KR100988728B1 - Biosensor using the selectivity of biomolecule - Google Patents

Abstract

The present invention relates to a biosensor using biomolecule selectivity.

The biosensor using the biomolecule selectivity according to the present invention includes a nanogap substrate portion and a nanogap substrate portion in which a pair of conductive substrates including different conductive materials and facing each other by a nanometer interval are connected in series. It includes a field effect transistor for detecting a change in the strength of the current according to the voltage difference.

According to the present invention, high biomolecule detection sensitivity can be increased by using a voltage amplifying structure to obtain accurate detection results. In addition, in the detection of biomolecules, parallel processing is possible, thereby increasing the detection speed, which is advantageous in terms of cost and time according to biomolecule analysis.

Biomolecule, Bio Sensor, Field Effect Transistor, Nano Gap, Conductive Material, Electrostatic Induction

Description

Biosensor using biomolecular selectivity {BIOSENSOR USING THE SELECTIVITY OF BIOMOLECULE}

The present invention relates to a biosensor using biomolecule selectivity.

Sensors that detect biomolecules include field effect transistor (FET) based biosensors that extract signals for biomolecules by electrochemical methods. FET-based biosensors are fabricated using conventional semiconductor processes, enabling easy integration and fast signal processing.

1 is a view schematically illustrating the configuration of a biosensor for measuring a biological response of a biomolecule using a change in the gate surface charge of the FET.

Referring to FIG. 1, a biosensor is formed on both sides of a substrate 70 and a substrate 70 of a FET and is doped with a source 80a and a drain 80b and a source 80a respectively opposite to the substrate 70. And a gate 60 in contact with the drain 80b and formed on the substrate 70.

The gate 60 has a structure in which the oxide layer 30, the polysilicon layer 20, and the gate electrode layer 10 are sequentially stacked. The gate region 60 to which the biomolecule is attached may be configured such that the biomolecule is directly attached to the oxide layer 30 or the gate electrode layer 10 is attached without the polysilicon layer 20 or the gate electrode layer 10.

The conventional biomolecule detection method is a method of attaching biomolecules to the gate region 60 and applying a voltage to the reference electrode 50 to measure the intensity of the current passing through the channel 40 in response to the biomolecule reaction. . In the conventional biosensor, there is a problem that the reference electrode 50 and the gate 60 of the FET are far from each other, and biomolecules are hardly fixed to the gate 60, thereby decreasing reproducibility. In addition, there is also found a problem that the amount of charge of the biomolecule attached to the gate region 60 is small, so that the sensitivity of detection of the change in current intensity is low. In addition, the effect of the electrolyte 90 ions existing between the reference electrode 50 and the gate region 60 may act as noise.

FIG. 2 is a diagram schematically showing the configuration of a conventional biosensor for measuring the biological response of biomolecules using the gate capacitance of the FET.

The biosensor shown in FIG. 2 is composed of a FET having a substrate 70, a source 801a, a drain 80b, and a gate 60, similarly to the biosensor shown in FIG.

The conventional biosensor shown in FIG. 2 has a structure in which the intermediate layer 20 formed on the oxide layer 30 of the gate 60 is etched. The biosensor shown in FIG. 2 may be referred to as a structure in which the reference electrode 50 of the biosensor shown in FIG. 1 is fixed as the gate electrode layer 10. The biosensor shown in FIG. 2 locates biomolecules in the gap and senses the change in the intensity of the current flowing through the channel according to the change in capacitance or dielectric constant present in the FET. Conventional biosensors have a problem that the sensitivity of detecting the change in intensity of the current is low because the amount of biomolecules located in the gap is limited to a very small amount.

Accordingly, there is a need for a biosensor capable of increasing detection sensitivity and detecting biomolecules more efficiently in a structure and manner different from conventional biosensors.

An object of the present invention to solve this problem is to provide a high-efficiency biosensor capable of obtaining high biomolecule detection sensitivity and miniaturization.

The biosensor using the biomolecule selectivity according to the present invention includes a nanogap substrate portion and a nanogap substrate portion in which a pair of conductive substrates including different conductive materials and facing each other by a nanometer interval are connected in series. It includes a field effect transistor for detecting a change in the strength of the current according to the voltage difference.

Conductive material,

Including a metal material containing at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium (Palladium) and ITO (Indum Tin Oxide),

It is preferable that the pair of conductive substrates include different metal materials.

