Implantable wireless passive chemical sensor system and preparation method and application thereof

Abstract

The invention belongs to the technical field of biosensing, and particularly relates to an implantable wireless passive chemical sensor system as well as a preparation method and application thereof. The sensor system comprises a miniature implantable sensor unit and a wearable relay coil network used for signal integration. Wherein the miniature implantable sensor unit adopts a three-module integrated framework, namely, the miniature implantable sensor unit comprises a chemical sensing module consisting of a miniature sensing electrode pair with potential response, a signal modulation module consisting of a variable capacitance diode pair which is connected back to back, and a wireless transmission module consisting of a spiral coil; the wearable relay network is a conductive coil network formed by embroidering a conductive wire or depositing and printing a conductive material on a flexible fabric substrate and patterning, and is used for realizing collaborative acquisition of chemical signals of multiple sensors; the system can synchronously monitor various biochemical indexes such as glucose, electrolyte, neurotransmitter and the like in body fluid and biological tissues in real time, and has important application value in the fields of wearable medical monitoring and implantable diagnosis.

Description

Technical Field

[0001] The present invention belongs to the technical field of biosensing, and particularly relates to an implantable wireless passive chemical sensor system, a preparation method thereof, and an application thereof. Background Art

[0002] In the field of biomedicine, the monitoring of chemical substances in the human body is of great significance for understanding physiological processes, disease mechanisms, and achieving precision medicine. Under normal physiological conditions, various chemical substances in the body, such as glucose, ions, acetylcholine, etc., maintain an accurate balance and jointly coordinate various physiological activities of the human body. However, once this balance is disrupted, such as the abnormal increase in blood glucose in diabetes, it will not only cause direct metabolic disorders, but may also lead to a series of complications, such as electrolyte imbalance, and even endanger life in severe cases. Another example is in the stress response, which involves complex interactions of multiple chemical mediators between different organs. The monitoring of a single chemical signal is difficult to comprehensively reveal the physiological state of the body and the disease development process.

[0003] Currently, implantable systems dominate in vivo chemical monitoring. Through multifunctional sensors, various analytes can be monitored, providing valuable information for physiological and pathological states. However, the existing technologies have obvious limitations. Their larger components need to be left outside the body and connected to the electrodes implanted in the body through transdermal wires. Although this structure can achieve local real-time monitoring, it increases the risk of infection, hinders wound healing, and reduces the clinical feasibility and long-term applicability of the system. Therefore, the development of a safer, wireless, and minimally invasive in vivo chemical sensing technology has become an urgent need to achieve multi-site and multi-pathway detection of chemical substances in the body, and to promote the exploration of complex physiological mechanisms and the development of disease precision diagnosis. Summary of the Invention

[0004] The purpose of the present invention is to provide a safe, wireless, and minimally invasive implantable wireless passive chemical sensor system, a preparation method thereof, and an application thereof.

[0005] The implantable wireless passive chemical sensor system provided by the present invention includes a micro-implantable sensor unit and a wearable relay coil network for signal integration; wherein, the micro-implantable sensor unit adopts a three-module integrated architecture, that is, it includes a chemical sensing module composed of a micro-sensing electrode pair with potential response, a signal modulation module composed of a pair of varactor diodes connected back-to-back, and a wireless transmission module composed of a spiral coil; the wearable relay network is a conductive coil network formed by embroidering conductive wires or depositing and printing conductive materials on a flexible fabric substrate and patterning, and is used to realize the collaborative acquisition of multi-sensor chemical signals.

[0006] The functions of the three are connected through multi-level physical and circuit integration: the micro-sensing electrodes of the chemical sensing module are spot-welded to the varactor diodes of the signal modulation module to form a potential signal transmission path; both ends of the back-to-back connected varactor diode pairs are directly connected in parallel with the spiral coil of the wireless transmission module to form an inductance-capacitance resonance circuit, converting the chemical signal into a frequency change that can be wirelessly transmitted; the wearable relay network is formed by embroidering conductive wires or depositing and printing conductive materials on a fabric or flexible substrate and patterning them to form a conductive coil network. Covering all the implanted positions with the wearable relay network and normal-aligning it with the spiral coil of the micro-implanted sensing unit can synchronously collect the frequency offsets of each channel and achieve the collaborative collection of multi-sensor chemical signals.

[0007] In the present invention, the system converts the potential chemical signal into a capacitance signal by utilizing the voltage-capacitance conversion mechanism of the varactor diode, and then through the inductance-capacitance circuit, uses the near-field electromagnetic coupling effect of the coil to achieve wireless passive transmission of multi-channel signals. Finally, with the multi-path collaborative collection of the fabric relay network, the synchronous analysis and monitoring of multiple biochemical indicators such as glucose, electrolytes, and neurotransmitters in biological fluids are completed.

