CN115266879A - High-sensitivity suspension two-dimensional nano-biomolecule sensor and application thereof - Google Patents
High-sensitivity suspension two-dimensional nano-biomolecule sensor and application thereof Download PDFInfo
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Abstract
The invention discloses a high-sensitivity suspension two-dimensional nano-biomolecule sensor and application thereof. The sensor comprises a substrate layer, an electrode layer and a plurality of graphene strips, wherein the substrate layer comprises a silicon dioxide layer and a silicon layer which are arranged up and down, a groove with an open upper part and a closed lower part is formed on the substrate layer, and the groove extends from the silicon dioxide layer to the silicon layer; the electrode layer comprises a source electrode, a drain electrode and a grid electrode, wherein the source electrode, the drain electrode and the grid electrode are arranged on the silicon dioxide layer, the source electrode and the drain electrode are respectively arranged on two opposite sides of the groove, and the grid electrode is not in contact with the source electrode and the drain electrode; the graphene strips are arranged above the groove at intervals in a suspending mode, one end of each graphene strip is located between the source electrode and the silicon dioxide layer, and the other end of each graphene strip is located between the drain electrode and the silicon dioxide layer. The sensor can effectively solve the problems of detection sensitivity reduction, limited effective sensing area, weak molecular bonding force and the like caused by the existence of the substrate in the bio-FET, and meanwhile, the arrangement of a plurality of spaced graphene strips in the sensor can further increase the biomolecule detection flux.
Description
Technical Field
The invention belongs to the technical field of biomolecule detection, and particularly relates to a high-sensitivity suspension two-dimensional nano biomolecule sensor and application thereof.
Background
In recent years, bio-Field effect transistor (Field-effect transistor, referred to as bio-FET) technology has attracted more and more attention in the Field of detection and analysis of biomolecules. For example, daehon Kim et al can detect AFP protein in plasma of liver cancer patients and Phosphate Buffered Saline (PBS) solution by performing AFP antibody protein modification on the graphene surface in graphene field effect transistors; eric Danielson et al can achieve detection of lactose concentration by human galectin modification of graphene surface in graphene field effect transistors; jingxia Liu et al detect DNA molecules by gold particle modification on the surface of molybdenum disulfide in a molybdenum disulfide field effect transistor. The two-dimensional nano material is widely applied to a channel part (namely a channel of electrons between a source electrode and a drain electrode) of a bio-FET device due to excellent performance, and can effectively avoid a short channel effect, eliminate carrier scattering and keep good electrostatic regulation and control capability when being used as the channel part of the bio-FET. The detection principle of the bio-FET with the two-dimensional nano material as the channel part is as follows: the channel surface is specifically modified before the experiment, when the biomolecule to be detected is combined to the bio-FET channel surface, the output of the current between the source electrode and the drain electrode is changed according to the combination state of the biomolecule under the control of the grid voltage, so that qualitative and quantitative analysis of the biomolecule can be realized by detecting the electrical signal output of the bio-FET. Compared with the traditional enzyme-linked immunosorbent assay and fluorescence detection method, the bio-FET has the advantages of label-free property, simple operation, high specificity, wide detection range and the like when used for detecting biomolecules.
At present, the two-dimensional nano material is generally applied to the bio-FET, and the substrate is usually held, the lower surface of the two-dimensional nano material will contact with the substrate, and the contact will cause the following influences on the detection result: 1) Partial electrons between the source electrode and the drain electrode are lost from the substrate, so that the detection sensitivity is influenced; 2) The two-dimensional nano material usually has only one surface contacting with the molecules to be detected, and cannot completely utilize the sensing areas of the upper surface and the lower surface; 3) The interaction between the bottom surface of the two-dimensional nano material and the substrate can cause the charges in the two-dimensional nano material to be suspended at the substrate, and the binding force between the upper surface of the two-dimensional nano material and biomolecules is weakened. Therefore, the influence factors cause that the stability of the detection process and the accuracy of the detection result of the traditional two-dimensional nano material bio-FET supported by the substrate are not ideal enough, and the application and the development of the bio-FET in the field of biomolecule detection are limited.
Disclosure of Invention
The present invention is directed to solving, at least in part, one of the technical problems in the related art. Therefore, an object of the present invention is to provide a high-sensitivity suspended two-dimensional nano-biomolecule sensor and a use thereof. The sensor can effectively solve the problems of detection sensitivity reduction, limited effective sensing area, weak molecular binding force and the like caused by the existence of the substrate in the bio-FET, and meanwhile, the arrangement of a plurality of spaced graphene strips in the sensor can further increase the biomolecule detection flux.
