JP2017134036A - Sensor IC - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sensor IC capable of improving the detection sensitivity of a molecule/cell/tissue.SOLUTION: The sensor IC includes: a base plate; and at least one resonator 50 disposed on the base plate. The at least one resonator 50 is configured to change the resonant frequency depending on the physical properties of an object to be inspected adjacent thereto. A sensor IC 1 for detecting a state of the object to be inspected based on the resonant frequency of the at least one resonator 50, includes an antibody 201 for capturing protein on the surface of the sensor IC1.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a sensor IC that includes a high-frequency oscillator and detects a change in an object to be inspected containing moisture.

  A human body diagnostic device used in each home, a simple diagnostic laboratory, and the like is required to be low in price, downsized, shortened examination time, and easy to operate. A sensor IC (Integrated Circuit: semiconductor integrated circuit) formed on a semiconductor integrated circuit can satisfy such requirements.

  For example, Patent Document 1 discloses an example of a sensor IC formed on a semiconductor integrated circuit. 9A and 9B are diagrams for explaining a sensor IC according to Patent Document 1. FIG.

  FIG. 9A is a diagram showing a state in which the magnetic particles 113 and the test object 114 are brought into contact with the inductor 111. When the inspection object 114 is brought into contact with the semiconductor substrate 101, the magnetic permeability changes due to the fluctuation of the magnetic particles 113 attached to the inspection object 114, and the inductance of the inductor 111 is affected by the change of the magnetic permeability. As a result, the oscillation frequency output from the oscillator changes, and the detector (not shown) detects the change in the oscillation frequency. The change in the oscillation frequency indicates a change in the property of the inspection object 114.

US Patent Application Publication No. 2009/0267596 (published on October 29, 2009)

H. Yada, M. Nagai, K. Tanaka, "Origin of the fast relaxation component of water and heavy water revealed by terahertz time-domain attenuated total reflection spectroscopy", Chemical Physics Letters, pp.166-170, 2008

  In many cases, a subject to be inspected in a human body diagnostic device used in each home or a simple diagnostic laboratory is a liquid containing various molecules, cells, and tissues. A sensor like patent document 1 has the characteristics that inspection sensitivity is high near the sensor surface. However, in the sensor according to Patent Document 1, there is no means for selectively placing a target molecule / cell / tissue on the sensor surface when the sensor is placed in the liquid. There is a problem that inspection sensitivity is not good.

  The present invention has been made in view of the above problems, and an object of the present invention is to provide a sensor IC capable of improving detection sensitivity.

  In order to solve the above-described problem, a sensor IC according to one embodiment of the present invention includes a substrate and at least one resonator disposed on the substrate, and the at least one resonator has its own resonator. A sensor IC that changes a resonance frequency in accordance with a physical property of an object to be inspected in the vicinity, and detects a state of the object to be inspected based on the resonance frequency of the at least one resonator, the sensor IC It is characterized by having a capturing part that captures at least one of specific molecules, cells, and tissues on the surface of the IC.

  According to one aspect of the present invention, by providing the sensor surface with a capturing unit that captures a target molecule, cell, or tissue, by measuring the resonance frequency of the resonator of the sensor IC before and after the test object is introduced. It becomes possible to examine whether or not the target molecule, cell, or tissue exists in the object to be examined by the shift of the resonance frequency. Furthermore, by capturing the target molecule / cell / tissue on the sensor surface, the detection sensitivity of the target molecule / cell / tissue in the test object is improved.

  Therefore, according to one embodiment of the present invention, detection sensitivity can be improved.

  Furthermore, by immobilizing a plurality of types of capture parts on the surface of the sensor IC, it is possible to detect a plurality of types of molecules, cells, and tissues present in the object to be inspected with one sensor IC.

