer 5 on the first region 3A of the magnetoresistive element 3, the noise on the output from the biosensor 1 It can be set appropriately to the extent that it does not overlap. _{As will be described later, if the height H 3A} of the upper surface of the protective layer 5 in the first region 3A is 40 nm or more, it becomes difficult for noise to be superimposed on the output from the biosensor 1, and the biomolecule is generated by using the magnetic beads 10. It can be detected with high accuracy. Therefore, for example, when the thickness _{T 5} of the protective layer 5 is about 30nm, the thickness _{T 4} of the height adjustment layer 4 may be at 10nm or more.

The shape of the height adjusting layer 4 is as long as the height of the upper surface of the protective layer 5 in the first region 3A of the magnetoresistive element 3 can be made higher than the height of the upper surface of the protective layer 5 in the second region 3B. It is not particularly limited. For example, the height adjusting layer 4 may be provided so as to extend from the first region 3A of the magnetoresistive sensor 3 to the first surface 21 of the substrate 2 (see FIG. 1), or the magnetism in the first region 3A. It has a base 41 that stands upward from the upper surface of the resistance effect element 3 and an extension portion 42 that extends from the base 41 toward the outside of the magnetoresistive element 3 along the in-plane direction. The insulating layer 7 may be provided between the 42 and the magnetoresistive element 3 (see FIG. 6), or may be provided only on the upper surface of the magnetoresistive element 3 in the first region 3A (FIG. 6). 7). Further, the height adjusting layer 4 may be made of the same material as the magnetoresistive element 3 (see FIG. 8). In the embodiment shown in FIG. 8, in the milling process of the MR film 70 in the manufacturing process of the biosensor 1, the height adjusting layer 4 uses the material of the milled MR film 70 as the material of the magnetoresistive element 3 in the first region 3A. It may be formed by reattaching to the upper surface.

In the present embodiment, the protective layer 5 that covers the entire first surface 21, the magnetoresistive element 3 and the height adjusting layer 4 of the substrate 2 is a layer on which biomolecules accumulated in the magnetic beads 10 can be captured. .. The biomolecules accumulated in the magnetic beads 10 are captured by the protective layer 5 by, for example, electrostatic interaction, hydrogen bond interaction, or the like with the protective layer 5. Therefore, the protective layer 5 has, for example, electrostatic interaction, hydrogen bond interaction, and the like with biomolecules such as _{SiO 2} , Al ₂ O ₃ , Si ₃ N _{4, TiN, TaN, TaO, TiO, and AlN.} It suffices if it is composed of a material that can be exerted. The surface of the protective layer 5, particularly the surface of the protective layer 5 on the second region 3B of the magnetoresistive element 3, is specific to the biomolecule to be detected so that the biomolecule can be easily captured. It may be provided with an affinity substance capable of binding to.

The thickness T ₅ of the protective layer 5, the degree of stray magnetic field H _S generated from the magnetic beads 10 to bind to biological molecules captured on the upper surface of the protective layer 5 in the second region 3B can be applied to the magnetoresistive element 3 _{The height H 3A} (height from the upper surface of the magnetoresistive sensor 3) of the upper surface of the protective layer 5 in the first region 3A is 40 nm or more, and the height of the upper surface of the protective layer 5 in the second region 3B is 40 nm or more. The height H _3B (height from the upper surface of the magnetoresistive sensor 3) can be appropriately set according to _{the thickness T 4 of the height adjusting layer 4 so as to be about 30 nm.} For example, when the thickness _{T 4} of the height adjustment layer 4 is about 10 nm, a thickness _{T 5} of the protective layer 5, for example, may be set to approximately 30 nm.

