CN116124351B - Implantable full-protein LC wireless passive pressure sensor and preparation method thereof - Google Patents

Abstract

An implantable all-protein LC wireless passive pressure sensor and a preparation method thereof, relating to flexible electronic devices. The pressure sensor is a seven-layer structure stacked vertically, and is provided with an upper packaging layer, an upper electrode, an upper substrate, a dielectric layer, a lower substrate, a lower electrode, and a lower packaging layer from top to bottom; the upper packaging layer, the upper substrate, the lower substrate, and the lower packaging layer are all transparent composite films of regenerated silk fibroin; the upper electrode and the lower electrode are both composed of spiral coils of different sizes wound with magnesium wire; the dielectric layer is a transparent hydrogel of silk fibroin with a microstructure. The preparation method is simple, the cost is low, the device performance is stable, the flexibility is good, the biocompatibility is good, and the device is degradable. It can be used in medical health monitoring.

Description

An implantable all-protein LC wireless passive pressure sensor and preparation method thereof

Technical Field

The invention relates to flexible electronic devices, and in particular to an implantable all-protein LC wireless passive pressure sensor and a preparation method thereof.

Background technique

In recent years, flexible wireless passive pressure sensors have become a research hotspot in the fields of medical health monitoring due to their good flexibility, no need for battery power, and no need for connecting wires for signal processing. For example, they can monitor intracranial pressure, abdominal pressure and other body pressure values. Among them, LC wireless passive pressure sensors have attracted much attention due to their simple structure and principle, low cost and long service life. It is based on the principle of electromagnetic mutual inductance coupling. When the pressure changes, the capacitance will change accordingly, thereby changing the resonant frequency of the LC loop, which can be detected by wireless coupling with an external antenna.

However, the existing technology has the following shortcomings: 1) The materials used in the implantable pressure sensors that have been studied are artificially synthesized high-molecular polymer materials with general biocompatibility. Long-term implantation in the body may sometimes cause rejection reactions. 2) The device preparation process is complicated and costly. 3) The materials used to prepare the device are not easy to degrade and are prone to environmental pollution. 4) The device structure is complex and multi-level, and the volume is large. The inductance and capacitance parts of the device are mostly placed in a plane, requiring sufficient space to accommodate the inductance and capacitance. 5) The device is mostly made of hard materials and is not easy to bend, which affects the comfort of use.

Chinese patent CN 105832327 A discloses an implantable wireless passive intracranial pressure monitoring system, including: an intracranial pressure sensor for sensing intracranial pressure values, an external patch reader, which generates mutual inductive coupling with the intracranial pressure sensor, and a detection instrument, which is connected to the external patch reader, detects the resonant frequency of the intracranial pressure sensor, and obtains the intracranial pressure value. Chinese patent CN 111407251 A discloses a structure of an implantable pressure sensor capable of wireless communication, including two matching glass wafers compatible with human biology as pressure sensor substrates, L-C oscillation is located in a sealed cavity formed by anode bonding of two glass wafers, forming a thin film layer that can sense absolute pressure changes, and an air absorption layer is added to the cavity.

Summary of the invention

The purpose of the present invention is to provide an implantable all-protein LC wireless passive pressure sensor and its preparation method with good flexibility, good biocompatibility, degradability, high integration, stable performance, simple preparation method and low cost in response to the various problems existing in the above-mentioned actual situation.

An implantable all-protein LC wireless passive pressure sensor has a seven-layer structure stacked vertically, and is provided with an upper packaging layer, an upper electrode, an upper substrate, a dielectric layer, a lower substrate, a lower electrode, and a lower packaging layer from top to bottom; the upper packaging layer, the upper substrate, the lower substrate, and the lower packaging layer are all transparent composite films of regenerated silk fibroin; the upper electrode and the lower electrode are both composed of spiral coils of different sizes wound with magnesium wire; the dielectric layer is a transparent hydrogel of silk fibroin with a microstructure, and the entire device is composed of a degradable silk fibroin material and a degradable metal electrode.

The light transmittance of the regenerated silk fibroin film of the upper substrate and the lower substrate is greater than 95%, the thickness is 100-150 μm, and the stretchability exceeds 100%.