The present application is primarily based on the following problems and findings:
in a conventional two-dimensional nanomaterial biosensor based on the bio-FET principle, a two-dimensional nanomaterial is usually disposed on a substrate, and the presence of the substrate affects the transport of electrons during the detection process, thereby affecting the corresponding detection result. In addition, the two-dimensional nanomaterial has a limited effective detection area because only the upper surface of the two-dimensional nanomaterial is in contact with biomolecules due to the direct contact between the lower surface of the two-dimensional nanomaterial and the substrate, and the bonding force between the biomolecules and the material is weak due to the non-uniform distribution of charges inside the two-dimensional nanomaterial in the manner that only the upper surface of the two-dimensional nanomaterial is bonded with the biomolecules. Therefore, the inventors imagine that the above problems can be solved by etching the substrate under the two-dimensional nanomaterial strip to reduce the influence of the substrate on the detection process, and to achieve the simultaneous binding of the biomolecules to the upper and lower surfaces of the two-dimensional nanomaterial during the detection process, thereby increasing the effective detection area and the binding force between the two-dimensional nanomaterial and the biomolecules.
To this end, in one aspect of the present invention, the present invention proposes a high-sensitivity suspended two-dimensional nano-biomolecule sensor. According to an embodiment of the invention, the sensor comprises:
the silicon-based solar cell comprises a substrate layer and a substrate layer, wherein the substrate layer comprises a silicon dioxide layer and a silicon layer which are arranged up and down, a groove with an opened upper part and a closed lower part is formed on the substrate layer, and the groove extends to the silicon layer from the silicon dioxide layer;
the electrode layer comprises a source electrode, a drain electrode and a grid electrode, wherein the source electrode, the drain electrode and the grid electrode are arranged on the silicon dioxide layer, the source electrode and the drain electrode are respectively arranged on two opposite sides of the groove, and the grid electrode is not in contact with the source electrode and the drain electrode;
the graphene strips are arranged above the groove at intervals in a suspending mode, one end of each graphene strip is located between the source electrode and the silicon dioxide layer, and the other end of each graphene strip is located between the drain electrode and the silicon dioxide layer.
The suspension two-dimensional nano-biomolecule sensor provided by the embodiment of the invention is based on a biological field effect tube sensing mechanism, and the mode that the channel material of the traditional biological field effect tube is contacted with the single surface of the biomolecule is changed into the mode that the channel material is contacted with the biomolecule on the double surfaces by suspending. The sensor can avoid the contact of the two-dimensional nano material and the substrate, and has at least the following beneficial effects: 1) The loss of electrons from the substrate can be avoided, and the detection sensitivity is improved; 2) The upper surface and the lower surface of the graphene two-dimensional nano material strip can be contacted with biomolecules, so that the effective detection area of the sensor can be effectively increased; 3) The mode of double-sided combination of the biomolecules and the graphene two-dimensional nano material strip can ensure the uniform distribution of charges on the upper surface and the lower surface of the two-dimensional nano material and ensure the stable combination between the biomolecules and the two-dimensional nano material, thereby effectively improving the stability of the biomolecule detection process and the accuracy of the detection result and realizing high-precision and high-reliability biomolecular detection; 4) The plurality of graphene strips arranged in the sensor at intervals can further increase the biomolecule detection flux and the detection reliability, and detection can be completed through other graphene strips even if a single graphene strip structure is damaged.
In addition, the high-sensitivity suspension two-dimensional nano-biomolecule sensor according to the above embodiment of the invention may also have the following additional technical features:
in some embodiments of the invention, the high-sensitivity suspended two-dimensional nanobiotolecular sensor further comprises: the first external circuit comprises a first power supply and a first ammeter, and two ends of the first power supply are respectively connected with the source electrode and the drain electrode; and the second external circuit comprises a second power supply and a first ammeter, wherein one end of the second power supply is connected with the source electrode or the drain electrode, and the other end of the second power supply is connected with the grid electrode.
In some embodiments of the present invention, the silicon layer has a thickness of 200 to 500 μm, and the silicon dioxide layer has a thickness of 100 to 300nm.
In some embodiments of the present invention, the suspended length of a single graphene strip is 1 to 3 μm, the suspended width is 1 to 2 μm, and the distance between two adjacent graphene strips is 3 to 5 μm; the thickness of the graphene strip is 0.3-0.4 nm.
In some embodiments of the present invention, the number of the plurality of graphene strips is 2 to 8.
In some embodiments of the present invention, the plurality of graphene strips are uniformly distributed along the length direction of the source electrode and the drain electrode.
In some embodiments of the present invention, the electrode layer has a thickness of 100 to 150nm, and the source electrode, the drain electrode and the gate electrode independently have a length distribution of 40 to 60 μm and a width distribution of 25 to 35 μm.
In a further aspect of the invention, the invention provides the use of the high-sensitivity suspension two-dimensional nano-biomolecule sensor in biomolecule detection. Compared with the prior art, the application has all the characteristics and effects of the high-sensitivity suspension two-dimensional nanometer biomolecule sensor, and the description is omitted here. In general, adverse effects of contact between the substrate and the two-dimensional nano material on stability and detection accuracy of the detection process can be eliminated, and detection sensitivity, stability, reliability and detection accuracy are ensured.
