TW201716779A - Sensor - Google Patents

Abstract

The present invention addresses the problem of providing a compact sensor with which it is possible to perform simultaneous measurements of glucose and biologically relevant substances other than glucose. The present invention pertains to a sensor characterized by having at least: a first detection element for detecting glucose in a biological liquid; and a second detection element for detecting biologically relevant substances other than glucose, the second detection element including a semiconductor element.

Description

Sensor

The present invention relates to a sensor capable of simultaneously measuring a plurality of living body related substances.

In order to perform screening tests and treatments for diabetes, it is also necessary to measure glucose in the blood, and to measure glycosylated hemoglobin (hereinafter also referred to as HbA1c) and glycated albumin (hereinafter referred to as glycated albumin (hereinafter referred to as glycated albumin). Glycoalbumin)) and so on.

In diabetes, the production of glycated proteins is increased, and the concentration of HbA1c contained in red blood cells and glycated albumin in serum reflects the average blood glucose level in a certain period in the past. Glucose shows the current state of blood glucose. In contrast, glycated albumin reflects a blood glucose state of about 1 week to 2 weeks, and HbA1c reflects a blood glucose state of about 1 month to 2 months ago. Therefore, the determination of these glycated proteins can determine the blood glucose concentration over time, and thus is important for the temporal diagnosis or symptom management of diabetic symptoms. Therefore, as an indicator of diabetes management, a rapid and accurate quantitative method for glucose concentration and HbA1c and glycated albumin has been sought.

A method of measuring glucose in a biological fluid is, for example, an electrochemical detection method called an enzyme electrode method. The method is to output information relating to the glucose concentration in the biological sample from the electrode in contact with the biological sample, and calculate the glucose concentration based on the output. Since the enzyme electrode method can be applied to a small blood glucose sensor, the method is mainly adopted by diabetic patients in the world.

On the other hand, as a method for measuring HbA1c, for example, a chromatography method such as HPLC (High Performance Liquid Chromatography) or a latex immuno-coagulating method is known. The measurement method and the enzymatic method using an enzyme which acts on a glycated protein, etc. These methods are widely used in clinical sites and the like as a method of detecting light.

In addition, at the clinical site, a part of a device capable of measuring both glucose and glycated hemoglobin (glycohemoglobin (including glycated hemoglobin including HbA1c)) was introduced. In such a device, a device obtained by connecting a device for measuring glucose and glycated hemoglobin, and a device for measuring both glucose and glycated hemoglobin by one device (see, for example, Patent Document 1). [Prior Art Document] [Patent Literature]

Patent Document 1: Japanese Patent Laid-Open Publication No. 2014-95715

In the technique described in Patent Document 1, by increasing various elements in the measurement of glucose and glycated hemoglobin, the size of the device is suppressed. However, in each of the measurement mechanisms, for example, it is difficult to further downsize the device due to the necessity of a light source or the like.

[Problems to be Solved by the Invention] In view of the above problems, an object of the present invention is to provide a small-sized sensor capable of simultaneously measuring a biological substance other than glucose such as glucose and HbA1c and glycated albumin. [Means for solving the problem]

In order to solve the above problems, the present invention has the following configuration. 1. A sensor comprising: at least: a first detecting element that detects glucose in a biological fluid; and a second detecting element that detects a biologically relevant substance other than glucose, and the second detecting element includes a semiconductor element. 2. The sensor according to the above 1, wherein the organism-related substance is glycated hemoglobin or glycated albumin. 3. The sensor according to the above 1 or 2, characterized in that it further has a third detecting element, and the third detecting element detects hemoglobin. 4. A sensor according to the above 3, wherein the third detecting element comprises a semiconductor element. 5. The sensor according to any one of the above 1 to 4, wherein the area of the detecting portion of the second detecting element is twice or more the area of the detecting portion of the third detecting element. 6. The sensor according to any one of the above 1 to 5, wherein the semiconductor element contains a carbon nanotube. 7. The sensor according to any one of the above 1 to 6, wherein the semiconductor element includes at least a substrate, a first electrode, a second electrode, and a semiconductor layer, and the first electrode and the second electrode are selected from the group consisting of 80 At least one of a metal-type single-layer carbon nanotube, a double-layer carbon nanotube, and a multilayer carbon nanotube having a weight percentage or more. 8. The sensor according to any one of the above 1 to 7, wherein the semiconductor layer contains a carbon nanotube. 9. The sensor according to any one of the above 6 to 8, wherein at least a part of the surface of the carbon nanotube is attached with a conjugated polymer. 10. The sensor according to any one of the items 7 to 9, wherein the bio-related substance selectively interacting with the bio-related substance is fixed to the semiconductor layer. 11. The sensor according to any one of the above 1 to 10, wherein the sensor has an injection port and a path of a biological body fluid, and the path is connected to the injection port and the first detecting element and the second detecting, respectively element. 12. The sensor according to any one of the above 1 to 11, wherein the biological fluid is blood. 13. The sensor according to any one of the above 1 to 12, wherein the path has a space in which the blood and the hemolytic agent are mixed between the blood injection port and the second detecting element. [Effects of the Invention]

According to the present invention, it is possible to provide a small sensor capable of simultaneously measuring a plurality of living body related substances.

The sensor of the present invention has at least a first detecting element that detects glucose in a biological fluid and a second detecting element that detects a biologically relevant substance other than glucose, and the second detecting element includes a semiconductor element.

A sensor of the present invention will be described with reference to Fig. 1, which shows an embodiment of a sensor. 1 is a schematic perspective view of a sensor having a first detecting element 401 and a second detecting element 402. The two detecting elements are formed on the substrate 10 and bonded to the upper substrate 20 to form a wafer.

(First Detection Element) The first detection element 401 detects glucose in the biological fluid. The first detecting element 401 has at least one pair of electrodes 101 on the substrate 10, and has a reaction layer 110 between the pair of electrodes. The pair of electrodes is a detecting electrode, and is electrically connected to the connecting portion 102 via the wiring 107. With this connection, a voltage can be applied between the electrodes by a power source connected to the connection portion, or an electrical signal generated in the reaction layer can be output from the connection portion.

The reaction layer contains an enzyme that reacts with glucose. When glucose in the biological fluid reacts with the enzyme in the reaction layer, the glucose is decomposed and further oxidized to generate hydrogen peroxide. Since the current when the hydrogen peroxide is decomposed reflects the blood glucose concentration, the amount of current is detected as the glucose concentration.

The enzyme that reacts with glucose is not particularly limited, and examples thereof include glucose oxidase (GOD) and glucose dehydrogenase (GDH).

Further, in the reaction layer, a mediator may be contained in addition to the above enzyme. The medium temporarily receives electrons generated when the glucose is decomposed, and then releases electrons when a voltage is applied between the pair of electrodes. The amount of current thus generated reflects the concentration of glucose in the blood, and thus the amount of current is detected as the glucose concentration.

Examples of the medium include various ions, and specific examples thereof include ferricyanide, ferrocene and derivatives thereof, methylene blue, benzoquinone, and derivatives thereof. An ion produced by naphthoquinone, phenazine methosulfate, and thionine. Particularly preferred is ferricyanide ion produced by potassium ferricyanide. The ferricyanide ion is converted to ferrocyanide ion if it accepts electrons, and then returns to ferricyanide ion by applying a voltage.

The method in which the detecting element is used is generally referred to as an electrode method using electrochemistry, and in recent years, the method has become the mainstream of blood glucose measuring devices. Depending on the enzyme in which the reaction takes place, there are a glucose oxidase method (GOD method) and a glucose dehydrogenase method (GDH method), and any of the enzymes can be used in the electrode method. The advantages of the electrode method are as follows: the measurement time is short, the amount of blood collected is small, and the device is simple and easy to understand.

Examples of the material used in the substrate include inorganic materials such as silicon wafer, glass, and alumina sintered body; polyimide, polyester, polycarbonate, and polysulfone. ), polyether sulfone, polyethylene, polyphenylene sulfide, polyparaxylylene, aliphatic polyester, polyethylene terephthalate, poly pair Polybutylene terephthalate, polypropylene, polyvinyl alcohol, polyvinyl chloride, polyvinylidene fluoride, polysiloxane, polyvinylphenol An organic material such as phenol) or polyaramide; or a mixture of an inorganic material powder and an organic material, but is not limited thereto. These materials can be used alone, but they can also be laminated or mixed with a variety of materials.

Examples of the material used for the electrode include conductive metal oxides such as tin oxide, indium oxide, and indium tin oxide (ITO); or platinum, gold, silver, copper, iron, tin, zinc, aluminum, indium, chromium, and lithium. Metals such as sodium, potassium, barium, calcium, magnesium, palladium, molybdenum, amorphous silicon, and polysilicon, or alloys thereof; inorganic conductive materials such as copper iodide and copper sulfide; polythiophene ), polypyrrole, polyaniline, and organic conductive substances such as polyethylenedioxythiophene and polystyrene sulfonic acid; glassy carbon , carbon carbon such as amorphous carbon, graphite, carbon fiber, and diamond; carbon nanomaterials such as carbon nanotubes and graphene; and conductive carbon black, etc. Not limited to these.

These electrode materials may be used alone, but may be laminated or mixed with a plurality of materials. When used as a sensor, the electrode is preferably selected from the group consisting of gold, platinum, palladium, an organic conductive material, and a nanocarbon material from the viewpoint of stability in an aqueous solution or the like to be contacted.

The electrode may be directly adhered to the substrate, or may have an adhesive layer between the electrode and the substrate. When the adhesive layer functions as an insulating layer capable of electrical insulation, a metallic or semiconductive substance may be used as the substrate.

The material used in the connecting portion may be any material as long as it is a conductive material which can usually be used as an electrode. Specific examples thereof include, but are not limited to, various compounds (for example, oxides, hydroxides, halides, sulfides, nitrides, and carbides) of carbon materials, metals, alloys, metals, and alloys.

Carbon materials, platinum, palladium, gold, silver, aluminum, and the like can be suitably used. Examples of the carbon material include CNT (carbon nanotube), graphite, pyrolytic carbon, vitreous carbon, acetylene black, and carbon black.

The material used in the wiring may be any material as long as it is a conductive material which can also be used as an electrode. Specific examples thereof include, but are not limited to, various compounds (for example, oxides, hydroxides, halides, sulfides, nitrides, and carbides) of a carbon material, a metal, an alloy, a metal, and an alloy.

Suitable for carbon materials, platinum, palladium, gold, silver and aluminum. Examples of the carbon material include CNT, graphite, pyrolytic carbon, vitreous carbon, acetylene black, and carbon black.

(Second Detection Element) The second detection element 402 detects a biologically relevant substance other than glucose. The second detecting element 402 has at least a semiconductor element on the substrate 10, and the semiconductor element includes a first electrode 103 and a second electrode 104, and a semiconductor layer 111 is included between the electrodes. The first electrode and the second electrode are detection electrodes, and are electrically connected to the connection portion 102 via the wiring 107. A power source or a detecting unit is connected to the connecting unit 102, but is not shown. With this connection, a voltage can be applied between the electrodes by the power source, or an electrical signal generated in the semiconductor layer can be output from the connection portion.

