JP2022154947A - Biomaterial detection sensor and method for detecting biomaterial - Google Patents

Abstract

To provide a biomaterial detection sensor and a method for detecting biomaterial with excellent selectivity for the biomaterial to be detected, high sensitivity, and low detection limit.SOLUTION: A biomaterial detection sensor has a first electrode, a second electrode, a third electrode, an organic semiconductor film connecting the first electrode and the second electrode, and an inorganic solid electrolyte film laminated to the organic semiconductor film, and has an exposed portion where at least a portion of either or both of the organic semiconductor film and the inorganic solid electrolyte film is exposed to the outside, and the third electrode is at least partially connected to the exposed portion.SELECTED DRAWING: Figure 1

Description

The present invention relates to a biological substance detection sensor and a biological substance detection method.

PCR (polymerase chain reaction) and next generation sequencing are known as methods for detecting biological substances such as mRNA/DNA. The PCR method is a method of amplifying a specific region (target region) on a DNA sequence using a heat-stable DNA polymerase, and since it can be detected from a single DNA molecule, it can detect a specific DNA sequence with high sensitivity. is possible. Next-generation sequencing is a method in which DNA is fragmented to prepare a library, and the DNA fragments in the library are sequenced in parallel, making it possible to comprehensively decode all DNA sequences from a single molecule. It has become. These detection methods for biosubstances require a long detection time.

As a method for detecting biological substances such as DNA in a short period of time, the use of a sensor having a thin film transistor (TFT) structure is being studied. For example, a method has been reported in which homo-oligomer DNA strands are immobilized using 3-aminopropylethoxysilane, and hybridization with the above-mentioned oligomer strands is directly detected by the displacement of the gate potential under constant drain current. (Non-Patent Document 1).

J. Phys. Chem. B, 1997, 101, 2980-2985

In the biosubstance detection sensor, the sample is a mixture (liquid) in which biosubstances other than the biosubstance to be detected coexist. Therefore, it is desirable that the biosubstance detection sensor has excellent selectivity for the biosubstance to be detected, high sensitivity, and a low detection limit. However, the thin-film transistor structure sensor described in Non-Patent Document 1 has a detection limit of about 1 μg/mL, and further improvement in sensitivity is desired.

SUMMARY OF THE INVENTION An object of the present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a biosubstance detection sensor and a biosubstance detection method which are excellent in selectivity to a target biosubstance and have high sensitivity and a low detection limit. That's what it is.

As a result of intensive research, the present inventors have discovered a first electrode, a second electrode, a third electrode, an organic semiconductor film connecting the first electrode and the second electrode, and the organic semiconductor film. At least a portion of one or both of the organic semiconductor film and the inorganic solid electrolyte film is exposed to the outside, and a third electrode is formed on the exposed portion. The inventors have found that the connected sensor has superior selectivity to the substance to be detected, high sensitivity, and a low detection limit as compared with the conventional thin-film transistor structure sensor, and completed the present invention.

That is, the present invention provides the following means in order to solve the above problems.

[1] A first electrode, a second electrode, a third electrode, an organic semiconductor film connecting the first electrode and the second electrode, and an inorganic solid electrolyte film laminated on the organic semiconductor film , has
At least a part of one or both of the organic semiconductor film and the inorganic solid electrolyte film has an exposed portion exposed to the outside,
The biological substance detection sensor, wherein at least a portion of the third electrode is connected to the exposed portion.

[2] The biological substance detection sensor according to [1] above, wherein the first electrode, the second electrode, and the third electrode are arranged on the inorganic solid electrolyte membrane.

[3] The biological substance detection sensor according to [1] or [2] above, wherein the inorganic solid electrolyte membrane is proton conductive.

[4] The inorganic solid electrolyte membrane is formed of either a metal oxide containing a rare earth element and zirconium (Zr) or a metal oxide containing a rare earth element and tantalum (Ta), The content of carbon (C) in the inorganic solid electrolyte membrane is 0.5 atom % or more and 15 atom % or less, and the content of hydrogen (H) in the inorganic solid electrolyte membrane is 2 atom % or more and 20 atom % or less. The biological substance detection sensor according to any one of [1] to [3] above.

[5] The biological substance detection sensor according to any one of [1] to [4] above, wherein the inorganic solid electrolyte membrane has an ionic conductivity of 1×10 ⁻⁸ S/cm or more.

[6] The biological substance detection sensor according to any one of [1] to [5] above, wherein the organic semiconductor film is a polycyclic aromatic hydrocarbon or a thienoacene compound.

[7] The exposed portion of either or both of the organic semiconductor film and the inorganic solid electrolyte film has a capture field that directly or indirectly captures a biological substance, above [1] to [6] ] The biological substance detection sensor according to any one of the above.

[8] The biosubstance detection sensor according to [7] above, wherein probe molecules for capturing the biosubstance are immobilized in the capture field.

[9] The biological substance detection sensor according to any one of [1] to [8] above, further comprising a holding portion capable of holding a liquid containing a biological substance around the exposed portion.

[10] Further, a conductive material film is provided in contact with at least a part of the inorganic solid electrolyte film, and the conductive material film is electrically connected to the first electrode, the second electrode, and the third electrode. The biosubstance detection sensor according to any one of [1] to [9] above, which is physically independent.