In still another aspect of the present invention, the present invention provides a method for detecting biomolecules by using the above-mentioned high-sensitivity suspended two-dimensional nano-biomolecule sensor. According to an embodiment of the invention, the method comprises:
(1) Specific combination of the biological molecules to be detected and the upper and lower surfaces of the graphene strip is realized;
(2) Applying a direct current voltage to the gate and setting a bias voltage between the source and the drain;
(3) And detecting circuit parameter changes including current signals between the source electrode and the drain electrode under the regulation and control of the grid voltage so as to realize qualitative and quantitative detection and analysis of the to-be-detected biomolecule.
Compared with the prior art, the method for detecting biomolecules according to the above embodiment of the present invention has all the features and effects of the above-mentioned high-sensitivity suspension two-dimensional nano-biomolecule sensor, and will not be described herein again. In general, the method is simple in process, can realize the analysis of qualitative and quantitative information of the biomolecules, and can also solve the problems of limited sensitivity, small detection effective area, unstable combination of the biomolecules and the channel material and the like caused by the contact of the channel material and the substrate in the traditional biological field effect tube detection mode.
In some embodiments of the invention, step (1) further comprises: (1-1) surface-treating the graphene strip so as to enable the graphene strip to immobilize an antibody or aptamer corresponding to a biomolecule to be detected; (1-2) carrying out surface specificity modification on the graphene strip subjected to surface treatment by using the antibody or aptamer corresponding to the biomolecule to be detected; (1-3) treating non-specific sites remaining on the surface of the graphene strip so as to prevent non-specific adsorption on the surface of the graphene strip; and (1-4) contacting the graphene strip obtained in the step (1-3) with a to-be-detected biomolecule sample solution to realize specific binding of the to-be-detected biomolecule and the upper and lower surfaces of the graphene strip.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
fig. 1 is a schematic structural diagram of a high-sensitivity suspended two-dimensional nano-biomolecule sensor according to an embodiment of the invention.
Fig. 2 is a schematic structural diagram of a high-sensitivity suspended two-dimensional nano-biomolecule sensor according to still another embodiment of the invention.
FIG. 3 is a flow chart of a partial method for fabricating a high sensitivity suspended two-dimensional nano-biomolecule sensor according to an embodiment of the present invention.
FIG. 4 is a flow chart of a partial method for preparing a high-sensitivity suspended two-dimensional nano-biomolecule sensor according to still another embodiment of the invention.
FIG. 5 is a flow chart of a method for detecting biomolecules using a high sensitivity suspended two-dimensional nanobiotolecule sensor according to an embodiment of the present invention.
FIG. 6 is a diagram illustrating the effect of specific binding of a biomolecule to be detected by a high-sensitivity suspension two-dimensional nano-biomolecule sensor according to an embodiment of the present invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative and intended to explain the present invention and should not be construed as limiting the present invention.
In one aspect of the invention, the invention provides a high-sensitivity suspension two-dimensional nano-biomolecule sensor. According to an embodiment of the invention, the sensor comprises: a substrate layer 10, an electrode layer and a plurality of graphene strips 30. The substrate layer 10 comprises a silicon dioxide layer 12 and a silicon layer 11 which are arranged up and down, a groove 40 with an open upper part and a closed lower part is formed on the substrate layer 10, and the groove 40 extends from the silicon dioxide layer 12 to the silicon layer 11; the electrode layer comprises a source electrode 21, a drain electrode 22 and a grid electrode 23 which are arranged on the silicon dioxide layer 12, the source electrode 21 and the drain electrode 22 are respectively arranged on two opposite sides of the groove 40, and the grid electrode 23 is not in contact with the source electrode 21 and the drain electrode 22; the graphene strips 30 are spaced and suspended above the trench 40, and one end of each graphene strip 30 is located between the source electrode 21 and the silicon dioxide layer 12, and the other end is located between the drain electrode 22 and the silicon dioxide layer 12. It will be appreciated that the trench 40 shown in fig. 1 is in fact closed at its lower part, i.e. the lower surface and the side walls of the trench 40 enclose a closed recess in the substrate layer, with only the top being open.
The high-sensitivity suspension two-dimensional nano-biomolecule sensor is provided based on a biological field effect tube sensing mechanism, and the mode that the channel material of the traditional biological field effect tube is contacted with the single surface of a biomolecule is changed into the mode that the channel material is contacted with the biomolecule on the double surfaces by suspending. The sensor can avoid the contact of the two-dimensional nano material and the substrate, and has at least the following beneficial effects: 1) The loss of electrons from the substrate can be avoided, and the detection sensitivity is improved; 2) The upper surface and the lower surface of the graphene two-dimensional nano material strip can be contacted with biomolecules, so that the effective detection area of the sensor can be effectively increased; 3) The mode of double-sided combination of the biomolecules and the graphene two-dimensional nanomaterial strips can ensure that charges are uniformly distributed on the upper surface and the lower surface of the two-dimensional nanomaterial and ensure stable combination between the biomolecules and the two-dimensional nanomaterial, so that the stability of a biomolecule detection process and the accuracy of a detection result can be effectively improved, and high-precision and high-reliability biomolecular detection is realized; 4) The plurality of graphene strips arranged in the sensor at intervals can further increase the biomolecule detection flux and the detection reliability, and detection can be completed through other graphene strips even if a single graphene strip structure is damaged.