When a living body-related substance other than glucose is disposed in the vicinity of the semiconductor layer, a current value or a resistance value flowing between the first electrode and the second electrode changes. By measuring the change, the detection of the organism-related substance can be performed. Various organism-related substances can be detected by changing a substance that selectively interacts with a biological-related substance contained in the semiconductor layer.

The advantages of the detecting element using the semiconductor element are as follows: the measurement time is short, the amount of collected blood is small, and the device is simple and easy to understand. In particular, a Field Effect Transistor (FET) type detecting element is not required to be labeled with a phosphor or the like, and the conversion of an electric signal is rapid, and it is easy to connect with an integrated circuit, which is preferable.

Since the first detecting element obtains the same characteristics and size as the sensor chip of the blood sugar level sensor, it is small in size as in the current wafer size. Moreover, the second detecting element is also of the same size, but is slightly larger because of having a flow path.

The size of the sensor having the two detecting elements is at least larger than the current blood glucose sensor wafer size, but it is not as large as the device described in Patent Document 1. As described above, the measurement of glucose is mainly an electrochemical method using an electrode method, and the measurement of a biological substance other than glucose is an electrical method using a semiconductor element. Since neither of the two methods uses light, the conversion of the electric signal is rapid and can be easily integrated, which is preferable.

In FIG. 1, the first detecting element and the second detecting element have a common substrate 10, but each may have a different substrate. The same applies to the upper substrate 20. Further, as the material used in the upper substrate 20, the same material as that used in the substrate 10 can be cited. In one sensor, the materials of the substrate 10 and the upper substrate 20 may be the same or different.

(Third Detection Element) In the present invention, as shown in FIGS. 8 and 9, a third detection element 403 may be provided in addition to the first detection element and the second detection element. The third detecting element 403 detects hemoglobin. The third detecting element 403 may be exemplified by the following elements: (I) an element having at least a pair of electrodes 121 on the substrate 10 and a reaction layer 112 between the pair of electrodes, as shown in FIG. 8; The element (II), as shown in FIG. 9, has at least a semiconductor element 202 on the substrate 10, and the semiconductor element 202 includes a first electrode 122 and a second electrode 123, and a semiconductor layer 201 is included between the electrodes.

In the present invention, either method can be employed. Here, the ratio of HbA1c to the total hemoglobin or the ratio of glycated hemoglobin can be calculated from the total hemoglobin concentration in the sample.

As the concentration of the total hemoglobin, for example, the methaemoglobin method, the cyanide/no methemoglobin method, the azide methemoglobin method, and the sodium dodecylsulfonate may be mentioned. A known method such as a method, an alkaline hematin method, a green chromophore formation method, and an oxyhemoglobin method. Among them, regarding the measurement of hemoglobin, an electrochemical method in which a reagent such as potassium ferricyanide is reacted, and a method using light based on an antigen-antibody reaction using an anti-hemoglobin antibody as an antibody have been established.

However, to date, a specific method of detecting hemoglobin using the semiconductor element described in the second detecting element has not been reported, and detection is first realized according to the present invention. In the second detecting element and the third detecting element, the (II) element 202, which has a semiconductor element as shown in FIG. 9, is preferable from the viewpoint of the necessity of performing hemolysis of blood described below and manufacturing of a sensor wafer. The semiconductor element includes a first electrode 122 and a second electrode 123, and a semiconductor layer 201 is included between the electrodes.

Further, it is preferable that the detection portion area of the second detecting element is twice or more the area of the detecting portion of the third detecting element. This is because there is a large amount of hemoglobin detected by the third detecting element in the blood, and the glycated hemoglobin or glycated albumin as its saccharide is more than 50% or less, so when the second detecting element is When the area of the detecting portion is twice or more larger than the area of the detecting portion of the third detecting element, the detection reliability of hemoglobin and the saccharide thereof is improved. More preferably, the detection portion area of the second detecting element is twice or more and 10 times or less, more preferably 2 times or more and 5 times or less, and further preferably 2 times or more and 3 times or less, of the area of the detecting portion of the third detecting element. It is particularly preferably 2 times or more and 2.5 times or less.

(Injection port and path) The sensor of the present invention preferably has a biological body fluid injection port 301 and a path 302, which are respectively connected to the injection port and the first detecting element 401, the second detecting element 402 and the third detecting Element 403. By using this path, the biological fluid can be sent to the first detecting element, the second detecting element, and the third detecting element by injecting the biological fluid once, and the operability is excellent. In addition, since only the biological fluid can be collected once, the amount of biological fluid collected can be reduced. Further, the measurement can be performed using the biological fluid in the same state, and the measurement error due to the temporal fluctuation of the biological fluid or the collection method can be reduced as much as possible.

The injection inlet is provided in any part of the sensor body. In FIG. 1, the injection port is provided on the upper surface of the upper substrate 20. However, the present invention is not limited thereto, and may be, for example, a side surface of the upper substrate 20 or a side surface of the substrate 10.

As shown in FIG. 1, in the substrate 10, a pot 304 may be provided at a position corresponding to the injection port 301 provided in the upper substrate 20.

The path is connected to the first detecting element and the second detecting element from the injection port. In FIG. 1, the path is formed in a groove shape on the substrate 10, and the biological fluid injected from the injection port 301 is accumulated in the pot 304, and flows therefrom to the path 302.

At this time, in the surface of the upper substrate 20 that is bonded to the substrate 10, a groove having substantially the same shape as the path 302 may be provided at a position corresponding to the path 302. Thereby, the size of the groove can be enlarged when the upper substrate 20 and the substrate 10 are bonded together.

In addition, the positional relationship between the injection port and the path is not limited to these. For example, the passage may be provided in a tubular shape inside the upper substrate 20 so as to be excavated from the injection port to the first detecting element and the second detecting element, respectively. The tubular path and the grooved path can be used in combination. When the position of the injection port is changed, the position of the set path is also different.

The injection inlet and the passage are produced by processing the substrate. The processing method is largely related to the material. For example, in the case of ruthenium or glass, microfabrication using photolithography, laser processing, or the like may be employed. Further, in the case of plastic, in addition to the above methods, injection molding, imprinting, hot embossing, and drill processing may be employed. However, the processing method is not particularly limited to these in any case.

The shape of the passage is represented by a groove shape and a tubular shape, but it is not limited to these shapes as long as it can flow through the biological fluid. After the substrate is processed, the processed surface can also be treated to make the biological fluid flow easily. The width of the passage is not particularly limited, but is preferably about 1 μm to 1 mm. Further, the depth of the passage is not particularly limited, but is preferably about 1 μm to 1 mm.

As a method of bonding the substrate 10 and the upper substrate 20, for example, a method using an adhesive can be mentioned. The adhesive may be any material that can form a liquid layer. For example, an ultraviolet curing type, a thermosetting type, and a two-component mixing type adhesive can be cited. In view of the affinity of the adhesive to the substrate, an adhesive which can be applied in the same thickness of several micrometers is preferable. For example, when the substrate is a hydrophilic glass substrate, the adhesive is also preferably hydrophilic.

When the substrate or the upper substrate is a glass substrate, as another method of bonding them, a method of melting the inner faces thereof by a laser and integrating the two may be mentioned. When the biological fluid is caused to flow in the path, various methods such as capillary action, pumping, pressurization, and centrifugation can be employed.

(Biological Fluid) Biological fluid refers to a liquid held by an organism in any form in the body. Specific examples thereof include blood, lymph, tissue fluid, body cavity fluid, digestive juice, sweat, tears, sputum, urine, semen, vaginal secretions, amniotic fluid, sputum, synovial fluid, cell suspension, and milk. Body fluids can be used directly. Further, it may be a sample obtained by previously breaking or removing a cell component or the like from a biological sample. The digestive juice includes, for example, saliva, gastric juice, bile, pancreatic juice, and intestinal fluid.

As a sample for supplying the sensor including the semiconductor element of the present invention, blood, saliva, sweat, tears, urine, and the like are preferably selected in the biological fluid, and since the blood contains a large amount of biological information, Preferably.

(Bio-related substance) The biological substance other than glucose is not particularly limited as long as it is detected by the second detecting element, and any substance can be used. Specific examples thereof include an enzyme, an antigen, an antibody, a hapten, a hapten antibody, a peptide, an oligopeptide, a polypeptide (protein), a hormone (hormone), a nucleic acid, an oligonucleotide (oligonucleotide), and biotin ( Biotin), biotinylated protein, avidin, streptavidin, lipids, steroids, sugars, oligosaccharides, polysaccharides and other sugars (excluding glucose), low molecular compounds, high molecular compounds, Inorganic substances and their complexes, viruses, bacteria, cells, living tissues, and substances constituting them.

The above-mentioned organism-related substance utilization and a hydroxyl group, a carboxy group, an amino group, a mercapto group, a sulfo group, a phosphonic acid group, an organic salt thereof or an inorganic salt thereof Reaction or interaction of a functional group such as a foryl group, a maleimide group, and a succinimide group, or a substance related to a living organism, The electrical characteristics of the semiconductor layer in the sensor of the present invention change

The low molecular weight compound is not particularly limited, and examples thereof include a compound such as ammonia or methane produced by a living body, which is a gas at normal temperature and pressure, or a solid compound such as uric acid. Preferably, a solid compound such as uric acid is mentioned.

Among them, proteins, viruses, and bacteria are preferred as the substance to be sensed. Examples of the protein include PSA (prostate specific antigen), hCG (human chorionic gonadotrophin, human chorionic gonadotropin), IgE (Immunoglobulin E, immunoglobulin E), and BNP (B type natriuretic peptide, type B). Natriuretic peptide), NT-proBNP (N-terminal pronatriuretic peptide, B-type amino-terminal natriuretic peptide), AFP (α-fetoprotein, alpha-fetoprotein), CK-MB (creatinine kinase-isoenzyme), PIVKA II, CA15-3, CYFRA, anti-p53, troponin T, procalcitonin, hemoglobin, HbA1c, glycated albumin, apolipoprotein, and C-reactive protein (CRP) )Wait.

Examples of the virus include Human Immunodeficiency Virus (HIV), influenza virus, hepatitis B virus, and hepatitis C virus. Examples of the bacteria include Chlamydia, Staphylococcus aureus, and Enterohaemorrhagic Escherichia coli.

Among the above-mentioned sensing target substances, hemoglobin, HbA1c, and glycated albumin which are one type of polypeptide are also preferable. This is because they can be a disease marker for diabetes, and it is of great significance to combine it with the first detection element capable of detecting glucose.

(Hemolysis) When blood is used as the biological fluid used in the measurement of the present invention, hemolysis treatment of blood is required. Since there are millions of red blood cells and thousands to 10,000 white blood cells in 1 μL of blood, it is usually impossible to directly detect hemoglobin and the like in red blood cells. Therefore, it is necessary to carry out the following treatment: the cell membrane of the red blood cell is damaged or dissolved by various factors such as physical factors or chemical factors and biological factors, so that hemoglobin or the like leaks out of the cell. This treatment is called hemolysis.

As a physical factor, various mechanical stresses can be cited in addition to pressure and centrifugal force. A representative method of hemolysis has the following methods: excessively forming a negative pressure in the syringe during blood collection; or placing excess centrifugal force during centrifugation; and bluntly stirring or blistering the red blood cell solution. In addition, a method of mixing red blood cells in a solution having a low osmotic pressure (hypotonic solution) can also be employed. Depending on the osmotic pressure, extracellular water continuously flows into the cells through the cell membrane as a semipermeable membrane, and eventually the red blood cells rupture. In this case, water, purified water, and a buffer solution can also be used as a hemolytic agent.