[11] A biosubstance detection method using the biosubstance detection sensor according to any one of [1] to [10] above,
a step of supplying a liquid containing a biological substance to the exposed portion;
A voltage is applied between the third electrode and the first electrode, a current between the first electrode and the second electrode is measured, a voltage between the third electrode and the first electrode, and the and detecting the biological material based on the current between the first electrode and the second electrode.

ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the biosubstance detection sensor and the biosubstance detection method which are excellent in the selectivity with respect to the substance of the detection objective, and which have high sensitivity and a low detection limit.

FIG. 1 is a plan view showing an example of the configuration of a biological substance detection sensor according to a first embodiment of the present invention. FIG. 2 is a sectional view taken along line II-II' of FIG. 3A and 3B are schematic diagrams for explaining a biological substance detection method using the biological substance detection sensor shown in FIG. 1 is an enlarged cross-sectional view, and (b) is an enlarged view of (a). FIG. 4 is a schematic diagram for explaining a biosubstance detection method using the biosubstance detection sensor shown in FIG. 1, and is an enlarged view of the biosubstance detection sensor along line IV-IV' in FIG. . FIG. 5 is a plan view showing an example of the configuration of the first modified example of the biological substance detection sensor according to the first embodiment of the present invention. FIG. 6 is a sectional view taken along line VI-VI' of FIG. FIG. 7 is a plan view showing an example of the configuration of a second modified example of the biological substance detection sensor according to the first embodiment of the present invention. FIG. 8 is a cross section taken along line VIII-VIII' of FIG. FIG. 9 is a cross-sectional view showing an example of the configuration of a third modified example of the biological substance detection sensor according to the first embodiment of the present invention. FIG. 10 is a cross-sectional view showing an example of the configuration of a fourth modified example of the biological substance detection sensor according to the first embodiment of the present invention. FIG. 11 is a cross section taken along line XI-XI' of FIG. FIG. 12 is a plan view showing an example of the configuration of the biological substance detection sensor according to the second embodiment of the present invention. 13 is a cross-sectional view taken along the line XIII-XIII' of FIG. 12. FIG. 14A and 14B are schematic diagrams for explaining the biological substance detection method using the biological substance detection sensor according to the second embodiment, and FIG. 1 is an enlarged cross-sectional view as seen, and (b) is an enlarged view of (a).

A biosubstance detection sensor and a biosubstance detection method according to an embodiment of the present invention will be described in detail below with reference to the drawings. In the drawings used in the following description, characteristic parts may be enlarged for the sake of convenience in order to make it easier to understand the characteristics of this embodiment, and the dimensional ratios of each component may differ from the actual ones. There is

[Configuration of biological substance detection sensor]
FIG. 1 is a plan view showing an example of the configuration of the biological substance detection sensor according to the first embodiment of the present invention, and FIG. 2 is a cross-sectional view taken along line II-II' of FIG.
As shown in FIGS. 1 and 2, the biological substance detection sensor 10a includes a substrate 11, a conductive material film 12, an inorganic solid electrolyte film 13, a first electrode 15, a second electrode 16, and a third electrode. 17 and an organic semiconductor film 14 . The conductive material film 12 is laminated on one surface (upper surface in FIG. 2) of the substrate 11 . The inorganic solid electrolyte film 13 is laminated on the surface of the conductive material film 12 opposite to the substrate 11 . The first electrode 15 , the second electrode 16 and the third electrode 17 are arranged on the inorganic solid electrolyte membrane 13 . The organic semiconductor film 14 is arranged between the first electrode 15 and the second electrode 16 and connects the first electrode 15 and the second electrode 16 . Also, the organic semiconductor film 14 between the first electrode 15 and the second electrode 16 is laminated on the inorganic solid electrolyte film 13 . The third electrode 17 is arranged at a position not electrically connected to the first electrode 15 and the second electrode 16 . The first electrode 15 , the second electrode 16 and the organic semiconductor film 14 constitute a sensor piece 19 . In the biological substance detection sensor 10a of FIG. 1, three sensor pieces 19 are arranged. The three sensor pieces 19 are arranged so that the distances from the third electrode 17 are the same. The first electrode 15 is connected to a first terminal 15b via a first lead wire 15a. The second electrode 16 is connected to a second terminal 16b via a second lead wire 16a. The third electrode 17 is connected to a third terminal 17b via a third lead wire 17a. The first terminal 15b, the second terminal 16b, and the third terminal 17b are arranged at the same end.

Surfaces of the inorganic solid electrolyte membrane 13, the first electrode 15, the second electrode 16, the first lead wire 15a, the second lead wire 16a, and the third lead wire 17a are covered with an insulating film 18. FIG. The organic semiconductor film 14, a portion of the inorganic solid electrolyte film 13 around the organic semiconductor film 14, and the third electrode 17 are not covered with an insulating coating and are exposed to the outside to form an exposed portion 20. . The organic semiconductor film 14 forming the exposed portion 20 and the inorganic solid electrolyte film 13 around the organic semiconductor film 14 preferably have a trapping field 21 that directly or indirectly traps the biological substance to be detected. It is preferable that the capture field 21 has the probe molecules 1 immobilized thereon for capturing the biological substance to be detected. The exposed portion 20 is surrounded by a wall portion 22 . The wall portion 22 forms a holding portion capable of holding a liquid containing a biological substance above the exposed portion 20 .