Conductive materials include metallic and inorganic materials,

Any one of the pair of conductive substrates comprises a metallic material, another conductive substrate comprises an inorganic material,

The metal material includes at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO).

The inorganic material preferably includes polysilicon.

The spacing between the pair of conductive substrates is preferably 30 nm to 100 nm.

The nanogap substrate portion is connected to the gate of the field effect transistor,

It is preferable that the strength of the current flowing through the channel changes according to the gate voltage change of the field effect transistor.

The biosensor using the biomolecule selectivity according to the present invention includes a nanogap substrate portion and a nanogap substrate portion in which a pair of conductive substrates including different conductive materials and facing each other by a nanometer interval are connected in series. An output unit for outputting a voltage corresponding to the voltage difference.

Conductive material,

Including a metal material containing at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium (Palladium) and ITO (Indum Tin Oxide),

It is preferable that the pair of conductive substrates include different metal materials.

Conductive materials include metallic and inorganic materials,

Any one of the pair of conductive substrates comprises a metallic material, another conductive substrate comprises an inorganic material,

The metal material includes at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO).

The inorganic material preferably includes polysilicon.

The spacing between the pair of conductive substrates is preferably 30 nm to 100 nm.

Output part,

An offset capacitor having one end connected to one end of the nanogap substrate portion, a differential amplifier having an inverting input terminal connected to the other end of the offset capacitor, a differential amplifier having a non-inverting input terminal connected to the common voltage, and a first switch connected between the offset capacitor and the common voltage, and differential A second switch connected between the inverting input terminal and the output terminal of the amplifier, a third switch connected between the offset capacitor and the nanogap substrate section, and one end thereof is connected between the other end of the nanogap substrate section and the output end of the differential amplifier, and the other end of the output section of the amplifier A fourth switch connected with the

The first switch and the second switch may be switched in synchronization with the first control signal, and the third switch and the fourth switch may be switched in synchronization with the second control signal.

The biosensor according to the present invention can increase the detection sensitivity of high biomolecules using a voltage amplification structure to obtain accurate detection results. In addition, in the detection of biomolecules, parallel processing is possible, thereby increasing the detection speed, which is advantageous in terms of cost and time according to biomolecule analysis.

Hereinafter, with reference to the accompanying drawings will be described in detail with respect to the biosensor using the selectivity of biomolecules according to an embodiment of the present invention.

[First Embodiment]

3 is a view showing a pair of conductive substrates according to the present invention. 4 is a view showing a nanogap substrate portion formed in a structure in which a pair of conductive substrates are connected in series.

3 and 4, the biosensor according to the present invention includes a nanogap substrate unit 400 and a nanogap in which a plurality of pairs of conductive substrates 100 and 200 facing each other with a nanometer spacing therebetween are connected in series. A field effect transistor (hereinafter, referred to as a FET) for detecting a change in intensity of a current due to a voltage difference across the substrate 400 is included.

Referring to FIG. 3A, the pair of conductive substrates 100 and 200 have an interval of about 30 nm to 100 nm. The pair of conductive substrates 100 and 200 include different conductive materials such that the biomolecule is selectively attached to the top of one conductive substrate.

The conductive material forming the conductive substrate may include a metal material including at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO). However, it is preferable that the pair of conductive substrates include different metal materials.

In addition, the conductive material forming the conductive substrate may include a metal material and an inorganic material. However, it is preferable that any one of the pair of conductive substrates includes a metal material, and the other conductive substrates include an inorganic material. The metal material may include at least one or more of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO), and the inorganic material may include polysilicon. have.

The pair of conductive substrates 100 and 200 should be formed of different materials because when the biomolecules are immobilized, the biomolecules can be selectively immobilized on only one substrate. Even if a pair of conductive substrates are formed of the same material, as long as the substrates are surface treated differently and biomolecules can be adsorbed on only one substrate, the conductive substrate can be used as the nanogap substrate portion of the present invention.

Referring to FIG. 3B, the surface of one conductive substrate is negatively charged by the negatively charged biomolecule 500 in the pair of conductive substrate portions 100 and 200, and the biomolecule 500 is negatively charged. Another conductive substrate, which is not fixed, is positively charged by electrostatic induction. Positive and negative charge signs can change depending on the nature of the biomolecule. In the pair of conductive substrates 100 and 200, an electrolyte including biomolecule may be a dielectric and serve as one capacitor. The difference in charge and the difference in voltage appearing in the pair of conductive substrates 100 and 200 may be represented by the following equation.