The high-sensitivity suspended two-dimensional nano-biomolecule sensor according to the above-described embodiment of the present invention will be described in detail with reference to fig. 1 to 4.
According to an embodiment of the present invention, as understood with reference to fig. 2, the high-sensitivity suspended two-dimensional nanobiotolen sensor may further include: the first external circuit 50, the first external circuit 50 includes a first power source 51 and a first electric meter 52, both ends of the first power source 51 are respectively connected with the source 21 and the drain 22, wherein the first electric meter 52 is used for acquiring parameters such as source current, and the first power source and the first electric meter can be integrated into a source meter; and a second external circuit 60, wherein the second external circuit 60 comprises a second power source 61 and a second electric meter 62, one end of the second power source 61 is connected with the source 21 or the drain 22, and the other end is connected with the grid 23, wherein the purpose of the second electric meter 62 comprises obtaining parameters such as grid voltage, and the like, and the second power source and the second electric meter can also be integrated into a source meter. Optionally, the first power supply and the second power supply may be each independently a direct current power supply, the first power supply may set a bias voltage between the source and the drain, and the second power supply may apply a direct current voltage to the gate. Optionally, the first external circuit 50 and the second external circuit 60 may be independently grounded, respectively. Therefore, under the regulation and control of the grid voltage, the current change condition between the source electrode and the drain electrode after the combination of the biomolecule to be detected and the graphene strip of the sensor can be observed, and the quantitative or qualitative analysis of the biomolecule can be realized by analyzing the current change condition. For example, whether the biomolecule to be detected is the target biomolecule expected to be detected can be determined according to whether the current changes, and the concentration of the biomolecule to be detected can be determined according to the degree of the current change.
According to an embodiment of the present invention, the silicon layer 11 may have a thickness of 200 to 500 μm, silicon dioxide (SiO) 2 ) The thickness of the layer 12 may be 100 to 300nm. Wherein the surface of one side of the silicon layer can be subjected to thermal oxidation or chemical vapor deposition to form SiO 2 The layer, further, siO can be controlled by varying the time of thermal oxidation of the silicon layer or controlling the parameter conditions of chemical vapor deposition 2 The thickness of the layer. Wherein, the substrate layer mainly plays a supporting role, the thickness of the silicon layer can be 200-500 μm, such as 250 μm, 300 μm, 350 μm, 400 μm or 450 μm; siO 2 2 The thickness of the layer may be in the range 100 to 300nm, for example 150nm, 200nm or 250nm, etc., and the inventors have found that if the silicon layer and the SiO are present 2 The thickness of the layer is too thin, the overall support strength of the sensor device is not sufficient, the yield and the service life of the sensor are affected, and if the silicon layer and the SiO are used 2 The thickness of the layer is too thick, which leads to an increase in raw material costs, on the one hand, andon the one hand, the formation of SiO is influenced 2 Layer efficiency, in the present invention, by controlling the silicon layer and SiO 2 The layer is in the thickness range, so that the overall support strength, the production efficiency and the raw material cost of the device can be better taken into consideration, and the comprehensive performances of the device such as yield, production efficiency and quality are improved.
According to the embodiment of the present invention, the suspended length of a single graphene strip 30 may be 1 to 3 μm, for example, 1.5 μm, 2 μm, or 2.5 μm, etc., the suspended width may be 1 to 2 μm, for example, 1.5 μm, etc., and the distance between two adjacent graphene strips 30 may be 3 to 5 μm, for example, 3.5 μm, 4 μm, or 4.5 μm, etc. The inventor finds that if the suspension size of a single-layer graphene strip is too large, the graphene strip is easy to break, and the ratio of the suspension size of the too large graphene strip to the size of a molecule to be detected can also cause the reduction of detection sensitivity. In addition, if the distance between two adjacent graphene strips is too large, on one hand, the size of the device is significantly increased, and more importantly, when the graphene strips are subjected to (specificity) modification by using a solution and are subjected to specificity combination by using a molecule solution to be detected, significant difference may exist in solution environments between the two adjacent graphene strips, and significant difference exists in the state or concentration of the molecule to be detected combined with the two adjacent graphene strips, so that the detection result is affected.
According to the embodiment of the present invention, the graphene strip 30 may be a single-layer or few-layer graphene strip, preferably, the thickness of the few-layer graphene strip is not greater than 1nm, and more preferably, the thickness of the graphene strip 30 may be 0.3 to 0.4nm, that is, the graphene strip is a single-layer graphene strip, so that it is more favorable to realize uniform combination of the molecule to be detected and the upper and lower surfaces of the graphene strip, and further, uniform distribution of charges in the graphene two-dimensional nanomaterial is ensured.
