A silicon-based continuous glucose detection micro-device and its manufacturing method

Abstract

The present invention belongs to the fields of medical detection equipment and integrated circuit technology design, and discloses a silicon-based continuous glucose detection micro-device and a manufacturing method thereof, which includes a receiving end, a transmitting end, and a mutual inductance antenna. The transmitting end includes a matching network, a switch, and a detection unit. The transmitting antenna T2 is connected to the matching network, the matching network is connected to the switch, and the switch is connected to the detection unit. The detection unit includes a power management unit, a current-frequency conversion unit, and a silicon-based sensor. The power management unit is used to generate standard voltage and current signals. The current-frequency conversion unit converts the electrical signal detected by the silicon-based sensor into a frequency signal, and this signal controls the switch. The switch modulates the load of the transmitting antenna through on-off. The present invention has good compatibility with silicon-based chips and can achieve wireless transmission. Compared with traditional continuous blood glucose monitoring systems, the sensor of the present invention is small in size, relatively simple in manufacturing process, and low in manufacturing cost.

Description

Technical Field

[0001] The present invention belongs to the fields of medical detection equipment and integrated circuit technology design, and particularly relates to a silicon-based continuous glucose detection micro-device and a manufacturing method thereof. Background Art

[0002] Existing blood glucose meters detect the blood glucose concentration by finger-prick blood sampling method to adjust diet and thus control blood sugar. Once the blood sugar of diabetic patients is not well controlled, some complications will occur, such as ketoacidosis, coma, renal failure, and lower limb gangrene. The existing blood glucose monitors and detection methods cannot provide real-time feedback on the blood sugar changes of patients, so they cannot truly reflect the physiological conditions of patients. Continuous blood glucose monitoring is to implant a glucose sensor subcutaneously to continuously monitor the glucose concentration value in interstitial fluid, and adjust the blood sugar level of diabetic patients according to the measured glucose concentration, so as to keep the blood sugar stable within the normal range.

[0003] However, most current detection systems have the disadvantages of large size and short service life. In order to make implantable devices convenient to use and capable of long-term monitoring of blood glucose concentration, a new type of precision continuous glucose detection micro-system is very necessary.

[0004] Traditional electrical signal detection methods use an analog-to-digital converter (ADC) for detection and an active antenna for transmission. These methods first convert the electrical signal into a digital signal and then transmit it through an active antenna. Although this can achieve better detection accuracy and transmission distance, it will greatly increase the overall power consumption and area of the chip circuit, which is not suitable for wireless power supply systems and is also not suitable for use with tiny sensors for long-term wear. Summary of the Invention

[0005] The object of the present invention is to provide a silicon-based continuous glucose detection micro-device and a manufacturing method thereof to solve the above technical problems.

[0006] To solve the above technical problems, the specific technical solutions of a silicon-based continuous glucose detection micro-device and a manufacturing method thereof of the present invention are as follows:

[0007] A silicon-based continuous glucose detection microdevice, comprising a receiving end, a transmitting end and a mutual inductance antenna. The receiving end and the transmitting end transmit signals through the mutual inductance antenna. The mutual inductance antenna is composed of a receiving antenna T1 arranged at the receiving end and a transmitting antenna T2 arranged at the transmitting end. The transmitting end includes a matching network, a switch and a detection unit. The transmitting antenna T2 is connected to the matching network. The matching network is connected to the switch. The switch is connected to the detection unit. The detection unit includes a power management unit, a current-frequency conversion unit and a silicon-based sensor. The silicon-based sensor is connected to the current-frequency conversion unit. The current-frequency conversion unit is connected to the switch. The power management unit is connected to the current-frequency conversion unit and the silicon-based sensor. The power management unit is used to generate standard voltage and current signals. The current-frequency conversion unit converts the electrical signal detected by the silicon-based sensor into a frequency signal, and this signal controls the switch. The switch modulates the load of the transmitting antenna through on-off modulation.

[0008] Further, the receiving end is provided with a reader for receiving and reading the radio frequency signal reflected by the transmitting end. The transmitting antenna T2 and the matching network are used for radio frequency signal transmission. The matching network is used to achieve the maximum gain transmission of the radio frequency signal. The switch controls the load of the transmitting antenna T2 and the resonant network through on-off, thereby modulating the intensity of the transmitted signal.