As a chemical factor, it is exemplified that the lipid constituting the cell membrane is dissolved or damaged by various solvents or surfactants. Examples of such a solvent or a surfactant include various organic solvents, soaps, and the like in addition to alcohols such as methanol and ethanol, and acetone.

As a biological factor, hemolysis caused by an antibody or complement is known. When the binding of the antibody to the red blood cells or the signalling of complement activation is initiated by other activation mechanisms, the components of the complement are sequentially activated (cascade reaction) to form a cell membrane. A channel-like protein complex that opens pores in the cell membrane, causing hemolysis.

The method of hemolysis to be used in the present invention is not particularly limited, and a method using osmotic pressure is preferred from the viewpoint of easiness of acquisition and cost. For example, hemolysis can be caused by adding a method of diluting with respect to a volume of blood having a volume of 2 to 100 times the volume of blood.

The space for performing the hemolysis treatment is not particularly limited. For example, the blood is injected into the front portion of the injection port in the sensor or sometimes between the injection port and the detecting element, and the hemolytic agent is preliminarily provided in the sensor. Or no hemolytic agent is available.

In order to perform hemolysis treatment between the injection port and the detecting element, it is preferable that the above-described path has a space for mixing blood and a hemolytic agent between the blood injection port and the second detecting element or the third detecting element. For example, in FIG. 1, by immersing a hemolytic agent such as the above-mentioned surfactant, purified water, and buffer in the space 303, blood and hemolytic agent injected from the injection port are mixed in the space, and the mixed solution flows into the semiconductor layer. .

(Semiconductor Element) The semiconductor element included in the second detecting element or the third detecting element will be described in detail. An embodiment of the semiconductor device used in the present invention includes a substrate, a first electrode, a second electrode, and a semiconductor layer, and the semiconductor layer contains a carbon nanotube (hereinafter referred to as CNT). Further, in another embodiment, the semiconductor element further includes a third electrode and an insulating layer, and the third electrode is electrically insulated from the first electrode, the second electrode, and the semiconductor layer by the insulating layer.

2 and 3 are schematic cross-sectional views showing an example of a semiconductor element. In the semiconductor device of FIG. 2, the first electrode 103 and the second electrode 104 are formed on the substrate 10, and the semiconductor layer 111 is disposed between the first electrode 103 and the second electrode 104.

In the semiconductor device of FIG. 3, the third electrode 105 and the insulating layer 106 are formed on the substrate 10, and the first electrode 103 and the second electrode 104 are further formed, and the first electrode 103 and the second electrode 104 are disposed between the first electrode 103 and the second electrode 104. The semiconductor layer 111 of the CNT. In the semiconductor device of FIG. 3, the first electrode 103, the second electrode 104, and the third electrode 105 correspond to a source electrode, a drain electrode, and a gate electrode, respectively. The insulating layer 106 corresponds to the gate insulating layer and functions as an FET.

Examples of the material used in the substrate 10 include inorganic materials such as ruthenium wafer, glass, and alumina sintered body; polyimine, polyester, polycarbonate, polyfluorene, polyether oxime, polyethylene, and poly Phenyl sulfide, parylene, aliphatic polyester, polyethylene terephthalate, polybutylene terephthalate, polypropylene, polyvinyl alcohol, polyvinyl chloride, polyvinylidene fluoride, poly An organic material such as a siloxane, a polyvinyl phenol, or a polyarylamine; or a mixture of an inorganic material powder and an organic material, but is not limited thereto. These materials may be used singly or in combination of a plurality of materials.

In order to suppress the non-specific adsorption of the protein in the measurement sample solution, the surface of the substrate 10 may be processed. For example, an uncharged hydrophilic group such as an oligoethylene glycol chain or an oligo (3,4-dihydroxyphenylalanine) or a positively and negatively charged such as a phosphorylcholine group The hydrophilic groups of the two charges are more effective.

When a bioactive substance other than glucose is detected by selective interaction with other organism-related substances described below, in order to manufacture the sensor, the semiconductor layer is sometimes exposed to other organism-related substances. In the solution, other biological related substances are fixed to the sensing portion. In this case, by adhering the other living body-related substance to the outside of the sensing unit, the other living body-related substance is selectively fixed to the sensing unit. Thereby, it is possible to suppress the bio-related substance other than glucose from being captured by other living body-related substances at a position other than the sensing unit, and the selective detection of the sensing unit is advantageous, and the detection sensitivity is improved.

Examples of the material used for the first electrode 103, the second electrode 104, and the third electrode 105 include conductive metal oxides such as tin oxide, indium oxide, and indium tin oxide (ITO); or platinum, gold, silver, and the like. Metals such as copper, iron, tin, zinc, aluminum, indium, chromium, titanium, lithium, sodium, potassium, barium, calcium, magnesium, palladium, molybdenum, amorphous germanium and polycrystalline germanium or alloys thereof; copper iodide and copper sulfide Inorganic conductive materials; organic conductive substances such as polythiophene, polypyrrole, polyaniline, and complexes of polyethylene dioxythiophene and polystyrenesulfonic acid; carbon nanotubes and graphene and other nano carbon materials; And conductive carbon black, etc., but are not limited to these.

As the nanocarbon material, any one of a single-layer carbon nanotube including a metal type of 80% by weight or more, a double-layer carbon nanotube, and a multilayer carbon nanotube can be used. Among them, in order to obtain high conductivity characteristics, it is preferred to use a double-layer carbon nanotube. These electrode materials may be used alone, but may be laminated or mixed with a plurality of materials.

When used as a sensor, the first electrode 103 and the second electrode 104 are preferably selected from the viewpoints of resistance value and ease of film formation, stability of the film, and stability in an aqueous solution or the like to be contacted. Gold, platinum, palladium, organic conductive materials and nano carbon materials. In particular, when it is composed of gold or a carbon nanotube, it is more preferable because the difference in work function from the semiconductor element including the carbon nanotube is small and the power consumption can be reduced.

The width, thickness, interval, and arrangement of the first electrode 103 and the second electrode 104 are arbitrary. The width is preferably 1 μm or more and 1 mm or less, and the thickness is preferably 1 nm or more and 1 μm or less, and the electrode interval is preferably 1 μm or more and 10 mm or less. Further, the width and thickness of the first electrode 103 and the second electrode 104 may be different. The shape of the electrode is not necessarily a rectangular parallelepiped, and it may be curved or formed into a comb shape.

The width, thickness, distance from the semiconductor layer, and arrangement of the third electrode 105 are arbitrary. The width is preferably 1 μm or more and 1 mm or less, and the thickness is preferably 1 nm or more and 1 μm or less, and the distance from the semiconductor layer is preferably 1 μm or more and 10 cm or less. For example, an electrode having a width of 100 μm and a thickness of 500 nm is disposed at a distance of 2 mm from the semiconductor layer, but the invention is not limited thereto.

In FIG. 3, the third electrode 105 and the second electrode 104 are arranged in parallel, but they may be arranged vertically or at any angle other than the vertical. The shape of the third electrode 105 is not limited to a straight line, and may be a curved line or a curved surface. The third electrode 105 is not limited to being disposed directly on the substrate, and may be disposed on other members disposed on the substrate.

As the material used in the insulating layer 106, for example, inorganic materials such as cerium oxide and aluminum oxide; polyimide, polyvinyl alcohol, polyvinyl chloride, polyethylene terephthalate, and polybutylene can be used. An organic polymer material such as difluoroethylene, polyoxyalkylene, or polyvinyl phenol (PVP); or a mixture of an inorganic material powder and an organic polymer material.

The thickness of the insulating layer 106 is preferably 10 nm or more and 5 μm or less. It is more preferably 50 nm or more and 3 μm or less, and still more preferably 100 nm or more and 1 μm or less. The film thickness can be measured by an atomic force microscope, an ellipsometry method, or the like.

The semiconductor layer 111 preferably contains CNTs. The semiconductor layer 111 may further include an organic semiconductor or an insulating material in a range that does not hinder the electrical characteristics of the CNT. The film thickness of the semiconductor layer 111 is preferably 1 nm or more and 100 nm or less. By setting the film thickness within this range, the change in electrical characteristics caused by the interaction with the substance to be sensed can be sufficiently output as an electrical signal. The film thickness of the semiconductor layer 111 is more preferably 1 nm or more and 50 nm or less, and still more preferably 1 nm or more and 20 nm or less.

As a method of forming the semiconductor layer 111, dry methods such as resistance heating evaporation, electron beam, sputtering, and chemical vapor deposition (CVD) may be employed, but from the viewpoint of manufacturing cost and suitability for a large area. Preferably, a coating method is employed.

In the coating method, the following process is included: a semiconductor layer is formed by coating a semiconductor component. Specifically, a spin coat method, a plaque coat method, a slit die coat method, a screen printing method, or a bar coet method can be preferably used. The casting method, the printing transfer method, the immersion pull-up method, the ink jet method, and the like can be selected according to the coating film characteristics desired to be obtained by coating film thickness control or alignment control. Further, the formed coating film may be subjected to an annealing treatment in the atmosphere, under reduced pressure, or in an inert gas atmosphere (nitrogen or argon atmosphere).

The general FET theory is explained. The current flowing between the source electrode and the drain electrode can be controlled by varying the applied gate voltage. The mobility of the FET can be calculated by the following formula (a). μ=(δId/δVg)L·D/(W·ε _r ·ε·Vsd) (a) where Id is the current between the source and the drain, Vsd is the voltage between the source and the drain, and Vg is Gate voltage, D is the thickness of the insulating layer, L is the channel length, W is the channel width, ε _r is the relative dielectric constant of the gate insulating layer, and ε is the vacuum dielectric constant (8.85×10 ^-12 F/m) . Further, the on/off ratio can be obtained from the ratio of the maximum value of Id to the minimum value of Id.

(CNT) CNT may be any one of the following: a single-walled CNT obtained by winding a single carbon film (graphene/sheet) into a cylindrical shape, and two graphene/sheets wound into a concentric shape. The double-layered CNT and the multilayer CNT obtained by winding a plurality of graphene sheets are concentrically formed, but in order to obtain high semiconductor characteristics, it is preferable to use a single-layer CNT. The CNT can be obtained by an arc discharge method, a chemical vapor growth method (CVD method), and a laser/ablation method.

Further, the CNT more preferably contains 80% by weight or more of the semiconductor type CNT. More preferably, it contains 95% by weight or more of the semiconductor type CNT. As a method of obtaining CNTs having a semiconductor type of 80% by weight or more, a known method can be employed. For example, the following methods may be mentioned: ultracentrifugation in the presence of a density gradient agent; selective adhesion of a specific compound to the surface of a semiconductor type or metal type CNT, separation by solubility difference; and utilization of electrical properties The difference is separated by electrophoresis or the like. As a method of measuring the content rate of the semiconductor-type CNT, a method of calculating the absorption area ratio of the visible-near-infrared absorption spectrum or the intensity ratio of the Raman spectrum can be cited.