For the substrate 11, for example, an insulating substrate and a semiconductor substrate can be used. Examples of insulating substrates include high heat resistant glass, alumina (Al ₂ O ₃ ) substrates, STO (SrTiO) substrates, SiO ₂ /Si substrates (Si substrates with SiO 2 films formed thereon), Si substrates with A multi-layer substrate in which an STO (SrTiO) layer is formed via a SiO ₂ layer and a Ti layer can be mentioned. Examples of semiconductor substrates include Si substrates, SiC substrates, and Ge substrates. Although the thickness of the substrate 11 is not particularly limited, it is, for example, 10 μm or more and 1 mm or less.

The conductive material film 12 is a conductive material film containing a conductive material. The conductive material film 12 may be made of only a conductive material. As the conductive material, for example, metal materials and metal oxides can be used. Examples of metal materials include platinum (Pt), gold (Au), silver (Ag), copper (Cu), aluminum (Al), molybdenum (Mo), palladium (Pd), ruthenium (Ru), iridium (Ir ), tungsten (W), titanium (Ti), and alloys of these metals. Examples of metal oxides include indium tin oxide (ITO) and ruthenium oxide (RuO ₂ ). The conductive material film 12 may be a single layer or may be a multi-layer formed by laminating a plurality of conductive material films. Although the thickness of the conductive material film 12 is not particularly limited, it is, for example, 50 nm or more and 200 nm or less.

It is preferable that the conductive material film 12 is in contact with at least a portion of the inorganic solid electrolyte film 13 . Also, the conductive material film 12 may be electrically insulated from other than the inorganic solid electrolyte film 13 . The conductive material film 12 may be electrically independent of the first electrode 15 , the second electrode 16 and the third electrode 17 . The conductive material film 12 may be arranged inside the inorganic solid electrolyte film 13, for example.

The inorganic solid electrolyte membrane 13 contains a solid electrolyte. The inorganic solid electrolyte membrane 13 is preferably formed only from an inorganic solid electrolyte. The inorganic solid electrolyte membrane 13 can be formed of, for example, a metal oxide containing a rare earth element and zirconium (Zr) or a metal oxide containing a rare earth element and tantalum (Ta). Further, the content of carbon (C) in the inorganic solid electrolyte membrane 13 is 0.5 atom % or more and 15 atom % or less, and the content of hydrogen (H) in the inorganic solid electrolyte membrane 13 is 2 atom % or more and 20 atom %. % or less. When the inorganic solid electrolyte membrane 13 is composed of the above metal oxide and the contents of carbon (C) and hydrogen (H) in the inorganic solid electrolyte membrane 13 are both within the above range, the organic semiconductor membrane 14 is formed. By combining with a metal oxide, which will be described later, the sensitivity of the biosubstance detection sensor 10a is increased, the detection limit is significantly lowered, and the stability of detection in the presence of moisture or the like is enhanced. From the viewpoint of further improving the characteristics of the above, the content of carbon (C) is 1 atom% or more and 10 atom% or less, and the content of hydrogen (H) in the inorganic solid electrolyte membrane 13 is 5 atom% or more and 18 atom%. You can do the following.

The inorganic solid electrolyte membrane 13 preferably has an ionic conductivity of 1×10 ⁻⁸ S/cm or more. The ion conductivity of the inorganic solid electrolyte membrane 13 may be 1×10 ⁻² S/cm or less. Specifically, the inorganic solid electrolyte membrane 13 can be formed by any one of (A1) to (A5) below, for example.
(A1) metal oxide containing lanthanum (La) and zirconium (Zr) (A2) metal oxide containing lanthanum (La) and tantalum (Ta) (A3) cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu) and any metal element selected from the group consisting of yttrium (Y) and a metal oxide containing zirconium (Zr) or tantalum (Ta) (A4) hafnium (Hf), zirconium (Zr) and Metal oxide containing at least one metal element selected from the group consisting of aluminum (Al) (A5) Oxide containing lanthanum (La), hafnium (Hf), and zirconium (Zr)

For example, when the inorganic solid electrolyte membrane 13 is formed of a metal oxide containing lanthanum (La) and zirconium (Zr) (A1), lanthanum (La) and zirconium (Zr) in the inorganic solid electrolyte membrane 13 Although the atomic ratio is not particularly limited, for example, when lanthanum (La) is 1, zirconium (Zr) is preferably 0.43 or more and 2.33 or less, and is 1 or more and 2.33 or less. is more preferred. The atomic ratio of lanthanum (La) and zirconium (Zr) in the inorganic solid electrolyte film 13 is within the above range, so that high sensing performance (typically, high field effect mobility, high gate capacitor capacity) can be achieved. Obtainable. Further, when the inorganic solid electrolyte membrane 13 is formed of a metal oxide containing lanthanum (La) and tantalum (Ta) (A2), lanthanum (La) and tantalum (Ta) in the inorganic solid electrolyte membrane 13 The atomic number ratio is also not particularly limited. Further, when the inorganic solid electrolyte membrane 13 is formed of any one of the metal oxides (A3) to (A5) above, the atomic ratio of each metal element is not particularly limited.