[0009] Further, the current-frequency conversion unit includes a potentiostat and a current-controlled frequency generator. The potentiostat is connected to the reference electrode and the counter electrode in the silicon-based sensor. The potentiostat controls the voltage between the reference electrode and the counter electrode to keep the voltage constant. The current-controlled frequency generator inputs the detected current signal and converts it into a frequency.

[0010] Further, the input of the current-controlled frequency generator is the detection current of the silicon-based sensor. A detection current proportional to the concentration of the detected substance is generated through an electrochemical reaction. The detection current is proportional to the frequency output by the current-controlled frequency generator.

[0011] Further, it includes a radio frequency signal source, a power amplifier, a duplexer, a rectifier and a filter. The radio frequency signal source is input to the power amplifier. The power amplifier is connected to the duplexer. The duplexer is connected to the reader and the receiving antenna T1. The rectifier is connected in parallel between the matching network and the switch. The output of the rectifier is connected to the filter. The filter is connected to the detection unit. The rectifier and the filter supply power to the detection unit.

[0012] Further, the detection micro-device is fabricated on a substrate through MEMS processing technology. One end of the substrate is an implantation end with sharp spikes, and the other end is a data processing and transmitting end exposed on the skin surface. The implantation end includes sensor electrodes and wires. The sensor electrodes include a working electrode, a reference electrode, and a counter electrode. The data processing and transmitting end includes pads, a chip, and a mutual inductance antenna. The chip includes a rectifier, a filter, a current-frequency conversion unit, a power management unit, a switch, and a matching network. The chip is electrically connected to the mutual inductance antenna and the implantation end and operates through wireless power supply.

[0013] Further, the substrate includes a substrate and an insulating layer covering the substrate. The sensor electrodes are connected to the pads through wires, and the pads are connected to the chip. The material of the substrate is silicon, and the material of the insulating layer is silicon oxide. The shape of the sensor electrodes is square. The reference electrode includes a reference electrode layer and a silver layer. The wire includes a wire layer and an insulating layer, and the insulating layer is silicon oxide.

[0014] Further, the surface of the working electrode is composed of a metal conductive layer, an enzyme catalytic layer, and a polymer material diffusion layer. The metal conductive layer is composed of platinum nanoparticles. The enzyme catalytic layer is composed of polyaniline fibers and glucose oxidase. The polymer material diffusion layer is composed of polyurethane.

[0015] The present invention also discloses a method for fabricating a silicon-based continuous glucose detection micro-device, which includes the following steps:

[0016] Step 1: Coat a layer of photoresist on the substrate. After exposure and development, the shapes of the sensor electrodes, wires, and pads are formed, where the sensor electrodes include a working electrode, a reference electrode, and a counter electrode.

[0017] Step 2: Then, form sensor electrode grooves through plasma etching technology. Deposit a metal thin film on the substrate surface through sputtering technology, and strip the photoresist and the gold on its surface through glass technology, leaving the working electrode, the reference electrode layer, and the counter electrode on the substrate surface.

[0018] Step 3: Use the same process as in Step 2 to fabricate a silver layer on the surface of the reference electrode layer, and put it into hydrochloric acid solution for chlorination to further form a silver / silver chloride surface layer.

[0019] Step 4: Use the same process as in Step 2 to deposit an insulating layer on the wire surface.

[0020] Step 5: Deposit several microns of aluminum on the substrate through sputtering technology as the mutual inductance antenna material. Then, form the shape of the mutual inductance antenna through photolithography exposure and development technology, and finally form the mutual inductance antenna through wet etching and photoresist removal technology.

[0021] Further, in step 2, a gold metal thin film with a thickness of 100 nanometers is deposited on the surface of the substrate through a sputtering process. In step 3, the thickness of the silver layer is 100 nanometers. Step 3 includes immersing the working electrode in a chloroplatinic acid solution for depositing nano platinum particles, then immersing it in an aniline-hydrochloric acid solution for electro-polymerization to form polyaniline nanofibers. Finally, glucose oxidase is surface-titrated and cross-linked with 25% glutaraldehyde at 37°C for 1 hour. In step 4, the insulating layer is titanium or silicon dioxide.