It is a figure for demonstrating the sensor IC which concerns on Embodiment 1 of this invention, (a) shows the position of cross section AA 'of a semiconductor substrate, (b) is cross section AA' of a semiconductor substrate. (C) shows a corresponding circuit diagram. It is a figure for demonstrating the sensing principle of sensor IC which concerns on Embodiment 1 of this invention, (a), (c), (e) is the cross section AA 'of the semiconductor substrate of (a) of FIG. (A) is a state in which water is in contact with the protective film, (c) is a state after injecting a test object in which the target protein is not contained in water, and (e) is a state in which water is in contact with water. Is a state in which the antibody captures the target protein after injecting the test object containing the target protein in (b), (d), and (f), respectively, the states (a), (c), and (e) In the sensor IC, the oscillation frequency of the oscillator measured using the detection circuit is shown. It is sectional drawing of sensor IC which concerns on Embodiment 2 of this invention, (a) forms a groove | channel in a protective film, and immobilizes the antibody which is a capture part, (b) is gold on a protective film. It is a figure in the case of forming a thin film and immobilizing an antibody. It is sectional drawing of sensor IC which concerns on Embodiment 3 of this invention, (a) is the case where the antibody which is a capture part is fix | immobilized to a protective film through an immobilization part, (b) is a gel layer. It is a figure in the case of fixing to a protective film through this. It is sectional drawing of sensor IC which concerns on Embodiment 5 of this invention, (a) is a figure when probe DNA capture | acquires target DNA, when probe DNA is a capture part. It is sectional drawing of sensor IC which concerns on Embodiment 6 of this invention, (a) is a figure when the protein capture | acquires the antibody which becomes a target, (b) is a capture part. It is a figure for demonstrating the sensor IC which concerns on Embodiment 7 of this invention, and is a case where it senses with a capacitor instead of an inductor, (a) shows the position of the cross section BB 'of a semiconductor substrate, b) is a cross-sectional view showing a cross-section BB ′ of the semiconductor substrate, and (c) is a corresponding circuit diagram. It is a block diagram of sensor IC which concerns on Embodiment 8 of this invention, and is a figure when it comprises multiple oscillators and multiple types of antibodies are immobilized. FIG. 2 is a configuration diagram of Patent Document 1, in which (a) shows a position of a cross section C-C ′ of a semiconductor substrate, and (b) is a cross sectional view showing a cross section C-C ′ of the semiconductor substrate. It is a figure which shows an example of a silane coupling reaction.

  Hereinafter, embodiments of the present invention will be described in detail. However, the configuration described in this embodiment is merely an illustrative example, and is not intended to limit the scope of the present invention only to that unless otherwise specified. In the drawings described below, components having the same function are denoted by the same reference numerals, and repeated description thereof is omitted.

  In the sensor IC according to the embodiment of the present invention, when the object to be inspected is brought into contact with the surface of the semiconductor substrate (substrate), the dielectric constant, magnetic permeability, or property of the object to be inspected changes. This is a sensor IC (Integrated Circuit: semiconductor integrated circuit) that detects a dielectric constant and a magnetic permeability that change.

Embodiment 1
First, the sensor IC 1 according to the first embodiment of the present invention will be described with reference to FIGS. FIG. 1A is a configuration diagram of the sensor IC 1 and shows the position of the cross section AA ′. FIG. 1B is a cross-sectional view showing a cross section AA ′ of the sensor IC1. FIG. 1C is a circuit diagram corresponding to the sensor IC1.

(Configuration of oscillator)
As shown in FIG. 1C, the oscillator (oscillator) 20 includes a differential circuit 40, a resonator 50 formed between the differential circuits 40, and a current source 60. The resonator 50 has a resonance frequency of 30 to 200 GHz. 30 to 200 GHz is a frequency at which the change in the complex dielectric constant of water is large, and the change in the frequency characteristic of the dielectric constant can be detected with high sensitivity.

  Differential circuit 40 includes an NMOS transistor M1 and an NMOS transistor M2 that are cross-coupled to each other. Note that another differential circuit may be used as appropriate. For example, a bipolar transistor may be used.

  The resonator 50 includes an inductor 52 and a capacitor 54 connected in parallel between the differentials of the differential circuit 40. The resonance frequency at which the resonator 50 resonates is the oscillation frequency at which the oscillator 20 oscillates. Since the resonator 50 is not a narrowly defined antenna that transmits and receives electromagnetic waves, the resonator 50 is not limited by the aperture diameter due to the wavelength. For this reason, the size of the resonator 50 can be set to 200 μm square or less (a size that fits in a square having a side of 200 μm), which is smaller than a quarter wavelength of a wavelength of about 1.5 mm of an electromagnetic wave of 200 GHz.

  The inductor 52 is formed in the uppermost layer (the layer closest to the contact position between the substrate and the object to be inspected) among the metal layers of the semiconductor substrate 10 (that is, the uppermost metal layer 130). The inductor 52 occupies most of the circuit size of the resonator 50. The resonator 50 occupies most of the circuit size of the oscillator 20. In the present embodiment, the area of the inductor 52 is determined so that the size of the resonator 50 in a plan view is a size that fits in a square having a side of 200 μm. The capacitor 54 may be formed by gate capacitances of the transistors M1 and M2, parasitic capacitances of wirings not shown, and the like.

  The inductor 52 and the capacitor 54 form an LC circuit, and the resonance frequency of the resonator 50 and the oscillation frequency of the oscillator 20 are determined by the inductance of the inductor 52 and the capacitance of the capacitor 54.

  In this case, the oscillation frequency f of the oscillator 20 is expressed by the following formula (1).

f = 1 / {2π√ (LC)} (1)
Here, L is the value of the inductance (number of flux linkages / current) of the inductor 52, C is the capacitance (electric capacity) of the capacitor 54 and the test object 203 as a reference (see (c) and (e) of FIG. 2). ) The sum of the parasitic capacitances generated in the inductor 52 when mounted. The inductance and the capacitance are determined so that the oscillator 20 oscillates at any frequency of 30 GHz or more and 200 GHz or less.