[0008] Furthermore:

[0009] The potential sensor can be a potential ion sensor, a potential glucose sensor, etc.; the potential ion sensor is composed of a reference electrode and a working electrode, and the potential glucose sensor is based on the principle of a biofuel cell and is composed of a cathode and an anode;

[0010] The spiral inductance coil is a planar or three-dimensional spiral coil wound with insulated conductive enameled copper wire.

[0011] The wire diameter of the enameled wire is 0.05 - 0.5 mm, the inner diameter of the coil is 0.5 - 10 mm, and the distance between adjacent coils ≤ 3 mm; by controlling the number of turns of the coil, a gradient inductance value is formed, and the difference in the number of turns of the coils of different sensors is 1 - 10 turns, corresponding to a resonance frequency interval ≥ 10 MHz, realizing the frequency-division multiplexing transmission of multi-channel signals.

[0012] The varactor diode pair is selected from at least one of commercial varactor diodes: SMV1247 type, SMV1248 type, SMV1249 type, SMV1251 type, SMV1253 type, SMV1255 type, BBY57 type.

[0013] In the wearable relay network, the flexible fabric substrate is selected from suede, cotton-linen blended fabric, polydimethylsiloxane, polystyrene-butadiene-styrene block copolymer, partially hydrogenated polystyrene-butadiene-styrene block copolymer, and polyurethane; the conductive material is selected from metal-based insulated enameled copper wire, silver-plated nylon wire, gold wire, carbon-based carbon nanotube fiber, carbon fiber, and carbon fiber braided wire; the patterning process of the multi-channel spiral inductor coil network is an embroidery process or a deposition process.

[0014] Furthermore:

[0015] In the potentiometric ion sensor, it contains an ion-selective functional component responsive to Ca 2+ , K + ; the reference electrode is composed of a functional component compounded on the surface of a conductive substrate material and is used to provide a steady-state reference potential; wherein, the conductive substrate material is in a fibrous or planar structure and is selected from at least one of carbon nanotube fiber, carbon fiber, metal wire, conductive polymer fiber, or thin film; the functional component includes an Ag / AgCl composite layer and a polyvinyl butyral (PVB) outer film, the Ag / AgCl composite layer is formed by electrochemical deposition or physical coating, and the PVB outer film is coated on the surface of the Ag / AgCl composite layer; the working electrode is composed of a functional component compounded on the surface of a conductive substrate material and is used to specifically respond to the target analyte; wherein: the conductive substrate material is in a fibrous or planar structure and is selected from at least one of carbon nanotube fiber, carbon fiber, metal wire, conductive polymer fiber, or thin film; the functional component is configured in any of the following ways according to the detection target: for Ca 2+ detection: it contains a bilayer structure of a hydrophobic-treated polythiophene transduction layer and a Ca 2+ selective membrane; for K+ detection: it contains a bilayer structure of a hydrophobic-treated polythiophene transduction layer and a K+ selective membrane.

[0016] The potentiometric glucose sensor is composed of a cathode and an anode and contains a functional component that specifically responds to glucose, and its functional component includes platinum-carbon catalyst, perfluorosulfonic acid resin, tetrathiafulvalene electron mediator, glutaraldehyde cross-linking agent, and glucose oxidase.

[0017] The preparation method of the above-mentioned implantable wireless passive chemical sensor system provided by the present invention is specifically as follows:

[0018] (1) Construct a conductive layer formed of an inert metal or a conductive polymer composite material on the surface of a biocompatible polymer film according to a predetermined pattern;

[0019] (2) Integrate the varactor diode pair, the potentiometric sensor, and the spiral inductor coil to the designated nodes of the conductive layer pattern formed in step (1) through a micro-welding process;

[0020] (3) Three-dimensionally encapsulate the functional components except the sensing interface with biocompatible insulating materials;

[0021] (4) Form a multi-channel spiral inductor coil network on the surface of the flexible fabric substrate through embroidery / deposition process;

[0022] (5) Distributively implant and layout multiple single-parameter wireless passive chemical sensors prepared in steps (1)-(3), and axially magnetically couple and align them with the wearable relay network prepared in step (4) to construct an implantable sensor system.

[0023] Furthermore:

[0024] In step (1), the biocompatible polymer film is selected from polyimide, polyethylene terephthalate, polydimethylsiloxane, styrene-butadiene-styrene block copolymer, partially hydrogenated styrene-butadiene-styrene block copolymer, polyurethane, epoxy resin, etc.;

[0025] The conductive layer is gold, copper, polythiophene-based, polyaniline-based, polypyrrole-based;

[0026] The process of constructing the conductive layer according to a predetermined pattern adopts a mask deposition or photolithography etching method.

[0027] In step (3), the biocompatible insulating material is selected from at least one of biocompatible polymer materials: polydimethylsiloxane, styrene-butadiene-styrene block copolymer, partially hydrogenated styrene-butadiene-styrene block copolymer, fluororubber, parylene, polyurethane, epoxy resin, acrylate resin, etc.; The encapsulation method is spin coating process or chemical vapor deposition.