In the present invention, the length of the CNT is preferably shorter than the distance between the first electrode and the second electrode in the applied semiconductor element or sensor. Specifically, the average length of the CNTs is preferably 2 μm or less, and more preferably 1 μm or less, depending on the channel length. The average length of the CNTs refers to the average of the lengths of the 20 CNTs randomly picked up. As a method of measuring the average length of the CNT, a method in which 20 CNTs are randomly selected from an image obtained by using an atomic force microscope, a scanning electron microscope, a transmission electron microscope, or the like, and an average value of the lengths thereof is obtained.

Generally, commercially available CNTs sometimes contain CNTs which are distributed in length and longer than the electrodes, and therefore it is preferable to add a process for making the CNTs shorter than the distance between the electrodes. For example, a method of cutting into a short fiber shape by an acid treatment such as nitric acid or sulfuric acid, an ultrasonic treatment, or a freeze pulverization method is effective. Further, in terms of improving the purity, it is further preferred to use a filter in combination.

Further, the diameter of the CNT is not particularly limited, but is preferably 1 nm or more and 100 nm or less, and more preferably 50 nm or less.

In the present invention, it is preferred to provide a process in which CNTs are uniformly dispersed in a solvent, and the dispersion is filtered by a filter. By obtaining CNTs having a smaller pore diameter than the filtrate from the filtrate, it is possible to efficiently obtain CNTs shorter than the electrodes. In this case, as the filter, a membrane filter is preferably used. The pore diameter of the filter for filtration is not less than the channel length, and is preferably 0.5 μm or more and 10 μm or less. In addition to the above, a method of shortening the CNTs may be exemplified by an acid treatment, a freeze pulverization treatment, or the like. In the semiconductor layer of the present invention, it is preferred to include a carbon nanotube having a large mobility and a large specific surface area.

(Conjugated Polymer) In the present invention, it is preferred that a conjugated polymer adheres to at least a part of the surface of the CNT. The conjugated polymer prevents unintended changes in electrical characteristics caused by direct contact of the semiconductor component with the sample solution, and also functions to assist electron transfer of the semiconductor component by means of the conjugated system.

Examples of the conjugated polymer include a polythiophene polymer, a polypyrrole polymer, a polyaniline polymer, a polyacetylene polymer, and a poly-p-phenylene polymer. Further, the poly-p-phenylene vinylene polymer or the like is not particularly limited. The polymer obtained by arranging a single monomer unit in a matrix is preferably used, but a block copolymer obtained by block copolymerization of different monomer units or a random copolymerization may be used. Random copolymer. Further, a graft copolymer obtained by graft copolymerizing different monomer units can also be used.

In the present invention, even in the above polymer, a polythiophene-based polymer which is easily attached to CNTs and which easily forms a complex with CNTs is particularly preferable. The preferred molecular weight of the conjugated polymer is 800 or more and 100,000 or less in terms of the number average molecular weight. Further, the above polymer is not necessarily a high molecular weight, and may be an oligomer containing a linear conjugated system.

Further, it is preferable that the conjugated polymer contains a side chain, and at least a part of the side chain thereof is selected from a hydroxyl group, a carboxyl group, an amine group, a thiol group, a sulfo group, a phosphonic acid group, an organic salt or an inorganic salt thereof, a formazan group, At least one functional group in the group consisting of a maleimine group and an amber quinone group, particularly preferably containing a group selected from the group consisting of an amine group, a maleimine group, and an amber quinone group At least one functional group. Thereby, it is easy to fix the bio-related substance that selectively interacts with the substance to be sensed.

In the above functional group, the amine group, the maleimide group, and the amber quinone group may have a substituent or may have no substituent. The substituent may, for example, be an alkyl group or the like, and the substituent may be further substituted. These functional groups are bonded to each other to form a ring. Moreover, other compounds having the above functional groups may be attached to at least a portion of the surface of the CNT.

The side chain in the present invention means a chain containing at least one carbon atom which is substituted and substituted on the atom constituting the main chain of the conjugated polymer. Further, the fact that the functional group is contained in the side chain means that the functional group is contained at the terminal of the side chain or branched from the side chain to include the above functional group. Further, a chain refers to a structure obtained by connecting two or more atoms in series. At this time, one of the atoms contained in the above functional group may be contained in the atom constituting the molecular chain. Therefore, for example, when a group represented by CH ₂ -COOH is attached to the main chain, the chain is a side chain containing a carboxyl group.

The side chain preferably contains an alkylene group in at least a portion of its chain. The alkylene group may be directly bonded to an atom constituting the conjugated polymer as a main chain, or may be bonded thereto via an ether bond, an ester bond or the like.

Here, alkylene means, for example, methylene, ethyl, n-propyl, iso-propyl, n-butyl, second butyl, tert-butyl, cyclopropyl, cyclohexyl And a divalent saturated aliphatic hydrocarbon group such as a norbornylene group, which may or may not have a substituent. The additional substituent in the case of having a substituent is not particularly limited, and examples thereof include an alkyl group, an alkoxy group such as a methoxy group or an ethoxy group, and the like, and these additional substituents may further have a substituent. In addition, the carbon number of the alkylene group is not particularly limited, but from the viewpoint of availability and cost, the number of carbon atoms is preferably 1 or more and 20 or less, and more preferably 1 or more and 8 or less.

Specific examples of the conjugated polymer having the above functional group in the side chain include the following structures. Further, n in each structure represents the number of repetitions, and n is a range of 2 or more and 1000 or less. Further, the conjugated polymer may be a single polymer of each structure or a copolymer. Further, the conjugated polymer may also be a copolymer having a structure having no side chain in each structure and structure.

[Chemical Formula 1]

[Chemical Formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 7]

The conjugated polymer used in the present invention can be synthesized by a known method. In the case of synthesizing a monomer, for example, as a method of linking a thiophene to a thiophene derivative having a carboxyl group at the terminal and an alkyl group introduced into the side chain, a method in which a halogenated thiophene derivative and a thiophene boric acid are mixed under a palladium catalyst can be exemplified. Or a thiophene borate coupling; and coupling the halogenated thiophene derivative to a ruthenium reagent under a nickel or palladium catalyst. Further, when another unit to which a functional group has been introduced is linked to thiophene, the halogenated unit may be used for coupling in the same manner. Further, a polymerizable substituent is introduced into the terminal of the monomer obtained in this manner, and polymerization is carried out under a palladium catalyst or a nickel catalyst to obtain a conjugated polymer.

The conjugated polymer used in the present invention preferably removes impurities such as raw materials or by-products used in the synthesis. For example, silicone column chromatography, Soxhlet extraction method, filtration method, ion exchange method, and chelation can be used. These methods may be a combination of two or more.

When the CNT composite is used as the semiconductor component in the semiconductor layer in the present invention, by attaching the organic substance to at least a part of the surface of the CNT, the CNT can be uniformly dispersed in the solution without impairing the high CNT retention. Electrical characteristics. Further, it is also possible to form a uniformly dispersed CNT film from a solution in which CNTs are uniformly dispersed by a coating method. Thereby, high semiconductor characteristics can be achieved.

Examples of the method of attaching the organic substance to the CNT include the following methods: (I) adding CNTs to the molten organic substance for mixing; (II) dissolving the organic substance in a solvent, and adding CNTs thereto for mixing; (III) The CNTs are pre-dispersed by ultrasonic waves or the like, and an organic substance is added thereto for mixing; and (IV) an organic substance and CNTs are added to the solvent, and the mixed system is irradiated with ultrasonic waves and mixed. In the present invention, either method may be employed, or any method may be combined.

The organic substance is not particularly limited, and specific examples thereof include polyvinyl alcohol and cellulose such as carboxymethyl cellulose; polyalkylene glycols such as polyethylene glycol; and acrylic acid such as polymethyl methacrylate. a polycyclic aromatic compound such as a conjugated polymer such as poly-3-hexylthiophene, an anthracene derivative, or a pyrene derivative; sodium lauryl sulfate and sodium cholate Cholate) an isopy chain alkyl organic salt or the like.

The organic substance is preferably an organic substance having a hydrophobic group such as an alkyl group or an aromatic hydrocarbon group or an organic substance having a conjugated structure from the viewpoint of the interaction with the CNT, and particularly preferably a conjugated polymer. When the organic substance is a conjugated polymer, the effect of uniformly dispersing the CNT in the solution and the effect of high semiconductor characteristics are further improved without impairing the high electrical characteristics possessed by the CNT.

(Protective Agent) When the semiconductor element-containing sensor of the present invention is used, the semiconductor layer can be treated with a reagent (referred to as a "protective agent") for preventing the proximity and adsorption of substances other than the substance to be detected. . Thereby, it is possible to selectively detect the substance to be detected. The protective agent may be physically adsorbed to the semiconductor layer or may be introduced into any of the semiconductor layers by bonding.

As a method of adhering the protective agent to the semiconductor layer, for example, a method in which the semiconductor component is pre-dispersed by ultrasonic waves or the like, and a protective agent is added thereto for mixing, and (II) is introduced into the solvent. And the semiconductor component, the mixed system is irradiated with ultrasonic waves for mixing; (III) the semiconductor component coated on the substrate is immersed in the molten protective agent; and (IV) the protective agent is dissolved in the solvent, and then The semiconductor component coated on the substrate is immersed therein. In the present invention, either method may be employed, or any method may be combined. From the viewpoint of detection sensitivity, a method of attaching a protective agent to a semiconductor component by a solid-liquid reaction (III) or (IV) is preferred.

The conjugated polymer and the protective agent may be the same compound or different compounds. From the viewpoint of detection sensitivity, it is preferred that the conjugated polymer and the protective agent are different compounds. Examples of the protective agent include proteins such as bovine serum albumin, casein, and skim milk; celluloses such as carboxymethyl cellulose; polyalkylene glycols such as polyethylene glycol; and ethanolamine; Polyvinyl alcohol and the like. The order in which the conjugated polymer and the protective agent are attached to the semiconductor component is not particularly limited, but it is preferred to adhere the protective agent after attaching the conjugated polymer.

(Other Organism-Related Substances) The sensor of the present invention preferably has another bio-related substance in which a semiconductor layer is selectively bonded to a living body-related substance as a sensing target substance. Hereinafter, other organism-related substances are referred to as "receptors".

The receptor is not particularly limited as long as it can selectively interact with the substance to be sensed, and any substance can be used. Specific examples thereof include enzymes, antigens, antibodies, haptens, hapten antibodies, peptides, oligopeptides, polypeptides (proteins), hormones, nucleic acids, oligonucleotides, biotin, biotinylated proteins, and avidin. A saccharide such as streptavidin, a sugar, an oligosaccharide, or a polysaccharide, a low molecular compound, a polymer compound, an inorganic substance, a complex thereof, a virus, a bacterium, a cell, a living tissue, and a substance constituting the same.

Among them, preferred are antibodies, aptamers, enzymes, low molecular compounds, proteins, and oligonucleotides, more preferably low molecular compounds, antibodies, aptamers, and enzymes, particularly preferably biotin, antibodies, and Aptamer.

Examples of the low molecular weight compound include a compound having a molecular weight of about 100 to 1,000, and examples thereof include biotin, pyrenebutanoic acid succinimidyl ester, and pyrenebutanoic acid succinimidyl ester. Wait.