The various atomic composition ratios described above are determined by performing elemental analysis using Rutherford backscattering spectroscopy (RBS method) or the like. In particular, the content of carbon (C) and hydrogen (H) was analyzed by Rutherford Backscattering Spectrometry (RBS analysis method) and Hydrogen Forward Scattering Spectrometry (RBS analysis method) using Pelletron 3SDH manufactured by National Electrostatics Corporation. elemental analysis using scattering spectrometry (HFS analysis method) and nuclear reaction analysis (NRA analysis method).

The inorganic solid electrolyte membrane 13 can be composed of, for example, a single layer formed of any one of the above metal oxides. When the inorganic solid electrolyte membrane 13 is composed of a metal oxide layer composed of lanthanum (La) and zirconium (Zr), it is also called an LZO layer. Further, when the inorganic solid electrolyte membrane 13 is composed of a metal oxide layer composed of lanthanum (La) and tantalum (Ta), it is also called an LTO layer.

Although the thickness of the inorganic solid electrolyte membrane 13 is not particularly limited, it is, for example, 50 nm or more and 300 nm or less. If the thickness of the inorganic solid electrolyte membrane 13 exceeds 300 nm, the interfacial characteristics of the organic semiconductor membrane 14 may be affected, which is not preferable. On the other hand, if the thickness is less than 50 nm, it is not preferable from the viewpoints of an increase in leakage current and deterioration of the film covering the substrate.

The organic semiconductor film 14 contains an organic semiconductor. The organic semiconductor film 14 is preferably formed only from an organic semiconductor. The organic semiconductor is preferably a polycyclic aromatic hydrocarbon or a thienoacene-based compound.

The polycyclic aromatic hydrocarbon preferably contains 4 or more benzene rings. The polycyclic aromatic hydrocarbon is preferably acene. Acene may have a substituent (for example, a phenyl group). Examples of polycyclic aromatic hydrocarbons include pentacene and rubrene. Examples of thienoacene-based compounds include BTBT, DNTT, C8-DNTT, and C10-DNBOT. These organic semiconductors may be used individually by 1 type, and may be used in combination of 2 types. By forming the organic semiconductor film 14 with the above organic semiconductor, the combination of the inorganic solid electrolyte film 13 and the above inorganic solid electrolyte greatly improves the sensitivity of the biological substance detection sensor 10a and greatly increases the detection limit. In addition, it is possible to improve the stability of detection in the presence of moisture or the like.

The organic semiconductor forming the organic semiconductor film 14 is preferably in an amorphous phase or a nanocrystalline phase. By making the organic semiconductor constituting the organic semiconductor film 14 in an amorphous phase or a nanocrystalline phase, the organic semiconductor film 14 can obtain a favorable interface state with the inorganic solid electrolyte film 13 in an amorphous phase. As a result, the biological substance detection sensor 10a with good electrical properties can be formed.

The organic semiconductor film 14 can be composed of, for example, a single layer formed of the above organic semiconductor. Although the thickness of the organic semiconductor film 14 is not particularly limited, it is, for example, 5 nm or more and 80 nm or less from the viewpoint of covering the inorganic solid electrolyte film 13 and the like with high accuracy and from the viewpoint of facilitating the modulation of the conductivity of the organic semiconductor film 14. is preferred.

The width of the organic semiconductor film 14 is preferably 100 μm or more, for example, 1000 μm, although a larger width is more advantageous from the viewpoint of noise. The length L of the organic semiconductor film 14 is, for example, 50 μm or more and 200 μm or less.

Further, in the present embodiment, the organic semiconductor film 14 has a thickness thinner than both the first electrode 15 and the second electrode 16, but the present invention is not limited to this. may have the same film thickness, or may have a thicker film thickness.

As electrode materials for the first electrode 15, the second electrode 16 and the third electrode 17, metal materials and metal oxides can be used. Examples of metallic materials include refractory metals such as platinum (Pt) and alloys thereof. Examples of metal oxides include indium tin oxide (ITO) and ruthenium oxide (RuO ₂ ). Each of the first electrode 15, the second electrode 16, and the third electrode 17 may be a single-layer body, or may be a multi-layer body in which a plurality of electrode layers are laminated. The thicknesses of the first electrode 15, the second electrode 16, and the third electrode 17 are not particularly limited, but are, for example, 50 nm or more and 200 nm or less.

The material of the insulating coating 18 may be organic or inorganic. Examples of organic substances include polyimide and epoxy resin. Examples of inorganic substances include alumina and silica. Although the thickness of the insulating coating 18 is not particularly limited, it is, for example, 50 nm or more and 5000 nm or less.

The material of the wall portion 22 may be organic or inorganic. Examples of organic substances include polyimide and epoxy resin. Examples of inorganic substances include alumina and silica. Although the height of the insulating coating 18 is not particularly limited, it is, for example, 0.10 mm or more and 5 mm or less.

[Manufacturing method of biological substance detection sensor]
The biological substance detection sensor 10a can be manufactured, for example, as follows.
(1) Formation of Conductive Material Film 12 First, the conductive material film 12 is formed on the substrate 11 (eg, SiO ₂ /Si substrate). As a method for forming the conductive material film 12, a sputtering method can be used.