By contacting the biosensor 1 having the above-described configuration with a sample containing the biomolecule 11 to be detected, the biomolecule 11 can be captured on the surface of the protective layer 5. Then, after binding the biomolecule 11 captured on the surface of the protective layer 5 and the magnetic beads 10, the biomolecule 11 is captured on the surface of the protective layer 5 on the first region 3A of the magnetoresistive element 3 by a gradient magnetic field or cleaning. The biomolecule 11 and the magnetic bead 10 are selectively removed. In the present embodiment, the surface height of the protective layer 5 on the first region 3A of the magnetoresistive element 3 is higher than the surface height of the protective layer 5 on the second region 3B, so that the surface of the cleaning liquid The flow velocity is higher than that on the protective layer 5 in the second region 3B, so that cleaning is easily promoted, and the magnetic beads 10 desorbed by a gradient magnetic field or the like are likely to collide with each other. As a result, the biomolecule 11 and the magnetic beads 10 trapped on the surface of the protective layer 5 on the first region 3A of the magnetoresistive element 3 can be easily and selectively removed by a gradient magnetic field or cleaning.

After leaving the biomolecule 11 and the magnetic beads 10 on the surface of the protective layer 5 on the second region 3B of the magnetoresistive sensor 3 as described above, a magnetic field is applied along the direction orthogonal to the first surface 21 of the substrate 2. by applying a H, magnetic beads 10 magnetized, stray magnetic field H _S is generated from the magnetic beads 10 (see FIG. 5). The stray magnetic field H _S is that applied to the magnetoresistance effect element 3, changes the magnetization direction of the free layer 64, the resistance value of the magnetoresistance effect element 3 is changed as a result. Since this resistance value change has a correlation (linear correlation) with the number of magnetic beads 10 bound to the biomolecule 11 captured on the surface of the protective layer 5, this resistance value change is used as a signal for the biosensor 1. By outputting from, the presence and abundance of the biomolecule to be detected in the sample can be detected.

Examples of the biomolecule 11 that can be detected using the biosensor 1 according to the present embodiment include DNA, mRNA, miRNA, siRNA, and artificial nucleic acid (for example, LNA (Locked Nucleic Acid), BNA (Bridged Nucleic Acid), etc.). Nucleic acids such as (naturally derived or chemically synthesized); peptides such as ligands, cytokines and hormones; proteins such as receptors, enzymes, antigens and antibodies; cells and viruses , Bacteria, fungi and the like.

Examples of the sample containing the biomolecule 11 to be detected include blood, serum, plasma, urine, puffy coat, saliva, semen, pleural effusion, cerebrospinal fluid, tears, sputum, mucus, lymph, and ascites. Examples thereof include pleural effusion, sheep's fluid, bladder lavage fluid, bronchial alveolar lavage fluid, cell extract, and cell culture supernatant.

The magnetic beads 10 may be particles that can be magnetized, and may be particles composed of gold, iron oxide, or the like. The average particle size of the magnetic beads 10 may be, for example, about 5 to 250 nm, and preferably about 20 to 150 μm. The average particle size of the magnetic beads 10 can be measured using, for example, a laser diffraction type particle size distribution measuring device (product name: SALD-2300, manufactured by Shimadzu Corporation).

The surface of the magnetic beads 10 may be immobilized with a protein such as streptavidin, or may further be provided with an affinity substance capable of specifically binding to a biomolecule. The magnetic beads 10 preferably have a hydrophilic surface when used to capture the ligand as the biomolecule 11, and the magnetic beads 10 when used to capture the antibody as the biomolecule 11. Preferably have a hydrophobic surface.

According to the biosensor 1 having the above-described configuration, by providing the height adjusting layer 4 in the first region 3A of the magnetoresistive element 3, it is possible to make it difficult to capture the magnetic beads 10 on the first region 3A. can, or stray field H _S of the magnetic beads 10 captured on the on the first region 3A can be made difficult to affect the resistance change of the magnetoresistive element 3. Therefore, biomolecules can be detected with high accuracy using the magnetic beads 10 without superimposing noise on the output signal from the biosensor 1.

The biosensor 1 having the above-described configuration can be manufactured, for example, as follows. 9A to 9F are process flow charts showing each step of the manufacturing method of the biosensor 1 according to the present embodiment on the cut end face.

AlTiC substrate, a ceramic substrate of alumina substrate or the like; a semiconductor substrate such as a silicon wafer resin substrate; glass substrate Al ₂ O ₃ in the region where to form the magnetoresistance effect element 3 on the first surface 21 of the substrate 2, such as such as MR film 70 (anti-ferromagnetic film, ferromagnetic film, non-magnetic film and ferromagnetic film is laminated in this order on the first surface 21 of the substrate 2 to form a base layer (not shown). ) Is formed by sputtering or the like (see FIG. 9A).

