Sensing and discharging integrated biosensor based on fully-depleted silicon-on-insulator complementary circuit

Abstract

The invention provides a fully-depleted silicon-on-insulator complementary circuit-based sensing and discharging integrated biosensor, which comprises a bulk silicon substrate, an oxide layer is arranged on the surface of the bulk silicon substrate, and a p-channel and an n-channel are arranged on the surface of the oxide layer; two sides of the n-channel are provided with a metal erbium source electrode and a metal erbium drain electrode; two sides of the p-channel are provided with a metal platinum source electrode and a metal platinum drain electrode; the surfaces of the metal platinum source electrode, the metal platinum drain electrode, the metal erbium source electrode, the metal erbium drain electrode, the p-channel and the n-channel are covered with insulating layers; an AuNP coupler is arranged on the surface of the insulating layer, and outer layer packages are arranged on the two sides of the AuNP coupler. The AuNP coupler and the surface of the outer layer package form a cavity for storing a to-be-detected solution. The invention provides a biosensor in an induction-amplification integrated mode, so that the detection sensitivity and the sensing efficiency are improved, and the biosensor can be applied to the aspects of specific cancer screening, genetic engineering, food safety and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of biosensors, in particular to a sensing-amplifying integrated biosensor based on a fully depleted silicon-on-insulator complementary circuit. Background Art

[0002] Sensor technology can sense the surrounding environment and transmit data to the system for calculation, analyze, judge and respond to the situation in real time, and together with communication technology and computer technology, it constitutes the three pillars of modern information technology. Among them, a biosensor is an instrument or device that is sensitive to target biological molecules and converts concentration information into readable electrical signals. It realizes the conversion of "bioinformation-electrical signal" through receptors (molecular recognition elements) and transducers (signal conversion elements). Since the 21st century, biosensor technology has become a new growth point between information science and biotechnology, and has broad application prospects in clinical diagnosis, industrial control, food analysis, environmental protection, and biochips in the national economy. Low cost, high sensitivity, high specificity, high stability and long life are the basic conditions for the marketization and commercialization of biosensors. In recent years, with the promotion of technologies such as the Internet of Things, artificial intelligence, 5G networks and wearable devices, biosensors have gradually developed in the direction of functional diversification, miniaturization, intelligence and integration.

[0003] There are two main ways to match the commonly used signal amplification strategy and information sensing process in current FET biosensors. The first is to first use molecular biology to achieve signal amplification, and then perform information sensing. The second is to first perform information sensing, and then use the voltage amplifier measurement circuit approach to achieve signal amplification. Although these FET biosensors can effectively improve sensitivity, their signal amplification strategy and information sensing process are usually completed separately in two structures and are mutually separable. This sensor working mode with separated sensing and release faces many problems such as design difficulties, high cost, high power consumption, and slow data acquisition speed, which seriously hinders the continuous miniaturization and integration of sensors. Therefore, it is urgent to develop a sensing-and-release integrated FET biosensor that integrates information sensing and signal amplification functions on a single structure. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention aims to provide a biosensor based on a fully depleted silicon-on-insulator complementary circuit that can solve the existing problems.

[0005] In order to achieve the above object, the technical solution of the present invention is as follows:

[0006] The present invention is realized by the following technical scheme: a sensing-amplifying integrated biosensor based on a fully depleted silicon-on-insulator complementary circuit comprises a bulk silicon substrate, an oxide layer is provided on the surface of the bulk silicon substrate, and a p-channel and an n-channel are provided on the surface of the oxide layer; a metal erbium source and a metal erbium drain are provided on both sides of the n-channel, and a metal platinum source and a metal platinum drain are provided on both sides of the p-channel; the surfaces of the metal platinum source, the metal platinum drain, the metal erbium source, the metal erbium drain, the p-channel and the n-channel are covered with an insulating layer; an AuNP connector is provided on the surface of the insulating layer, and outer packaging is provided on both sides of the AuNP connector; the surfaces of the AuNP connector and the outer packaging form a chamber for storing a solution to be tested.