(2) Formation of Inorganic Solid Electrolyte Membrane 13 Next, the inorganic solid electrolyte membrane 13 is formed on the conductive material film 12 . The inorganic solid electrolyte membrane 13 can be formed, for example, by applying an inorganic solid electrolyte membrane precursor liquid onto the conductive material membrane 12 and heating the resulting coating film. As the inorganic solid electrolyte membrane precursor liquid, a liquid in which the inorganic solid electrolyte material constituting the inorganic solid electrolyte membrane 13 is dissolved or dispersed can be used. , a spin coating method, an inkjet printing method, a nanoimprint method, or the like can be used. The heating temperature of the coating film is not particularly limited as long as it is a temperature at which the solvent of the inorganic solid electrolyte membrane precursor liquid volatilizes and the inorganic solid electrolyte membrane 13 is formed. Therefore, by using a solvent with a low boiling point as the solvent for the inorganic solid electrolyte membrane precursor liquid, the inorganic solid electrolyte membrane 13 can be formed by heating at a relatively low temperature, thereby widening the range of materials to be selected. .

As materials for the inorganic solid electrolyte, for example, chlorides, nitrates, acetates, octylates, and alkoxides can be used. In addition, the content of carbon (C) in the finally formed inorganic solid electrolyte membrane 13 is 0.5 atom % or more and 15 atom % or less, and the content of hydrogen (H) in the inorganic solid electrolyte membrane 13 is The inorganic solid electrolyte membrane precursor liquid may be adjusted so that the is 2 atom % or more and 20 atom % or less. Specifically, the inorganic solid electrolyte membrane precursor liquid may be prepared by the following methods (2-1) to (2-3).
(2-1) Dissolve lanthanum acetate in propionic acid by heating at 110° C. for 30 minutes to obtain a 0.2 mol/kg solution.
(2-2) Dissolve zirconium butoxide in propionic acid by heating at 110° C. for 30 minutes to obtain a 0.2 mol/kg solution.
(2-3) Mix the above solutions (2-1) and (2-2) at room temperature.

(3) Formation of electrode pattern Next, an electrode pattern (first electrode 15, first lead wire 15a, first terminal 15b, second electrode 16, second lead wire 16a, second electrode pattern) is formed on the inorganic solid electrolyte film 13. Two terminals 16b, a third electrode 17, a third lead wire 17a, and a third terminal 17b) are formed. The electrode pattern is formed, for example, by forming a patterned resist film on the inorganic solid electrolyte film 13 by photolithography, then forming an electrode film on the inorganic solid electrolyte film 13 containing the resist film, and then applying a resist. It can be formed by a method of removing a film. As a method for forming the electrode film, for example, a sputtering method can be used.

(4) Formation of Organic Semiconductor Film 14 Next, the organic semiconductor film 14 is formed between the first electrode 15 and the second electrode 16 . The organic semiconductor film 14 is formed by, for example, forming a patterned resist film on the inorganic solid electrolyte film 13 by photolithography, and then forming an organic semiconductor film on the inorganic solid electrolyte film 13 containing the resist film. After that, it can be formed by a method of removing the resist film. The organic semiconductor film can be formed, for example, by applying an organic semiconductor film precursor liquid and heating the resulting coating film. As the organic semiconductor film precursor liquid, a liquid in which an organic semiconductor material constituting the organic semiconductor film 14 is dissolved or dispersed can be used. As a method for applying the organic semiconductor film precursor liquid, for example, a spin coating method, an inkjet printing method, a nanoimprint method, or the like can be used. The heating temperature of the coating film is not particularly limited as long as it is a temperature at which the solvent of the organic semiconductor film precursor liquid volatilizes and the organic semiconductor film 14 is formed. Therefore, by using a solvent with a low boiling point as the solvent for the organic semiconductor film precursor liquid, the organic semiconductor film 14 can be formed by heating at a relatively low temperature, thereby widening the selection of materials.

(5) Formation of insulating coating 18 Next, the insulating coating 18 is formed on the inorganic solid electrolyte membrane 13, the first electrode 15, the first lead wire 15a, the second electrode 16, the second lead wire 16a and the third lead wire 17a. to form For the insulating coating 18, for example, a resist film patterned by photolithography is formed on the inorganic solid electrolyte film 13, and then an insulating coating is formed on the inorganic solid electrolyte film 13 containing the resist film. It can be formed by a method of removing a resist film. The insulating coating can be formed, for example, by applying an insulating coating precursor liquid and heating the obtained coating film. As the insulating coating precursor liquid, a liquid in which a material constituting the insulating coating 18 is dissolved or dispersed can be used. A compound that forms the insulating coating 18 upon heating may be used as the material forming the insulating coating 18 . A spin coating method, an ink jet printing method, a nanoimprint method, or the like can be used as a method for applying the insulating film precursor liquid. The heating temperature of the coating film is not particularly limited as long as it is a temperature at which the solvent of the insulating film precursor liquid volatilizes and the insulating film 18 is formed. By forming the insulating coating 18, an exposed portion 20 exposed to the outside without being covered with the insulating coating 18 is formed.