Next, the first resist layer 80 and the second resist layer 81 covering the MR film 70 are laminated and formed in this order (see FIG. 9B), and the first resist corresponding to the magnetoresistive element 3 is subjected to exposure / development processing. A resist pattern 84 having a laminated structure of the pattern 82 and the second resist pattern 83 is formed (see FIG. 9C).

The resist material constituting the first resist layer 80 and the second resist layer 81 may be either a positive type or a negative type, but the resist material constituting the first resist layer 80 (for example, cyclopenta) may be used. The non-based material) has lower resistance to a developing solution (for example, an organic alkaline developing solution such as tetramethylammonium hydroxide (TMAH)) than the resist material (for example, novolak resin type) constituting the second resist layer 81. It is preferable to have it. As a result, when the first resist layer 80 and the second resist layer 81 are developed at the same time, the side surfaces of the first resist pattern 82 are eroded, and the side surfaces of the MR film 70, the first resist pattern 82, and the second resist pattern 83 are formed. A space SP surrounded by the bottom surface can be formed. The space SP formed in this way can define a region in which the height adjusting layer 4, which will be described later, is formed, that is, a first region 3A. _{The width W 3A} of the first region 3A is controlled by the amount of erosion of the first resist layer 80 in the in-plane direction, and this erosion amount can be controlled, for example, by appropriately setting exposure conditions and the like.

Next, the MR film 70 is subjected to a milling treatment using the resist pattern 84 as a mask, and then a magnetic field is applied while performing a predetermined annealing treatment to apply a plurality of magnetoresistive elements 3 on the first surface of the substrate 2. A line-shaped portion 31 is formed (see FIG. 9D). The applied magnetic field is the constituent material of each layer of the magnetic resistance effect element 3, the film thickness, size, shape of each layer, and the effective effect given by the perpendicular magnetic anisotropy energy Ku and the shape anisotropy energy Kd of the magnetization fixing layer 62. It can be appropriately set to induce a predetermined exchange magnetic anisotropy between the antiferromagnetic layer 61 and the magnetization fixing layer 62 according to the vertical magnetic anisotropy energy Keff or the like.

Subsequently, the lead electrode 6 continuous between the longitudinal ends of the adjacent line-shaped portions 31 is formed by sputtering or the like of a conductive material, and the height adjusting layer 4 is formed in the first region 3A of each line-shaped portion 31. (See FIG. 9E). As described above, a resist pattern 84 having a laminated structure of the first resist pattern 82 and the second resist pattern 83 is formed on the upper surface of the line-shaped portion 31, and is inward from the end edge of the upper surface of the line-shaped portion 31. A space SP is formed on a predetermined region toward the (see FIG. 9C). With such a space SP, it is possible to define a region (first region 3A) in which the height adjusting layer 4 is formed by sputtering or the like of a conductive material. That is, the width W _{3A of the first region 3A and the thickness T 4} of the height adjusting layer 4 formed in the first region 3A can be controlled by the size of the space SP. Specifically, the size of the space SP is adjusted by adjusting the thickness and width (erosion amount) of the first resist pattern 82, thereby adjusting the widths W _3A and the first region 3A of the first region 3A. _{The thickness T 4} of the height adjusting layer 4 formed in can be controlled.

When the height adjusting layer 4 is made of the same conductive material as the lead electrode 6, the height adjusting layer 4 is conductive to the first region 3A of each line-shaped portion 31 at the same time as forming the lead electrode 6. It is formed by sputtering the material. On the other hand, when the height adjusting layer 4 is made of an insulating material, the height adjusting layer 4 forms an insulating material on the first region 3A of each line-shaped portion 31 before or after the formation of the lead electrode 6. Can be formed by

Finally, after the resist pattern 84 is peeled off, a protective layer 5 covering the first surface 21, the magnetoresistive element 3 and the height adjusting layer 4 of the substrate 2 is formed (see FIG. 9F). As a result, the biosensor 1 according to the present embodiment can be manufactured.