  For example, when the inductance of the inductor 52 is around 1 nH and the capacitance of the capacitor 54 is around 27 fF, the resonance frequency of the resonator 50 and the oscillation frequency of the oscillator 20 are around 30 GHz.

(Configuration of sensor IC)
As shown in FIG. 1A, the sensor IC 1 includes an oscillator 20, a frequency divider (frequency divider) 30, and a detection circuit (estimator) 3. At least the oscillator 20 is formed on a semiconductor substrate (substrate) 10. The frequency divider 30 and the detection circuit 3 may be formed on the semiconductor substrate 10 or may be formed on a member different from the semiconductor substrate 10, and the detection circuit 3 may be replaced by, for example, a commercially available microcomputer. Good.

  The frequency divider 30 is a frequency divider that divides the oscillation frequency oscillated by the oscillator 20 and outputs an output signal having the divided frequency to the detection circuit 3. The frequency dividing ratio of the frequency divider 30 is 1 / N (N is a rational number of 1 or more). The frequency divider 30 sets the frequency of the signal input to the detection circuit 3 to 1 / N times the oscillation frequency of the oscillator 20 so that the detection circuit 3 can easily handle the signal input to the detection circuit 3. As a result, the frequency of the signal input to the detection circuit 3 falls within the frequency band in which the detection circuit 3 operates. The frequency divider 30 is not an essential configuration for solving the problems of the present invention.

  The detection circuit 3 calculates the oscillation frequency of the oscillator 20 from the frequency output from the frequency divider 30 and the frequency division ratio 1 / N of the frequency divider 30. That is, the detection circuit 3 refers to the output signal of the frequency divider 30 and counts the input signal for a predetermined period (for example, 100 msec), and the count value is the reciprocal N of the frequency division ratio of the frequency divider 30. And the oscillation frequency of the oscillator 20 is estimated by integrating 1 second / predetermined period. The detection circuit 3 includes a counter circuit that counts a change in the frequency of the signal output from the frequency divider 30 for a predetermined period.

(Configuration of sensor IC with antibody immobilized on the surface)
The antibody 201 is immobilized on the protective film 115 by physical adsorption such as intermolecular force acting between molecules or electrostatic force via an electric dipole or the like. That is, the sensor IC 1 further includes a protective film 115 formed so as to cover at least the inductor 52 (for example, the entire oscillator 20) on the semiconductor substrate 10 on which the inductor 52 and the other circuit 112 are formed. And an antibody (capture part) 201 formed on the surface of the protective film 115. The other circuit 112 includes at least the capacitor 54 and the differential circuit 40.

  The antibody 201 serves as a capturing unit that captures target molecules, cells, and tissues in the first embodiment. FIG. 1A is a view of the sensor IC 1 as viewed from the upper side of the protective film 115 (for simplicity of illustration, the protective film 115 is not shown in FIG. 1A). FIG. 1B is a cross-sectional view of the sensor IC 1 taken along a cross-section AA ′ in FIG.

(Target protein detection)
A method for detecting the presence or absence of the protein 204 in the test object 203 with the sensor IC 1 will be described below with reference to FIGS. 1 (a) to (c) and FIGS. 2 (a) to (f). .

  FIGS. 2A to 2F are diagrams for explaining the sensing principle of the sensor IC1, and FIGS. 2A, 2C, and 2E are semiconductors of FIG. 3 is a cross-sectional view of a cross section AA ′ of the substrate 10. FIG. 2A shows a state in which water 202 is in contact with the protective film 115, and FIG. 2C shows a state after injecting a test object 203 that does not contain the target protein protein 204 into the water 202. FIG. 2E shows a state in which the antibody 201 captures the protein 204 after injecting the test object 203 containing the protein 204 in the water 202. (B), (d), and (f) of FIG. 2 respectively show the oscillator 20 measured by using the detection circuit 3 in the sensor IC 1 in (a), (c), and (e) of FIG. It is a figure of an oscillation frequency.

  First, water 202 is brought into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f1 of the oscillator 20. Next, the test object 203 is injected into the water 202 that has come into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f2 of the oscillator 20.

  First, the user brings the water 202 into contact with the protective film 115 of the sensor IC1, and measures the sensor IC1 in the state shown in FIG. The oscillation frequency of the oscillator 20 is divided by the frequency divider 30 to a frequency of 1 / N and counted by the detection circuit 3 for a predetermined period. Then, the detection circuit 3 estimates the oscillation frequency f1 of the oscillator 20.