Examples of the antibody include anti-PSA, anti-hCG, anti-IgE, anti-BNP, anti-NT-proBNP, anti-AFP, anti-CK-MB, anti-PIVKA II, anti-CA15-3, anti-CYFRA, anti-HIV, anti-troponin T, Anti-procalcitonin, anti-HbA1c, anti-lipoprotein, and anti-C reactive protein (CRP). Among them, an IgG type is preferred, and an antibody having only a variable site (Fab) fragment is particularly preferred.

The aptamer can be exemplified by an oligonucleotide aptamer or a peptide aptamer. Specific examples thereof include an IgE aptamer, a PSA aptamer, and a thrombin aptamer. Examples of the enzyme include glucose oxidase, peroxidase, and the like. Among them, biotin, anti-IgE, anti-PSA, and IgE aptamers are more preferred.

The method of fixing the receptor in the semiconductor layer is not particularly limited, but it is preferable to use a bio-related substance other than glucose and a functional group contained in the semiconductor layer, that is, selected from a hydroxyl group, a carboxyl group, an amine group, a thiol group, a sulfo group, and a phosphonic acid. The reaction or interaction of at least one functional group in the group consisting of their organic or inorganic salts, formazan, maleimine, and amber quinone.

From the viewpoint of the strength of immobilization, it is preferred to use a reaction or interaction of a bio-related substance other than glucose with a functional group contained in the semiconductor layer. For example, when the organism-related substance other than glucose contains an amine group, a carboxyl group, an aldehyde group, and an amber quinone imide group are mentioned. When the organism-related substance other than glucose contains a thiol group, a maleic imine group or the like can be mentioned.

Even in the above groups, the carboxyl group and the amine group easily utilize the reaction or interaction with the acceptor, and it is easy to fix the acceptor in the semiconductor layer. Therefore, the functional group contained in at least a part of the CNT is preferably a carboxyl group and an amine group.

Specific examples of the reaction or interaction include a chemical bond, a hydrogen bond, an ionic bond, a coordinate bond, an electrostatic force, and a Van der Waals force, and the like, and are not particularly limited as long as the type and acceptor of the functional group are used. The chemical structure can be appropriately selected. Further, if necessary, a part of the functional group and/or the acceptor may be converted into another appropriate functional group and then fixed. Further, a linker such as terephthalic acid can be effectively utilized between the functional group and the acceptor.

The length of the functional group contained in the CNT is preferably short so that the acceptor is fastened in the vicinity of the semiconductor component. This is because the use of the receptor to capture the sensing target substance occurs closer to the semiconductor layer, and the detection signal becomes larger. More specifically, the length of the functional group contained in the CNT is preferably 0.1 nm or more and 5 nm or less, more preferably 0.15 nm or more and 3.1 nm or less, and particularly preferably 0.3 nm or more and 1.6 nm or less.

In order to secure the mobility of the functional group contained in the CNT in the sample solution, it is preferable to include a bond having a large affinity with water in the functional group contained in the CNT. Examples of such a bond include an ether bond, a thioether bond, an ester bond, a guanamine bond, a thioester bond, a dithioester bond, an acid anhydride bond, and a quinone bond. Among these bonds, an ether bond, an ester bond, a guanamine bond, and a quinone bond are particularly preferable from the viewpoint of stability and affinity with water. Further, a ring structure may exist in the functional group contained in the CNT.

The process for fixing is not particularly limited, and examples thereof include a solution containing a receptor on a semiconductor layer containing CNT, heating, cooling, vibration, and the like as needed, while fixing the receptor, followed by cleaning. Or dry to remove the remaining ingredients.

In the second detecting element of the sensor of the present invention, the combination of the functional group/acceptor/sensing target substance contained in the CNT can be exemplified by a carboxyl group/T-PSA-mAb (a monoclonal antibody for prostate specific antigen). Antibody)/PSA (prostate specific antigen), carboxyl/anti-hCG-mAb (anti-human chorionic gonadotropin antibody)/hCG (human chorionic gonadotropin), carboxyl/artificial oligonucleotide/IgE (immunoglobulin) E), carboxy/diisopropylcarbodiimide/IgE, carboxy/amino terminal RNA/HIV-1 (human immunodeficiency virus), carboxyl/anti-nauretic peptide antibody/BNP (brain natriuretic peptide), Carboxyl/anti-AFP multi-strain antibody (antibody for human tissue immunostaining)/alpha-fetoprotein, carboxyl/anti-troponin T (anti-troponin T antibody)/troponin T, carboxyl/antibody CK-MB (anti-creatine kinase MB antibody) / CK-MB (creatine kinase MB), carboxyl / anti-PIVKA-II (protein indμced by vitamin K absence or antagonist (PIVKA))-II antibody)/PIVKA-II, carboxyl group / CA15-3 (breast cancer C tumor marker) antibody / CA15-3, carboxyl / anti-CEA (anti-carcinoembryonic antigen antibody) / CEA (carcinoembryonic antigen), anti-CYFRA (anti-cytokeratin 19 fragment antibody) / CYFRA (cytokeratin 19 fragment), carboxyl/anti-p53 (anti-p53 protein antibody)/p53 (p53 protein), carboxyl/anti-human hemoglobin monoclonal antibody/hemoglobin, carboxyl/anti-mouse hemoglobin A1c monoclonal antibody/HbA1c, Carboxy/anti-human albumin antibody/albumin, carboxyl/anti-glycated albumin antibody/glycoprotein, amine/RNA/HIV-1, amine/biotin/avidin, thiol/T-PSA-mAb /PSA, thiol/hCG-mAb/hCG, sulfo/T-PSA-mAb/PSA, sulfo/hCG-mAb/hCG, phosphonate/T-PSA-mAb/PSA, phosphonate/hCG-mAb /hCG, aldehyde/oligonucleotide/nucleic acid, aldehyde/anti-AFP multi-strain antibody (antibody for human tissue immunostaining)/alphafetoglobin, maleimine/cysteine/, and amber Imine / streptavidin / biotin and the like.

Further, when the acceptor contains a functional group, a combination of a functional group-containing compound (=other biologically relevant substance)/sensing target substance may be preferably used, and specific examples thereof include IgE aptamer/IgE, and biological A combination of avidin/avidin, streptavidin/biotin, natriuretic peptide receptor/BNP (brain natriuretic peptide). Among them, in the sensor of the present invention, a significant target substance detected together with glucose is hemoglobin, HbA1c, and glycated albumin, and it is particularly preferable to form a sensor using these substances as a detection target.

(Sensor) As described above, the sensor of the present invention is a small sensor that can perform measurement on the same substrate, and has at least a first detecting element that detects glucose in the biological fluid, and an organism that detects glucose. A second detecting element of the related substance, and the second detecting element comprises a semiconductor element. Further, when the third detecting element includes a semiconductor element, it is also a small-sized sensor that can perform measurement on the same substrate. In particular, when the sensor portion including the semiconductor element is described in detail, the substrate, the first electrode, the second electrode, and the semiconductor layer are included, and the first electrode, the second electrode, and the semiconductor layer are formed on the substrate. The semiconductor layer includes a semiconductor element disposed between the first electrode and the second electrode. Further, it is preferable that the semiconductor layer has another bio-related substance that selectively interacts with a bio-related substance other than glucose.

The sensor including the semiconductor element formed in the manner of FIG. 2 flows through the first electrode 103 and the second electrode 104 when the detection target substance or a solution, gas or solid containing the substance is disposed in the vicinity of the semiconductor layer 111. The current value or resistance value will vary. By measuring the change, the detection of the substance to be detected can be performed.

Further, in the sensor including the semiconductor element of FIG. 3, the current value flowing through the semiconductor layer 111 can be controlled by the voltage of the third electrode 105. Therefore, when the current value flowing between the first electrode 103 and the second electrode 104 when the voltage of the third electrode 105 is changed is measured, a two-dimensional map (I-V map) can be obtained.

The detection target substance may be detected by using some or all of the characteristic values, or the detection target substance may be detected by using a ratio of the maximum current to the minimum current, that is, an on/off ratio. It is also possible to use known electrical characteristics obtained by semiconductor elements such as resistance value, threshold voltage change, impedance, mutual conductance, capacitance, and the like.

The substance to be detected may be used singly or in combination with other substances or solvents. The substance to be detected or a solution, gas or solid containing the substance is disposed in the vicinity of the semiconductor layer 111. As described above, the semiconductor layer 111 interacts with the substance to be detected, and the electrical characteristics of the semiconductor layer 111 are changed to detect changes in any of the above-described electrical signals.

The sensor of the present invention preferably further includes a covering member on the substrate to cover at least a portion of the substrate. For example, as a modification of the configuration shown in FIG. 4, as shown in FIGS. 5A and 5B, it is preferable that the substrate 10 is provided with an upper substrate 20 to form an internal space between the upper substrate 20 and the substrate 10. The broken line in the upper substrate 20 in Fig. 5A shows the boundary between the upper substrate 20 and the internal space. Fig. 5B is a cross-sectional view taken along line CC' of Fig. 5A, showing an internal space 108 between the substrate 10 and the upper substrate 20.

Further, as another modification of the configuration shown in FIG. 4, as shown in FIGS. 6A and 6B, it is preferable that the cover member 21 is provided on the substrate 10, and the cover member 21 forms a space 108 surrounding the semiconductor layer 111. Fig. 6B is a cross-sectional view taken along line DD' of Fig. 6A. Thereby, the semiconductor layer 111 can be brought into effective contact with the liquid containing the substance to be detected.

In still another embodiment of the sensor of the present invention, it is preferable that the upper substrate or the covering member is provided on the substrate, and the third electrode is provided on a surface of the upper substrate or the covering member that faces the semiconductor layer. In other words, it is preferable to include a substrate, a first electrode, a second electrode, and a semiconductor layer formed between the first electrode and the second electrode, and further include an upper substrate or a covering member on the substrate, and the upper substrate or the covering member The third electrode is provided on a surface facing the semiconductor layer, and another bio-related substance that selectively interacts with a bio-related substance other than glucose is provided on the semiconductor layer. The space between the first electrode, the second electrode, and the semiconductor layer and the third electrode may be any one of a gas layer, a liquid layer, and a solid layer, or a combination thereof, or may be a vacuum.

Fig. 7 is a schematic cross-sectional view showing an example of a sensor portion including a semiconductor element of the present invention. In the sensor of FIG. 7, the first electrode 103 and the second electrode 104 are formed on the substrate 10, the semiconductor layer 111 is disposed between the first electrode 103 and the second electrode 104, and the upper substrate 20 is disposed on the substrate 10. The third electrode 105 is disposed on the upper substrate 20 on the same side of the first electrode 103, the second electrode 104, and the semiconductor layer 111. The arrangement of the third electrode 105 on the upper substrate 20 is not limited to the upper surface of the above-described semiconductor layer, and may be an oblique upper side or the like. Further, the upper substrate 20 is not limited to the upper portion as viewed from the semiconductor layer, and may be disposed on the side surface. The third electrode 105 is not limited to the arrangement on the substrate 20, and may be disposed on the substrate 10.

Examples of the material used in the upper substrate 20 or the covering member include inorganic materials such as ruthenium wafer, glass, and alumina sintered body; polyimine, polyester, polycarbonate, polyfluorene, polyether oxime, polyethylene, and the like. Organic materials such as polyphenylene sulfide and parylene are not limited thereto. These materials may be used singly or in combination of a plurality of materials.