According to the embodiment of the present invention, the plurality of graphene strips 30 may be uniformly distributed along the length direction of the source electrode 21 and the drain electrode 22, and preferably, the thickness, the suspended length, the suspended width, and the distance between two adjacent graphene strips are all the same, so that the stability of the biomolecule detection process and the accuracy of the detection result can be further ensured.
According to the embodiment of the invention, the total number of the plurality of graphene strips 30 can be 2-8, preferably 4-8, so that the detection flux and the detection reliability of biomolecules can be increased, and the problems of overlarge sensor size, too low yield, overlarge difficulty in specific combination of molecules to be detected and the graphene strips, overlow detection efficiency and the like caused by the excessive total number of the graphene strips can be avoided.
According to the embodiment of the present invention, the thickness of the electrode layer may be 100 to 150nm, i.e., the lengths of the source electrode 21, the drain electrode 22 and the gate electrode 23 may be distributed independently to be 100 to 150nm; the source electrode 21, the drain electrode 22 and the gate electrode 23 may have a length ranging from 40 to 60 μm and a width ranging from 25 to 35 μm. By controlling the size range of the electrode layer, the source electrode, the drain electrode and the grid electrode can have good mechanical strength and conductivity, and the bonding strength with the graphene strip and the silicon dioxide layer can be ensured, so that the reliability, the service life and the practicability of the sensor are improved. Further, the source electrode, the drain electrode and the gate electrode may preferably be all gold electrodes, and the inventors have found that, compared to the disadvantages of other metal electrodes such as easy oxidation (e.g. silver) and poor adhesion to graphene (e.g. platinum, which is easy to curl when combined with graphene), the use of gold as an electrode layer has at least the following advantages: firstly, the chemical property of gold is relatively stable, the ductility is relatively good, and secondly, the adhesive force of gold is relatively strong.
In order to facilitate understanding of the high-sensitivity suspension two-dimensional nano-biomolecule sensor according to the above embodiments of the present invention, the structure thereof will be further described with reference to the method for preparing the above high-sensitivity suspension two-dimensional nano-biomolecule sensor. As will be understood with reference to fig. 3 to 4, the method for preparing the high-sensitivity suspension two-dimensional nano-biomolecule sensor comprises the following steps:
processing an unsettled graphene biofet device, as understood with reference to fig. 3, comprising: 1) Deposition of SiO on silicon wafers by chemical vapor deposition 2 A layer, resulting in a substrate layer; 2) Preparation of single-layer graphene on copper foil by chemical vapor deposition method and transfer to SiO using PMMA (polymethyl methacrylate) 2 Surface of the layer; 3) Spin-coating a layer of photoresist (the thickness can be 300nm and the like) of electron beams on the surface of the single-layer graphene, and forming a photoresist strip with the width of about 1-3 microns on the photoresist by exposure and development by using an electron beam lithography technology; 4) Exposing the part to plasma for a period of time (e.g. 30 seconds) to etch the single-layer graphene not covered by the photoresist, so as to obtain a graphene strip (which is a continuous graphene strip) as shown in (4) in fig. 3; 5) Spin-coating a layer of photoresist (the thickness can be 300nm and the like) on the surface of the reserved graphene strip again, and forming a plurality of patterns of the graphene strip which are distributed at intervals and matched with the target electrode structure through an electron beam lithography technology; 6) Forming a photoresist protection layer (as shown in (5) of fig. 3) in a region where the metal electrode layer is not disposed, and depositing the metal electrode layer; 7) Removing the photoresist protective layer: soaking the whole structure obtained in the step 6) in a dimethylacetamide solution at 45 ℃ (for 10 minutes) to remove the photoresist in the non-electrode area and the metal electrode deposited on the photoresist to obtain a metal electrode layer, wherein the metal electrode layer consists of three gold electrodes, as understood with reference to (6) and (7) in fig. 3, one electrode (in contact with the electrode and used as a source electrode and a drain electrode of a sensor) is uniformly arranged on both sides of the graphene material strip array (i.e. both sides in the length direction of a single graphene strip), and the graphene strip array is provided with a plurality of electrodesOne electrode (not in contact therewith, serving as a gate electrode of the sensor) is arranged on the front side (i.e., the side of the graphene strip in the width direction, on which the plurality of graphene strips are not disposed). Fig. 3 is a front view, showing only the source and drain, and the gate, although not shown in the front view, is involved in the processes associated with the metal electrode deposition steps 5) -7).