[0028] In step (4), for the fabric multi-channel spiral inductor coil network, the patterning process includes one of the following:

[0029] (1) Embroidery process: Use a computer numerical control embroidery machine to embroider the conductive material on the flexible fabric substrate at a rate of 50-200 stitches / min according to a preset spiral pattern;

[0030] (2) Deposition process: Define a mask pattern on the fabric surface, the mask line width is 50-200 μm, and use magnetron sputtering or thermal evaporation to form a metal conductive layer in the patterned area, and the thickness of the metal layer is 5-300 μm.

[0031] In the present invention, the deployment method of the chemical sensor includes any one of the following:

[0032] (1) Single-sensor mode: The sensor and the fabric coil adopt a normal alignment layout, with an alignment error ≤ 5°, and the spacing is controlled at 1 - 5 mm. The sensor is delivered to the subcutaneous or muscle tissue using a syringe;

[0033] (2) Multi-sensor array mode: 2 - 12 sensors are respectively injected into different subcutaneous tissue layers (depth 1 - 5 mm) or anatomical sites. Each sensor is designed with an independent inductance-capacitance resonant circuit, and the resonant frequency interval ≥ 10 MHz to avoid crosstalk; the fabric relay network covers all implanted positions and is normally aligned with the spiral coil of the implanted sensor, and synchronously collects the frequency offsets of each channel.

[0034] In the present invention, the preparation method of the reference electrode of the potentiometric ion sensor includes any one of the following processes:

[0035] (1) Coating method: Coating the Ag / AgCl paste on the surface of the conductive substrate, and modifying the PVB solution after curing;

[0036] (2) Electrochemical deposition method: Using the conductive substrate as the working electrode, in the electrolyte containing 0.1 - 1 M AgNO3, cyclic voltammetry is used to perform electro-deposition at a scanning rate of 10 - 100 mV / s in the range of -0.9 V to 0.9 V (vs. Ag / AgCl) to form an Ag layer; the substrate with the deposited Ag layer is transferred to the electrolyte containing 0.1 - 1 M KCl, and cyclic voltammetry is used to perform oxidation at a scanning rate of 10 - 100 mV / s in the range of -0.15 V to 1.05 V (vs. Ag / AgCl) to generate AgCl on the surface of the Ag layer; subsequently, 5 - 10% by mass of PVB, 3 - 6% of sodium chloride, 0.1 - 1% of Pluronic F127, and 0.01 - 1% of multi-walled carbon nanotubes are dissolved in methanol with a mass fraction of 82 - 91.89%, and ultrasonic dispersion is performed to form a homogeneous modification solution, which is coated on the surface of the chlorinated electrode and dried for 10 - 60 min to form an outer membrane.

[0037] In the present invention, the preparation method of the working electrode of the potentiometric ion sensor is the coating method: mixing the imidazole-based ionic liquid and the polythiophene solution at a mass fraction of 1.1 - 1.2 wt% and 98.8 - 98.9 wt% respectively for 30 - 60 min to form a hydrophobic treatment polythiophene precursor solution; loading the hydrophobic treatment polythiophene precursor solution on the surface of the conductive substrate by the coating method; soaking in a dimethyl sulfoxide / isopropanol mixed solution with a volume ratio of 8:2 to 9:1 for 30 - 100 min; Ca 2+ The working electrode is coated with a polyvinyl chloride-based Ca 2 + selective membrane solution, K + The working electrode is coated with a polyvinyl chloride-based K+ selective membrane solution.

[0038] In the present invention, the preparation method of the working electrode of the potentiometric glucose sensor comprises the following steps:

[0039] (1) Anode preparation: Immerse the conductive substrate in a 10 - 20 mM tetrathiafulvalene solution, which is prepared using a mixed solvent of ethanol and acetone with a volume ratio of 8:2 to 9:1. The impregnation time is 30 - 90 min. After taking it out, dry it under vacuum conditions of 25 - 40 °C and 10 - 50 kPa for 0.5 - 2 h. Subsequently, immerse the electrode in the glucose oxidase cross-linking solution and perform low-temperature treatment at 2 - 8 °C for 6 - 12 h. Then, rinse it with a phosphate buffer solution with a pH of 7.4 ± 0.2 to remove the un-fixed enzyme. The enzyme cross-linking solution contains 30 - 50 mg / mL of glucose oxidase, a glutaraldehyde cross-linking agent with a volume fraction of 0.1 - 0.2%, and a phosphate buffer solution with a pH of 7.4 ± 0.2 as the solvent;

[0040] (2) Cathode preparation: The catalyst dispersion is prepared according to the following volume ratio: 70 - 85% deionized water, 15 - 25% ethanol, and 1 - 5% perfluorosulfonic acid resin (Nafion). Disperse the platinum-carbon catalyst in the above mixed solvent at a concentration of 3 - 8 mg / mL and perform ultrasonic treatment for 10 - 30 min to form a homogeneous dispersion system. Immerse the conductive substrate in the dispersion for 3 - 12 h, and then dry it at 25 - 40 °C after taking it out.