(Manufacturing Method of Sensor) A method of manufacturing the sensor including the first detecting element 401 and the second detecting element 402 shown in Fig. 1 is given. The method of manufacturing the sensor includes a process of coating a semiconductor component on a substrate and drying it to form a semiconductor layer. Further, the manufacturing method is not limited to the method described below.

In particular, when the details are described for the sensor portion including the semiconductor element, the first electrode 103 and the second electrode 104 are formed on the substrate 10. Examples of the formation method include metal vapor deposition or spin coating, blade coating, slit die coating, screen printing, bar coating, mold casting, printing transfer, and immersion pulling, and A known method such as an inkjet method. Further, a pattern may be directly formed using a mask or the like, or a resist may be applied on the substrate, and the resist film may be exposed and developed to form a desired pattern, and then etched to form a gate pattern. . Here, the connection portion 102 and the wiring 107 may be formed in the same manner as the formation method of the first electrode and the second electrode, and they may be formed together.

The connection portion 102, the wiring 107, and the first electrode 103 are electrically connected to each other via the semiconductor layer 111 via the second electrode 104, the wiring 107, and the connection portion 102. A power source or a detecting unit is connected to the connecting unit 102, but is not shown. With this connection, a voltage can be applied between the electrodes by the power source, or an electrical signal generated in the semiconductor layer can be output from the connection portion.

Next, the semiconductor layer 111 is formed. The semiconductor layer preferably includes a manufacturing method of attaching a compound containing a linking group to a semiconductor layer; and other organism-related substances and linking groups that selectively interact with the organism-related substance. The process of forming a bond between them.

A method of attaching a compound containing a linking group to a semiconductor layer, for example, a method of vapor-depositing a compound containing a linking group in a vacuum; and immersing the semiconductor layer in a solution in which a compound containing a linking group is dissolved is used. The compound is attached; a compound containing a linking group is coated on the semiconductor layer; and a solution in which a compound containing a linking group is dissolved is coated on the semiconductor layer.

As a process for forming a bond between another bio-related substance and a linking group that selectively interacts with a substance related to a living body, for example, a method in which another living body-related substance collides with a semiconductor layer in a vacuum can be cited. To carry out the reaction; immersing the semiconductor layer in a solution in which other organism-related substances are dissolved; and coating a solution in which other organism-related substances are dissolved on the semiconductor layer.

The formation of the semiconductor layer and the fixation of other biological-related substances may be carried out independently or together. When it is carried out together, for example, a method of forming a semiconductor layer by using a semiconductor component which is previously bonded or adhered with another bio-related substance via a linker can be cited.

(Shape of Sensor) The shape of the sensor is preferably the shape shown in Fig. 1 of the present invention. Specific shapes may be exemplified by a shape such as a sensor-wafer used in a blood sugar level sensor, or a portable cassette sensor or the like. In the case of these shapes, it is preferable to downsize the connected power source and the body having the analysis algorithm.

In the conventional apparatus using light, since a light source is required and a unit that diffuses heat generated by the light source is required, the apparatus is enlarged, but according to the present invention, since the light source is not used, it is small compared with the conventional apparatus. Chemical.

(Detector for detecting hemoglobin, glycated hemoglobin, and glycated albumin, etc.) As another embodiment of the present invention, a sensor having a detecting element for detecting a hemoglobin, glycated hemoglobin, and the like may be cited. And at least one protein in the group consisting of glycated albumin, and the detecting element comprises a semiconductor element. This is to use the second detecting element portion described above as a separate sensor. Therefore, the structure of the sensor, the material used by the sensor, and the function of the sensor are all in common with the above description.

In the present embodiment, the combination of the functional group/acceptor/sensing target substance contained in the CNT composite in the semiconductor element may, for example, be a carboxyl group/anti-human hemoglobin monoclonal antibody/hemoglobin, a carboxyl group, or a carboxyl group. Anti-mouse hemoglobin A1c monoclonal antibody/glycated hemoglobin, carboxyl/anti-human albumin antibody/albumin, and carboxyl/anti-glycated albumin antibody/glycated albumin. [Examples]

Specific examples of the case where glucose, glycated hemoglobin or glycated albumin, and hemoglobin in blood are detected using the sensor of the present invention are listed below. In addition, the following examples are an example of the present invention, and the types of materials, hemolytic agents, and the like used in the semiconductor layer can be appropriately changed as described in the present specification. Further, as described in the present specification, various modifications may be made depending on the type of the bio-related substance detected by the second detecting element and the third detecting element.

First, blood as a measurement sample is injected into the sensor from the injection port 301. The injected blood flows through the path 302 and branches in the middle to the first detecting element side and the second detecting element. When the blood flowing to the first detecting element reaches the reaction layer 110, the glucose in the blood reacts with the glucose decomposing enzyme in the reaction layer 110. The glucose concentration was measured using this reaction.

The blood flowing to the second detecting element is mixed with the hemolytic agent in the space 303 in the middle. Thereby, HbA1c is outputted from the red blood cells. In the second detecting element, a CNT complex is contained in the semiconductor layer 111, and an anti-mouse hemoglobin A1c monoclonal antibody that selectively interacts with HbA1c is immobilized in the CNT complex. When HbA1c outputted from the red blood cells in the space 303 reaches the semiconductor layer 111, the current value flowing through the semiconductor layer 111 is changed by interaction with the anti-mouse hemoglobin A1c monoclonal antibody. The change was used to determine the HbA1c concentration.

The blood flowing to the third detecting element is mixed with the hemolytic agent in the space 303 in the middle. Thereby, hemoglobin is output from the red blood cells. In the third detecting element, a CNT composite is contained in the semiconductor layer 201, and an anti-hemoglobin antibody selectively interacting with hemoglobin is fixed in the CNT composite. When the hemoglobin output from the red blood cells in the space 303 reaches the semiconductor layer 201, the current value flowing through the semiconductor layer 201 is changed by the interaction with the anti-hemoglobin antibody. The hemoglobin concentration was measured using this change.

Hereinafter, the present invention will be more specifically described based on the examples. Further, the present invention is not limited to the following embodiments. Further, the CNTs used are as follows. SWCNT: manufactured by Nai Nippon Carbon Co., Ltd., single-layer CNT, semiconductor type CNT purity >95% DWCNT: manufactured by Toray Industries, double-layer CNT MWCNT: manufactured by Nagano Carbon Co., Ltd., multi-layer CNT

Further, among the compounds used in the examples and the comparative examples, the abbreviated compounds were used as follows. P3HT: poly-3-hexylthiophene PBS: phosphate buffered saline BSA: bovine serum albumin IgE: immunoglobulin E FBS: fetal bovine serum NT-proBNP: human brain natriuretic peptide before N-terminal fragment PBSE: 1-indole acid-N-hydroxysuccinimide PET: Polyethylene terephthalate PEN: polyethylene naphthalate o-DCB: o-dichloro Further, in the first to the thirteenth embodiments, the sensor shown in Fig. 1 was produced, and in the fourteenth to fourth embodiments, the sensor shown in Fig. 9 was produced and used for evaluation. Further, in the first to the seventh embodiments, the same operation as in the conventional method for producing the blood glucose sensor was performed, and the first detecting element was produced, and it was confirmed that the detection was possible.

Example 1 (1) Preparation of semiconductor solution 1.5 mg of CNT and 1.5 mg of P3HT were added to 15 mL of chloroform, and an ultrasonic homogenizer (VCX-500 manufactured by Tokyo Chemical and Chemical Instruments Co., Ltd.) was used while cooling to 250 W. The power was ultrasonically stirred for 30 minutes to obtain a CNT dispersion A (the concentration of the CNT composite was 0.1 g/l with respect to the solvent). Next, fabrication of a semiconductor solution for forming a semiconductor layer was performed. The CNT dispersion A was filtered with a membrane filter (a pore size of 10 μm, a diameter of 25 mm, and Omnipore Membrane manufactured by MILLIPORE Co., Ltd.), and then a membrane filter (a pore size of 3 μm, a diameter of 25 mm, and Omnipore Membrane manufactured by MILLIPORE Co., Ltd.) was used. ) Filtering. 45 mL of o-DCB was added to the obtained 5 mL of the filtrate to prepare a semiconductor solution A (the concentration of the CNT complex was 0.01 g/l with respect to the solvent).

(2) Preparation of polymer solution for insulating layer 61.29 g (0.45 mol) of methyltrimethoxydecane and 12.31 g (0.05 mol) of β-(3,4-epoxycyclohexyl)ethyl Trimethoxydecane and 99.15 g (0.5 mol) of phenyltrimethoxydecane were dissolved in 203.36 g of propylene glycol monobutyl ether (boiling point 170 ° C), and 54.90 g of water and 0.864 g were added thereto with stirring. Phosphoric acid. The obtained solution was heated at a bath temperature of 105 ° C for 2 hours to raise the internal temperature to 90 ° C, and a component mainly composed of by-product methanol was distilled off. Then, the mixture was heated at a bath temperature of 130 ° C for 2.0 hours, the internal temperature was raised to 118 ° C, and a component mainly composed of water and propylene glycol monobutyl ether was distilled off, and then cooled to room temperature to obtain a solid concentration of 26.0% by weight. Polymer solution A. 50 g of the obtained polymer solution A was weighed, and 16.6 g of propylene glycol monobutyl ether (boiling point: 170 ° C) was mixed, and the mixture was stirred at room temperature for 2 hours to obtain a polymer solution B (solid content concentration: 19.5 wt%).

(3) Fabrication of Semiconductor Element A semiconductor element shown in Fig. 3 was produced. The first electrode 103 and the second electrode 104 were formed by vacuum-depositing gold of 50 nm by masking on a glass substrate 10 (thickness: 0.7 mm) by a resistance heating method. The width (channel width) of the first electrode and the second electrode was 400 μm, and the interval (channel length) between the first electrode and the second electrode was 60 μm. Using the inkjet apparatus (manufactured by CLUSTER TECHNOLOGY), 400 pl of the semiconductor solution A produced by the method described in the above (1) was dropped onto the organic film on which the electrode was formed to form the semiconductor layer 111. The heat treatment was performed on a hot plate at 120 ° C for 30 minutes in a nitrogen stream to obtain a semiconductor element A. Next, the semiconductor layer was immersed overnight at 4 ° C in a solution obtained by adjusting Anti-HbA1c (manufactured by Shipbuilding) to 100 μg/mL using 0.01 M PBS. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS. Next, the semiconductor layer was immersed in 5.0 mL of 0.01 M PBS solution of 5.0 mg BSA (manufactured by Wako Pure Chemical Industries, Ltd.) for 2 hours. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS to obtain a semiconductor element modified with Anti-HbA1c as a bio-related substance that selectively interacts with the sensing target substance and BSA modified as a protective agent.

(4) Evaluation as a sensor The semiconductor layer of the produced semiconductor element was immersed in 100 μl of 0.01 M PBS, and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. After 60 minutes from the start of the measurement, 20 μl of 5 μg/mL BSA-0.01M PBS solution was added to 0.01 M PBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of 5 μg/mL avidin was added (Wako Pure Chemicals) Industrial (manufactured)) - 0.01 M PBS solution, after 90 minutes, 20 μl of 5 μg/mL HbA1c (manufactured by Shipbuilding)-0.01 M PBS solution was added. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 5.0% compared with the current value before the addition.