A detection device using the biosensor 1 having the above-described configuration and a detection system including the detection device will be described. FIG. 10 is a cut end view showing a schematic configuration of the detection system according to the present embodiment.

The detection system 100 in the present embodiment includes a biosensor 1 and a detection device having a support portion 110 that supports the biosensor 1, a magnetic field generator 120, and a plurality of reservoirs 140 that accommodate a sample 200 containing a biomolecule. It is provided with a plate 130 having a plate 130.

A probe (for example, a ligand or the like) capable of specifically binding to a biomolecule in the sample 200 may be provided on the surface of the protective layer 5 of the biosensor 1. Of course, the probe is not provided on the surface of the protective layer 5 of the biosensor 1, and the surface of the protective layer 5 of the biosensor 1 is protected by biomolecules by, for example, electrostatic interaction, hydrogen bond interaction, or the like. It may be configured to be captured by layer 5. The biomolecule in the sample 200 may be accumulated on the magnetic beads 10 (see FIG. 5). The support portion 110 that supports the biosensor 1 has a plurality of strip-shaped portions having a size that can be inserted into each reservoir 140. The biosensor 1 is attached to the tip of each strip so that the biosensor 1 can be brought into contact with the sample 200 contained in each reservoir 140 when the tip of the strip is inserted into the reservoir 140. Has been done. The support portion 110 is provided so as to be able to move up and down, whereby each strip-shaped portion can be inserted into or removed from each reservoir 140.

The magnetic field generation unit 120 is composed of, for example, a coil or the like capable of generating a magnetic field in a direction orthogonal to the first surface 21 of the substrate 2 of the biosensor 1, and the biosensor 1 is included in the sample 200 housed in each reservoir 140. Is provided so that a magnetic field can be applied to the biosensor 1 when the biosensor 1 is in contact with the biosensor 1.

In the detection system 100 having such a configuration, when the biosensor 1 is brought into contact with the sample 200 contained in each reservoir 140, the biomolecules accumulated in the magnetic beads 10 (see FIG. 5) become the biosensor 1. It is captured by the protective layer 5 of. In this state, the magnetic field generating unit 120, when generating the magnetic field along the direction perpendicular to the first surface 21 of the substrate 2, the magnetic beads 10 magnetized, stray magnetic field H _S of the magnetic beads 10 _(see FIG. 5) Occurs. By this stray magnetic field H _S is applied to the magnetoresistive effect element 3, changes the magnetization direction of the free layer 64, resulting resistance value of the magnetoresistance effect element 3 is changed as the signal is output from the biosensor 1 Will be done. Since the change in the resistance value of the magnetoresistive element 3 has a correlation (linear correlation) with the number of magnetic beads 10 bound to the biomolecule 11 captured on the surface of the protective layer 5, in the detection system 100. Can detect the presence and abundance of biomolecules in a sample based on the signal output from the biosensor 1.

In the detection system 100, the magnetic field generating unit 120 generates a magnetic field for magnetizing the magnetic beads 10, and biomolecules accumulated in the magnetized magnetic beads 10 are transferred to the protective layer 5 of the biosensor 1. In the captured state, an alternating magnetic field in the in-plane direction (in-plane direction of the XY plane) of the magnetoresistive sensor 3 may be generated. In the detection system 100 of this aspect, first, the biosensor 1 is brought into contact with the sample 200 housed in each reservoir 140, and the magnetic beads 10 are magnetized and magnetized by the magnetic field generated from the magnetic field generating unit 120. The biomolecules accumulated in the magnetic beads 10 are captured by the protective layer 5 of the biosensor 1. In that state, when the AC magnetic field is generated from the magnetic field generating unit 120, a floating magnetic field is generated from the magnetic beads 10. When this stray magnetic field is applied to the magnetoresistive element 3, the magnetization direction of the free layer 64 changes, and as a result, the resistance value of the magnetoresistive element 3 changes, and a signal is output from the biosensor 1. ..

The embodiments described above are described for facilitating the understanding of the present invention, and are not described for limiting the present invention. Therefore, each element disclosed in the above embodiment is intended to include all design changes and equivalents belonging to the technical scope of the present invention.