[0041] The present invention mainly has the following characteristics and advantages:

[0042] (1) The system of the present invention innovatively converts the in-vivo chemical signal into a change in capacitance parameters, and then realizes the wireless detection of in-vivo chemical substances by means of the frequency change of the capacitance-inductance resonance circuit. Different from the traditional percutaneous wire detection method, this system does not need to penetrate tissues, completely eliminating the use of percutaneous wires. This not only significantly reduces the risk of damage caused by tissue penetration but also greatly reduces the possibility of immune infection;

[0043] (2) The implant unit of the present invention can be implanted into different sites in the body by injection, and combined with the external fabric relay network, it can simultaneously perform multi-site and multi-path parallel detection of multiple chemical substances in the body, such as Ca 2+ , K + and glucose, etc. In addition, this wireless detection platform changes the resonance frequency of the system by adjusting the number of turns of the spiral inductor to ensure that the detection processes of different chemical substances do not interfere with each other, and the detection results are accurate and reliable. With these advantages, the system of the present invention is expected to become a new and important monitoring platform in the field of health monitoring and disease diagnosis and treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 It is a schematic diagram of the implantable wireless passive chemical sensor system of the present invention.

[0045] Figure 2 This is a schematic diagram of the working principle of the implantable wireless passive chemical sensor system of the present invention.

[0046] Figure 3 This is a schematic diagram of the structure of the implantable wireless passive chemical sensor (a) and a photograph of a single wireless passive chemical sensor (b).

[0047] Figure 4 This is a photograph of a wearable multi-channel spiral inductor coil network.

[0048] Figure 5 This is the variation of the frequency of the wireless sensor with different turns of the spiral inductor coil of the wireless passive potentiometric sensor with the bias voltage.

[0049] Figure 6 This is for Ca 2+ , K + And the frequency response of the wireless passive chemical sensors for glucose to the change in the concentration of the test solution.

[0050] Figure 7 This is the in-vivo test of the implantable wireless passive chemical sensor system. (a) Schematic diagram of the application of the wireless system to a mouse. (b) Signals of the wireless system before and after intraperitoneal injection of CaCl2. (c) Enlarged characteristic frequency curve of the Ca 2+ Response of the wireless sensor, showing the process of the resonant frequency value increasing (up) and decreasing (down) with the increase of the Ca 2+ Concentration. (d) During the whole experiment, the resonant frequencies of Ca 2 + , K + And glucose change with time. Specific embodiments

[0051] The present invention will be further introduced below through embodiments in conjunction with the accompanying drawings.

[0052] Embodiment 1, a wireless passive potentiometric sensor system, the preparation steps include:

[0053] Step 1: Prepare a wireless passive potentiometric sensor. By means of thermal evaporation, a copper conductive layer is deposited on the surface of a polyimide film according to a designed pattern. A pair of varactor diodes (SMV1249) are welded back to back at the circuit nodes. Subsequently, two wires are connected to the specified positions on the substrate, and then encapsulated with polydimethylsiloxane, leaving only the tips exposed for clamping the digital source meter. Enameled copper wire with a diameter of 200 μm is wound around the outer surface of the package to form a spiral inductor coil, and it is welded to the specified position on the polyimide substrate, and the solder joints are insulated with polydimethylsiloxane to obtain a wireless passive potentiometric sensor.

[0054] Step 2: Prepare the wearable relay network. Using a computer numerical control embroidery machine, an enameled copper wire with a diameter of 200 μm is used to embroider a spiral coil on the fabric to obtain the wearable relay network, as shown in Figure 4 shown.

[0055] Through the above steps, a wireless passive potential sensor system is obtained.

[0056] Step 3: Frequency response test of the wireless passive potential sensor system. One end of the fabric relay coil is aligned and fixed, while the other end is arranged dispersedly, and the normal direction is aligned with the wireless passive potential sensor. The external readout coil is normally aligned with the aligned and fixed fabric relay coil, and the external readout coil is connected to a vector network analyzer for precise acquisition of wireless signals. By changing the number of turns of the spiral inductance coil of the wireless passive potential sensor (6 turns, 12 turns, 18 turns), the integration output of the wireless detection system signals with resonance frequencies at ~30, ~50, and ~70 MHz is realized, as shown in Figure 5 (b). Reverse bias voltages from 0 V to 0.8 V are respectively applied to the wireless sensors with spiral inductance coils configured with different numbers of turns. It is observed that the resonance frequency of the wireless passive potential sensor with the applied voltage changes with the voltage, while the resonance frequencies of the other wireless sensors without the applied voltage remain unchanged, as shown in Figure 5 (c - e). The wireless system can be sensitively responsive to the reverse bias voltage and has good anti-interference performance.