[0007] Furthermore, the preparation method of the sensing-releasing integrated biosensor comprises:

[0008] Step 1, obtaining an initial wafer, including forming a bulk silicon substrate with silicon as a substrate, depositing an oxide layer on the surface of the bulk silicon substrate, and forming a top silicon film on the surface of the oxide layer;

[0009] Step 2: modifying the p-Si of the top silicon film to n-Si, and then wet-etching the wafer to completely etch the top silicon film with the window opened, leaving only a plurality of laterally isolated square silicon islands, that is, forming a p-channel and an n-channel;

[0010] Step 3: Electron beam evaporation coating is performed on the surface of the device obtained in step 2 to obtain a metal erbium source electrode, a metal erbium drain electrode, a metal platinum source electrode and a metal platinum drain electrode;

[0011] Step 4: Depositing a high-K dielectric hafnium dioxide thin film on the surface of the device obtained in step 3 through an atomic layer deposition process to form an insulating layer;

[0012] Step 5: using electron beam exposure technology to evaporate a gold film on the surface of the insulating layer in step 4, and then rapidly annealing the wafer to prepare an AuNP connector;

[0013] Step 6: performing device surface packaging, that is, coating a layer of negative photoresist on the surface formed in step 5, and opening the channel area and electrode area by ultraviolet lithography;

[0014] Step 7: A micro chamber is fabricated on the surface formed in step 6 to store the solution to be tested.

[0015] Furthermore, it also includes step eight, performance testing and application measurement, using the probe DNA molecule that is completely complementary to the target RNA as a bioreceptor, and then self-assembling the Au-S bond between the probe DNA and the AuNP connector to test the electrical characteristic parameters of the AuNP / HfO2 / FDSOI CMOS inverter biosensor platform.

[0016] Furthermore, the step eight is specifically as follows: when assembling the probe, the 3' end of the probe DNA molecule must first be modified with a thiol (-SH) group, and then the probe DNA solution is mixed with a 1M tris(2-carbonylethyl)phosphine hydrochloride aqueous solution to open the generated disulfide bond, a small amount of the mixed solution is taken out and injected into the micro chamber, and after standing for a period of time, the Au-S bond self-assembly reaction between the probe DNA and the AuNP connector is completed;

[0017] After probe assembly, the microchamber needs to be repeatedly flushed to remove unsolidified probe DNA;

[0018] After the construction is completed, the target RNA is detected and measured. A small amount of RNA is injected into the chamber, and the single-molecule fluorescence labeling method is used for auxiliary confirmation. After confirmation, the back gate scanning / liquid gate bias and liquid gate scanning / back gate bias measurement configurations are used at certain time intervals to measure V IN -V OUT Scanning the curve, when the curve stabilizes, it indicates that the recognition and hybridization between the target RNA and the probe DNA are complete, and the time before stabilization is the response time of the biosensor platform.

[0019] Furthermore, the p-Si of the top silicon film is modified to n-Si, including introducing a hexamethyldisilazane adhesion layer on the top silicon film, coating it with a layer of photoresist, and placing it on a heating plate for baking; after naturally cooling to room temperature, ultraviolet exposure opens the ion implantation window, and lightly dopes the wafer surface with arsenic impurities, so that the p-Si of the top silicon film is modified to n-Si.

[0020] Furthermore, the wet etching is performed to completely etch the top silicon film with the windows opened, leaving only a plurality of laterally isolated square silicon islands, including:

[0021] A silicon island window is opened on the basis of modifying p-Si to n-Si, and the manufactured active area is immersed in tetramethylammonium hydroxide for development, then immersed in dilute hydrofluoric acid to remove the natural oxide layer, and then quickly transferred to a mixed solution of tetramethylammonium hydroxide and isopropyl alcohol for wet etching; the top silicon film with the window opened is completely etched, leaving only multiple square silicon islands isolated laterally.

[0022] Furthermore, the step three specifically includes:

[0023] 3.1. Apply a layer of LOR stripping glue on the upper surface of the silicon island, and then apply a layer of photoresist, and ultraviolet exposure is performed to obtain the metal contact electrode area with the window opened, and the remaining area is covered with a double layer of glue;

[0024] 3.2. After removing the natural oxide layer with a dilute hydrofluoric acid solution, the wafer is quickly transferred to an electron beam evaporation coating apparatus to deposit metal erbium; the wafer is immersed in an N-methylpyrrolidone solution to remove the double-layer mask, while retaining the erbium layer in the window, and a rapid thermal annealing treatment is performed to generate erbium silicide to obtain electrodes on both sides of the n-channel, namely, a metal erbium source and a metal erbium drain;

[0025] 3.3. Replace the metal erbium with metal platinum and repeat step 3.2 to obtain electrodes on both sides of the P-channel, namely, the metal platinum source and the metal platinum drain.