[0022] A silicon-based continuous glucose detection micro-device and its manufacturing method of the present invention have the following advantages: The present invention realizes a silicon-based sensor micro-system for detecting glucose concentration, has good compatibility with a silicon-based chip, and can achieve wireless transmission. Compared with the traditional continuous blood glucose monitoring system, the present invention can achieve good compatibility with the silicon-based chip, and the sensor of the present invention has a small volume, a relatively simple manufacturing process, and a low manufacturing cost. Brief Description of the Drawings

[0023] Figure 1 is the overall circuit module block diagram of the present invention;

[0024] Figure 2 is the block diagram of the current-frequency conversion unit module of the present invention;

[0025] Figure 3 is the schematic diagram of the backscattered electrical signal wireless power supply signal detection circuit of the current-frequency conversion unit of the present invention;

[0026] Figure 4 is the block diagram of the wireless power supply module of the present invention

[0027] Figure 5 is the schematic diagram of the structure of the silicon-based continuous glucose detection micro-device of the present invention;

[0028] Figure 6 is Figure 5 the A-A sectional view of;

[0029] Figure 7 is Figure 5 the B-B sectional view of the working electrode in;

[0030] Explanation of the marks in the figure: 1. Substrate; 1-1. Data processing and transmitting end; 1-2. Implanting end; 2. Working electrode; 3. Reference electrode; 4. Counter electrode; 5. Lead wire; 6. Pad; 7. Chip; 8. Mutual inductance antenna; 9. Metal conductive layer; 10. Enzyme catalytic layer; 11. Polymer material diffusion layer; 1a. Substrate; 1b. Insulating layer; 3a. Reference electrode layer; 3b. Silver layer. Detailed Embodiments

[0031] To better understand the purpose, structure and function of the present invention, the following further describes in detail a silicon-based continuous glucose detection microdevice and its manufacturing method of the present invention with reference to the accompanying drawings.

[0032] As Figure 1 shown, a silicon-based continuous glucose detection microdevice of the present invention includes: a receiving end, a transmitting end and a mutual inductance antenna. The receiving end and the transmitting end transmit signals through the mutual inductance antenna. Among them, the mutual inductance antenna is composed of a receiving antenna T1 arranged at the receiving end and a transmitting antenna T2 arranged at the transmitting end. The transmitting end includes: a matching network, a switch and a detection unit. The transmitting antenna T2 is connected to the matching network, the matching network is connected to the switch, and the switch is connected to the detection unit. The detection unit includes a power management unit, a current-frequency conversion unit and a silicon-based sensor. The silicon-based sensor is connected to the current-frequency conversion unit, the current-frequency conversion unit is connected to the switch, and the power management unit is connected to the current-frequency conversion unit and the silicon-based sensor. The power management unit is used to generate standard voltage and current signals. The current-frequency conversion unit converts the electrical signal detected by the silicon-based sensor into a frequency signal, and this signal controls the switch. The switch modulates the load of the transmitting antenna through on-off control.

[0033] The receiving end is provided with a reader for receiving and reading the radio frequency signal reflected by the transmitting end. The transmitting antenna T2 and the matching network are used for radio frequency signal transmission. The matching network is used to achieve maximum gain transmission of the radio frequency signal. The switch controls the load of the transmitting antenna T2 and the resonant network through on-off, thereby modulating the intensity of the transmitted signal.

[0034] As Figure 2 shown, the current-frequency conversion unit includes a constant potentiometer and a current-controlled frequency generator. The constant potentiometer is connected to the reference electrode and the counter electrode in the silicon-based sensor, and thus the voltage between the reference electrode and the counter electrode is controlled by the constant potentiometer to keep the voltage constant. The current-controlled frequency generator inputs the detected signal and converts it into a frequency.

[0035] As Figure 3 shown, the input of the current-controlled frequency generator is the detection current of the silicon-based sensor, and a detection current proportional to the concentration of the detected substance is generated through an electrochemical reaction. The detection current is proportional to the frequency output by the current-controlled frequency generator. That is, the concentration of the detected substance is proportional to the output frequency, and thus the glucose concentration value of the body fluid around the sensor is judged. The output of the current-controlled frequency generator is a frequency signal.