  Next, the test object 203 is injected into the water 202 that is in contact with the protective film 115 of the sensor IC1, and the sensor IC1 is measured. Similarly, the oscillation frequency of the oscillator 20 is divided by the frequency divider 30 to a frequency of 1 / N and counted by the detection circuit 3 for a predetermined period. Then, the detection circuit 3 estimates the oscillation frequency f2 of the oscillator 20.

  Here, when the protein 204 does not exist in the test object 203, the antibody 201 does not capture anything, and the antibody 201 does not capture the non-target substance 205, and the state shown in FIG. As shown in FIG. 2D, f2 = f1.

  On the other hand, when the protein 204 that is the target of the antibody 201 is present in the test object 203, the antibody 201 captures the protein 204 and enters the state shown in FIG. 2E, and the dielectric constant of the water 202 changes. To do.

  The reason why the dielectric constant of the water 202 changes is as follows. In an aqueous solution, electrostatic forces and hydrogen bonds are caused by ionization of solute ions in the case of electrolyte solutes such as NaCl, and by polarity bias in solute molecules in the case of non-electrolyte solutes such as sugars. Arise. In an aqueous solution containing sugar, etc., in which water molecules are bound to the solute through this electrostatic force or hydrogen bond, the solute or solute molecule is ionized, and ions are bound by electrostatic force or hydrogen bond to hydrate. The phenomenon is known to occur. Hydration is also a major factor in the activity of macromolecules such as proteins. In aqueous solution, the hydration phenomenon and water molecules are replaced by proteins themselves, and the bulk water (water that is not sufficiently bound away from the solute) is reduced, so the dielectric constant of the bulk water changes to the dielectric constant of the protein. To do. FIG. 2 is a graph showing the complex dielectric constant of bulk water. Due to the relaxation phenomenon of bulk water, the fluctuation of the complex dielectric constant is particularly large in the frequency range of 30 GHz to 200 GHz. It is suggested that when the amount of bulk water varies, the complex dielectric constant also varies in the above-described frequency region.

  When the dielectric constant (ε) changes in this way, the parasitic capacitance component generated in the inductor 52 of the oscillator 20 in the capacitor C changes. This is apparent from the equation C = ε × d / S (d: thickness of dielectric, S: area of dielectric). Then, the difference ΔC of the entire capacitance value C corresponding to the sum of the capacitance of the capacitor 54 and the parasitic capacitance value before and after the property change appears as a difference Δf between the oscillation frequencies f1 and f2 of the oscillator 20. A relational expression between the difference Δf and the difference ΔC is shown in the following mathematical formula (2).

Δf = 1 / [2π√ {L (C + ΔC)}] − 1 / {2π√ (LC)} (2)
That is, if the protein 204 is present in the test object 203, f2 ≠ f1. Thus, when the detection circuit 3 detects the oscillation frequency f1 of the oscillator 20 before injecting the test object 203 into the water 202 in contact with the protective film 115 and the oscillation frequency f2 after injection,
If f2 ≠ f1, there is a protein 204 in the test object 203. If f2 = f1, it can be determined that there is no protein 204 in the test object 203.

(effect)
The user compares the oscillation frequency f1 of the oscillator 20 before injecting the test object 203 with the oscillation frequency f2 after injection to determine whether or not the protein 204 is present in the test object 203. It becomes possible.

  For example, when the antibody 201 is an anti-ovalbumin antibody, a food allergen test for determining the presence or absence of ovalbumin, which is a main protein constituting egg white, in the test subject 203 is possible with the sensor IC1. The antibody 201 is not limited to the anti-ovalbumin antibody, and may be an antibody that captures other proteins such as whey and casein.

  Furthermore, if the antibody 201 is an anti-A antibody, it is possible to detect whether or not the A antigen present on the surface of red blood cells in the blood of type A and type AB is present in the test subject 203. The antibody 201 is not limited to the anti-A antibody, and may be an anti-B antibody.

  Furthermore, the water 202 is not limited to water, and may be other liquids such as phosphate buffered saline (PBS) as long as the antibody-antigen reaction between the antibody 201 and the protein 204 is not inhibited.

[Embodiment 2]
In the first embodiment, the antibody 201 serving as a capturing part is immobilized on the protective film 115 by physical adsorption as shown in FIG. 1B, but may be immobilized by physical adsorption described below.

  3A shows a case where a groove 210 is formed in the protective film 115 to immobilize the antibody 201 as a capturing part. FIG. 3B shows a case where a gold thin film 211 is formed on the protective film 115. It is a figure in the case of immobilizing the antibody 201.

  As shown in FIG. 3A, the antibody 201 may be immobilized by forming a groove 210 in the protective film 115 by a combination of photolithography and etching, and physically adsorbing the antibody 201 on the groove 210. .