[0026] Furthermore, the step 4 specifically includes:

[0027] The deposition of high-K dielectric HfO2 thin film is completed by atomic layer deposition process, the metal organic precursor is tetraethyl hafnium hydroxide, the oxygen source is water, and the inert gas is argon; wherein, the pulse time of tetraethyl hafnium hydroxide is 1.6s / cycle, the purge time is 12s / cycle, the pulse time of water is 0.6s / cycle, the purge time is 12s / cycle, the deposition temperature is 250-280℃, and the deposition thickness is 1-10nm;

[0028] Then, the HfO2 film above the source and drain electrodes is removed by UV lithography and reactive ion etching; the wafer is subjected to a 300°C rapid thermal annealing treatment.

[0029] Furthermore, the etchant for ion etching is sulfur hexafluoride; the thickness of the bulk silicon substrate is 20 to 600 μm; the thickness of the top silicon film is 5 nm to 30 nm, and the thickness of the oxide layer is 10 nm to 145 nm; the bulk silicon substrate and the top silicon film are weakly p-type doped, with a doping concentration of 1×10 13 cm -3 ~1×10 18 cm -3 between.

[0030] Furthermore, the process conditions of the electron beam exposure technology are that the vacuum degree is less than 1×10 -6 torr, evaporation rate as low as The end point gold thickness is 1 nm to 10 nm, and the rapid annealing treatment time is 10 min to 30 min.

[0031] Compared with the prior art, the beneficial effects of the present invention include:

[0032] The present invention embeds the biological detection cavity into the p-channel and the n-channel, and increases the volume of the effective biological detection cavity under the condition of the same channel length, making it more sensitive to biological molecules, thereby improving the sensitivity and sensing efficiency of the biosensor.

[0033] The present invention uses an "integrated sensing-amplification" biosensor to quantitatively detect specific RNA, and the sensor has excellent selectivity and stability. The biosensor of the present invention cleverly integrates the biomolecule identifier and the transducer into a single MOS structure, constructing an ultra-sensitive biosensor platform that has strongly promoted the continuous miniaturization and integration of sensors. The ultra-sensitive biosensor with integrated sensing and amplification of the present invention has a wide range of applications and can be used in specific cancer screening, genetic engineering, food safety and other aspects. The present invention has a simple operation process, low cost, does not require expensive detection equipment, and has good biocompatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The disclosure of the present invention is described with reference to the accompanying drawings. It should be understood that the drawings are only for illustrative purposes and are not intended to limit the scope of protection of the present invention. In the drawings, the same reference numerals are used to refer to the same components. Among them:

[0035] Figure 1 It is a structural diagram of the sensing-releasing integrated biosensor in the implementation case of the present invention;

[0036] Figure 2 It is a simplified circuit diagram of the sensing-releasing integrated biosensor in the embodiment of the present invention;

[0037] Figure 3 The schematic diagram of the device structure and preparation process flow of the sensing-releasing integrated biosensor in the embodiment of the present invention;

[0038] Figure 4 It is a schematic diagram of the voltage output characteristic curve response of the sensing-releasing integrated biosensor before and after adding single-molecule RNA in the implementation case of the present invention.

[0039] Notes in the figure: 1. Bulk silicon substrate; 2. Oxide layer; 3. Metal platinum source; 4. Metal platinum drain; 5. Metal erbium source; 6. Metal erbium drain; 7. p-channel; 8. n-channel; 9. Insulating layer; 10. AuNP connector; 11. Outer package; 12. Chamber. DETAILED DESCRIPTION

[0040] It is easy to understand that according to the technical solution of the present invention, without changing the essential spirit of the present invention, a person skilled in the art can propose a variety of interchangeable structural modes and implementation modes. Therefore, the following specific implementation modes and drawings are only exemplary descriptions of the technical solution of the present invention, and should not be regarded as the whole of the present invention or as a limitation or restriction to the technical solution of the present invention.