(6) Formation of wall portion 22 Next, the wall portion 22 is formed so as to surround the exposed portion 20 . The wall portion 22 can be formed by joining a wall member formed in a cylindrical shape in advance to the insulating coating 18 .

[Biological substance detection method]
A biological substance detection method using the biological substance detection sensor 10a will be described.
3A and 3B are schematic diagrams for explaining a biological substance detection method using the biological substance detection sensor shown in FIG. 1 is an enlarged cross-sectional view, and (b) is an enlarged view of (a). 4 is a schematic diagram for explaining a biological substance detection method using the biological substance detection sensor shown in FIG. 1, and is an enlarged view of the biological substance detection sensor along line IV-IV' of FIG. is.

As shown in FIGS. 3 and 4, a liquid Lq containing the biological material 2 to be detected is injected inside the wall portion 22 . As a result, the exposed portion 20 (the organic semiconductor film 14, a portion of the inorganic solid electrolyte film 13 around the organic semiconductor film 14, and the third electrode 17) of the biological substance detection sensor 10a is brought into contact with the liquid Lq containing the biological substance 2. do. The biological material 2 is, for example, nucleic acids such as DNA and mRNA. The liquid Lq containing the biological substance 2 is, for example, a mixture of a buffer solution and serum containing nucleic acids.

The biological material 2 is specifically captured with the probe molecules 1 immobilized on a part of the organic semiconductor film 14 and the inorganic solid electrolyte film 13 . As a result, the target biological substance can be detected with high selectivity.

After that, it is preferable to wash the biological substances not captured by the probe molecules 1 (biological substances not to be detected) or non-specifically captured biological substances with a washing liquid. After washing, a measurement solution such as a buffer solution is supplied to the exposed portion of the biological substance detection sensor 10a. Thereby, the organic semiconductor film 14 and the third electrode 17 can be electrically connected via the measurement liquid.

A voltage V _DS is then applied between the first electrode 15 and the second electrode 16 and then a voltage V _TG is applied between the first electrode 15 and the third electrode 17 . With the biological substance 2 to be detected captured by the probe molecules 1 of the organic semiconductor film 14 and the inorganic solid electrolyte film 13, a voltage V _DS is applied to the organic semiconductor film 14, thereby connecting the first electrode 15 and the second electrode. The current _IDS flowing between the electrodes 16 changes. A change in the V _TG -I _DS characteristic is detected according to the change in the current I _DS . Thereby, the amount of biological substance 2 captured by probe molecule 1 can be quantified.

In the biosubstance detection sensor 10a of this embodiment, as shown in FIG. As the ions move inside the solid electrolyte membrane 13, an electric field (arrow D2) created by the charge of the biological material 2 captured by the probe molecules 1 captured on the surface of the inorganic solid electrolyte membrane 13 is transmitted to the organic semiconductor membrane 14. , can contribute to changes in electrical properties (antenna effect). As a result, the electric field generated by the charges of more biological substances 2 is accumulated in the organic semiconductor film 14, thereby improving the sensitivity and stability.

In addition, in the biological substance detection sensor 10a of the present embodiment, by having the conductive material film 12 having electron conductivity in a form of contact with the inorganic solid electrolyte film 13, more quickly, farther, and more trapped This has the effect of transmitting the electric field created by the charge of the biological substance 2 to the organic semiconductor film 14 . In the biosubstance detection sensor 10a of the present embodiment, no voltage is applied to the conductive material film 12, but the voltage _VBG may be applied to the conductive material film 12. FIG.

According to the biological substance detection sensor 10a of the present embodiment configured as described above, the inorganic solid electrolyte film 13 contains an inorganic solid electrolyte and the organic semiconductor film 14 contains an organic semiconductor. The sensitivity is greatly improved, the detection limit is greatly lowered, the stability of detection is high in the presence of moisture, etc., and it is possible to detect biological substances quickly and easily at low cost. Become. In particular, due to its high sensitivity and high detection limit, it is possible to detect biological substances in single molecule units in a shorter time than before. , cell-free RNA/DNA, etc. can be analyzed with high precision in a short time. Also, in the medical field, it becomes possible to detect biomaterials related to a patient during examination of the patient, and to perform prompt and appropriate diagnosis and treatment based on the detection results. Furthermore, according to the manufacturing method described above, it is possible to provide the biological substance detection sensor 10a that is excellent in industrial and mass productivity.

Further, in the biological substance detection sensor 10a of the present embodiment, when the inorganic solid electrolyte contained in the inorganic solid electrolyte membrane 13 is proton conductive, the sensitivity of the biological substance detection sensor 10a is further improved. In particular, the inorganic solid electrolyte membrane 13 is formed of either a metal oxide containing a rare earth element and zirconium (Zr) or a metal oxide containing a rare earth element and tantalum (Ta), The carbon (C) content in the electrolyte membrane 13 is 0.5 atom % or more and 15 atom % or less, and the hydrogen (H) content in the inorganic solid electrolyte membrane 13 is 2 atom % or more and 20 atom % or less. In this case, the proton conductivity of the inorganic solid electrolyte membrane 13 is increased, so the sensitivity of the biological substance detection sensor 10a is improved. Furthermore, when the ion conductivity of the inorganic solid electrolyte membrane 13 is 1×10 ⁻⁸ S/cm or more, the sensitivity of the biological substance detection sensor 10a is improved.