  Further, as shown in FIG. 3B, the antibody 201 may be immobilized by forming a gold thin film 211 on the protective film 115 and physically adsorbing the antibody 201 on the gold thin film 211. Further, the gold thin film 211 may be formed in an island shape on the inductor 52 by a combination of photolithography and etching.

(effect)
By forming the groove 210, the region where the antibody 201 is formed can be limited to the groove 210. Since it is known that the antibody strongly adsorbs to gold, the adsorption force for immobilizing the antibody 201 is improved by forming the gold thin film 211. Furthermore, the formation region of the antibody 201 can be limited by making the gold thin film 211 into an island shape.

[Embodiment 3]
In the first embodiment, the method for immobilizing the antibody 201 on the protective film 115 by physical adsorption has been described. In the third embodiment, the immobilization of the antibody 201 on the protective film 115 using the immobilization unit 212 will be described with reference to FIGS. 4A and 4B and FIG.

  4A shows a case where the antibody 201 as a capturing part is immobilized on the protective film 115 via the immobilization part 212. FIG. 4B shows a case where the antibody 201 is protected via the gel layer 213. FIG. FIG. 10 is a diagram illustrating an example of a silane coupling reaction.

  First, the protective film 115 is oxidized to form OH groups on the surface. Next, the surface of the protective film 115 is aminated with 3-aminopropyltriethoxysilane (APTMS) or the like to form amino groups 221 on the surface of the protective film 115. Next, the surface of the protective film 115 on which the amino group 221 is formed is maleimidized with 3-maleimidopropionic acid N-succinimide (SMP) or the like to form a maleimide group 222 on the surface of the protective film 115. Next, biotinylation is performed on the surface of the protective film 115 on which the maleimide group 222 is formed using thiol / biotin or the like, and the biotin 223 is immobilized on the protective film 115. Next, avidin 224 is introduced to the surface of the protective film 115 on which biotin 223 is immobilized, and a biotin-avidin reaction is performed to bind avidin 224 to biotin 223. Finally, the antibody 201 labeled with biotin (for labeling) is introduced onto the surface of the protective film 115 on which the avidin 224 is immobilized, and biotin (for labeling) is bound to the avidin 224 by the biotin-avidin reaction. Let In other words, the antibody 201 is produced through biotin (for labeling), avidin 224, biotin 223, and a group of molecules formed by biotinylation / maleimidation / amination as shown in FIG. 201 can be fixed to the protective film 115. 4A is an organic compound between the protective film 115 and the antibody 201 generated by silane coupling, biotin (for labeling), avidin 224, biotin 223, and biotinylation. -It is a group of molecules formed by maleimidation / amination.

  The above series of reactions is called silane coupling. If the purpose of immobilizing the antibody 201 on the semiconductor substrate 10 is achieved, the reaction is not limited to the above reaction, and other silane couplings may be used.

  Furthermore, in the silane coupling, avidin 224 is bound to biotin 223 by a biotin-avidin reaction, but streptavidin may be used instead of avidin 224.

  Furthermore, if the purpose of immobilizing the antibody 201 on the semiconductor substrate 10 is achieved, the intermediate substance may be an alternative substance, and the immobilization technique is not limited to silane coupling.

  For example, the antibody 201 may be immobilized by amine coupling using dithiopropionic acid or the like. Further, the antibody 201 may be immobilized by amine coupling in which the length of a single substance is increased via a spacer substance such as polyethylene glycol.

  Alternatively, avidin or streptavidin may be immobilized by amine coupling, and antibody 201 may be immobilized by biotin-avidin reaction with antibody 201 labeled with biotin.

  Further, a sol-gel method in which an alcohol is removed from an alkoxide (silica precursor) such as tetraethyl orthosilicate (TEOS) by hydrolysis or polycondensation reaction under acidic or basic conditions. Thus, the gel layer 213 may be formed, and the antibody 210 may be immobilized during the formation of the gel layer 213 as shown in FIG.

(effect)
Adsorption is higher than physical adsorption because it uses bonds by chemical reaction.

[Embodiment 4]
In the fourth embodiment, it is assumed that the antibody 201 that is the capturing unit of the first embodiment is an anti-cytokeratin antibody. Anti-cytokeratin antibodies capture cytokeratin, an intermediate filament that forms the cytoskeleton of epithelial cells. That is, when the antibody 201 is an anti-cytokeratin antibody, the cells are captured.

As in the first embodiment, the detection circuit 3 detects the oscillation frequency f1 of the oscillator 20 before the test object 203 is injected into the water 202 in contact with the protective film 115 and the oscillation frequency f2 after the injection. When
If f2 ≠ f1, there is a cell in the inspection object 203. If f2 = f1, it can be determined that there is no cell in the inspection object 203.

  By comparing the oscillation frequencies f1 and f2, it is possible to detect the presence or absence of the target cell in the test subject 203.