The dielectric layer is prepared by cross-linking catalyzed by horseradish peroxidase (HRP), and the specific process is as follows: in the presence of hydrogen peroxide, HRP can oxidize tyrosine on the silk fibroin molecule to form tyrosine free radicals, and two tyrosine free radicals react to form dityrosine bonds, thereby covalently cross-linking the silk fibroin molecular chains together, and finally forming a transparent, elastic hydrogel.

The upper electrode and the lower electrode are both made of magnesium hollow nanowires used in spiral coils, and the preparation method is electrospinning, magnetron sputtering and transfer method. The specific process is: polyvinyl alcohol (PVA) nanowires are prepared by electrospinning, and then nanomagnesium is sputtered on the PVA surface by magnetron sputtering, and finally magnesium nanowire electrodes are prepared on the surface of silk protein substrate by template transfer method.

A method for preparing an implantable all-protein LC wireless passive pressure sensor comprises the following steps:

1) mixing the silk fibroin solution and the reinforcing agent evenly, dispersing them in a culture dish without bubbles, and forming a regenerated silk fibroin transparent composite film after solidification;

2) Customized molds of different sizes are made by 3D printing, and the magnesium wire is wound into two spiral coils of different sizes according to the molds;

3) Preparation of silk fibroin transparent hydrogel;

4) The two spiral coils are fixed on the upper substrate and the lower substrate with polyurethane, and the silk fibroin transparent hydrogel is then wrapped with the upper substrate and the lower substrate on the other side to obtain the main element. The main element is then encapsulated with the upper encapsulation layer and the lower encapsulation layer, and sealed around with a sealing machine to obtain the implantable all-protein LC wireless passive pressure sensor.

The implantable all-protein LC wireless passive pressure sensor can be used in medical health monitoring, such as intracranial pressure monitoring devices, intraabdominal pressure monitoring devices, etc., to monitor the intracranial pressure, abdominal pressure and other pressure values of the human body.

Compared with the prior art, the present invention has the following beneficial effects:

1. The present invention does not require power supply or connecting wires. The device has a simple structure, stable performance, and a sensitivity of 4.44MHz/mmHg. When pig skin is used for in vitro simulation, a strong output signal is still detected, and the device has a long service life.

2. The materials used in the present invention are all full-protein biomaterials with excellent biocompatibility and no immune rejection reaction, which are very suitable for constructing implantable electronic devices. In addition, the materials are degradable, green and environmentally friendly, and will not cause environmental pollution.

3. The present invention transforms the two plates of the capacitor into an inductor coil to construct a highly integrated LC pressure sensor, so that the sensor is small in size and meets the clinical size requirements for implanted sensors, making it more suitable in environments with limited space and improving the flexibility of the device.

4. The material used in the present invention has good mechanical properties, the substrate stretchability exceeds 100%, the substrate and the dielectric layer have good flexibility, and the implant is comfortable. The device still maintains sensing performance after multiple compressions, and the device preparation method is simple and low-cost.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a schematic diagram of the structure of an implantable all-protein LC wireless passive pressure sensor.

FIG2 is a schematic diagram of the three-dimensional structure of an implantable all-protein LC wireless passive pressure sensor.

FIG3 is a scanning electron microscope image of a cross section of a silk fibroin transparent hydrogel prepared in an embodiment of the present invention.

FIG. 4 is an immunofluorescence image of MC3T3-E1 cells cultured on the regenerated silk fibroin transparent composite film prepared in an example of the present invention.

FIG5 is a graph showing data obtained by in vitro simulation of the implantable all-protein LC wireless passive pressure sensor prepared in an embodiment of the present invention.

Detailed ways

To make the objectives, technical solutions and advantages of the embodiments of the present invention more clear, the following embodiments will further illustrate the present invention in conjunction with the accompanying drawings.

As shown in Figures 1 and 2, the implantable all-protein LC wireless passive pressure sensor is a vertically stacked seven-layer structure, which is provided with an upper packaging layer 1, an upper electrode 2, an upper substrate 3, a dielectric layer 4, a lower substrate 5, a lower electrode 6, and a lower packaging layer 7 from top to bottom.

The upper packaging layer 1, the upper substrate 3, the lower substrate 5 and the lower packaging layer 7 are all transparent composite films of regenerated silk fibroin with a light transmittance greater than 95%, a thickness of 100-150 μm and a stretchability exceeding 100%.