The voltage difference ΔV appearing across the pair of conductive substrates 100, 200 is determined by the charged amount ΔQ of the biomolecule. That is, the difference in charge between the pair of conductive substrates 100 and 200 depends on the amount of biomolecule, whether the biomolecule is immobilized on the surface of the substrate, and whether the biomolecule is bonded to the immobilized biomolecule. ), Which causes a voltage difference ΔV.

4 is a diagram illustrating a nanogap substrate having a voltage amplifying structure in which the conductive substrate illustrated in FIG. 3 is connected in series.

As shown in FIG. 4, the nanogap substrate unit 400 has a structure in which a pair of conductive substrates 100 and 200 shown in FIG. 3 are connected in series. The nanogap substrate portion 400 is the same as connecting a capacitor having a predetermined voltage ΔV in series. When a DC voltage V _A is applied to one end of the nanogap substrate part 400 including n conductive substrates connected in series, a voltage of V _A + n ΔV appears on the other end of the nanogap substrate part 400. Accordingly, the nanogap substrate 400 may obtain an effect of amplifying the input voltage V _A. The conductive substrates of the nanogap substrate portion 400 may be connected in series with substrates including different conductive materials. In the structure of the nanogap substrate 400 connected in series, when the position of the terminal to which the input voltage V _A is applied is reversed or the substrate to which the biomolecule is selectively adsorbed is reversed, the reduced voltage V _A -nΔV is decreased. It is also possible to obtain.

5 is a diagram illustrating a biosensor according to a first embodiment of the present invention.

Referring to FIG. 5, the biosensor includes a nanogap substrate 400 and an FET for detecting a change in intensity of a current according to a voltage difference across the nanogap substrate 400.

The FET consists of a substrate 70, a source 80a, a drain 80b and a gate 60. The source 80a and the drain 80b are formed on both sides of the substrate 70 and doped with opposite polarities to the substrate 70, respectively. The gate 60 is in contact with the source 80a and the drain 80b and is formed on the substrate 70. The gate 60 has a structure in which an oxide layer 30, a polysilicon layer 20, and a gate electrode layer 10 are stacked. The gate electrode layer 10 is connected to one end of the nanogap substrate portion 400. The other end of the nanogap substrate portion 400 is connected to the gate voltage V _G. As a result, the voltage V _G appearing in the gate electrode layer 10 becomes V _G + nΔV. Since the voltage appearing on the gate electrode layer 10 is determined by the degree of charge of the biomolecule, the voltage depends on the amount of the biomolecule, whether the biomolecule is fixed to the conductive substrate, and whether or not the biomolecule is bonded to the target biomolecule. The difference nΔV will be different. That is, the voltage applied to the gate 60 is changed by the nanogap substrate portion 400 to which biomolecules are attached. As a result, the amount of electrons 80 moving through the channel between the source 80a and the drain 80b of the FET changes, and the current strength between the drain 80b in the source 80a changes. The biosensor detects the current in this FET to detect the target biomolecule. The current flowing through the channel of the FET can be defined in the saturation region (Saturation region) like the CMOS device as shown in the following formula.

Factors affecting the intensity of the current I _D by the biomolecule are limited to the amplified voltage appearing in the gate electrode layer 10.

The capacitance C _OX appearing between the gate oxide layer 30 and the conductive substrate is much smaller than the total capacitance (C1 / n) of the series-connected conductive substrates such that the capacitance that determines the current strength of the FET is mainly C _OX . . Therefore, the nanogap substrate portion 400 has a sufficiently large structure so that the capacitance of the nanogap substrate portion 400 does not affect the current flowing through the channel of the FET. That is, the nanogap substrate portion 400 is preferably designed such that the conductive substrate portion has a sufficient area so as to increase the capacitance and increase the amount of biomolecule fixed on the surface of the conductive substrate. The capacitance C _OX that appears between the gate oxide layer 30 and the conductive substrate is preferably represented by the following formula.

As well as the biosensor of the current detection method according to the first embodiment of the present invention, it is also possible to implement a biosensor that can directly detect the voltage difference across the nanogap substrate portion by using a field effect transistor.