(II) carrying out suspension processing on the graphene strip, and understanding by referring to FIG. 4 (wherein the left side of FIG. 4 is a front view, and the right side corresponds to a top view), the method comprises the following steps: 1) Referring to (1) in fig. 4, a layer of photoresist (thickness may be 300nm, etc.) is spin-coated on the whole device surface as a protective layer; 2) Referring to (2) in fig. 4, etching windows are provided at the intervals of the graphene strip array, the intervals are exposed, and then the photoresist at the positions of the etching windows is removed in the photoresist layer by developing to expose the underlying silicon dioxide layer; 3) As can be understood with reference to (3) in FIG. 4, a reactive ion etching method (CHF is used as an etching gas) 3 /Ar mixed gas) etches away the silicon dioxide layer not covered by the photoresist. Due to the protection of the photoresist, the graphene cannot be damaged; 4) As can be understood with reference to (4) in fig. 4, the device is placed in a xenon difluoride gas reactor and the over-etching of the silicon below the window by the xenon difluoride is achieved by controlling the relevant reaction parameters. The over-etching can not only etch the silicon at the etching window, but also widen the etching width along with the etching depth, so as to realize the communication between the etching windows at different intervals and finally show that the silicon layers below the graphene strip array region are all etched (the etching depth and the over-etching range are shown in the dotted line of (4) in fig. 4); 5) Dipping the device into acetone to remove the top photoresist portion, resulting in the structure shown in fig. 4 as fig. 5; 6) Rinsing the part in deionized water and transferring the part into hydrofluoric acid buffer solution for soaking to remove silicon dioxide on the bottom surface of the graphene and form a groove; transferring the whole into deionized water, dripping ethanol at low speed until the concentration of the ethanol reaches about 90%, and transferring the whole into 100% ethanol and amyl acetate; the above-mentioned part was dried by a supercritical point drying method, thereby obtaining a suspended single-layer graphene structure with electrodes at both ends, as shown in fig. 4 as (6).
Accordingly, the sensor structure obtained by adopting the method at least has the following advantages: the design of the suspension two-dimensional nano material strip can effectively reduce the influence of the substrate on the detection result so as to improve the sensitivity of the sensor; the design of the suspension two-dimensional nano material strip can realize effective combination of biomolecules and the upper and lower surfaces of the two-dimensional nano material so as to improve the effective detection area of the sensor; the design of the suspension two-dimensional nanomaterial strip can ensure the uniform distribution of charges in the two-dimensional nanomaterial and effectively ensure the stable combination of the surface of the two-dimensional nanomaterial and biomolecules; the two-dimensional nano material strip array design can effectively improve the detection flux.
In a further aspect of the invention, the invention provides the use of the high-sensitivity suspension two-dimensional nano-biomolecule sensor in biomolecule detection. Compared with the prior art, the application has all the characteristics and effects of the high-sensitivity suspension two-dimensional nanometer biomolecule sensor, and the description is omitted here. In general, adverse effects of contact between the substrate and the two-dimensional nano material on stability and detection accuracy of the detection process can be eliminated, and detection sensitivity, stability, reliability and detection accuracy are ensured.
In yet another aspect of the invention, the invention provides a method for detecting biomolecules by using the high-sensitivity suspension two-dimensional nano-biomolecule sensor. As understood with reference to fig. 5, the method includes, according to an embodiment of the invention: (1) Specific binding is realized between the biomolecule to be detected and the upper and lower surfaces of the graphene strip, wherein the specific implementation process for realizing the specific binding can be adaptively adjusted according to actual needs such as the type of the biomolecule to be detected; (2) Applying a direct current voltage to the gate and setting a bias voltage between the source and the drain; (3) And detecting circuit parameter changes (such as only current changes) including current signals between the source electrode and the drain electrode under the control of the grid voltage so as to realize qualitative and quantitative detection and analysis of the biomolecule to be detected. It is understood that the kind of the biomolecule to be detected is not particularly limited, and those skilled in the art can flexibly select the biomolecule according to actual needs, for example, it may be a DNA molecule, an antigen, etc. Compared with the prior art, the method for detecting the biomolecule according to the above embodiment of the present invention has all the features and effects of the above-mentioned high-sensitivity suspension two-dimensional nano-biomolecule sensor, and will not be described herein again. In general, the method is simple in process, can realize the analysis of qualitative and quantitative information of the biomolecules, and can also solve the problems of limited sensitivity, small detection effective area, unstable combination of the biomolecules and the channel material and the like caused by the contact of the channel material and the substrate in the traditional biological field effect tube detection mode.