The upper electrode 2 and the lower electrode 6 are both composed of spiral coils of different sizes formed by magnesium wire according to template transfer; the preparation method is electrospinning, magnetron sputtering and transfer method, and the specific process is: polyvinyl alcohol (PVA) nanowires are prepared by electrospinning, and then nanomagnesium is sputtered on the PVA surface by magnetron sputtering, and finally magnesium nanowire electrodes are prepared on the surface of silk protein substrate by template transfer method.

The dielectric layer 4 is a transparent hydrogel of silk fibroin with microstructure, with a thickness of 1 to 2 mm and a compressibility of 50 to 80%. The dielectric layer is prepared by cross-linking catalyzed by horseradish peroxidase (HRP), and the specific process is as follows: in the presence of hydrogen peroxide, HRP can oxidize tyrosine on the silk fibroin molecule to form tyrosine free radicals, and two tyrosine free radicals react to form dityrosine bonds, thereby covalently cross-linking the silk fibroin molecular chains together, and finally forming a transparent and elastic hydrogel.

Example 1

The preparation method of the implantable all-protein LC wireless passive pressure sensor is as follows:

Step 1: Evenly mix the silk fibroin solution obtained from silk with the reinforcing agent, disperse them in a culture dish without bubbles, and solidify them to form a transparent composite film of regenerated silk fibroin. The curing temperature is 20-40°C, the curing humidity is 30-50%, and the curing time is 1-3 days. Furthermore, polyurethane is selected as the reinforcing agent in this embodiment, and the mass ratio of the silk fibroin solution to the reinforcing agent is 1:9.

Step 2: Customize templates of different sizes through 3D printing, transfer the magnesium wire to the silk fibroin substrate under the mask of different templates, and obtain spiral coils of different sizes. The side length of the mold is 1 to 3 cm, and the shape of the spiral coil is square.

Step 3: Dissolve 1 mg of dopamine hydrochloride powder and 12 mg of montmorillonite powder into 1 ml of aqueous solution, stir magnetically at room temperature, then add 5.6 ml of silk fibroin solution, 400 μL of HRP solution, and 50 μL of H ₂ O ₂ solution. Stir the mixture evenly and inject it into a culture dish with a microstructure mold at the bottom, and then put it into a constant temperature drying oven to obtain a silk fibroin transparent hydrogel.

Step 4: Fix the two spiral square coils on the upper substrate and the lower substrate with polyurethane, and then wrap the silk fibroin transparent hydrogel with the other side of the upper substrate and the lower substrate to obtain the main component. Then, encapsulate the main component with the upper encapsulation layer and the lower encapsulation layer, and seal it around with a sealing machine, and adjust the gear number of the sealing machine to the fourth gear. The implantable all-protein LC wireless passive pressure sensor is obtained.

Example 2

In the preparation method of the implantable all-protein LC wireless passive pressure sensor, the second to fourth steps are the same as those in Example 1, and the first step is different from that in Example 1 in that the mass ratio of the silk fibroin solution to the reinforcing agent is 1:1.

Example 3

In the preparation method of the implantable all-protein LC wireless passive pressure sensor, the first, third and fourth steps are the same as those in Example 1, and the second step is different from that in Example 1 in that the shape of the spiral coil is circular.

Example 4

In the preparation method of the implantable all-protein LC wireless passive pressure sensor, the first, second and fourth steps are the same as those in Example 1, except that the third step is different from Example 1 in that 1 mg of dopamine hydrochloride powder, 12 mg of montmorillonite powder and 1 ml of aqueous solution mixture are not added.

Example 5

In the preparation method of the implantable all-protein LC wireless passive pressure sensor, the second to fourth steps are the same as those in Example 1, and the first step is different from that in Example 1 in that the mass ratio of the silk fibroin solution to the reinforcing agent is 1:5.