Biosensors using biomolecular selectivity according to the present invention can achieve more efficient and higher detection sensitivity than conventional FET-based biosensors. In addition, the conductive substrate on which the biomolecule is located has a dominant voltage amplification property, so that unlike the conventional FET-based biosensors, the ion effect of the electrolyte can be ignored.

Second Embodiment

6 illustrates a biosensor using biomolecule selectivity according to a second embodiment of the present invention.

Unlike the FET-based biosensor described above, the biosensor shown in FIG. 6 has a configuration of directly measuring a change in amplified voltage in the nanogap substrate portion. 6A illustrates a biosensor using a differential amplifier with a single output. 6B illustrates a biosensor using an amplifier with a fully differential output.

Referring to FIG. 6A, a biosensor according to a second exemplary embodiment of the present invention includes a nanogap substrate 400 and an output 500.

Since the nanogap substrate portion 400 according to the second embodiment of the present invention has the same configuration as the nanogap substrate portion according to the first embodiment of the present invention, the nanogap substrate portion according to the second embodiment of the present invention ( The detailed description of 400 is replaced with the detailed description of the nanogap substrate unit according to the first embodiment of the present invention.

The output unit 500 includes an offset capacitor C1, an output capacitor C2 differential amplifier 510, and first to fourth switches S1, S2, S3, and S4.

One end of the offset capacitor C1 is connected to one end of the nanogap substrate portion 400. In the differential amplifier 510, an inverting input terminal (−) is connected to the other end of the offset capacitor C1 and a non-inverting input terminal (+) is connected with a common voltage. The first switch S1 is connected between the offset capacitor C1 and the common voltage. The second switch S2 is connected between the inverting input terminal (−) and the output terminal of the differential amplifier 510. The third switch S3 is connected between the offset capacitor C1 and the nanogap substrate portion 400. One end of the fourth switch S4 is connected between the other end of the nanogap substrate 400 and the output end of the differential amplifier 400, and the other end is connected to the output Vout of the output unit 500.

Hereinafter, the operation of the biosensor according to the present invention will be described. The output unit 500 is switched and driven by two control signals? 1 and? 2 having different phases.

1) First, the first and second switches S1 and S2 are turned on in synchronization with the first control signal? 1. Accordingly, the offset error value of the differential amplifier 510 is stored in the offset capacitor C1.

2) The third and fourth switches S3 and S4 are turned on in synchronization with the second control signal? 2. At this time, the first and second switches S1 and S2 are turned off, and the offset value of the differential amplifier 510 and the offset error value stored in the capacitor C1 cancel each other out. As a result, an amplification voltage nΔV by the nanogap substrate 400 without an error appears at the output terminal Vout of the output unit 500.

In this manner, the biosensor may output the amplification voltage nΔV by repeating 1) and 2) in one cycle, thereby measuring the voltage change of the nanogap substrate unit 400. Unlike the biosensor of the first embodiment, this method corresponds to a method of directly measuring the voltage induced by the biomolecule selectivity.

When detecting biomolecules using the biosensors according to the first and second embodiments of the present invention, the following matters should be considered.

(1) Change of output according to the concentration of electrolyte ions including biomolecules.

(2) The change of output according to the change of the concentration of the biomolecule contained in electrolyte.

(3) The change in output that occurs while the water in the electrolyte evaporates.

(4) Changes in output according to processes before and after immobilization of biomolecules and before and after coupling reactions with target biomolecules.

(5) Change in output over time until the combination of immobilized biomolecules with target biomolecules is complete.

(6) The change of output according to the change of ambient temperature at the time of measurement.

The change in output described in (1) to (6) corresponds to the change in the intensity of the drain current in the case of the FET-based biosensor, and the change in the final output voltage in the case of the voltage change measurement biosensor.

7 illustrates a process implementation of a biosensor in accordance with the present invention.

As shown in FIG. 7, the nanogap substrate 300 may be implemented as a voltage amplifying structure connected in series with the FET. VIA 700 may be used to connect in series between conductive substrates.

In the FET-based biosensor according to the first embodiment of the present invention, the nanogap substrate portion may be implemented by connecting to a gate of a single FET. The nanogap substrate portion in the voltage change measurement biosensor according to the second embodiment may be connected to a CMOS circuit including one or more FETs. In this case, the connection may be a connection between the nanogap substrate portion and the gate, source, or drain of the FET.