(Example 2) (1) Preparation of semiconductor element The same operation as in Example 1 was carried out to fabricate a semiconductor element A. Next, the semiconductor layer was treated with 6.0 mg of 1-pyrenebutyric acid-N-hydroxysuccinimide ester (AnaSpec, PBSE) in 1.0 mL of acetonitrile (and pure light). The pharmaceutical industry (manufactured by the company) was immersed in the solution for 1 hour. Thereafter, the semiconductor layer was sufficiently washed with acetonitrile and methanol (manufactured by Wako Pure Chemical Industries, Ltd.). The semiconductor layer was immersed overnight at 4 ° C in a solution obtained by dissolving Anti-HbA1c (manufactured by Shipbuilding) into 100 μg/mL using 0.01 M PBS. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS. Next, the semiconductor layer was immersed in 5.0 mL of 0.01 M PBS solution of 5.0 mg BSA (manufactured by Wako Pure Chemical Industries, Ltd.) for 30 minutes. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS to obtain a semiconductor element modified with Anti-HbA1c as a bio-related substance that selectively interacts with the sensing target substance and BSA modified as a protective agent.

(2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 4.8% compared with the current value before the addition.

Embodiment 3 (1) Fabrication of Semiconductor Element A semiconductor element shown in Fig. 3 was produced. The substrate 10 made of glass (having a film thickness of 0.7 mm) was subjected to ultraviolet ozone treatment (photo sμrface processor, PL30-200, manufactured by SEN LIGHTS CORP.) for 30 minutes, and then applied to a decane coupling agent containing a polyethylene glycol chain. The solution was immersed in a 10% by weight ethanol solution (manufactured by SIH6188, manufactured by Gelest) for 1 hour. After washing with ethanol for 30 seconds, it was dried at 120 ° C for 30 minutes to form an organic film 106. The first electrode 103 and the second electrode 104 were formed by depositing gold on the organic film to a film thickness of 50 nm. The width (channel width) of the first electrode and the second electrode was 400 μm, and the interval (channel length) between the first electrode and the second electrode was 60 μm. By using an inkjet apparatus (manufactured by Jiji Technology Co., Ltd.), 400 pl of the semiconductor solution A produced by the method described in the above (1) was dropped onto the organic film on which the electrode was formed, and the semiconductor layer 4 was formed on a hot plate. The heat treatment was performed at 150 ° C for 30 minutes in a nitrogen stream to obtain a semiconductor element B. Next, the semiconductor layer was immersed in a solution of 6.0 mg of 1-indole acid-N-hydroxysuccinimide (manufactured by AnaSpec Co., Ltd.) in 1.0 mL of acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) for 1 hour. Thereafter, the semiconductor layer was sufficiently washed with acetonitrile and methanol (manufactured by Wako Pure Chemical Industries, Ltd.). The semiconductor layer was immersed overnight at 4 ° C in a solution obtained by adjusting Anti-HbA1c (manufactured by Shipbuilding) to 100 μg/mL using 0.01 M PBS. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS. Next, the semiconductor layer was immersed in 5.0 mL of 0.01 M PBS solution of 5.0 mg BSA (manufactured by Wako Pure Chemical Industries, Ltd.) for 30 minutes. Thereafter, the semiconductor layer was sufficiently washed with 0.01 M PBS to obtain a semiconductor element modified with Anti-HbA1c as a bio-related substance that selectively interacts with the sensing target substance and BSA modified as a protective agent.

(2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 6.0% compared with the current value before the addition.

Example 4 (1) Preparation of semiconductor element A semiconductor element was obtained by the same operation as in Example 3 except that Anti-HbA1c fragment antibody (Fab) was used instead of Anti-HbA1c, and a semiconductor element was obtained. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 6.5% compared with the current value before the addition.

Example 5 (1) Preparation of Semiconductor Element A semiconductor layer was formed in the same manner as in Example 4 except that a single-layer carbon nanotube (SWCNT) containing 90% by weight of a metal type was used instead of gold, and a semiconductor was obtained. element. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 5.8% compared with the current value before the addition.

[Example 6] (1) Preparation of semiconductor element A semiconductor element was obtained by performing the same operation as in Example 4 except that a double-layer carbon nanotube (DWCNT) was used instead of gold. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 6.0% compared with the current value before the addition.

Example 7 (1) Preparation of semiconductor element A semiconductor element was obtained by performing the same operation as in Example 4 except that a multilayer carbon nanotube (MWCNT) was used instead of gold. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 5.7% compared with the current value before the addition.

Example 8 (1) Preparation of semiconductor solution A semiconductor solution B was prepared in the same manner as in Example 1 except that the compound represented by the formula (69) was used instead of P3HT (the concentration of the CNT composite was relative to the solvent). 0.01g/l). (2) Preparation of Semiconductor Element A semiconductor element was obtained by performing the same operation as in Example 4 except that the semiconductor solution B was used instead of the semiconductor solution A. (3) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 6.6% compared with the current value before the addition.

Example 9 (1) Preparation of semiconductor solution A semiconductor solution C (relative to a solvent, a concentration of a CNT composite) was prepared by the same operation as in Example 1 except that a compound represented by the formula (71) was used instead of P3HT. It is 0.01 g/l). (2) Preparation of Semiconductor Element A semiconductor element was obtained by performing the same operation as in Example 4 except that the semiconductor solution C was used instead of the semiconductor solution A. (3) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 1 was carried out, and the measurement was performed. The results are shown in Table 1. Only when HbA1c was added, the current value was increased by 6.9% compared with the current value before the addition.

Example 10 (1) Preparation of semiconductor element A semiconductor element was obtained by the same operation as in Example 9 except that anti-glycated albumin was used instead of Anti-HbA1c. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 10 was carried out, and the measurement was performed. The results are shown in Table 1. Only when the glycated albumin was added, the current value was increased by 8.1% compared with the current value before the addition.

[Example 11] (1) Preparation of semiconductor element A semiconductor element was obtained by the same operation as in Example 10 except that PBSE was not used, and a semiconductor element was obtained. (2) Evaluation as a sensor The semiconductor layer of the produced semiconductor element was immersed in 100 μl of 0.01 M PBS, and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. 60 minutes after the start of the measurement, 20 μl of 5 μg/mL BSA-0.01M PBS solution was added to 0.01 M PBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of 5 μg/mL HbA1c (manufactured by Shipbuilding)-0.01 M PBS solution was added. After 90 minutes, 20 μl of 5 μg/mL glycated albumin (manufactured by Shipao)-0.01 M PBS solution was added. The results are shown in Table 1. Only when added glycated albumin, the current value was increased by 9.8% compared with the current value before the addition.

Example 12 (1) Preparation of semiconductor element A semiconductor element was obtained by the same operation as in Example 11 except that anti-NT-proBNP was used instead of the anti-glycated albumin. (2) Evaluation as a sensor The semiconductor layer of the produced semiconductor element was immersed in 100 μl of 0.01 M PBS, and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. 60 minutes after the start of the measurement, 20 μl of 5 μg/mL BSA-0.01M PBS solution was added to 0.01 M PBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of 5 μg/mL HbA1c (manufactured by Shipbuilding)-0.01 M PBS solution was added. After 90 minutes, 20 μl of 5 μg/mL NT-proBNP (manufactured by Shipbuilding)-0.01 M PBS solution was added. The results are shown in Table 1. Only when NT-proBNP was added, the current value was increased by 7.7% compared with the current value before the addition.

Example 13 (1) Preparation of semiconductor element A semiconductor element was obtained by the same operation as in Example 10 except that anti-NT-proBNP was used instead of the anti-glycated albumin. (2) Evaluation as a sensor In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 12 was carried out, and the measurement was performed. The results are shown in Table 1. Only when NT-proBNP was added, the current value was increased by 7.5% compared with the current value before the addition.

[Example 14] (1) Preparation of semiconductor element The same operation as in Example 9 was carried out to fabricate a second detecting element. Further, the same operation as in Example 10 was carried out except that anti-hemoglobin was used instead of the glycated albumin to form a semiconductor layer, and a semiconductor element was produced, and a third detecting element was obtained. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) The semiconductor layer of the produced semiconductor element was immersed in 100 μl of 0.01 M PBS, and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. After 60 minutes from the start of the measurement, 20 μl of 5 μg/mL BSA-0.01M PBS solution was added to 0.01 M PBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of 5 μg/mL HbA1c (manufactured by Shipao)-0.01 M PBS solution, 90 was added. After a minute, 20 μl of 5 μg/mL hemoglobin (manufactured by Shipao)-0.01 M PBS solution was added. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 3.2% compared with the current value before the addition.

Example 15 (1) Production of Semiconductor Element A second detecting element was produced in the same manner as in Example 9. In addition, the same operation as in Example 14 was carried out except that the width (channel width) of the first electrode and the electric two electrode was 400 μm, and the interval (channel length) between the first electrode and the electric two electrode was 40 μm. A semiconductor layer was formed, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 4.0% compared with the current value before the addition.

[Example 16] (1) Production of semiconductor element The same operation as in Example 9 was carried out to fabricate a second detecting element. In addition, the same operation as in Example 14 was carried out except that the width (channel width) of the first electrode and the second electrode was 400 μm and the interval (channel length) between the first electrode and the second electrode was 30 μm. A semiconductor layer was formed, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 4.8% compared with the current value before the addition.

[Example 17] (1) Production of semiconductor element The same operation as in Example 9 was carried out to fabricate a second detecting element. In addition, the same operation as in Example 14 was carried out except that the width (channel width) of the first electrode and the electric two electrode was 400 μm, and the interval (channel length) between the first electrode and the electric two electrode was 25 μm. A semiconductor layer was formed, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 5.1% compared with the current value before the addition.

Example 18 (1) Preparation of semiconductor element A second detecting element was produced in the same manner as in Example 9. Further, the same operation as in Example 16 was carried out except that glass was used as the substrate to form a semiconductor layer, and a semiconductor element was produced, and a third detecting element was obtained. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 4.5% compared with the current value before the addition.

Example 19 (1) Production of Semiconductor Element A second detecting element was produced in the same manner as in Example 9. Further, except that a PET film was used as the substrate, the same operation as in Example 16 was carried out to form a semiconductor layer, and a semiconductor element was produced, and a third detecting element was obtained. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 4.7% compared with the current value before the addition.

Example 20 (1) Preparation of semiconductor element A second detecting element was produced in the same manner as in Example 9. Further, the same operation as in Example 16 was carried out except that the PEN film was used as the substrate to form a semiconductor layer, and a semiconductor element was produced, and a third detecting element was obtained. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 4.6% compared with the current value before the addition.

Example 21 (1) Production of semiconductor element A second detecting element was produced in the same manner as in Example 9. Further, the same operation as in Example 16 was carried out to form a semiconductor layer, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) The semiconductor layer of the produced semiconductor element was immersed in 100 μl of FBS (manufactured by BioWest Co., Ltd.), and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. After 60 minutes from the start of the measurement, 20 μl of 5 μg/mL BSA-FBS solution was added to the FBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of 5 μg/mL HbA1c (manufactured by Shipbuilding)-FBS solution was added, and after 20 minutes, 20 μl of health was added. Human blood. The results are shown in Table 1. Only when adding healthy human blood, the current value was increased by 5.2% compared with the current value before the addition, and hemoglobin in the blood was selectively detected.