[0041] A biosensor based on a fully depleted silicon-on-insulator complementary circuit comprising an inverter field effect transistor, specifically Figure 1As shown, it includes a bulk silicon substrate 1, an oxide layer 2, a metal platinum source 3, a metal platinum drain 4, a metal erbium source 5, a metal erbium drain 6, a p-channel 7, an n-channel 8, an insulating layer 9, an AuNP connector 10, an outer package 11, and a chamber 12;

[0042] Its specific position relationship is as follows Figure 1 The structure shown includes: the oxide layer 2 is arranged on the bulk silicon substrate 1, the p-channel 7 is arranged in the left middle part of the oxide layer 2; the n-channel 8 is arranged in the right middle part of the oxide layer 2; the metal platinum source 3, the metal erbium source 5 and the metal platinum drain 4, the metal erbium drain 6 are arranged on the left and right sides of the p-channel 7 and the n-channel 8 respectively; the insulating layer 9 covers the two metal sources and drains (metal platinum source 3, metal platinum drain 4, metal erbium source 5, metal erbium drain 6) and the p-channel 7 and the n-channel 8; the insulating layer 9 directly above the p-channel 7 is surface modified by the EBE process to obtain the AuNP connector 10; similarly, the n-channel 8 is also modified by the same method; the outer package 11 is coated on the wafer surface with SU-8 negative photoresist; the chamber 12 is located outside the outer package 11, covering the channel area and exposing the electrode pad area. Among them, the n-channel 7 and the p-channel 8 are integrated together. The circuit diagram of the sensing and releasing integrated biosensor is shown in FIG. Figure 2 shown.

[0043] The preparation method of the sensing-releasing integrated biosensor comprises:

[0044] Step 1, obtaining an initial wafer, including forming a bulk silicon substrate with silicon as a substrate, depositing an oxide layer on the surface of the bulk silicon substrate, and forming a top silicon film on the surface of the oxide layer;

[0045] The present invention is processed by an initial wafer, wherein the initial wafer adopts a starting FDSOI wafer (Fully Depleted Silicon On Insulator wafer), which includes a top silicon film, an oxide layer (BOX layer) and a substrate silicon layer. The thickness of the bulk silicon substrate is 20 to 600 μm; the thickness of the top silicon film is 5 nm to 30 nm, and the thickness of the oxide layer is 10 nm to 145 nm; the bulk silicon substrate and the top silicon film are weakly p-type doped, with a doping concentration of 1×10 13 cm -3 ~1×10 18 cm -3 The top silicon film and the substrate silicon layer are both weakly p-type doped, exemplarily by light doping with arsenic (As) impurities, with a doping concentration of 1×10 20 cm -3 .

[0046] Step 2: modifying the p-Si of the top silicon film to n-Si, and then wet-etching the wafer to completely etch the top silicon film with the window opened, leaving only a plurality of laterally isolated square silicon islands, that is, forming a p-channel and an n-channel;

[0047] Specifically, the p-Si of the top silicon film is modified to n-Si, including introducing a HMDS (hexamethyldisilazane) adhesion layer on the top silicon film, coating a layer of AZ-5214 photoresist (AZ-5214 is a commonly used positive photoresist), placing it on a heating plate for baking; after naturally cooling to room temperature, ultraviolet exposure opens the ion implantation window, and lightly doping the wafer surface with arsenic impurities, so that the top p-Si in a specific area is modified to n-Si.

[0048] The wet etching is performed to completely etch the top silicon film with the window opened, leaving only a plurality of laterally isolated square silicon islands, including:

[0049] On the basis of modifying p-Si to n-Si, a silicon island window is opened, and the manufactured active area is immersed in TMAH (tetramethylammonium hydroxide) for development, and then immersed in DHF (Dilute Hydrofluoric Acid) to remove the natural oxide layer, and then quickly transferred to a mixed solution of TMAH and isopropyl alcohol for wet etching; the top silicon film with the window opened is completely corroded, leaving only a plurality of square silicon islands isolated laterally.

[0050] Step 3: Electron beam evaporation coating is performed on the surface of the device obtained in step 2 to obtain a metal erbium source electrode, a metal erbium drain electrode, a metal platinum source electrode and a metal platinum drain electrode;

[0051] Specifically, they include:

[0052] 3.1. Apply a layer of LOR (Lightly Oxidized Resist) stripping glue on the surface of the silicon island, and then apply a layer of AZ-5214 photoresist, and expose to ultraviolet light to obtain the metal contact electrode area with the window opened, and the rest of the area is covered with a double layer of glue;

[0053] 3.2. After removing the natural oxide layer with DHF solution, the wafer is quickly transferred to an electron beam evaporation coating apparatus to deposit metal erbium; the wafer is immersed in NMP (N-Methyl-2-Pyrrolidone, N-methylpyrrolidone) solution to remove the double-layer mask, while retaining the erbium layer in the window, and rapidly thermally annealed to generate erbium silicide to obtain electrodes on both sides of the n-channel, namely, the metal erbium source and the metal erbium drain; the thickness of the metal erbium deposition layer obtained by electron beam evaporation coating is 10nm to 100nm;

[0054] 3.3. Replace the metal erbium with metal platinum and repeat step 3.2 to obtain electrodes on both sides of the P-channel, namely, the metal platinum source and the metal platinum drain.