As shown in FIG. 7, the nanogap substrate portion may be disposed side by side with the FET, stacked vertically, or disposed in a form surrounding the FET. In addition, when the nanogap substrate portion is arranged to surround the FET, it is preferable to connect the conductive substrate by dividing the same size.

The biosensor according to the present invention can increase the detection sensitivity of high biomolecules using a voltage amplification structure to obtain accurate detection results. In addition, in the detection of biomolecules, parallel processing is possible, thereby increasing the detection speed, which is advantageous in terms of cost and time according to biomolecule analysis. In addition, FET-based biosensors can be fixed by terminating the reference electrode as a nanogap series structure, thereby increasing reproducibility and miniaturization.

As described above, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without changing the technical spirit or essential features. Therefore, the embodiments described above are to be understood in all respects as illustrative and not restrictive, and the scope of the present invention is indicated by the following claims rather than the above description, and the meaning and scope of the claims And all changes or modifications derived from the equivalent concept should be construed as being included in the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 schematically shows the configuration of a conventional biosensor using gate surface charge.

2 is a diagram schematically showing a configuration of a conventional biosensor using a gate capacitance.

Figure 3 shows a conductive substrate having a nanogap according to the present invention.

4 is a view showing a nanogap substrate according to the present invention in which the structure shown in FIG. 3 is connected in series.

5 illustrates a FET based biosensor including a nanogap substrate portion.

6 is a view showing a voltage change measurement biosensor including a nanogap substrate.

7 shows a process implementation of a biosensor.

Claims (10)

A nanogap substrate portion including a plurality of conductive substrates connected to each other in series and facing each other by a nanometer interval; And Biosensor using a biomolecule selectivity comprising a field effect transistor for detecting a change in the intensity of the current according to the voltage difference across the nanogap substrate. The method of claim 1, The conductive material, Including a metal material containing at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium (Palladium) and ITO (Indum Tin Oxide), A pair of conductive substrate is a biosensor using the selectivity of biomolecules containing different metal materials. The method of claim 1, The conductive material includes a metal material and an inorganic material, Any one of the pair of conductive substrates comprises the metallic material, another conductive substrate comprises the inorganic material, The metal material includes at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO). The inorganic material is a biosensor using the selectivity of biomolecules containing polysilicon. The method of claim 1, The biosensor using the selectivity of the biomolecule is 30nm to 100nm between the pair of conductive substrates. The method of claim 1, The nanogap substrate portion is connected to the gate of the field effect transistor, A biosensor using biomolecule selectivity in which the intensity of a current flowing through a channel is changed according to a gate voltage change of the field effect transistor. A nanogap substrate portion including a plurality of conductive substrates connected to each other in series and facing each other by a nanometer interval; And Biosensor using the selectivity of the biomolecule including an output unit for outputting a voltage corresponding to the voltage difference across the nanogap substrate portion. The method of claim 6, The conductive material, Including a metal material containing at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium (Palladium) and ITO (Indum Tin Oxide), A pair of conductive substrate is a biosensor using the selectivity of biomolecules containing different metal materials. The method of claim 6, The conductive material includes a metal material and an inorganic material, Any one of the pair of conductive substrates comprises the metallic material, another conductive substrate comprises the inorganic material, The metal material includes at least one of gold, silver, chromium, titanium, platinum, copper, aluminum, palladium, and indium tin oxide (ITO). The inorganic material is a biosensor using the selectivity of biomolecules containing polysilicon. The method of claim 6, The biosensor using the selectivity of the biomolecule is 30nm to 100nm between the pair of conductive substrates. The method of claim 6, The output unit, An offset capacitor having one end connected to one end of the nanogap substrate portion; A differential amplifier having an inverting input terminal connected to the other end of the offset capacitor and a non-inverting input terminal connected to a common voltage; A first switch connected between the offset capacitor and the common voltage; A second switch connected between an inverting input terminal and an output terminal of the differential amplifier; A third switch connected between the offset capacitor and the nanogap substrate portion; And The other end of the nanogap substrate portion and the output end of the differential amplifier; A fourth switch connected between the other end and the output end of the output unit; The first switch and the second switch is switched in synchronization with the first control signal, The biosensor using the selectivity of the biomolecule that the third switch and the fourth switch is switched in synchronization with the second control signal.

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