(Example 22) (1) Preparation of semiconductor element The same operation as in Example 9 was carried out to fabricate a second detecting element. Further, the same operation as in Example 16 was carried out to form a semiconductor layer, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as a sensor (second detecting element) The semiconductor layer of the produced semiconductor element was immersed in 100 μl of FBS (manufactured by BioWest Co., Ltd.), and the flow between the first electrode and the second electrode was measured. Current value. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. After 60 minutes from the start of the measurement, 20 μl of a 5 μg/mL BSA-FBS solution was added to the FBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of healthy human blood was added. The results are shown in Table 1. Only when adding healthy human blood, the current value was increased by 8.0% compared with the current value before the addition, and the blood HbA1c was selectively detected. (Third Detection Element) The semiconductor layer of the produced semiconductor element was immersed in 100 μl of FBS (manufactured by BioWest Co., Ltd.), and the current value flowing between the first electrode and the second electrode was measured. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed with the voltage between the first electrode and the second electrode (Vsd)=−0.2 V and the voltage between the first electrode and the third electrode (Vg)=−0.7 V. After 60 minutes from the start of the measurement, 20 μl of a 5 μg/mL BSA-FBS solution was added to the FBS impregnated with the semiconductor layer, and after 75 minutes, 20 μl of healthy human blood was added. The results are shown in Table 1. Only when adding healthy human blood, the current value was increased by 5.3% compared with the current value before the addition, and hemoglobin in the blood was selectively detected.

Example 23 (1) Fabrication of Semiconductor Element The same operation as in Example 9 was carried out to fabricate a second detecting element. In addition, anti-hemoglobin was used instead of Anti-HbA1c, and the width (channel width) of the first electrode and the second electrode was 400 μm, and the interval (channel length) between the first electrode and the second electrode was 120 μm. The same operation as in Example 14 was carried out to form a semiconductor layer, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. The results are shown in Table 1. Only when hemoglobin was added, the current value was increased by 1.7% compared with the current value before the addition.

Embodiment 24 (1) Fabrication of Semiconductor Element A second detecting element was produced in the same manner as in Example 9. In addition, the same operation as in Example 14 was carried out except that the width (channel width) of the first electrode and the electric two electrode was 400 μm, and the interval (channel length) between the first electrode and the electric two electrode was 600 μm. A semiconductor layer was formed, and a semiconductor element was fabricated to obtain a third detecting element. (2) Evaluation as Sensor (Second Detection Element) The same results as in Example 9 were obtained. (Third Detection Element) In order to evaluate the semiconductor element produced above as a sensor, the same operation as in Example 14 was carried out, and the measurement was performed. By adding BSA, HbA1c, and hemoglobin, respectively, it was found that the current value increased by 0.3% compared with the current value before the addition. The results are shown in Table 1.

[Example 25] (1) Preparation of semiconductor element A first detecting element was produced in the same manner as in the conventional blood sugar level sensor. The same operation as in Example 9 was carried out to fabricate a second detecting element. Further, the same operation as in Example 16 was carried out to form a semiconductor layer, and a semiconductor element was fabricated to obtain a third detecting element. (2) The sensor shown in Fig. 9 was produced as a sensor. The flow path was filled with 200 μl of FBS (manufactured by BioWest Co., Ltd.), and the electrodes flowing through the second detecting element and the third detecting element were measured. Current value. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed under the first electrode and the second electrode voltage (Vsd)=−0.2 V and the first electrode and the third electrode voltage (Vg)=−0.7 V between the second detection element and the third detection element. 20 μl of healthy human blood was added to the FBS 60 minutes after the start of the assay. The blood is hemolyzed in the space in the flow path, and then reaches each detecting element. The results are shown in Table 1. The change in current value from the blood glucose level was obtained from the first detecting element, and the current value found by the second detecting element was increased by 8.4% from the current value before the addition, and HbA1c in the blood was selectively detected. Moreover, it was found by the third detecting element that the current value was increased by 5.5% compared with the current value before the addition, and hemoglobin in the blood was selectively detected.

[Example 26] (1) Preparation of semiconductor element A first detecting element was produced in the same manner as in the conventional blood sugar level sensor. The same operation as in Example 9 was carried out to fabricate a second detecting element. Further, the same operation as in Example 17 was carried out to form a semiconductor layer, and a semiconductor element was produced, and a third detecting element was obtained. (2) The sensor shown in Fig. 9 was produced as a sensor. The flow path was filled with 200 μl of FBS (manufactured by BioWest Co., Ltd.), and the electrodes flowing between the second detecting element and the third detecting element were measured. Current value. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed under the first electrode and the second electrode voltage (Vsd)=−0.2 V and the first electrode and the third electrode voltage (Vg)=−0.7 V between the second detection element and the third detection element. 20 μl of healthy human blood was added to the FBS 60 minutes after the start of the assay. The results are shown in Table 1. The change in current value from the blood glucose level was obtained by the first detecting element. In addition, the current value found by the second detecting element was increased by 8.5% compared with the current value before the addition, and HbA1c in the blood was selectively detected. Moreover, the current value found by the third detecting element was increased by 5.8% compared with the current value before the addition, and hemoglobin in the blood was selectively detected.

[Embodiment 27] (1) Preparation of semiconductor element A first detecting element was produced in the same manner as in the conventional blood sugar level sensor. The same operation as in Example 9 was carried out to fabricate a second detecting element. Further, the same operation as in Example 14 was carried out to form a semiconductor layer, and a semiconductor element was fabricated to obtain a third detecting element. (2) The sensor shown in Fig. 9 was produced as a sensor. The flow path was filled with 200 μl of FBS (manufactured by BioWest Co., Ltd.), and the electrodes flowing through the second detecting element and the third detecting element were measured. Current value. A semiconductor characteristic evaluation system Model 4200-SCS (manufactured by Keithley Instruments Co., Ltd.) was used for the measurement. The measurement was performed under the first electrode and the second electrode voltage (Vsd)=−0.2 V and the first electrode and the third electrode voltage (Vg)=−0.7 V between the second detection element and the third detection element. 20 μl of healthy human blood was added to the FBS 60 minutes after the start of the assay. The results are shown in Table 1. The change in current value from the blood glucose level was obtained by the first detecting element, and the current value found by the second detecting element was increased by 8.5% compared with the current value before the addition, and HbA1c in the blood was selectively detected. Moreover, the current value found by the third detecting element was increased by 3.7% compared with the current value before the addition, and hemoglobin in the blood was selectively detected.

Comparative Example 1 Instead of using a semiconductor element in the second detecting element and the third detecting element, HbA1c and hemoglobin were measured using a 7180 type Hitachi automatic analyzer described in the examples of JP-A-2015-165827. As a result, since the analysis device is an optical device and the processing method is large in scale, it is difficult to perform electrical measurement by the same wafer formation as the glucose measurement.

[Table 1]

The present invention has been described in detail with reference to the preferred embodiments of the invention, and various modifications and changes may be made without departing from the spirit and scope of the invention. In addition, the present application is based on Japanese Patent Application No. 2015-219207, filed on Nov. 2009. [industrial use]

The sensor using the present invention can be applied to various kinds of sensing such as chemical analysis, physical analysis, biological analysis, and the like, and is particularly suitable for use as a medical sensor or a biosensor.

10‧‧‧Substrate
20‧‧‧Upper substrate
21‧‧‧ Covering parts
101, 121‧‧‧ electrodes
102‧‧‧Connecting Department
103, 122‧‧‧ first electrode
104, 123‧‧‧ second electrode
105‧‧‧3rd electrode
106‧‧‧Insulation
107‧‧‧Wiring
108‧‧‧Internal space
110‧‧‧Reaction layer
111, 201‧‧‧ semiconductor layer
112‧‧‧Reaction layer
200, 202‧‧‧ semiconductor components
301‧‧‧Injection
302‧‧‧The road
303‧‧‧ Space
304‧‧‧Pit
401‧‧‧First detection element
402‧‧‧Second detection element
403‧‧‧ third detection element

1 is a perspective view showing an embodiment of a sensor of the present invention. 2 is a schematic cross-sectional view showing an example of a semiconductor element. 3 is a schematic cross-sectional view showing an example of a semiconductor element. 4 is a schematic cross-sectional view showing an example of a semiconductor element. Fig. 5A is a schematic cross-sectional view showing an example of a semiconductor element. Fig. 5B is a cross-sectional view taken along line CC' of Fig. 5A. Fig. 6A is a schematic cross-sectional view showing an example of a semiconductor element. Fig. 6B is a cross-sectional view taken along line DD' of Fig. 6A. Fig. 7 is a schematic cross-sectional view showing an example of a semiconductor element. Figure 8 is a perspective view showing an embodiment of the sensor of the present invention. Figure 9 is a perspective view showing an embodiment of the sensor of the present invention.

10‧‧‧Substrate

20‧‧‧Upper substrate

101‧‧‧ electrodes

102‧‧‧Connecting Department

103‧‧‧1st electrode

104‧‧‧2nd electrode

107‧‧‧Wiring

110‧‧‧Reaction layer

111‧‧‧Semiconductor layer

200‧‧‧Semiconductor components

301‧‧‧Injection

302‧‧‧The road

303‧‧‧ Space

304‧‧‧Pit

401‧‧‧First detection element

402‧‧‧Second detection element

Claims (13)

A sensor characterized by comprising: at least: a first detecting element that detects glucose in a biological fluid; and a second detecting element that detects a biologically relevant substance other than glucose, and the second detecting element includes a semiconductor element. The sensor of claim 1, wherein the organism-related substance is glycated hemoglobin or glycated albumin. A sensor according to claim 1 or 2, further comprising a third detecting element, the third detecting element detecting hemoglobin. The sensor of claim 3, wherein the third detecting element comprises a semiconductor element. The sensor according to any one of claims 1 to 4, wherein the detection portion area of the second detecting element is more than twice the area of the detecting portion of the third detecting element. The sensor of any one of claims 1 to 5, wherein the semiconductor element contains a carbon nanotube. The sensor according to any one of claims 1 to 6, wherein the semiconductor element includes at least a substrate, a first electrode, a second electrode, and a semiconductor layer, and the first electrode and the The second electrode contains at least one selected from the group consisting of a single-layer carbon nanotube including a metal type of 80% by weight or more, a double-layer carbon nanotube, and a multilayer carbon nanotube. The sensor of any one of claims 1 to 7, wherein the semiconductor layer contains a carbon nanotube. The sensor according to any one of claims 6 to 8, wherein a conjugated polymer is attached to at least a part of a surface of the carbon nanotube. A sensor according to any one of the preceding claims, wherein the semiconductor layer is fixed with other organism-related substances that selectively interact with the organism-related substance. The sensor according to any one of claims 1 to 10, wherein the sensor has an injection port and a path of biological body fluid, and the path is connected to the injection port and the port respectively The first detecting element and the second detecting element are described. The sensor of any one of claims 1 to 11, wherein the biological fluid is blood. The sensor according to any one of claims 1 to 12, wherein the path has a mixture of the blood and hemolysis between the injection port of the blood and the second detecting element. Space for the agent.