In the above embodiment, a conductive material (the same material as the lead electrode 6) or an insulating material constituting the height adjusting layer 4 is formed on the entire surface, and a resist pattern is formed in a region corresponding to the first region 3A of the magnetoresistive element 3. The height adjusting layer 4 may be formed by an etching process using the resist pattern as a mask. Further, by adjusting the irradiation angle of the ion beam in the milling process of the MR film 70 using the resist pattern 84 as a mask, the constituent material of the MR film 70 is regenerated in the region corresponding to the first region 3A of the magnetoresistive element 3. It may be adhered to form the height adjusting layer 4. In this case, the height of the height adjusting layer 4, that is, the reattachment amount of the constituent material of the MR film 70 is the size of the space SP defined by the thickness and width (erosion amount) of the first resist pattern 82 and the ions. It can be adjusted by the irradiation angle of the beam.

Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited to the following Examples and the like.

[Test Example 1]
_{The height H 3B} of the upper surface of the protective layer 5 in the second region 3B of the biosensor 1 having the configuration shown in FIG. 1 _{is 30 nm, and the height H 3A} of the upper surface of the protective layer 5 in the first region 3A is shown in Table 1. For each of the different samples (Samples 1 to 4), the resistance change rate of the magnetoresistive element 3 in the state where the magnetic beads 10 are captured in the first region 3A and the second region 3B (before the magnetic beads 10 are captured (zero). The rate of change based on the resistance value of the magnetoresistive element 3 in the magnetic field) was obtained by simulation. The results are shown in Table 1. The sample 4 is a biosensor 1 having the configuration shown in FIG. 1 and does not have the height adjusting layer 4, that is, the heights H _3A and the second region 3B of the upper surface of the protective layer 5 in the first region 3A. _{The height H 3B} of the upper surface of the protective layer 5 is the same. The resistance change rate of each sample is a relative value when the design value of the resistance change rate of the magnetoresistive effect element 3 for obtaining the output required for the biosensor 1 is 1.

As is clear from the results shown in Table 1, the biosensor 1 does not have the height adjusting layer 4, and the height H _3A of the upper surface of the protective layer 5 in the first region 3A and the protective layer 5 in the second region 3B. If the height H _{3B of the} upper surface is the same (Sample 4), the resistance change rate of the magnetoresistive element 3 deviates from the ideal value, and noise is superimposed on the output of the biosensor 1. In that respect, as in Samples 1 to 3, the height H _3A of the upper surface of the protective layer 5 in the first region 3A is made higher than _{the height H 3B} of the upper surface of the protective layer 5 in the second region 3B. The resistance change rate of the resistance effect element 3 can be brought close to the ideal value. _{By setting the height H 3A} of the upper surface of the protective layer 5 in the first region 3A to 40 nm or more, the influence of noise on the output of the biosensor 1 can be reduced. Therefore, the magnetic beads 10 are used as a sample. It was confirmed that the biomolecule 11 inside can be detected with high accuracy.

Further, from the results shown in Table 1, it can be seen that if the magnetic beads 10 are present within a radius of 40 nm around the end edge of the magnetoresistive element 3 in a cross-sectional view, noise is likely to be superimposed on the output of the biosensor 1. can. Therefore, the width W _3A of the first region 3A is equal to or 40nm or more from the edge of the magnetoresistive element 3, is that the biomolecules 11 in the sample using magnetic beads 10 can be detected with high precision can.

1 ... Biosensor 2 ... Substrate 21 ... First surface 22 ... Second surface 3 ... Magnetoresistive element 31 ... Line-shaped part 3A ... First region 3B ... Second region 4 ... Height adjustment layer 5 ... Protective layer

Claims (12)