[0057] Example 2, an implantable wireless passive chemical sensor system and its frequency response test

[0058] The preparation steps of the chemical sensor system are as follows:

[0059] Step 1: Prepare an implantable wireless passive multi-parameter chemical sensor; the specific process is as follows:

[0060] a. Prepare a potentiometric ion sensor: Use carbon nanotube fiber as the conductive substrate. Modify poly(3,4-ethylenedioxythiophene):polystyrene sulfonic acid treated by hydrophobic treatment on its surface as the conduction layer, and then modify 4 μL of the corresponding ion-selective membrane to construct the ion sensor. The + mixing ratio of the K 2+The formulation of the selective membrane is as follows: 0.8 - 1.2 mg / mL calcium ionophore II, 0.3 - 0.5 mg / mL sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 24 - 28 mg / mL polyvinyl chloride, 48 - 52 mg / mL diisooctyl sebacate, and the solvent is tetrahydrofuran. The reference electrode is fabricated by electrodeposition. In an electrolyte containing 0.1 M AgNO3, cyclic voltammetry is used to perform cyclic scanning at a scanning rate of 100 mV s -1 in the range from -0.9 V to 0.9 V (vs. Ag / AgCl) for 14 cycles to form an Ag layer; then, in a mixed solution of 0.1 M HCl and 0.01 M KCl, cyclic voltammetry is used to perform 4 cyclic scans at a scanning rate of 50 mV s-1 in the potential range from -0.15 V to 1.05 V to form AgCl on the surface of the Ag layer; subsequently, 2 μL of polyvinyl butyral solution is evenly coated on the electrode surface. The solution formulation is 8.57 wt% polyvinyl butyral, 5.42% sodium chloride, 0.22% Pluronic F127, and 0.022% multi-walled carbon nanotubes dissolved in 85.77 wt% methanol.

[0061] b. Preparation of a potentiometric glucose sensor: Using a carbon nanotube fiber as the conductive substrate, immerse it in a 9:1 ethanol / acetone mixed solution of 20 mM tetrathiafulvalene for 1 h. After treatment, rinse it with a phosphate buffer solution of pH 7.4 and dry it at room temperature. Subsequently, immerse the electrode in a glucose oxidase cross-linking solution for 12 h, and then wash it with a phosphate buffer solution of pH 7.4 to obtain the anode of the glucose sensor. The glucose oxidase cross-linking solution contains 40 mg / mL glucose oxidase, 0.15 vol% glutaraldehyde cross-linking agent, and the solvent is a phosphate buffer solution of pH 7.4 ± 0.2. Immerse the carbon nanotube fiber in a platinum-carbon catalyst dispersion solution for 3 h, take it out and dry it at room temperature. The dispersion solution is prepared according to the following volume ratio: 75% deionized water, 22% ethanol, 3% perfluorosulfonic acid resin (Nafion), and the platinum-carbon catalyst is dispersed in the above mixed solvent at a concentration of 5 mg / mL and ultrasonically treated for 30 min to form a homogeneous dispersion system.

[0062] c. Circuit preparation: By means of thermal evaporation, deposit a copper conductive layer on the surface of a polyimide film according to a designed pattern. Weld a pair of varactor diodes (SMV1249) back-to-back to the circuit nodes. Subsequently, connect the potentiometric sensor to a specified position on the substrate, and then encapsulate it with polydimethylsiloxane, leaving only the detection unit of the sensor exposed. Wind an enameled copper wire with a diameter of 200 μm around the outer surface of the package to form a spiral inductance coil, and weld it to a specified position on the polyimide substrate. The solder joints are insulated with polydimethylsiloxane to obtain an implantable wireless passive multi-parameter chemical sensor, as shown inFigure 3 as shown

[0063] Step 2: Prepare the wearable relay network. Using a computer numerical control embroidery machine, an enameled copper wire with a diameter of 200 μm is used to embroider a spiral coil on the fabric to obtain the wearable relay network, as shown Figure 4 as shown

[0064] The implantable wireless passive chemical sensor system is obtained through the above steps.

[0065] Step 3: Frequency response test of the wireless passive chemical sensor system. One end of the fabric relay coil is aligned and fixed, while the other end is arranged dispersedly, and the normal direction is aligned with the implantation site of the corresponding implantable wireless passive multi-parameter chemical sensor. The external readout coil is normally aligned with the aligned and fixed fabric relay coil, and this external readout coil is connected to a vector network analyzer for precise acquisition of wireless signals. By changing the number of turns of the coil of the implantable sensor (Ca 2+ : 18 turns, glucose: 12 turns, K + : 6 turns), the integrated output of the wireless detection system signals with resonant frequencies at ~30, ~50, and ~70 MHz is realized, as shown Figure 6 (a). Add Ca 2+ solution to the solution. The change in concentration from 0 mM to 8 mM corresponds to the change in resonant frequency from 29.2 MHz to 29.8 MHz, while the corresponding resonant frequencies of glucose and K + do not change, as shown Figure 6 (b). Add glucose solution to the solution. The change in concentration from 0 mM to 8 mM corresponds to the change in resonant frequency from 51.3 MHz to 52.5 MHz, while the characteristic resonant frequencies of Ca 2+ and K + remain unchanged, as shown Figure 6 (c). Add K + solution to the solution. The change in concentration from 0 mM to 8 mM causes the resonant frequency of K + to change from 77.2 MHz to 77.8 MHz, while the characteristic resonant frequencies of Ca 2+ and glucose remain unchanged, as shown Figure 6 (d).