  Furthermore, depending on whether the state of the cell is normal or cancerous, a change in the dielectric constant of the cell itself or a change in the dielectric constant of water around the cell due to a change in the hydration state by the cell occurs. Due to the difference in dielectric constant, the oscillation frequency of the oscillator 20 also changes. That is, by estimating the oscillation frequency of the oscillator 20 of the sensor IC1, it is possible to detect whether the cell captured by the antibody 201 is a normal cell or a cancer cell.

  In addition, activation of cells by external stimuli such as temperature, pH, drug solution, and antigen also causes changes in the dielectric constant of the cells themselves and the dielectric constant of water around the cells due to changes in the hydration state by the cells. . First, it is confirmed by the oscillation frequency of the oscillator 20 that the antibody 201 has captured the cell. After confirming the cell capture, it is possible to detect whether the cell is activated by the stimulus by comparing the oscillation frequency f1 of the oscillator 20 before applying the stimulus and the oscillation frequency f2 after applying the stimulus.

  The difference in the state of the cells is not limited to normal cells / cancer cells, and the activity / inactivity of the cells, but the differences in the states that change the dielectric constant of the cells themselves or the surrounding water are generally defined in the present invention. Can be detected.

  The antibody 201 is not limited to anti-cytokeratin. For example, when the antibody 201 is an anti-basophil antibody, basophils can be selectively captured.

  The capture unit is not limited to the antibody 201, and biotin, avidin, streptavidin, peptide, fusion protein, aptamer, etc. can be used as long as the purpose of capturing the molecule, cell, or tissue is achieved. good.

(effect)
Detection of cells and activation of cells by external stimuli such as temperature, pH, drug solution, antigen, etc. can be sensed, and the influence of drugs on molecules, cells, tissues, etc. can be applied to medicine and pharmacy It becomes.

[Embodiment 5]
In the fifth embodiment, it is assumed that the antibody 201 serving as the capturing unit in the first embodiment is a probe DNA (deoxyribonucleic acid). 5A is a diagram in the case where the probe DNA 214 is a capture unit, and FIG. 5B is a diagram in the case where the probe DNA 214 captures the target DNA 215. FIG. As shown in FIG. 5A, the probe DNA (deoxyribonucleic acid) 214 is immobilized by the immobilization unit 212. Target DNA 215 whose base sequences of adenine (A), guanine (G), cytosine (C), and thymine (T) are complementary to probe DNA 214 is targeted.

  When the target DNA 215 is introduced into the surface of the protective film 115 by the probe DNA 214, a complementary base by the probe DNA 214 is obtained by hybridization by hydrogen bonding between adenine (A) and thymine (T), or between guanine (G) and cytosine (C). The target DNA 215 of the sequence is captured. The oscillation frequency of the oscillator 20 changes due to a change in the dielectric constant of the DNA itself due to the DNA changing from a single strand to a double strand, and a change in the dielectric constant of the surrounding water due to the change in the hydration state due to hybridization.

The same method as that described in the first embodiment is performed. That is, when the detection circuit 3 detects the oscillation frequency f1 of the oscillator 20 before injecting the test object 203 into the water 202 in contact with the protective film 115 and the oscillation frequency f2 after injection,
If f2 ≠ f1, the target DNA 215 is present in the test object 203. If f2 = f1, it can be determined that the target DNA 215 is not present in the test object 203.

  In the above, although DNA (deoxyribonucleic acid) was demonstrated, it is not limited and RNA (ribonucleic acid) may be sufficient.

  The immobilization unit 212 is any of those described in the third embodiment. Furthermore, as described in the first and second embodiments, immobilization by physical adsorption without using the immobilization unit 212 may be used.

(effect)
Presence / absence of the target DNA 215 in the inspected object 203 can be detected by the sensor IC1, and application to medicine / pharmaceutics such as genetic analysis, DNA chip, and influence of drug on DNA is possible.

[Embodiment 6]
In the first embodiment, the antibody 201 is a capture unit and the protein 204 is a target. In the fourth embodiment, conversely, the protein 204 is used as a capture unit and the antibody 201 is used as a target. 6A is a diagram in the case where the protein 204 is a capture unit, and FIG. 6B is a diagram in the case where the protein 204 captures the target antibody 201. As shown in FIG. 6A, the protein 204 is immobilized on the protective film 115 by the immobilization unit 212.

  Next, the oscillation frequency of the oscillator 20 is measured using the sensor IC 1 in the same manner as described in the first embodiment.

  As in the first embodiment, first, water 202 is brought into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f1 of the oscillator 20. Next, the test object 203 is injected into the water 202 that has come into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f2.