A magnetic sensor used to detect a substance to be detected in a sample.
A substrate having a first surface and a second surface facing the first surface,
A magnetoresistive element provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a magnetoresistive element.
A protective layer capable of capturing the substance to be detected, which covers the magnetoresistive element, is provided.
The magnetoresistive element is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. Has 2 regions and
A magnetism characterized in that the height of the upper surface of the protective layer on the first region of the magnetoresistive element is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive element. Sensor. A magnetic sensor used to detect a substance to be detected in a sample.
A substrate having a first surface and a second surface facing the first surface,
A magnetoresistive element provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a magnetoresistive element.
With the protective layer that covers the magnetoresistive element
With
The magnetoresistive element is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. Has 2 regions and
The height of the upper surface of the protective layer on the first region of the magnetoresistive element is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive element.
Magnetic sensor you wherein height from the upper surface to the top surface of the protective layer the magnetoresistive element in the first region is 40nm or more of said magnetoresistive element. A magnetic sensor used to detect a substance to be detected in a sample.
A substrate having a first surface and a second surface facing the first surface,
A magnetoresistive element provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a magnetoresistive element.
With the protective layer that covers the magnetoresistive element
With
The magnetoresistive element is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. Has 2 regions and
The height of the upper surface of the protective layer on the first region of the magnetoresistive element is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive element.
It said first region, magnetic sensor you wherein a region from an end side of the above 40nm inward perpendicular to the end sides of the upper surface of the magnetoresistive element of the magnetoresistive element. A magnetic sensor used to detect a substance to be detected in a sample.
A substrate having a first surface and a second surface facing the first surface,
A magnetoresistive element provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a magnetoresistive element.
With the protective layer that covers the magnetoresistive element
With
The magnetoresistive element is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. Has 2 regions and
The height of the upper surface of the protective layer on the first region of the magnetoresistive element is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive element.
Wherein in the first region of the magnetoresistive element, the height adjustment layer is provided magnetic sensors you wherein between the protective layer and the magnetoresistive element. A lead electrode that is electrically connected to each of both ends of the magnetoresistive element in the longitudinal direction is further provided.
The height adjusting layer includes a first height adjusting layer located in the first region at both ends in the longitudinal direction of the magnetoresistive element, and the first one at both ends in the lateral direction of the magnetoresistive element. Includes a second height adjustment layer located in the region
The first height adjusting layer is composed of the lead electrodes.
The magnetic sensor according to claim 4, wherein the second height adjusting layer is made of the same material as the lead electrode. A lead electrode that is electrically connected to each of both ends of the magnetoresistive element in the longitudinal direction is further provided.
The height adjusting layer includes a first height adjusting layer located in the first region at both ends in the longitudinal direction of the magnetoresistive element, and the first one at both ends in the lateral direction of the magnetoresistive element. Includes a second height adjustment layer located in the region
The first height adjusting layer is composed of the lead electrodes.
The magnetic sensor according to claim 4, wherein the second height adjusting layer is made of an insulating material. A magnetic sensor used to detect a substance to be detected in a sample.
A substrate having a first surface and a second surface facing the first surface,
A magnetoresistive element provided on the first surface of the substrate and whose resistance value changes according to an input magnetic field, and a magnetoresistive element.
With the protective layer that covers the magnetoresistive element
With
The magnetoresistive element is configured in a line shape extending in the first direction on the first surface of the substrate, and is surrounded by a first region located on the outer peripheral edge in a plan view and the first region. Has 2 regions and
The height of the upper surface of the protective layer on the first region of the magnetoresistive element is higher than the height of the upper surface of the protective layer on the second region of the magnetoresistive element.
The height of the first region, magnetic sensor you being higher than the height of the second region of the magnetoresistive element of the magnetoresistive element. The magnetic sensor according to any one of claims 1 to 7, wherein the magnetoresistive element is a GMR element. The magnetic sensor according to any one of claims 1 to 8, wherein the substance to be detected is a biomolecule. The magnetic sensor according to any one of claims 1 to 9.
A detection device including a support portion that supports the magnetic sensor. The detection device according to claim 10, wherein a probe capable of specifically binding to the substance to be detected is present on the surface of the protective layer. The detection device according to claim 10 or 11.
Magnetic field generator and
It is provided with a holding portion capable of holding the sample.
The detection device is provided so that the magnetic sensor can be brought into contact with the sample held by the holding portion.
The detection system is characterized in that the magnetic field generating unit is provided so that a magnetic field is applied to the magnetic sensor that comes into contact with the sample held by the holding unit.

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