[0036] As Figure 4As shown in the figure, the silicon-based continuous glucose detection micro-device further includes a radio frequency signal source, a power amplifier, a duplexer, a rectifier, and a filter. The radio frequency signal source is input to the power amplifier, the power amplifier is connected to the duplexer, and the duplexer is connected to the reader and the receiving antenna T1. The rectifier is connected in parallel between the matching network and the switch, the output of the rectifier is connected to the filter, and the filter is connected to the detection unit. The radio frequency signal source generates a wireless power supply frequency f2 and inputs it to the power amplifier. The power amplifier transmits the signal to the duplexer. The reader reads the transmission data frequency f1 from the duplexer. The receiving antenna T1 transmits the wireless power supply frequency to the transmitting antenna T2. The rectifier inputs the alternating current signal from the transmitting antenna T2 and the matching network, converts it into a direct current signal, and inputs the output signal to the filter to further filter out high-frequency signals. The filter uses the direct current signal output by it as a direct current power supply to supply power to the entire detection unit. The power management unit generates standard voltage and current signals. The detection current of the silicon-based sensor is input into the current frequency conversion unit. The current frequency conversion unit converts the detected electrical signal into a frequency signal. This signal controls the switch to achieve mixing and then transmits the data signal frequency through the transmitting antenna T2 to the receiving antenna T1. The receiving antenna T1 transmits the signal back to the reader.

[0037] As Figure 5 Shown in the figure is the specific structure of the silicon-based continuous glucose detection micro-device. The silicon-based continuous glucose detection micro-device is fabricated on the substrate 1 through MEMS processing technology. One end of the substrate 1 is the implanted end 1-2 with a sharp spike, and the implanted end 1-2 is placed under the skin of the tester. The other end is the data processing and transmitting end 1-1 exposed on the skin surface. The implanted end 1-2 has a sensor for detecting the glucose concentration in the tester's body, and the data processing and transmitting end 1-1 is used to process the detected data and transmit it to the receiving end. The implanted end 1-2 includes sensor electrodes and a wire 5. The sensor electrodes include a working electrode 2, a reference electrode 3, and a counter electrode 4. The data processing and transmitting end 1-1 includes a pad 6, a chip 7, and a mutual inductance antenna 8. The chip 7 includes a rectifier, a filter, a current frequency conversion unit, a power management unit, a switch, and a matching network. The chip 7 is electrically connected to the mutual inductance antenna 8 and the implanted end 1-2 and operates through wireless power supply.

[0038] As Figure 6 Shown in the figure is a cross-sectional view of the silicon-based continuous glucose detection micro-device of the present invention along A-A. The substrate 1 of the detection micro-device includes a substrate 1a and an insulating layer 1b covering the substrate. The sensor electrodes are connected to the pads 6 through the wire 5, and the pads 6 are connected to the chip 7. The material of the substrate 1a is silicon, and the material of the insulating layer 1b is silicon oxide. The shape of the sensor electrodes is square. The reference electrode 3 includes a reference electrode layer 3a and a silver layer 3b. The wire 5 includes a wire layer 5a and an insulating layer 5b, and the insulating layer 5b is silicon oxide.

[0039] As Figure 7 Shown asFigure 5 B-B cross-sectional view of the working electrode, where the surface of the working electrode 2 is composed of a metal conductive layer 9, an enzyme catalytic layer 10, and a polymer material diffusion layer 11. It provides a highly sensitive and highly stable sensing structure for the micro silicon-based sensor. The metal conductive layer 9 is composed of platinum nanoparticles, which can effectively improve the sensitivity of the sensor. The enzyme catalytic layer 10 is composed of polyaniline fibers and glucose oxidase. The three-dimensional structure of the polyaniline fibers can immobilize an excessive amount of glucose oxidase on the electrode surface, thereby preventing enzyme saturation. The polymer material diffusion layer 11 is composed of polyurethane. The polyurethane semi-permeable membrane makes the silicon-based sensor more stable and can increase the detection range.