If the antibody 201 that is the target of the protein 204 exists in the test object 203, the antibody 201 is captured by the protein 204 as shown in FIG. On the other hand, if the test subject 203 does not have the antibody 201 that is the target of the protein 204, the protein 204 maintains the state shown in FIG. At this time,
If f2 <> f1, the antibody 201 is present in the test object 203. If f2 = f1, it can be determined that the antibody 201 is not present in the test object 203.

  The target substance is not limited to proteins and antibodies, and may be molecules, cells, or tissues other than proteins.

(effect)
For example, since the sensor IC1 can detect the presence or absence of the antibody 201 that captures the protein 204 in the subject 203 such as blood, it can be applied to medical pharmacy such as allergy diagnosis.

[Embodiment 7]
Next, a sensor IC 1 according to Embodiment 7 of the present invention will be described with reference to FIGS. FIG. 7A is a view of the sensor IC 1 according to the present embodiment as viewed from above, and shows the position of the cross section BB ′ of the semiconductor substrate 10. FIG. 7B is a cross-sectional view showing a cross section BB ′ of the semiconductor substrate 10. FIG. 7C is a circuit diagram of the oscillator 20 according to the present embodiment. Compared to the first embodiment of the present invention, the configurations of the inductor 52 and the capacitor 54 are different.

(Configuration of oscillator and sensor circuit)
The oscillator 20 includes a differential circuit 40, a resonator 50 formed between the differential circuits 40, and a current source 60 that controls driving of the oscillator 20 according to a control signal. The oscillator 20 has any resonance frequency of 30 to 200 GHz.

  In the configuration shown in FIGS. 7A and 7B, the capacitor 54 is formed on the uppermost metal layer (uppermost metal layer 130) among the metal layers of the semiconductor substrate 10. In plan view, the capacitor 54 is a large part of the area occupied by the oscillator 20 on the semiconductor substrate 10 and is formed in a comb shape.

  Further, the inductor 52 may be formed in a metal layer that is not the uppermost layer, or may be an active inductor formed of a transistor.

  Since the capacitor 54 is formed in the metal layer that is the uppermost layer, the capacitance of the capacitor 54 changes due to moisture adhering to the surface of the semiconductor substrate 10, an object to be inspected, and the like. And the oscillation frequency which the oscillator 20 oscillates changes.

  As described above, in the seventh embodiment, the sensing structure is changed from the inductor 52 of the first embodiment to the capacitor 54. However, the principle that the oscillation frequency of the oscillator 20 changes due to the change in the dielectric constant on the sensor and the principle that the detection circuit 3 estimates the oscillation frequency of the oscillator 20 are the same as in the first embodiment.

(Detection of protein 204)
As in the first embodiment, first, water 202 is brought into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f1 of the oscillator 20. Next, the test object 203 is injected into the water 202 that has come into contact with the protective film 115. The detection circuit 3 estimates the oscillation frequency f2.

If the protein 204 that is the target of the antibody 201 exists in the test object 203, the antibody 201 captures the protein 204 by the antibody antigen reaction. On the other hand, if the target protein 204 is not present in the test object 203, the antibody 201 will not capture the protein 204. At this time,
If f2 ≠ f1, there is a protein 204 in the test object 203. If f2 = f1, it can be determined that there is no protein 204 in the test object 203. That is, the presence or absence of the protein 204 in the test object 203 can be detected by the sensor IC1.

  The method described in the first to sixth embodiments may be used for the capturing unit and the immobilizing unit.

(effect)
The present invention is a sensor IC that detects a target molecule, cell, or tissue. The electric field distribution at a high frequency around 100 GHz differs between the inductor 52 and the capacitor 54. That is, a structure with high detection sensitivity can be selected depending on the shape and size of the target.

[Embodiment 8]
Next, a sensor IC 1 according to Embodiment 8 of the present invention will be described with reference to FIG. FIG. 8 is a configuration diagram of the sensor IC according to the present embodiment.

(Configuration of oscillator and sensor IC)
A plurality of oscillators 20 a, 20 b, 20 c,... Are formed on the semiconductor substrate 10. The oscillators 20a, 20b, 20c,... Each include a differential circuit 40, a resonator 50, and a current source 60, as described in the first embodiment (shown in FIG. 8). Not)

  An antibody (antibody a) 201a is immobilized on the oscillator 20a, an antibody (antibody b) 201b is immobilized on the oscillator 20b, and an antibody (antibody c) 201c is immobilized on the oscillator 20c.

  For convenience of explanation, the target protein of the antibody 201a is referred to as “protein 204a”, and the target protein of the antibody 201b is referred to as “protein 204b”.

  As in the first embodiment, the oscillation frequency f1 of each oscillator 20 is estimated before injecting the test object 203 into the sensor IC1, and the oscillation frequency f2 of the oscillator 20 is estimated after injection.

In the oscillator 20a,
If f2 ≠ f1, there is a protein 204a in the inspection object 203. If f2 = f1, it can be determined that there is no protein 204a in the inspection object 203.