According to an embodiment of the present invention, the step (1) may further include: (1-1) performing surface treatment on the graphene strip so as to enable the graphene strip to immobilize an antibody or aptamer corresponding to a biomolecule to be detected. Specifically, a cross-linking agent of the biomolecule to be detected and a solid-phase material graphene strip and the like can be adopted to carry out surface treatment on the graphene strip so as to improve the binding efficiency of the biomolecule to be detected and graphene in the subsequent detection process, according to a specific example of the invention, when the sensor is applied to most biomolecules, the graphene strip can be subjected to surface treatment by using a 1-pyrenebutyric acid N-hydroxysuccinimide ester (PASE) solution, for example, the PASE can be dissolved in an N, N-Dimethylformamide (DMF) solution at room temperature to prepare a solution, the prepared high-sensitivity suspension two-dimensional nano-biomolecule sensor and the PASE solution react together for 2 hours, and then the solution is washed by deionized water and dried by nitrogen; (1-2) carrying out surface specificity modification on the graphene strip after surface treatment by using an antibody or an aptamer corresponding to a biomolecule to be detected, so as to realize the fixation of the graphene strip and the antibody or the aptamer corresponding to the biomolecule to be detected, so that a subsequent sensor can realize the specificity detection of the biomolecule to be detected, for example, a protein (such as an antibody) capable of forming specific binding with the biomolecule to be detected can be dissolved in Phosphate Buffered Saline (PBS) solution, the protein solution is dropwise added to the surface of the graphene strip, the device is placed in a refrigerator overnight to fix the protein, and then the device is washed by deionized water; (1-3) nonspecific sites remaining on the surface of the graphene band (i.e., capable of nonspecific binding to molecules unrelated to the biomolecule to be detected)Sites) to prevent non-specific adsorption on the surface of the graphene strip, for example, a Bovine Serum Albumin (BSA) solution may be added on the surface of the graphene to prevent non-specific adsorption, followed by washing with deionized water; (1-4) contacting the graphene strip obtained in the step (1-3) with a to-be-detected biomolecule sample solution (such as soaking contact or dropwise adding sample solution droplets to perform soaking contact) to realize specific binding of the to-be-detected biomolecule and the upper and lower surfaces of the graphene strip, for example, incubating the device with to-be-detected biomolecule (such as a certain antigen protein) solutions with different concentrations at room temperature, then washing with deionized water and incubating with N 2 And (5) drying. The effect of double-sided bonding of graphene strips and biomolecules in the sensor is shown in fig. 6 (a), and fig. 6 (b) is a single-sided bonding effect diagram of a conventional device. It can be understood that, in order to ensure the detection effect, the first external circuit and the second external circuit can be used to detect the sensors before and after the molecules to be detected are combined, so as to improve the accuracy of the detection result.
The following describes in detail embodiments of the present invention. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
Preparing a high-sensitivity suspension two-dimensional nano-biomolecule sensor shown in figure 1:
(a) Processing an unsettled graphene biological field effect transistor device, comprising:
1) Deposition of SiO on silicon wafers by chemical vapor deposition 2 A layer, resulting in a substrate layer;
2) Preparation of single-layer graphene on copper foil by chemical vapor deposition and transfer to SiO using PMMA 2 Surface of the layer;
3) Spin-coating a layer of photoresist (the thickness is 300 nm) of electron beams on the surface of the single-layer graphene, and exposing and developing the photoresist by using an electron beam lithography technology to form a photoresist strip with the width of about 1-3 microns;
4) Exposing the part in plasma for 30 seconds to etch the single-layer graphene which is not covered by the photoresist to obtain a continuous graphene strip with a fixed width;
5) Spin-coating a layer of photoresist with the thickness of 300nm on the surface of the retained graphene strip again, and forming a pattern of 4 graphene strips distributed at intervals matched with a target electrode structure (shown in fig. 1) by using an electron beam lithography technology, wherein the length of the 4 graphene strips is the same as the width of the graphene strips in the step 4);
6) Forming a photoresist protective layer in a region where the metal electrode layer is not arranged, and depositing a gold electrode layer;
7) Removing the photoresist protective layer: and (3) soaking the whole structure obtained in the step 6) in a dimethylacetamide solution at 45 ℃ (for 10 minutes) to remove the photoresist in the non-electrode area and the gold deposited thereon, so as to obtain the electrode layer structure shown in the figure (1), wherein the electrode layer comprises a source electrode, a drain electrode and a grid electrode.
(b) Carrying out suspension treatment on the graphene strip:
1) Spin-coating a layer of photoresist (with the thickness of 300 nm) on the surface of one side of the whole device obtained in the step (a) provided with the silicon dioxide layer to serve as a protective layer;
2) Arranging etching windows at the intervals of the graphene strip array, exposing the intervals, and then removing the photoresist at the positions of the etching windows in the photoresist layer through development to expose the silicon dioxide layer below;
3) By reactive ion etching (CHF as etching gas) 3 /Ar mixed gas) to etch away the silicon dioxide layer not covered by the photoresist;
4) Placing the device in a xenon difluoride gas reactor, and realizing the over-etching of silicon below the window by the xenon difluoride by controlling related reaction parameters so as to realize the communication between different etching windows at intervals on the silicon layer and ensure that the silicon layer below the graphene strip array area is all etched;
5) Dipping the device into acetone to remove the top photoresist portion;
6) Rinsing the part in deionized water, transferring the part into a hydrofluoric acid buffer solution with the concentration of 37wt% and soaking for 5 minutes, and removing silicon dioxide on the bottom surface of the graphene to form a groove; transferring the whole into deionized water, dripping ethanol at low speed until the concentration of the ethanol reaches about 90%, and transferring the whole into 100% ethanol and amyl acetate; the above-mentioned part was dried by a supercritical point drying method, thereby obtaining a suspended single-layer graphene structure having electrodes at both ends, i.e., a sensor as shown in fig. 1.