[0055] Step 4: Depositing a high-K dielectric hafnium dioxide thin film on the surface of the device obtained in step 3 through an atomic layer deposition process to form an insulating layer;

[0056] Specifically, the deposition of high-K dielectric HfO2 (hafnium dioxide) thin film is completed by ALD (Atomic Layer Deposition) process, the metal organic precursor is TEMAH (tetrakis(ethylmethylamino)hafnium), the oxygen source is H2O (water), and the inert gas is argon; wherein, the pulse time of TEMAH is 1.6s / cycle, the purge time is 12s / cycle, the pulse time of water is 0.6s / cycle, the purge time is 12s / cycle, the deposition temperature is 250-280°C, and the deposition thickness is 1-10nm;

[0057] Then, the HfO2 film on the source and drain electrodes is removed by ultraviolet lithography and reactive ion etching, and the wafer is subjected to 300° C. RTA (rapid thermal annealing). The etchant for the ion etching is sulfur hexafluoride (SF6).

[0058] Step 5: Using EBE (Electron Beam Exposure) process to evaporate a gold film on the surface of the insulating layer in step 4, and then rapidly annealing the wafer to prepare an AuNP connector;

[0059] The process conditions of the EBE process are vacuum degree less than 1×10 -6 torr, evaporation rate as low as The final Au thickness is 1 nm to 10 nm, and the RTA treatment time is 10 min to 30 min.

[0060] Step 6: Surface encapsulation of the device is performed, that is, a layer of SU-8 negative photoresist is coated on the surface formed in step 5, and the channel area and the electrode area are opened by ultraviolet lithography; the thickness of the SU-8 negative photoresist is 1 μm to 10 μm,

[0061] Step 7: A PDMS micro chamber is made on the surface formed in step 6 for storing the solution to be tested; the total volume of the PDMS micro chamber is 30 μL to 100 μL.

[0062] Step 8: Performance testing and application measurement, the probe DNA molecule that is fully complementary to the target RNA is used as a bioreceptor, and then the Au-S bond between the probe DNA and the AuNP connector is self-assembled to test the electrical characteristic parameters of the AuNP / HfO2 / FDSOI CMOS inverter biosensor platform.

[0063] The step eight is specifically as follows: when assembling the probe, the 3' end of the probe DNA molecule must first be modified with a thiol (-SH) group, and then the probe DNA solution is mixed with a 1M tris(2-carbonylethyl)phosphine hydrochloride aqueous solution to open the disulfide bonds that may be generated, and a small amount of the mixed solution is injected into the micro chamber, and after standing for a period of time, the Au-S bond self-assembly reaction between the probe DNA and the AuNP connector is completed;

[0064] After probe assembly, the microchamber needs to be repeatedly flushed to remove unsolidified probe DNA;

[0065] After the construction is completed, the target RNA is detected and measured. A small amount of RNA is injected into the chamber, and the single-molecule fluorescence labeling method is used for auxiliary confirmation. After confirmation, the back gate scanning / liquid gate bias and liquid gate scanning / back gate bias measurement configurations are used at certain time intervals to measure V IN -V OUT Scanning the curve, when the curve stabilizes, it indicates that the recognition and hybridization between the target RNA and the probe DNA are complete, and the time before stabilization is the response time of the biosensor platform.

[0066] The solution used for flushing the micro chamber is a mixed solution of deionized water and 1×PBS solution; the time intervals of back gate scanning / liquid gate bias and liquid gate scanning / back gate bias are 15s to 100s.

[0067] The mechanism of the present invention reveals the physical mechanism (information sensing) of single-molecule RNA changing the electrical characteristics of the biosensor platform through the relationship between the inverter conversion voltage and the single-tube threshold voltage, promotes the voltage signal amplification model (signal amplification) through the synergistic effect of small signal gain and dual-gate capacitor coupling, and reveals the sensitivity enhancement principle of the biosensor platform, thereby explaining the integrated sensing and amplification ultra-sensitive detection mechanism.

[0068] Implementation Cases:

[0069] The preparation process of the sensor-release integrated biosensor and the process of detecting Alzheimer's RNA are as follows:

[0070] Step 1: Use 600μm thick silicon as the substrate, deposit a 145nm thick oxide layer on the substrate, and a 28nm thick top silicon film on the oxide layer. Figure 3 As shown in (1).