Moreover, in the biological substance detection sensor 10a of the present embodiment, if the organic semiconductor film 14 is a polycyclic aromatic hydrocarbon or a thienoacene compound, the sensitivity of the biological substance detection sensor 10a is further increased.

Further, according to the biological substance detection method of the present embodiment, the exposed portion 20 of the biological substance detection sensor 10a is brought into contact with the liquid Lq containing the biological substance such as target DNA, and the third electrode 17 and the first electrode 15 are brought into contact with each other. A voltage _VTG is applied between the first electrode 15 and the second electrode 16 while measuring the current _IDS between the first electrode 15 and the second electrode 16, the voltage _VTG between the third electrode 17 and the first electrode 15 and the first Since the biological substance is detected based on the current _IDS between the electrode 15 and the second electrode 16, the biological substance can be detected with high sensitivity in a short period of time at the same simple operation and cost as the conventional method. detection can be performed.

Further, it is possible to provide a biological substance detection device having a multi-structure or an array structure in which a plurality of the biological substance detection sensors 10a of this embodiment are arranged. Furthermore, it is possible to provide a biological substance detection device that includes both the biological substance detection sensor 10a of the present embodiment and another electrochemical sensor such as a known carbon sensor. As a result, highly accurate detection can be achieved in a short time, and both biological substances such as mRNA / DNA and other biological substances such as biomarkers can be detected at the same time or at the same time. Using the detection results of a plurality of biological substances obtained in the detection work of 1, analysis from various points of view becomes possible.

Although the first embodiment of the present invention has been described in detail above, the present invention is not limited to the above-described embodiment, and various modifications can be made within the scope of the gist of the present invention described in the scope of claims.・Changes are possible.

For example, in the biological substance detection sensor 10a of the present embodiment, the first electrode 15 and the second electrode 16 are formed on the inorganic solid electrolyte membrane 13, but the arrangement of the first electrode 15 and the second electrode 16 is not limited to this. In addition, in the biological substance detection sensor 10a of the present embodiment, the conductive material film 12 is arranged between the substrate 11 and the inorganic solid electrolyte film 13, but the arrangement of the conductive material film 12 is limited to this. not to be Modified examples of the biological substance detection sensor 10a of the first embodiment are shown in FIGS. 5 to 11 below.

FIG. 5 is a plan view showing an example of the configuration of the first modification of the biological substance detection sensor, and FIG. 6 is a sectional view taken along the line VI-VI' of FIG.
A biological substance detection sensor 10 b shown in FIGS. 5 and 6 has an inorganic solid electrolyte membrane 13 arranged on a substrate 11 . An organic semiconductor film 14 is arranged on the inorganic solid electrolyte film 13 , and a first electrode 15 and a second electrode 16 are formed on the organic semiconductor film 14 . The first electrode 15 and the second electrode 16 are sized such that their ends are inside the ends of the inorganic solid electrolyte membrane 13 .

FIG. 7 is a plan view showing an example of the configuration of the second modification of the biological substance detection sensor, and FIG. 8 is a cross section taken along line VIII-VIII' of FIG.
A first electrode 15 and a second electrode 16 are arranged on a substrate 11 in the biological substance detection sensor 10c shown in FIGS. The first electrode 15 and the second electrode 16 are covered with the inorganic solid electrolyte membrane 13 . The organic semiconductor film 14 is formed on the inorganic solid electrolyte film 13 . The organic semiconductor film 14 is connected to the first electrode 15 and the second electrode 16 through through holes provided in the inorganic solid electrolyte film 13 . The first lead wire 15a is connected to the first terminal 15b through the through hole 15c, the second lead wire 16a is connected to the second terminal 16b through the through hole 16c, and the third lead wire 17a is connected to the second terminal 16b through the through hole 16c. , is connected to the third terminal 17b through the through hole 17c.

FIG. 9 is a cross-sectional view showing an example of the configuration of the fourth modified example.
In a biosubstance detection sensor 10d shown in FIG. 9, an inorganic solid electrolyte membrane 13 is arranged on a substrate 11. As shown in FIG. The first electrode 15 and the second electrode 16 are arranged on the inorganic solid electrolyte membrane 13 . A biological substance detection sensor 10d shown in FIG. 11 is the same as the biological substance detection sensor 10a shown in FIGS. 1 and 2 except that the conductive material film 12 is not provided.

FIG. 10 is a plan view showing an example of the configuration of the sixth modification of the biological substance detection sensor, and FIG. 11 is a cross section taken along line XI-XI' of FIG.
In the biological substance detection sensor 10e shown in FIGS. 10 and 11, the first electrode 15 and the second electrode 16 are arranged on the substrate 11, and the organic semiconductor film 14 is arranged on the first electrode 15 and the second electrode 16. is formed in The organic semiconductor film 14 , first electrode 15 and second electrode 16 are covered with the inorganic solid electrolyte film 13 . The inorganic solid electrolyte membrane 13 is provided with through holes for connecting the first electrode 15 and the second electrode 16 to an external power source.