[0066] Example 3, an implantable wireless passive chemical sensor system and its in vivo subcutaneous implantation test

[0067] The preparation steps of this chemical sensor system are as follows:

[0068] Step 1: Prepare the implantable wireless passive multi-parameter chemical sensor. The specific process is as follows:

[0069] a. Preparation of potentiometric ion sensors: Carbon nanotube fibers are used as the conductive substrate. A hydrophobic-treated poly(3,4-ethylenedioxythiophene):polystyrene sulfonic acid is modified on its surface as the conduction layer, and then 4 μL of the corresponding ion-selective membrane is modified to construct the ion sensor. K + The ratio of the ion-selective membrane is: 1.5 - 2.0 mg / mL valinomycin, 0.4 - 0.6 mg / mL sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 25 - 30 mg / mL polyvinyl chloride, 45 - 55 mg / mL dioctyl sebacate, and the solvent is tetrahydrofuran. Ca 2+ The ratio of the ion-selective membrane is: 0.8 - 1.2 mg / mL calcium ionophore II, 0.3 - 0.5 mg / mL sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 24 - 28 mg / mL polyvinyl chloride, 48 - 52 mg / mL bis(2-ethylhexyl) sebacate, and the solvent is tetrahydrofuran. The reference electrode is fabricated by electrodeposition. In an electrolyte containing 0.1 M AgNO3, cyclic voltammetry is used to perform cyclic scanning at a scanning rate of 100 mV s -1 in the range from -0.9 V to 0.9 V (vs. Ag / AgCl) for 14 cycles to form an Ag layer; then, in a mixed solution of 0.1 M HCl and 0.01 M KCl, cyclic voltammetry is used to perform 4 cyclic scans at a scanning rate of 50 mV s-1 in the potential range from -0.15 V to 1.05 V to form AgCl on the surface of the Ag layer; subsequently, 2 μL of a polyvinyl butyral solution is evenly coated on the electrode surface. The solution ratio is 8.57% by mass of polyvinyl butyral, 5.42% of sodium chloride, 0.22% of Pluronic F127, and 0.022% of multi-walled carbon nanotubes dissolved in 85.77% by mass of methanol.

[0070] b. Preparation of potentiometric glucose sensors: Carbon nanotube fibers are used as the conductive substrate, and they are immersed in a 9:1 ethanol / acetone mixed solution of 20 mM tetrathiafulvalene for 1 h. After treatment, they are rinsed with a phosphate buffer solution at pH 7.4 and dried at room temperature. Subsequently, the electrode is immersed in a glucose oxidase cross-linking solution for 12 h, and then washed with a phosphate buffer solution at pH 7.4 to obtain the glucose sensor anode. The enzyme cross-linking solution contains 40 mg / mL of glucose oxidase, a cross-linking agent of 0.15% by volume of glutaraldehyde, and the solvent is a phosphate buffer solution at pH 7.4 ± 0.2. The carbon nanotube fibers are immersed in a platinum-carbon catalyst dispersion for 3 h, taken out and dried at room temperature. The dispersion is prepared according to the following volume ratio: 75% deionized water, 22% ethanol, 3% perfluorosulfonic acid resin (Nafion), and the platinum-carbon catalyst is dispersed in the above mixed solvent at a concentration of 5 mg / mL and ultrasonically treated for 30 min to form a homogeneous dispersion system.

[0071] c. Circuit preparation: By means of thermal evaporation, a copper conductive layer is deposited on the surface of a polyimide film according to a designed pattern. A pair of varactor diodes (SMV1249) are soldered back to back to the circuit nodes. Subsequently, a potential sensor is connected to a specified position on the substrate and then encapsulated with polydimethylsiloxane, leaving only the detection unit of the sensor exposed. An enameled copper wire with a diameter of 200 μm is wound around the outer surface of the package to form a spiral inductor coil, which is then soldered to a specified position on the polyimide substrate. The solder joints are insulated with polydimethylsiloxane to obtain an implantable wireless passive multi-parameter chemical sensor, as shown in Figure 3 shown.