[0071] Step 2: Introduce a layer of HMDS adhesion layer on the top silicon film, then apply a layer of AZ-5214 photoresist, and place it on a hot plate for baking. After cooling naturally to room temperature, UV exposure opens the ion implantation window to lightly dope the wafer surface with arsenic (As) impurities, such as Figure 3 As shown in (2), the top layer p-Si in a specific area is modified into n-Si.

[0072] Step 3: Open silicon island windows based on step 2, immerse the active area made in step 2 in TMAH for development, then immerse in DHF to remove the natural oxide layer, and then quickly transfer to a mixed solution of TMAH and isopropyl alcohol for wet etching. The top silicon film with the window opened is completely etched, leaving only multiple square silicon islands isolated laterally, such as Figure 3 As shown in (3).

[0073] Step 4: Apply a layer of LOR stripping glue on the upper surface of the silicon island formed in step 3, and then apply a layer of AZ-5214 photoresist, and ultraviolet exposure to obtain the metal contact electrode area with the window opened, and the remaining area is covered with a double layer of glue.

[0074] Step 5: After removing the natural oxide layer with DHF solution based on step 4, quickly transfer the wafer to an electron beam evaporation coating instrument with a vacuum degree of 1E-6Torr. Then, the wafer is immersed in NMP solution to remove the double-layer mask, while retaining the Er layer in the window, and rapid thermal annealing (RTA) is performed to generate Er-Si2 metal silicide to obtain electrodes on both sides of the p-channel, such as Figure 3 As shown in (4).

[0075] Step 6: The operation is similar to step 5. Just replace the metal erbium with metal platinum. Finally, the electrodes on both sides of the n-channel are obtained. Figure 3 As shown in (5).

[0076] Step 7: Deposition of high-K dielectric HfO2 film is completed by ALD process, metal organic precursor is TEMAH, oxygen source is H2O, and inert gas is argon. Among them, the pulse time of TEMAH is 1.6s / cycle, the purge time is 12s / cycle, the pulse time of H2O is 0.6s / cycle, the purge time is 12s / cycle, the deposition temperature is 250-280℃, and the deposition thickness is 10nm.

[0077] Step 8: Remove the HfO2 film above the source and drain electrodes by UV lithography and reactive ion etching (etchant: SF6). Then, perform RTA treatment at 300℃ on the wafer to repair the possible intrinsic defects of the HfO2 film and the interface state of the HfO2 / silicon channel. Figure 3As shown in (6).

[0078] Step 9: Using EBE process, Au thin film is evaporated on the surface of HfO2 medium obtained in step 8. The process condition is that the vacuum degree is less than 1×10 -6 torr, evaporation rate as low as The end point thickness was set to 2 nm. Then, the wafer was subjected to RTA treatment at 250 °C for 10 min to achieve the formation of AuNP connectors. Figure 3 As shown in (7).

[0079] Step 10: Apply a layer of SU-8 negative photoresist on the wafer surface, open the p-channel and n-channel regions and the metal electrode (measurement) region by UV lithography, and cover the remaining regions with SU-8 photoresist with a thickness of more than 1 μm. Figure 3 As shown in (8).

[0080] Step 11: Make a PDMS micro chamber on the wafer surface to store the test solution. The total volume of the chamber is 30 μL. The chamber ensures that the channel area is completely covered and the electrode pad area is exposed. Figure 3 As shown in (8).

[0081] Step 12: Take a small amount of probe DNA molecules that are completely complementary to the RNA of AD patients as bioreceptors, and the 3' end of the probe DNA molecules is modified by thiol (-SH). Mix 1 μM probe DNA solution dispersed in 1× phosphate buffer solution (1×PBS) with 1M tris(2-carbonylethyl)phosphine hydrochloride aqueous solution at a volume ratio of 30:1 and let it stand for 20 minutes to open the disulfide bonds that may be generated. Then, draw 20 μL of the above solution and inject it into the microchamber, and let it stand at 4°C for 12 hours to complete the Au-S bond self-assembly reaction between the probe DNA and AuNP, as shown in Figure 1. Figure 3 As shown in (9).

[0082] Step 13: After completing step 12, repeatedly rinse the microchamber with deionized water and 1×PBS solution to remove unsolidified probe DNA, and then add 20 μL of 1×PBS solution into the microchamber. Figure 3 As shown in (9).