In the biological substance detection sensor 10a of the first embodiment, the third electrode 17 is formed on the inorganic solid electrolyte membrane 13, but the position of the third electrode 17 is not limited to this. As long as the third electrode 17 is electrically connected to the first electrode 15 , the second electrode 16 and the inorganic solid electrolyte membrane 13 , the third electrode 17 may be arranged at a position other than above the inorganic solid electrolyte membrane 13 .

FIG. 12 is a plan view showing an example of the configuration of the biological substance detection sensor according to the second embodiment of the present invention. 13 is a cross-sectional view taken along the line XIII-XIII' of FIG. 12. FIG.

A biological substance detection sensor 30 shown in FIGS. 12 and 13 includes a substrate 11, a conductive material film 12, an inorganic solid electrolyte film 13, a first electrode 15, a second electrode 16, and an organic semiconductor film 14. have. The biosubstance detection sensor 30 has the same configuration as the biosubstance detection sensor 10a of the first embodiment, except that it does not have the third electrode 17 and has one sensor piece 19 .

14A and 14B are schematic diagrams for explaining a biological substance detection method using the biological substance detection sensor 30, and FIG. It is a figure and (b) is an enlarged view of (a).
When detecting a biological substance using the biological substance detection sensor 30, the third electrode 17 is inserted into the liquid Lq containing the biological substance 2 to be detected. Thereby, the third electrode 17 and the organic semiconductor film 14 of the exposed portion 20 are connected. The first electrode 15 and the second electrode 16 are connected to the first voltage supply section 31 . The first electrode 15 and the third electrode 17 are connected to the second voltage supply section 32 . A method for detecting the biosubstance 2 captured by the probe molecule 1 can be carried out in the same manner as in the case of using the biosubstance detection sensor of the first embodiment. That is, the voltage V DS is applied between the first electrode 15 and the second electrode 16 using the first voltage supply section 31 , and the voltage V _DS is applied between the first electrode 15 and the third electrode 16 using the second voltage supply section 32 . 17 is _applied . This changes the current I _DS flowing between the first electrode 15 and the second electrode 16 . Then, by detecting changes in V _TG -I _DS characteristics, the amount of biological material 2 captured by probe molecules 1 can be quantified.

Reference Signs List 1 probe molecule 2 biological substance 10a, 10b, 10c, 10d, 10e, 30 biological substance detection sensor 11 substrate 12 conductive material film 13 inorganic solid electrolyte film 14 organic semiconductor film 15 first electrode 16 second electrode 17 third electrode 18 Insulating coating 19 Sensor piece 20 Exposed part 21 Trapping field 22 Wall part 31 First voltage supply part 32 Second voltage supply part

Claims (11)

a first electrode, a second electrode, a third electrode, an organic semiconductor film connecting the first electrode and the second electrode, and an inorganic solid electrolyte film laminated on the organic semiconductor film; death,
At least a part of one or both of the organic semiconductor film and the inorganic solid electrolyte film has an exposed portion exposed to the outside,
The biological substance detection sensor, wherein at least a portion of the third electrode is connected to the exposed portion. 2. The biological material detection sensor according to claim 1, wherein said first electrode, said second electrode, and said third electrode are arranged on said inorganic solid electrolyte membrane. 3. The biological substance detection sensor according to claim 1, wherein said inorganic solid electrolyte membrane is proton conductive. The inorganic solid electrolyte membrane is formed of either a metal oxide containing a rare earth element and zirconium (Zr) or a metal oxide containing a rare earth element and tantalum (Ta), The content of carbon (C) in the film is 0.5 atom% or more and 15 atom% or less, and the content of hydrogen (H) in the inorganic solid electrolyte film is 2 atom% or more and 20 atom% or less. 4. The biological substance detection sensor according to any one of items 1 to 3. The biological substance detection sensor according to any one of claims 1 to 4, wherein the inorganic solid electrolyte membrane has an ionic conductivity of 1 x 10 ^-8 S/cm or more. The biological substance detection sensor according to any one of claims 1 to 5, wherein the organic semiconductor film is a polycyclic aromatic hydrocarbon or a thienoacene compound. Any one of claims 1 to 6, wherein the exposed portion of one or both of the organic semiconductor film and the inorganic solid electrolyte film has a trapping field that directly or indirectly traps a biological substance. The biological substance detection sensor according to . 8. The biological material detection sensor according to claim 7, wherein probe molecules for capturing said biological material are immobilized in said capture field. The biological substance detection sensor according to any one of claims 1 to 8, further comprising a holding portion capable of holding a liquid containing a biological substance around said exposed portion. Furthermore, a conductive material film is in contact with at least a part of the inorganic solid electrolyte film, and the conductive material film is electrically independent of the first electrode, the second electrode, and the third electrode. The biological substance detection sensor according to any one of claims 1 to 9, wherein A biological substance detection method using the biological substance detection sensor according to any one of claims 1 to 10,
a step of supplying a liquid containing a biological substance to the exposed portion;
A voltage is applied between the third electrode and the first electrode, a current between the first electrode and the second electrode is measured, a voltage between the third electrode and the first electrode, and the and detecting the biological material based on the current between the first electrode and the second electrode.

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