(c) Detecting fibroblast growth factor 21 (FGF 21) molecules using the prepared sensor:
1) Referring to fig. 2, an external detection circuit is built for the sensor to realize the capture of the detection signal.
2) Modifying the surface of graphene: dissolving 1-pyrenebutyric acid N-hydroxysuccinimide ester (PASE) in N, N-Dimethylformamide (DMF) solution at room temperature to prepare 5mmol/dm 3 The prepared devices were reacted with PASE solution for 2 hours, followed by washing with deionized water and blow drying with nitrogen.
3) Carrying out specific modification on the surface of graphene: FGF21 antibody was dissolved in PBS solution to a concentration of 50. Mu.g/cm 3 And the antibody solution was added dropwise to the surface of the graphene strip, the device was placed in a 4 ℃ refrigerator overnight to immobilize the antibody, and then rinsed with deionized water.
4) Non-specific adsorption treatment: the surface of the graphene strip is added with the concentration of 50 mu g/cm 3 For 60 minutes to prevent non-specific adsorption, followed by washing with deionized water.
5) FGF21 was specifically bound to the graphene sensing moiety (i.e. graphene strip surface): incubate devices with FGF21 solutions of various concentrations for 30 min at room temperature, rinse with deionized water and N 2 And (5) drying.
6) Acquisition of experimental data: in the processing process of the steps 2) to 5), after the graphene is processed in each step, the electrical characteristics of the graphene are changed, and after each step is finished, the device can be detected through an external circuit to obtain required experimental data.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A high-sensitivity suspension two-dimensional nano-biomolecule sensor is characterized by comprising:
the substrate layer comprises a silicon dioxide layer and a silicon layer which are arranged up and down, a groove with an open upper part and a closed lower part is formed on the substrate layer, and the groove extends from the silicon dioxide layer to the silicon layer;
the electrode layer comprises a source electrode, a drain electrode and a grid electrode, wherein the source electrode, the drain electrode and the grid electrode are arranged on the silicon dioxide layer, the source electrode and the drain electrode are respectively arranged on two opposite sides of the groove, and the grid electrode is not in contact with the source electrode and the drain electrode;
the graphene strips are arranged above the groove at intervals in a suspending mode, one end of each graphene strip is located between the source electrode and the silicon dioxide layer, and the other end of each graphene strip is located between the drain electrode and the silicon dioxide layer.
2. The sensor of claim 1, further comprising:
the first external circuit comprises a first power supply and a first ammeter, and two ends of the first power supply are respectively connected with the source electrode and the drain electrode;
and the second external circuit comprises a second power supply and a second ammeter, wherein one end of the second power supply is connected with the source electrode or the drain electrode, and the other end of the second power supply is connected with the grid electrode.
3. The sensor according to claim 1 or 2, wherein the silicon layer has a thickness of 200 to 500 μm and the silicon dioxide layer has a thickness of 100 to 300nm.
4. The sensor according to claim 1 or 2, wherein the suspended length of a single graphene strip is 1-3 μm, the suspended width is 1-2 μm, and the distance between two adjacent graphene strips is 3-5 μm; the thickness of the graphene strip is 0.3-0.4 nm.
5. The sensor according to claim 4, wherein the number of the plurality of graphene strips is 2 to 8.
6. The sensor of claim 4, wherein the plurality of graphene strips are uniformly distributed along the length of the source and drain electrodes.
7. The sensor according to claim 1 or 2, wherein the thickness of the electrode layer is 100 to 150nm, the length distribution of the source electrode, the drain electrode, and the gate electrode is 40 to 60 μm independently, and the width distribution is 25 to 35 μm independently.
8. Use of a sensor according to any one of claims 1 to 7 in the detection of biomolecules.
9. A method for detecting a biomolecule using the sensor according to any one of claims 1 to 7, comprising:
(1) Specific combination of the biological molecules to be detected and the upper and lower surfaces of the graphene strip is realized;
(2) Applying a direct current voltage to the gate and setting a bias voltage between the source and the drain;
(3) And detecting circuit parameter changes including current signals between the source electrode and the drain electrode under the regulation and control of the grid voltage so as to realize qualitative and quantitative detection and analysis of the to-be-detected biomolecule.
10. The method of claim 9, wherein step (1) further comprises:
(1-1) performing surface treatment on the graphene strip so as to enable the graphene strip to immobilize an antibody or an aptamer corresponding to a biomolecule to be detected;
(1-2) carrying out surface specificity modification on the graphene strip subjected to surface treatment by using the antibody or aptamer corresponding to the biomolecule to be detected;
(1-3) treating non-specific sites remaining on the surface of the graphene strip so as to prevent non-specific adsorption on the surface of the graphene strip;
and (1-4) contacting the graphene strip obtained in the step (1-3) with a biomolecule sample solution to be detected, so as to realize specific binding of the biomolecule to be detected and the upper and lower surfaces of the graphene strip.
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