[0083] Step 14: Inject 1aM, 2μL of AD patient RNA solution into the microchamber, and use single-molecule fluorescence to confirm the single-molecule RNA labeled with Cy3 fluorescence under the same conditions. Use back gate scanning / liquid gate bias and liquid gate scanning / back gate bias measurement configurations at 15s intervals. IN -V OUT The curve is scanned until it becomes stable. Figure 4 shown.

[0084] Step 15: Measurement of FDSOI N- / P-MOSFET transistor devices, the top silicon film is used as the conductive channel, the substrate silicon layer and the liquid gate are used as the back gate and top gate, two metal probes are connected to the source and drain, the BOX oxide layer and the HfO2 insulating layer are used as the back gate oxide layer and the top gate oxide layer, respectively.

[0085] Step 16: Measurement of FDSOI CMOS inverter, the top silicon film is used as the conductive channel, and the substrate silicon layer is used as the back gate V IN port, the solution to be tested is used as the top gate V IN Port, three metal probes are connected to VDD, VSS and V OUT The port, BOX layer and HfO2 layer serve as the back gate oxide layer and the top gate oxide layer, respectively.

[0086] In the description of the present invention, it should be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", "clockwise", "counterclockwise" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the referred device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0087] In the description of this patent, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", and "set" should be understood in a broad sense, for example, it can be fixedly connected or set, or it can be detachably connected or set, or connected or set in one piece. For ordinary technicians in this field, the specific meanings of the above terms in this patent can be understood according to specific circumstances.

[0088] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "several" is two or more, unless otherwise clearly and specifically defined.

[0089] The technical scope of the present invention is not limited to the contents in the above description. Those skilled in the art can make various deformations and modifications to the above embodiments without departing from the technical idea of ​​the present invention, and these deformations and modifications should all fall within the protection scope of the present invention.

Claims

1. A biosensor based on a fully depleted silicon-on-insulator complementary circuit, characterized in that: The invention comprises a bulk silicon substrate, wherein an oxide layer is provided on the surface of the bulk silicon substrate, and a p-channel and an n-channel are provided on the surface of the oxide layer; a metal erbium source electrode and a metal erbium drain electrode are provided on both sides of the n-channel, and a metal platinum source electrode and a metal platinum drain electrode are provided on both sides of the p-channel; the surfaces of the metal platinum source electrode, the metal platinum drain electrode, the metal erbium source electrode, the metal erbium drain electrode, the p-channel and the n-channel are covered with an insulating layer; an AuNP connector is provided on the surface of the insulating layer, and outer layer packaging is provided on both sides of the AuNP connector; the surfaces of the AuNP connector and the outer layer packaging form a chamber for storing a solution to be tested.

2. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 1 is characterized in that: The preparation method of the sensing-releasing integrated biosensor comprises: Step 1, obtaining an initial wafer, including forming a bulk silicon substrate with silicon as a substrate, depositing an oxide layer on the surface of the bulk silicon substrate, and forming a top silicon film on the surface of the oxide layer; Step 2: modifying the p-Si of the top silicon film to n-Si, and then wet-etching the wafer to completely etch the top silicon film with the window opened, leaving only a plurality of laterally isolated square silicon islands, that is, forming a p-channel and an n-channel; Step 3: Electron beam evaporation coating is performed on the surface of the device obtained in step 2 to obtain a metal erbium source electrode, a metal erbium drain electrode, a metal platinum source electrode and a metal platinum drain electrode; Step 4: Depositing a high-K dielectric hafnium dioxide thin film on the surface of the device obtained in step 3 through an atomic layer deposition process to form an insulating layer; Step 5: using electron beam exposure technology to evaporate a gold film on the surface of the insulating layer in step 4, and then performing rapid annealing to prepare an AuNP connector; Step 6: performing device surface packaging, that is, coating a layer of negative photoresist on the surface formed in step 5, and opening the channel area and electrode area by ultraviolet lithography; Step 7: A micro chamber is fabricated on the surface formed in step 6 to store the solution to be tested.

3. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 2 is characterized in that: It also includes step eight, performance testing and application measurement, using the probe DNA molecule that is completely complementary to the target RNA as a bioreceptor, and then self-assembling the Au-S bond between the probe DNA and the AuNP connector to test the electrical characteristic parameters of the AuNP / HfO2 / FDSOICMOS inverter biosensor platform.

4. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 3 is characterized in that: The step eight is specifically as follows: when assembling the probe, the 3' end of the probe DNA molecule must first be modified with a thiol (-SH) group, and then the probe DNA solution is mixed with a 1M tris(2-carbonylethyl)phosphine hydrochloride aqueous solution to open the generated disulfide bond, a small amount of the mixed solution is taken out and injected into the micro chamber, and after standing for a period of time, the Au-S bond self-assembly reaction between the probe DNA and the AuNP connector is completed; After probe assembly, the microchamber needs to be repeatedly flushed to remove unsolidified probe DNA; After the construction is completed, the target RNA is detected and measured. A small amount of RNA is injected into the chamber, and the single-molecule fluorescence labeling method is used for auxiliary confirmation. After confirmation, the back gate scanning / liquid gate bias and liquid gate scanning / back gate bias measurement configurations are used at certain time intervals to measure V IN -V OUT Scanning the curve, when the curve stabilizes, it indicates that the recognition and hybridization between the target RNA and the probe DNA are complete, and the time before stabilization is the response time of the biosensor platform.

5. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 2 is characterized in that: The method of modifying the p-Si of the top silicon film to n-Si includes introducing a hexamethyldisilazane adhesion layer on the top silicon film, coating it with a layer of photoresist, and placing it on a heating plate for baking; after naturally cooling to room temperature, ultraviolet exposure opens an ion implantation window, and lightly doping the surface of the wafer with arsenic impurities, so that the p-Si of the top silicon film is modified to n-Si.

6. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 5, characterized in that: The wet etching is performed to completely etch the top silicon film with the window opened, leaving only a plurality of laterally isolated square silicon islands, including: A silicon island window is opened on the basis of modifying p-Si to n-Si, and the manufactured active area is immersed in tetramethylammonium hydroxide for development, then immersed in dilute hydrofluoric acid to remove the natural oxide layer, and then quickly transferred to a mixed solution of tetramethylammonium hydroxide and isopropyl alcohol for wet etching; the top silicon film with the window opened is completely etched, leaving only multiple square silicon islands isolated laterally.

7. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 6, characterized in that: The step three specifically includes: 3.

1. Apply a layer of LOR stripping glue on the upper surface of the silicon island, and then apply a layer of photoresist, and ultraviolet exposure is performed to obtain the metal contact electrode area with the window opened, and the remaining area is covered with a double layer of glue; 3.

2. After removing the natural oxide layer with a dilute hydrofluoric acid solution, the wafer is quickly transferred to an electron beam evaporation coating apparatus to deposit metal erbium; the wafer is immersed in an N-methylpyrrolidone solution to remove the double-layer mask, while retaining the erbium layer in the window, and a rapid thermal annealing treatment is performed to generate erbium silicide to obtain electrodes on both sides of the n-channel, namely, a metal erbium source and a metal erbium drain; 3.

3. Replace the metal erbium with metal platinum and repeat step 3.2 to obtain electrodes on both sides of the P-channel, namely, the metal platinum source and the metal platinum drain.

8. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 2, characterized in that: The step 4 specifically includes: The deposition of high-K dielectric hafnium dioxide thin film is completed by atomic layer deposition process, the metal organic precursor is tetraethyl hafnium hydroxide, the oxygen source is water, and the inert gas is argon; wherein, the pulse time of tetraethyl hafnium hydroxide is 1.6s / cycle, the purge time is 12s / cycle, the pulse time of water is 0.6s / cycle, the purge time is 12s / cycle, the deposition temperature is 250-280°C, and the deposition thickness is 1-10nm; Then, the hafnium dioxide film above the source and drain electrodes is removed by ultraviolet lithography and reactive ion etching; and the wafer is subjected to a 300° C. rapid thermal annealing treatment.

9. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 7, characterized in that: The etchant for ion etching is sulfur hexafluoride; the thickness of the bulk silicon substrate is 20 to 600 μm; the thickness of the top silicon film is 5 nm to 30 nm, and the thickness of the oxide layer is 10 nm to 145 nm; the bulk silicon substrate and the top silicon film are weakly p-type doped, with a doping concentration of 1×10 13 cm -3 ~1×10 18 cm -3 between.

10. The sensing-amplifying integrated biosensor based on fully depleted silicon-on-insulator complementary circuit according to claim 2, characterized in that: The process conditions of the electron beam exposure technology are that the vacuum degree is less than 1×10 -6 torr, evaporation rate as low as The end point gold thickness is 1 nm to 10 nm, and the rapid annealing treatment time is 10 min to 30 min.

Images