Similarly, in the oscillator 20b,
If f2 ≠ f1, there is a protein 204b in the inspection object 203. If f2 = f1, it can be determined that there is no protein 204b in the inspection object 203.

(effect)
In this way, a plurality of oscillators 20 are formed on the same semiconductor substrate 10 and a plurality of types of antibodies 201 are immobilized to constitute the sensor IC 1. Thereby, it is possible to detect a plurality of types of proteins 204 with one sensor IC1.

  For example, it is assumed that the antibody 201a is an anti-casein antibody and the antibody 201b is an anti-whey antibody. In this case, the presence or absence of casein and whey, which are proteins contained in milk, in the inspected object 203 can be detected by one sensor IC1.

  For example, it is assumed that the antibody 201a is an anti-A antibody and the antibody 201b is an anti-B antibody. In this case, since the presence or absence of the A antigen and the B antigen can be detected in the subject 203, for example, the blood type ABO determination can be performed by one sensor IC1.

  The method described in the first to sixth embodiments may be used for the capturing unit and the immobilizing unit. Further, the sensing means may be the capacitor described in the seventh embodiment.

[Summary]
The sensor IC according to the first aspect of the present invention includes a substrate (semiconductor substrate 10) and at least one resonator disposed on the substrate, and the at least one resonator is in the vicinity of itself. A sensor IC that changes a resonance frequency in accordance with physical properties of an inspection object and detects a state of the object to be inspected based on the resonance frequency of the at least one resonator, and is provided on a surface of the sensor IC. , A capture unit (antibody 201, etc.) that captures at least one of specific molecules, cells, and tissues (protein 204).

  According to the above configuration, the sensor surface is provided with a capturing unit that captures a target molecule, cell, or tissue, so that the resonance frequency of the resonator of the sensor IC before and after the inspected object is measured can be measured. It becomes possible to examine whether or not the target molecule, cell, or tissue exists in the test subject by the frequency shift. Furthermore, by capturing the target molecule / cell / tissue on the sensor surface, the detection sensitivity of the target molecule / cell / tissue in the test object is improved.

  Therefore, according to the above configuration, detection sensitivity can be improved.

  The sensor IC which concerns on aspect 2 of this invention is equipped with the fixing | fixed part which fixes the said capture | acquisition part to the surface of the said sensor IC in the said aspect 1. FIG.

  According to said structure, it becomes easy to fix a capture part to the surface of sensor IC by an immobilization part.

  The sensor IC according to aspect 3 of the present invention is the above-described aspect 1 or 2, wherein the capturing unit includes an antibody.

  The sensor IC according to aspect 4 of the present invention is the sensor IC according to any one of the aspects 1 to 3, wherein the capturing unit includes DNA.

  According to said structure, a capture part is realizable with an antibody and / or DNA.

  A sensor IC according to aspect 5 of the present invention includes the at least two resonators according to any one of the above aspects 1 to 4, and the capturing unit included in one of the two resonators captures the sensor IC. At least one of molecules, cells, and tissues is different from at least one of the molecules, cells, and tissues that are captured by the capturing unit included in the other of the two resonators.

  According to the above configuration, it is possible to detect a plurality of types of molecules / cells / tissues present in the test object with a single sensor IC by immobilizing a plurality of types of capturing parts on the surface of the sensor IC. .

  The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention. Furthermore, a new technical feature can be formed by combining the technical means disclosed in each embodiment.

1 Sensor IC
10 Semiconductor substrate (substrate)
50 Resonator 201, 201a, 201b, 201c Antibody (capture part) (at least one of specific molecule, cell, and tissue)
203 Inspected object 204 Protein (at least one of specific molecule, cell, and tissue) (capture part)
212 Immobilization unit 214 Probe DNA (capture unit)

Claims (5)

A substrate,
And at least one resonator disposed on the substrate,
The at least one resonator changes a resonance frequency according to physical properties of an object to be inspected in the vicinity of the resonator,
A sensor IC for detecting a state of the device under test based on the resonance frequency of the at least one resonator;
A sensor IC comprising a capturing unit that captures at least one of specific molecules, cells, and tissues on a surface of the sensor IC.   The sensor IC according to claim 1, wherein the sensor IC includes an immobilization unit that fixes the capturing unit to a surface of the sensor IC.   The sensor IC according to claim 1, wherein the capturing unit includes an antibody.   The sensor IC according to any one of claims 1 to 3, wherein the capturing unit includes DNA. The sensor IC includes at least two of the resonators,
At least one of the molecules, cells, and tissues captured by the capture unit included in one of the two resonators, and the molecule captured by the capture unit included in the other of the two resonators, The sensor IC according to any one of claims 1 to 4, wherein at least one of the cells and the tissue is different from each other.

Images