[0072] Step 2: Prepare a wearable relay network. Using a computer numerical control embroidery machine, an enameled copper wire with a diameter of 200 μm is used to embroider a spiral coil on the fabric to obtain a wearable relay network, as shown in Figure 4 shown.

[0073] An implantable wireless passive chemical sensor system is obtained through the above steps.

[0074] Step 3: In-vivo implantation of the wireless passive chemical sensor system. Anesthetize the mouse with isoflurane. Then place a wireless passive chemical sensor at the tip of a syringe and inhale a certain amount of normal saline into the syringe. After marking the injection site, lift the skin at the corresponding site and insert the syringe subcutaneously. Inject a small amount of normal saline, and use the water flow impact force to transfer it from the syringe to the subcutaneous tissue. Then withdraw the syringe from the subcutaneous tissue of the mouse and bond the implantation wound with biological glue.

[0075] Step 4: In-vivo subcutaneous implantation test of the wireless passive chemical sensor system. Wear the fabric network with the relay coil on the mouse and align it with multiple wireless passive chemical sensors with different parameters in the body. Align the reading coil connected to the vector network analyzer with the fixed end of the relay coil. By intraperitoneal injection of CaCl2 solution, the characteristic frequency of Ca in the multi-channel signal shifts to the right. With the self-homeostasis of the mouse, the Ca concentration decreases, and the characteristic frequency of Ca also returns to the initial value. During the whole process, the characteristic frequencies of glucose and K remain stable, as shown in 2+ shown. This indicates that the wireless platform can effectively avoid crosstalk between different sensing signals and can achieve selective wireless passive detection of target chemical substances. 2+ concentration drops, and the characteristic frequency of Ca 2+ also returns to the initial value. During the whole process, the characteristic frequencies of glucose and K + remain stable, as shown in Figure 7 shown. This indicates that the wireless platform can effectively avoid crosstalk between different sensing signals and can achieve selective wireless passive detection of target chemical substances.

Claims

1. An implantable wireless passive chemical sensor system, characterized in that, It includes a micro-implantable sensor unit and a wearable relay coil network for signal integration; among them, the micro-implantable sensor unit adopts a three-module integrated architecture, that is, it includes a chemical sensing module composed of a pair of micro-sensing electrodes with potential response, a signal modulation module composed of a pair of varactor diodes connected back-to-back, and a wireless transmission module composed of a spiral coil; the wearable relay network is a conductive coil network formed by embroidering conductive wires or depositing and printing conductive materials on a flexible fabric substrate for realizing the collaborative acquisition of multi-sensor chemical signals; In the micro-implantable sensor unit, the pair of micro-sensing electrodes of the chemical sensing module is spot-welded to the varactor diode pair of the signal modulation module to form a potential signal transmission path; both ends of the varactor diode pair are directly connected in parallel with the spiral coil of the wireless transmission module to form an inductance-capacitance resonance circuit, converting the chemical signal into a frequency change that can be wirelessly transmitted; the wearable relay network is formed by embroidering conductive wires or depositing and printing conductive materials on a fabric or flexible substrate and patterning; covering all implantation positions with the wearable relay network and normal-aligning it with the spiral coil of the micro-implantable sensor unit can synchronously collect the frequency offsets of each channel and realize the collaborative acquisition of multi-sensor chemical signals; The system converts the potential-type chemical signal into a capacitance signal by using the voltage-capacitance conversion mechanism of the varactor diode; through the inductance-capacitance circuit, it realizes the wireless passive transmission of multi-channel signals by using the near-field electromagnetic coupling effect of the coil, and finally completes the synchronous analysis and monitoring of multiple biochemical indicators such as glucose, electrolytes, and neurotransmitters in biological fluids with the multi-path collaborative acquisition of the fabric relay network.

2. The implantable wireless passive chemical sensor system according to claim 1, wherein: The potential-type sensor is a potential-type ion sensor or a potential-type glucose sensor; the potential-type ion sensor is composed of a reference electrode and a working electrode, and the potential-type glucose sensor is based on the principle of a biofuel cell and is composed of a cathode and an anode; The pair of varactor diodes is selected from at least one of commercial varactor diodes: SMV1247 type, SMV1248 type, SMV1249 type, SMV1251 type, SMV1253 type, SMV1255 type, BBY57 type.

3. The implantable wireless passive chemical sensor system according to claim 1, characterized in that, The spiral inductance coil is a planar or three-dimensional spiral coil wound with insulated conductive enameled copper wire.

4. The implantable wireless passive chemical sensor system according to claim 3, wherein The wire diameter of the enameled wire is 0.05 - 0.5 mm, the inner diameter of the coil is 0.5 - 10 mm, and the spacing between adjacent coils ≤ 3 mm; by controlling the number of turns of the coil to form a gradient inductance value, the difference in the number of turns of the coils of different sensors is 1 - 10 turns, and the corresponding resonance frequency interval ≥ 10 MHz to realize the frequency-division multiplexing transmission of multi-channel signals.