FIG3 is a scanning electron microscope image of the cross section of the silk fibroin transparent hydrogel prepared in the embodiment of the present invention. It can be seen from FIG3 that the silk fibroin transparent hydrogel is a porous structure. FIG4 is an immunofluorescence image of MC3T3-E1 cells cultured on the regenerated silk fibroin transparent composite film prepared in the embodiment of the present invention. It can be seen from FIG4 that the cells can be well attached, diffused and grown on the regenerated silk fibroin transparent composite film, indicating that the regenerated silk fibroin transparent composite film has good biocompatibility. FIG5 is a data graph obtained by in vitro simulation of the implantable all-protein LC wireless passive pressure sensor prepared in the embodiment of the present invention. The sensitivity of the pressure sensor is 0.152MHz/mmHg.

The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (6)

1. An implantable full-protein LC wireless passive pressure sensor is characterized by being of a vertically stacked seven-layer structure, and sequentially provided with an upper packaging layer, an upper electrode, an upper substrate, a dielectric layer, a lower substrate, a lower electrode and a lower packaging layer from top to bottom; the upper packaging layer, the upper substrate, the lower substrate and the lower packaging layer are all regenerated silk fibroin transparent composite films; the upper electrode and the lower electrode are formed by winding magnesium wires into spiral coils with different sizes; the dielectric layer is silk fibroin transparent hydrogel with a microstructure, and the whole device consists of a degradable silk fibroin material and a degradable metal electrode;

the dielectric layer is prepared by horseradish peroxidase catalytic crosslinking, and the specific process is as follows: under the condition that hydrogen peroxide exists, horseradish peroxidase can oxidize tyrosine on silk fibroin molecules to form tyrosine free radicals, and the two tyrosine free radicals react to generate a di-tyrosine bond, so that silk fibroin molecular chains are covalently crosslinked together, and finally transparent and elastic hydrogel is formed;

The upper electrode and the lower electrode are both made of magnesium hollow nano-wires used by spiral coils, and the preparation method comprises the steps of electrostatic spinning, magnetron sputtering and transfer, wherein the specific flow is as follows: and preparing the polyvinyl alcohol nano wire by utilizing electrostatic spinning, sputtering nano magnesium on the surface of the polyvinyl alcohol by magnetron sputtering, and finally preparing the magnesium nano wire electrode on the surface of the silk fibroin substrate by a template transfer method.

2. The implantable holoprotein LC wireless passive pressure sensor of claim 1, wherein the upper and lower substrates regenerate silk fibroin films having a light transmittance of greater than 95%, a thickness of 100-150 μm, and a stretchability of more than 100%.

3. A method of making an implantable whole protein LC wireless passive pressure sensor according to claim 1, comprising the steps of:

1) Uniformly mixing the silk fibroin solution and the reinforcing agent, dispersing the mixture in a culture dish without bubbles, and solidifying the mixture to form a regenerated silk fibroin transparent composite film;

2) Transferring magnesium wires to a silk fibroin substrate with a mask by 3d printing and customizing moulds with different sizes, and preparing coil electrodes with different shapes;

3) Preparing silk fibroin transparent hydrogel;

4) Fixing two spiral coils on an upper substrate and a lower substrate by polyurethane, and wrapping silk fibroin transparent hydrogel on the other sides of the upper substrate and the lower substrate to obtain a main element; and packaging main elements by using an upper packaging layer and a lower packaging layer, and sealing the periphery by using a sealing machine to obtain the implantable full-protein LC wireless passive pressure sensor.

4. The method for preparing an implantable holoprotein LC wireless passive pressure sensor according to claim 3, wherein in the step 1), the reinforcing agent is at least one selected from polyurethane and glycerol, and the mass ratio of the silk fibroin solution to the reinforcing agent is 1:1-9.

5. A method for preparing an implantable holoprotein LC wireless passive pressure sensor according to claim 3, wherein in step 3), the specific steps for preparing the silk fibroin transparent hydrogel are: 1-5 mg of dopamine hydrochloride powder and 6-18 mg of montmorillonite powder are dissolved into 1mL of aqueous solution, magnetic stirring reaction is complete at normal temperature, 4-8 mL of silk fibroin solution, 200-600 mu LHRP solution and 50 mu LH ₂O₂ solution are added, the mixture is stirred uniformly and then is injected into a culture dish with a microstructure die at the bottom, and the culture dish is placed into a constant-temperature drying box.

6. Use of an implantable whole protein LC wireless passive pressure sensor according to claim 1 for medical health monitoring.