[0040] The manufacturing process of the silicon-based continuous glucose detection micro-device of the present invention is as follows:

[0041] 1. Coat a layer of photoresist on the substrate 1, and after exposure and development, form the shapes of the sensor electrode, the wire 5, and the pad 6, where the sensor electrode includes the working electrode 2, the reference electrode 3, and the counter electrode 4;

[0042] 2. Then, form the sensor electrode groove through the plasma etching process, deposit a metal thin film (chromium / gold) on the surface of the substrate 1 through the sputtering process. In this embodiment, gold with a thickness of 100 nanometers is used, and the photoresist and the gold on its surface are peeled off through the glass process, that is, the working electrode 2, the reference electrode layer 3a, and the counter electrode 4 are left on the substrate surface.

[0043] 3. Using the same process as in step 2, fabricate a silver layer 3b with a thickness of 100 nanometers on the surface of the reference electrode layer 3a, and immerse it in hydrochloric acid solution for chlorination to further form a silver / silver chloride surface layer. Immerse the working electrode in chloroplatinic acid solution for nano-platinum particle deposition, then immerse it in aniline-hydrochloric acid solution for electro-polymerization to form polyaniline nanofibers, and finally surface-titrate glucose oxidase and crosslink it with glutaraldehyde (25%) at 37°C for 1 hour.

[0044] 4. Using the same process as in step 2, deposit an insulating layer 5b on the surface of the wire 5a. The insulating layer 5b is titanium or silicon dioxide.

[0045] 5. Deposit aluminum with a thickness of several micrometers on the substrate 1 through the sputtering process as the material of the mutual inductance antenna 8, then form the shape of the mutual inductance antenna 8 through the photolithography exposure and development process, and finally form the mutual inductance antenna 8 through the wet etching and de-glue process.

[0046] It can be understood that the present invention is described by way of some embodiments. Those skilled in the art will appreciate that, without departing from the spirit and scope of the present invention, various changes or equivalent replacements can be made to these features and embodiments. Additionally, under the teachings of the present invention, these features and embodiments can be modified to adapt to specific circumstances and materials without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed herein, and all embodiments falling within the scope of the claims of this application belong to the scope protected by the present invention.