5. The implantable wireless passive chemical sensor system according to claim 1, characterized in that, In the wearable relay network, the flexible fabric substrate is selected from suede, cotton-linen blended fabric, polydimethylsiloxane, polystyrene-butadiene-styrene block copolymer, partially hydrogenated polystyrene-butadiene-styrene block copolymer, and polyurethane; the conductive material is selected from metal-based insulated enameled copper wire, silver-plated nylon wire, and gold wire, and carbon-based carbon nanotube fiber, carbon fiber, and carbon fiber braided wire; the patterning process of the multi-channel spiral inductor coil network is an embroidery process or a deposition process.

6. The implantable wireless passive chemical sensor system according to claim 2, wherein: In the described potentiometric ion sensor, it includes an ion-selective functional component that responds to Ca 2+ , K + ; the reference electrode is composed of a functional component compounded on the surface of a conductive substrate material and is used to provide a steady reference potential; the functional component includes an Ag / AgCl composite layer and an outer film of polyvinyl butyral (PVB). The Ag / AgCl composite layer is formed by electrochemical deposition or physical coating, and the PVB outer film is coated on the surface of the Ag / AgCl composite layer by physical coating; the working electrode is composed of a functional component compounded on the surface of a conductive substrate material and is used to specifically respond to the target analyte; the functional component is configured in any of the following ways according to the detection target: for Ca 2+ detection: it includes a bilayer structure of a hydrophobic-treated polythiophene transduction layer and a Ca 2+ selective membrane; for K+ detection: it includes a bilayer structure of a hydrophobic-treated polythiophene transduction layer and a K+ selective membrane. The hydrophobic-treated polythiophene transduction layer and the selective membrane are formed by physical coating; the conductive substrate material is in a fibrous or planar structure and is selected from carbon nanotube fibers, carbon fibers, metal wires, conductive polymer fibers or films; The potentiometric glucose sensor is composed of a cathode and an anode, and contains a functional component that specifically responds to glucose. The functional component includes a platinum-carbon catalyst, a perfluorosulfonic acid resin, a tetrathiafulvalene electron mediator, a glutaraldehyde crosslinking agent, and glucose oxidase; the conductive substrate material is in a fibrous or planar structure and is selected from carbon nanotube fiber, carbon fiber, metal wire, conductive polymer fiber or film.

7. The preparation method of the implantable wireless passive chemical sensor system according to any one of claims 1-6, characterized in that, The specific steps are as follows: (1) Construct a conductive layer formed of an inert metal or a conductive polymer composite material on the surface of the biocompatible polymer film according to a predetermined pattern; (2) Integrate the varactor diode pair, the potentiometric sensor, and the spiral inductor coil to the designated nodes of the conductive layer pattern formed in step (1) through a micro-welding process; (3) Three-dimensionally encapsulate the functional components except the sensing interface with a biocompatible insulating material; (4) Form a multi-channel spiral inductor coil network on the surface of the flexible fabric substrate through an embroidery / deposition process; (5) Perform a distributed implant layout on multiple single-parameter wireless passive chemical sensors prepared in steps (1)-(3), and perform axial magnetic coupling alignment with the wearable relay network prepared in step (4) to construct an implantable sensor system.

8. The preparation method according to claim 7, characterized in that, In step (1): The biocompatible polymer film is selected from polyimide, polyethylene terephthalate, polydimethylsiloxane, polystyrene-butadiene-styrene block copolymer, partially hydrogenated polystyrene-butadiene-styrene block copolymer, polyurethane, and epoxy resin; The conductive layer material is gold, copper, polythiophene, polyaniline, polypyrrole; The process of constructing the conductive layer according to the predetermined pattern is carried out by means of mask deposition or photolithographic etching.

9. The preparation method according to claim 7, characterized in that, In step (3), the biocompatible insulating material is selected from at least one of biocompatible polymer materials: polydimethylsiloxane, polystyrene-butadiene-styrene block copolymer, partially hydrogenated polystyrene-butadiene-styrene block copolymer, fluororubber, parylene, polyurethane, epoxy resin, acrylate resin; the encapsulation method is a spin coating process or chemical vapor deposition.

10. The deployment method of the chemical sensor system according to any one of claims 1-6 includes any one of the following: (1) Single-sensor mode: The sensor and the fabric coil are arranged in a normal alignment layout, the alignment error ≤ 5°, and the spacing is controlled to be 1-5 mm; the sensor is delivered to the subcutaneous or muscle tissue by a syringe; (2) Multi-sensor array mode: Inject 2 - 12 sensors into different subcutaneous tissue layers or anatomical sites respectively. Each sensor is designed with an independent inductance-capacitance resonant circuit, and the resonant frequency interval is ≥10 MHz to avoid crosstalk. The flexible fabric relay network covers all implanted positions and is normally aligned with the helical coils of the implanted sensors to synchronously collect the frequency offsets of each channel.

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