Claims

1. A method for fabricating a silicon-based continuous glucose detection micro-device, the silicon-based continuous glucose detection micro-device comprising a receiving end, a transmitting end, and a mutual inductance antenna, wherein signals are transmitted between the receiving end and the transmitting end through the mutual inductance antenna, and the mutual inductance antenna is composed of a receiving antenna T1 disposed at the receiving end and a transmitting antenna T2 disposed at the transmitting end; the transmitting end includes a matching network, a switch, and a detection unit, the transmitting antenna T2 is connected to the matching network, the matching network is connected to the switch, and the switch is connected to the detection unit, characterized in that, The detection unit includes a power management unit, a current frequency conversion unit, and a silicon-based sensor. The silicon-based sensor is connected to the current frequency conversion unit, the current frequency conversion unit is connected to a switch, and the power management unit is connected to the current frequency conversion unit and the silicon-based sensor. The power management unit is used to generate standard voltage and current signals. The current frequency conversion unit converts the electrical signal detected by the silicon-based sensor into a frequency signal, and this signal controls the switch. The switch modulates the load of the transmitting antenna through on-off control. The detection micro-device is fabricated on a substrate (1) by MEMS processing technology. One end of the substrate (1) is an implantation end (1-2) with a sharp tip, and the other end is a data processing and transmitting end (1-1) exposed on the skin surface. The implantation end (1-2) includes sensor electrodes and a wire (5). The sensor electrodes include a working electrode (2), a reference electrode (3), and a counter electrode (4). The data processing and transmitting end (1-1) includes pads (6), a chip (7), and a mutual inductance antenna (8). The chip (7) includes a rectifier, a filter, a current frequency conversion unit, a power management unit, a switch, and a matching network. The chip (7) is electrically connected to the mutual inductance antenna (8) and the implantation end (1-2) and operates through wireless power supply. The substrate (1) includes a substrate (1a) and an insulating layer (1b) covering the substrate. The sensor electrodes are connected to the pads (6) through the wire (5), and the pads (6) are connected to the chip (7). The material of the substrate (1a) is silicon, and the material of the insulating layer (1b) is silicon oxide. The shape of the sensor electrodes is square. The reference electrode (3) includes a reference electrode layer (3a) and a silver layer (3b). The wire (5) includes a wire layer (5a) and an insulating layer (5b), and the insulating layer (5b) is silicon oxide. It is characterized in that, The method includes the following steps: Step 1: Coat a layer of photoresist on the substrate (1). After exposure and development, the shapes of the sensor electrodes, the wire (5), and the pads (6) are formed, where the sensor electrodes include a working electrode (2), a reference electrode (3), and a counter electrode (4); Step 2: Then, form sensor electrode grooves through plasma etching technology, deposit a metal thin film on the surface of the substrate (1) through sputtering technology, and strip the photoresist and the gold on its surface through a glass process, that is, leave the working electrode (2), the reference electrode layer (3a), and the counter electrode (4) on the substrate surface; In Step 2, a metal thin film of gold with a thickness of 100 nanometers is deposited on the surface of the substrate (1) through sputtering technology; Step 3: Use the same process as in Step 2 to fabricate a silver layer (3b) on the surface of the reference electrode layer (3a), and place it in hydrochloric acid solution for chlorination to further form a silver / silver chloride surface layer; In Step 3, the thickness of the silver layer (3b) is 100 nanometers; Step 3 includes immersing the working electrode in a chloroplatinic acid solution for nano-platinum particle deposition, then immersing it in an aniline-hydrochloric acid solution for electro-polymerization to form polyaniline nanofibers, and finally surface-titrating glucose oxidase and cross-linking it with 25% glutaraldehyde at 37°C for 1 hour; Step 4: Deposit an insulating layer (5b) on the surface of the wire layer (5a) using the same process as in Step 2; The insulating layer (5b) in Step 4 is silicon dioxide; Step 5: Deposit aluminum of several microns on the substrate (1) as the material for the mutual inductance antenna (8) through a sputtering process, then form the shape of the mutual inductance antenna (8) through a photolithography exposure and development process, and finally form the mutual inductance antenna (8) through a wet etching and de-glue process.

2. The method according to claim 1, wherein The receiving end is provided with a reader for receiving and reading the radio frequency signal reflected by the transmitting end. The transmitting antenna T2 and the matching network are used for radio frequency signal transmission. The matching network is used to achieve the maximum gain transmission of the radio frequency signal. The switch controls the load of the transmitting antenna T2 and the resonant network by turning on and off, thereby modulating the intensity of the transmitted signal.

3. The method according to claim 1, wherein The current frequency conversion unit includes a potentiostat and a current-controlled frequency generator. The potentiostat is connected to the reference electrode and the counter electrode in the silicon-based sensor. The potentiostat controls the voltage between the reference electrode and the counter electrode to keep the voltage constant. The current-controlled frequency generator inputs the detected current signal and converts it into a frequency.

4. The method according to claim 1, wherein The input of the current-controlled frequency generator is the detected current of the silicon-based sensor. A detected current proportional to the concentration of the detected substance is generated through an electrochemical reaction. The detected current is proportional to the frequency output by the current-controlled frequency generator.

5. The method according to claim 1, characterized in that, It includes a radio frequency signal source, a power amplifier, a duplexer, a rectifier, and a filter. The radio frequency signal source is input to the power amplifier. The power amplifier is connected to the duplexer. The duplexer is connected to the reader and the receiving antenna T1. The rectifier is connected in parallel between the matching network and the switch. The output of the rectifier is connected to the filter. The filter is connected to the detection unit. The rectifier and the filter supply power to the detection unit.

6. The method according to claim 1, characterized in that, The surface of the working electrode (2) is composed of a metal conductive layer (9), an enzyme catalytic layer (10), and a polymer material diffusion layer (11). The metal conductive layer (9) is composed of platinum nanoparticles. The enzyme catalytic layer (10) is composed of polyaniline fibers and glucose oxidase. The polymer material diffusion layer (11) is composed of polyurethane.

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